KRAS modulators and uses thereof

Abstract

Provided herein are compounds that modulate KRAS, selected from fused pyrimidines, such as compounds of Formula (II) or pharmaceutically acceptable salts, solvates, stereoisomers, labeled atoms or tautomers of the foregoing, that are useful for modulating KRAS GD12 and / or other G12 mutants. # imgabs0 #

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 308,424, filed February 9, 2022; U.S. Provisional Patent Application No. 63 / 368,584, filed July 15, 2022; U.S. Provisional Patent Application No. 63 / 373,302, filed August 23, 2022; U.S. Provisional Patent Application No. 63 / 378,843, filed October 7, 2022; and U.S. Provisional Patent Application No. 63 / 384,374, filed November 18, 2022, the entire contents of each of which are incorporated herein by reference. Background Technology

[0003] The small GTPase protein Kirsten rat sarcoma type 2 virus oncogene homolog (KRAS) is a member of the Ras cell signaling switch family, which regulates the growth and survival of normal and cancer cells (see, for example, Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292e1). KRAS mutations drive approximately 25% of human cancers by aberrantly regulating the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (see, for example, Stephen, AG et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Although Ras has been considered a cancer target for about 40 years, Ras-driven cancers remain among the most difficult to treat due to their lack of responsiveness to available targeted therapies. Ras is encoded by three major genes, KRAS, NRAS, and HRAS, and mutations in any of these oncogenes are most frequent. All oncogenic Ras mutations drive the accumulation of switches in the active GTP-binding state. The most common Ras mutation found in human tumor types is KRAS G12D (see, for example, The AACR Project GENIEConsortium. Cancer Discovery, 2017.7(8):p.818-831.Dataset Version 4). Mutations in activation codon 12 impair the ability of small GTPases to hydrolyze GTP. This regulatory impairment is crucial for initiating and maintaining tumor progression.

[0004] Despite significant efforts, no small molecules have yet been identified that block effector binding or restore sensitivity to GTPase-activated proteins (GAPs). However, some small molecules, such as SOS, have been found that block the interaction between Ras and guanine nucleotide exchange factor (GEF), activating Ras in the plasma membrane. The KRAS G12C mutation, most commonly found in lung adenocarcinoma, has been clinically demonstrated to be more readily inhibited by covalent modification with small-molecule inhibitors, trapping the protein in an inactive GDP-binding state. The KRAS G12D mutation results in a significantly slower rate of intrinsic GTP hydrolysis than G12C, leading to more constitutive activation. Therefore, while a similar binding pocket exists in the GDP state, pharmacological targeting of the inactive state is unlikely to achieve similar results for G12D. Furthermore, the presence of cysteine ​​residues at the site of activation mutations generates covalent chemistry, while aspartic acid does not provide a typical medicinal chemical approach for selective covalent modification.

[0005] To potentially exploit the accumulation of GTP-bound KRAS G12D and other mutant variants as a weakness for selective inhibition of cancer cells while preserving normal Ras function, selective binding to the GTP state and conformational stabilization that prevents interaction with effector proteins in oncogenic signaling is attractive for small molecule inhibitors. Furthermore, it has been demonstrated that only constitutive activation of Raf, MEK, and ERK kinases in the downstream MAPK cascade can bypass the need for Ras proteins in proliferation signaling (see, e.g., Drosten, M. et al., Genetic analysis of Rassignalling pathways in cell proliferation, migration, and survival. EMBO J, 2010, 29(6): p. 1091-104). Since all evidence indicates that MAPK signaling is crucial for the growth of Ras in cancer, selective inhibition of KRAS mutants in this pathway is considered a key functional indication of the potential clinical benefits of novel therapeutic approaches. Summary of the Invention

[0006] There is a need to develop novel KRAS-driven cancer inhibitors that exhibit inhibition of MAPK signaling through a mechanism of action that selectively binds to the active GTP binding state compared to the inactive GDP binding state.

[0007] This disclosure relates to formula (I) or formula (II) or formula (III), including its stereoisomers, tautomers, solvates and pharmaceutically acceptable salts, and its use, for example, in inhibiting KRas G12D and / or other G12 mutants.

[0008] In one aspect, this disclosure provides a compound represented by the structure of formula (I):

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein:

[0011] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional replacement;

[0012] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0013] Y is selected from bonds, O, S, and NR. 5 ;

[0014] R 2 Selected from hydrogen, -N(R) 21 )2、-LN(R 21 )2、-L-OR 21Heterocyclic rings, C l -C6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R) 21 )2、-LC l -C6 haloalkyl, -L-OR 21 -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R) 21 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle and -L-NR 5 The aryl moiety of the C(O)-aryl group and the heterocyclic moiety of the -L-heterocyclic group and the cycloalkyl moiety of the -L-cycloalkyl group are separated by one or more R groups. 6 Optional substitution, wherein the aryl or heteroaryl group of said -L-aryl and said -L-heteroaryl is replaced by one or more R 7 Optional replacement;

[0015] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents are optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituent are replaced by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are selected from one or more elements selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0016] Each R 4 Selected independently from C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles, of which C 3-12 The carbide ring and the 3 to 12-membered heterocycle are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0017] Each R 5 Independently selected from hydrogen or C1-C6 alkyl;

[0018] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5 -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 )2、(C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(Cl -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl group of the -C3 alkyl)phenyl group is optionally substituted with one or more substituents selected from -C(O)H and OH, wherein -OC l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0019] Each R 7 Independently selected from halogens, hydroxyl groups, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 )2;

[0020] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0021] Each R 21 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0022] Each Q is independently selected from the bond, S, and O;

[0023] B is selected from heterocycles and carbocycles, wherein the heterocycles and carbocycles are independently selected from one or more halogens, cyano groups, hydroxyl groups, =O, -NO2, C l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted, and wherein B forms a spirocyclic ring with ring A; and

[0024] Ring A is selected from heterocyclic and carbocyclic rings, wherein the heterocyclic or carbocyclic ring is composed of one or more rings selected from R. 4 The substituents may be substituted by choice.

[0025] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0026] In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (I). In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0027] In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (I). In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0028] In one aspect, this disclosure provides a compound represented by the structure of formula (II):

[0029]

[0030] Or its pharmaceutically acceptable salt, wherein:

[0031] M is selected from O, S, SO, SO2, and NR. 3 ;

[0032] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-SO2R 20 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C 12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional substitution; and where M is NR 3 Y is O, and R 1 When it is piperazine, the piperazine is reacted with one or more R 9 replace;

[0033] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0034] Y is selected from bonds, O, S, and NR. 5 ;

[0035] R 2 Selected from -LN(R) 21 )2、-L-OR 21 Heterocyclic rings, C l -C6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R) 21 )2, -L-NHC(=NH)NH2, -LC(O)N(R 21 )2、-LC l -C6 haloalkyl, -L-OR 21 -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R) 21 )2 or -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the -L-NR 21 The aryl moiety of the C(O)-aryl group, the heterocyclic moiety of the -L-heterocyclic group, and the cycloalkyl moiety of the -L-cycloalkyl group are each separated by one or more R groups. 6 Optionally substituted, wherein the aryl portion of the -L-aryl group and the heteroaryl portion of the -L-heteroaryl group are each replaced by one or more R... 7 Optional substitution, where R is a bond, O, or S. 2 Further selected from hydrogen;

[0036] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l-C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents are optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituent are replaced by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are each substituted by one or more elements selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0037] R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyalkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles, of which C 3-12 The carbide ring and the 3 to 12-membered heterocycle are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0038] n is selected from 0 to 2;

[0039] Each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen, C 3-12 Carbocyclic rings and 3 to 12-membered heterocycles, wherein the C1-C6 alkyl, C 3-12 The carbon ring and 3 to 12-membered heterocycles are each independently selected from cyano, halogen, -OR5 and —N(R) 5 The substituents of )2 may be optionally substituted;

[0040] Each R 5 Independently selected from hydrogen or C1-C6 alkyl;

[0041] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5 -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl groups of the -C3 alkyl)phenyl groups are each optionally substituted by one or more substituents selected from -C(O)H and OH, wherein -OC lThe alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0042] Each Q is independently selected from the bond, S, and O;

[0043] Each R 7 Independently selected from halogens, hydroxyl groups, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 )2;

[0044] Each R 9 Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl groups;

[0045] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0046] Each R 21 Independently selected from hydrogen; and C1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3- to 12-membered heterocyclic rings may be optionally substituted; and

[0047] B is selected from heterocycles and carbocycles, wherein each of the heterocycles and carbocycles is independently selected from one or more halogens, cyano groups, hydroxyl groups, =O, -NO2, C l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0048] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound or salt of formula (II) and a pharmaceutically acceptable excipient.

[0049] In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (II). In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (II) and a pharmaceutically acceptable excipient.

[0050] In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (II). In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (II) and a pharmaceutically acceptable excipient.

[0051] In one aspect, this disclosure provides a compound represented by the structure of formula (III):

[0052]

[0053] Or its pharmaceutically acceptable salt, wherein:

[0054] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20)2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C 12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional replacement;

[0055] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0056] R 2 Selected from -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R) 21 )2 and L-bicyclic heterocycles, wherein the bicyclic heterocycle is composed of one or more R 6 Optional replacement;

[0057] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents are optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituent are replaced by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are each substituted by one or more elements selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0058] n is selected from 0 to 3;

[0059] Each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen, C 3-12 Carbocyclic rings and 3 to 12-membered heterocycles, wherein the C1-C6 alkyl, C 3-12The carbon ring and 3 to 12-membered heterocycles are each independently selected from cyano, halogen, -OR 5 and —N(R) 5 The substituents of )2 may be optionally substituted;

[0060] B is selected from heterocycles and carbocycles, wherein the heterocycle or carbocycle is independently selected from one or more halogens, cyano groups, hydroxyl groups, =O, -NO2, C l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0061] Y is selected from bonds, O, S, and NR. 5 ;

[0062] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5-Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl group of the -C3 alkyl)phenyl group is optionally substituted with one or more substituents selected from -C(O)H and OH, wherein -OC l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0063] Each Q is independently selected from the bond, S, and O;

[0064] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0065] Each R21 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3- to 12-membered heterocyclic rings may be optionally substituted; and

[0066] Each R 5 It is independently selected from hydrogen or C1-C6 alkyl.

[0067] In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound or salt of formula (III) and a pharmaceutically acceptable excipient.

[0068] In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (III). In some embodiments, this disclosure provides a method of treating a disease or condition using a compound or salt of formula (III) and a pharmaceutically acceptable excipient.

[0069] In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (III). In some embodiments, this disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is carried out using a compound or salt of formula (III) and a pharmaceutically acceptable excipient.

[0070] Incorporation

[0071] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent or patent application is expressly and individually indicated to be incorporated by reference. Detailed Implementation

[0072] The following description illustrates many exemplary configurations, methods, parameters, etc. However, it should be understood that such description is not intended to limit the scope of this disclosure, but is provided as a description of exemplary embodiments.

[0073] In the following description, certain specific details are set forth to provide a comprehensive understanding of various embodiments of this disclosure. However, those skilled in the art will understand that this disclosure can be practiced without these details.

[0074] definition

[0075] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. All patents and publications cited herein are incorporated herein by reference.

[0076] "Alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, and preferably having one to fifteen carbon atoms (i.e., C1-C1). 15 Alkyl groups. In some embodiments, the alkyl group comprises one to thirteen carbon atoms (i.e., C1-C1). 13 Alkyl group. In some embodiments, the alkyl group comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, the alkyl group comprises one to five carbon atoms (i.e., C1-C5 alkyl). In other embodiments, the alkyl group comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, the alkyl group comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, the alkyl group comprises one to two carbon atoms (i.e., C1-C2 alkyl). In other embodiments, the alkyl group comprises one carbon atom (i.e., C1 alkyl). In other embodiments, the alkyl group comprises five to fifteen carbon atoms (i.e., C5-C6 alkyl). 15 Alkyl group. In other embodiments, the alkyl group comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, the alkyl group comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, the alkyl group comprises three to five carbon atoms (i.e., C3-C5 alkyl). In some embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond.

[0077] Term "C" x-y When used in conjunction with a chemical part (such as alkyl, alkenyl, or alkynyl), it means to include a group containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbons. Term -C x-y Alkylene refers to an alkylene chain containing x to y carbons, whether substituted or unsubstituted. For example, -C 1-6 The alkylene group can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which may be optionally substituted.

[0078] "Alkoxy" refers to a group of the formula -O-alkyl that is bonded by an oxygen atom, wherein the alkyl group is an alkyl chain as defined above.

[0079] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms (i.e., C2-C). 12 Alkenyl group. In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In some embodiments, the alkenyl group comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). The alkenyl group is attached to the rest of the molecule by a single bond, such as ethenyl, propyl-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, etc.

[0080] "Alkyne group" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms (i.e., C2-C). 12 The alkynyl group (C2-C8 alkynyl group) is present in some embodiments. In other embodiments, the alkynyl group comprises two to eight carbon atoms (C2-C6 alkynyl group). In still other embodiments, the alkynyl group comprises two to four carbon atoms (C2-C4 alkynyl group). The alkynyl group is attached to the rest of the molecule by a single bond, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc.

[0081] Term "C" x-y "Alkenyl" and "C" x-y "Alkyne" refers to an alkyl group of similar length and possible substitution as described above, but containing at least one substituted or unsubstituted aliphatic group with a double or triple bond. Term -C x-y Idemenyl refers to an substituted or unsubstituted alkyl chain containing x to y carbons. For example, -C 2-6 The alkenyl group can be selected from vinylene, propenene, butenene, pentenene, and hexenene, any of which are optionally substituted. The alkenyl chain may have one or more double bonds. Terminology - C x-y Amyynyl group refers to a substituted or unsubstituted ynyl chain containing x to y carbons. For example, -C 2-6 The alkenyl group can be selected from alkenylene, propynylene, butynylene, pentylyne, and hexynylene, any of which are optionally substituted. The alkenylene chain can have one or more triple bonds.

[0082] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain, consisting only of carbon and hydrogen, without any degree of unsaturation, and preferably having one to twelve carbon atoms, with the remainder of the molecule attached to a group. Examples include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the remainder of the molecule and to the group via single bonds. The attachment points of the alkylene chain to the remainder of the molecule and to the group can be through any two carbons within the chain. In some embodiments, the alkylene comprises one to ten carbon atoms (i.e., C1-C1). 10 Alkylenes. In some embodiments, the alkylene comprises one to eight carbon atoms (i.e., C1-C8 alkylene). In other embodiments, the alkylene comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene).

[0083] "Alkenyl" or "alkenyl chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having two to twelve carbon atoms, to which the remainder of the molecule is attached via single bonds, and also to the group via single bonds. The attachment points of the alkenyl chain to the remainder of the molecule and to the group can be through any two carbons within the chain. In some embodiments, the alkenyl group comprises two to ten carbon atoms (i.e., C2-C). 10 (Alkenyl group). In some embodiments, the alkenyl group comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In other embodiments, the alkenyl group comprises two to five carbon atoms (i.e., C2-C5 alkenyl). In other embodiments, the alkenyl group comprises two to four carbon atoms (i.e., C2-C4 alkenyl). In other embodiments, the alkenyl group comprises two to three carbon atoms (i.e., C2-C3 alkenyl). In other embodiments, the alkenyl group comprises two carbon atoms (i.e., C2 alkenyl). In other embodiments, the alkenyl group comprises five to eight carbon atoms (i.e., C5-C8 alkenyl). In other embodiments, the alkenyl group comprises three to five carbon atoms (i.e., C3-C5 alkenyl).

[0084] "Alynyl" or "alynyl chain" refers to a straight-chain or branched divalent hydrocarbon chain in which the rest of the molecule is attached to a group, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having two to twelve carbon atoms. The alynyl chain is attached to the rest of the molecule and to the group via single bonds. The attachment points of the alynyl chain to the rest of the molecule and to the group can be through any two carbons within the chain. In some embodiments, the alynyl group contains two to ten carbon atoms (i.e., C2-C). 10 The alkynyl group comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises two to five carbon atoms (i.e., C2-C5 alkynyl). In other embodiments, the alkynyl group comprises two to four carbon atoms (i.e., C2-C4 alkynyl). In other embodiments, the alkynyl group comprises two to three carbon atoms (i.e., C2-C3 alkynyl). In other embodiments, the alkynyl group comprises two carbon atoms (i.e., C2 alkynyl). In other embodiments, the alkynyl group comprises five to eight carbon atoms (i.e., C5-C8 alkynyl). In other embodiments, the alkynyl group comprises three to five carbon atoms (i.e., C3-C5 alkynyl).

[0085] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic aromatic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. An aromatic monocyclic or polycyclic aromatic hydrocarbon ring system contains only hydrogen and carbon, with five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, that is, according to Hückel theory, it contains a cyclic, delocalized (4n+2)π-electron system. Ring systems from which aryl groups are derived include, but are not limited to, groups such as those in benzene, fluorene, indene, indene, tetrahydronaphthalene, and naphthalene.

[0086] "Aryl group" refers to the formula -R c -aryl groups, where R c It is an alkylene chain as defined above, such as methylene, ethylene, etc.

[0087] "Aryl" refers to the formula -R d -aryl groups, where R d This refers to an alkenyl group as defined above. "Arynyl group" refers to the formula -R e -aryl groups, where R e It is an alkyne chain as defined above.

[0088] A "carbocyclic ring" refers to a saturated, unsaturated, or aromatic ring in which every atom of the ring is carbon. Carbocyclic rings can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocyclic ring can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring (e.g., phenyl) can be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, or cyclohexene). Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbocyclic ring, where valence allows. Exemplary carbocyclic rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocyclic rings can be fused ring systems, bridged ring systems, or spirocyclic systems. In some cases, spirocyclic carbocyclic rings have at least two molecular rings with only one common atom.

[0089] The term "unsaturated carbide ring" refers to a carbide ring that has at least one degree of unsaturation and does not contain an aromatic carbide ring. Examples of unsaturated carbide rings include cyclohexadiene, cyclohexene, and cyclopentene.

[0090] “Cycloalkyl” refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, and preferably having three to twelve carbon atoms. In some embodiments, the cycloalkyl group contains three to ten carbon atoms. In other embodiments, the cycloalkyl group contains five to seven carbon atoms. The cycloalkyl group can be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptyl), norbornenyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc.

[0091] "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having three to twelve carbon atoms, and containing at least one double bond. In some embodiments, the cycloalkenyl group contains three to ten carbon atoms. In other embodiments, the cycloalkenyl group contains five to seven carbon atoms. The cycloalkenyl group can be attached to the rest of the molecule via a single bond. Examples of monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0092] "Cycloalkylalkyl" refers to the formula -R c -cycloalkyl groups, wherein R c It is an alkylene chain as described above.

[0093] "Cycloalkylalkoxy" refers to the formula -OR c - A cycloalkyl group bonded by an oxygen atom, wherein R c It is an alkylene chain as described above.

[0094] "Halogen" or "halogenated" refers to halogenated substituents, such as bromine, chlorine, fluorine, and iodine substituents.

[0095] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl group as defined above that is substituted with one or more halogen groups, such as trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl group is further optionally substituted. Examples of halogen-substituted alkanes (“haloalkanes”) include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalomethanes and trihalomethanes (e.g., chloroform, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of alkanes (or substituted alkanes) and halogens (e.g., Cl, Br, F, I, etc.). When the alkyl group is substituted by more than one halogen group, each halogen can be chosen independently, for example, 1-chloro,2-fluoroethane.

[0096] "Fluoroalkyl" refers to an alkyl group as defined above that is substituted with one or more fluorine groups, such as trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc.

[0097] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amine groups, such as propane-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine, etc.

[0098] "Hydroxyalkyl" refers to an alkyl group as defined above that is replaced by one or more hydroxyl groups, such as propan-1-ol, butan-1,4-diol, pentan-1,2,4-triol, etc.

[0099] "Alkoxyalkyl" refers to an alkyl group as defined above that is substituted with one or more alkoxy groups, such as methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, etc.

[0100] As used in this article, "cyanoalkyl" refers to an alkyl group as defined above that is substituted with one or more cyano groups, such as acetonitrile, 2-ethyl-3-methylsuccinate, butyronitrile, etc.

[0101] As used herein, "heterocycle" refers to a saturated ring, unsaturated ring, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. Where valence permits, a heterocycle can be attached to the remainder of the molecule by any atom of the heterocycle, such as a carbon or nitrogen atom. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Where valence permits, bicyclic heterocycles include any combination of saturated bicyclic, unsaturated bicyclic, and aromatic bicyclic rings. In one exemplary embodiment, an aromatic ring (e.g., pyridyl) may be fused with a saturated or unsaturated ring (e.g., cyclohexane, cyclopentane, morpholine, piperidine, or cyclohexene). Bicyclic heterocycles include any combination of ring sizes, such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles can be fused ring systems, bridged ring systems, or spirocyclic systems. Spirocyclic systems can be called "spiroheterocycles (spiro heterocycles or spiro-heterocycles)". In some cases, spiroheterocycles have at least two molecular rings with only one common atom. Spiroheterocycles contain one or more heteroatoms.

[0102] "Subheterocyclic" refers to a divalent heterocycle in which the rest of the molecule is attached to a group.

[0103] "Heteroaryl" or "aromatic heterocycle" refers to a group derived from a heteroaryl ring group containing one to eleven carbon atoms and at least one heteroatom, each of which may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems, wherein at least one ring in the ring system is aromatic, i.e., according to Hückel theory, it contains a cyclic, delocalized (4n+2)π– electron system. The heteroatom in the heteroaryl group may be optionally oxidized. One or more nitrogen atoms (if present) may be optionally quaternized. Where valence permits, the heteroaryl group may be attached to the remainder of the molecule by any atom of the heteroaryl group (such as the carbon or nitrogen atom of the heteroaryl group). Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzothiazole, and imidazopyridine.

[0104] "X-membered heteroaryl" refers to the number of inner ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 inner ring atoms, such as triazole, oxazole, thiophene, etc.

[0105] The term "unsaturated heterocycle" refers to a heterocycle having at least one degree of unsaturation and not containing aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle may be optionally substituted with one or more substituents (such as those described herein).

[0106] The term "substituted" refers to a portion having a substituent that replaces a hydrogen atom or a substituted heteroatom (e.g., NH) on one or more carbons of the structure. It should be understood that "substituted" or "replaced by" includes the implicit precondition that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution produces a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. In some embodiments, "substituted" refers to a portion having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon atom with an oxo, imino, or thio group. As used herein, the term "substituted" is envisioned to include all permissible substituents in organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents in organic compounds. For suitable organic compounds, permissible substituents can be one or more and can be the same or different. For the purposes of this disclosure, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any permitted substituents of the organic compounds described herein that satisfy the valence of the heteroatoms.

[0107] In some embodiments, the substituents may include any substituents described herein, such as: halogen, hydroxyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-Rb -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, areneyl, arynyl, cycloalkyl, cycloalkylalkyl and heterocyclic, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t Ra (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) are arbitrarily replaced; where each R a Independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each R is selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein, where the valence allows, each R a It can be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thio (=S), cyano (-CN), nitro (-NO2), imino (=NH), oxime (=N-OH), hydrazine (=N-NH2), -R b -OR a -R b -OC(O)-R a -R b -OC(O)-OR a -R b -OC(O)-N(R a )2、-R b -N(R a )2、-R b -C(O)R a -R b -C(O)OR a -R b -C(O)N(R a )2、-R b -OR c -C(O)N(R a )2、-R b -N(R a )C(O)OR a -R b -N(R a )C(O)R a -R b -N(R a S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O)t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) are arbitrarily replaced; and each R b Independently selected from direct-chain or straight-chain or branched alkylene, alkenyl, or ynylene chains, and each R c It is a straight-chain or branched alkylene, alkenyl, or ynylene chain.

[0108] As used herein, the term "electrophile" or "electrophilic moiety" refers to any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partially negative charge, and / or an excess of electrons, such as an -SH group). Electrophiles are typically electron-deficient or contain electron-deficient atoms. In some embodiments, the electrophile contains a positive charge or a partially positive charge, has a resonance structure containing a positive charge or a partially positive charge, or is a moiety where electron delocalization or polarization results in one or more atoms containing a positive charge or a partially positive charge. In some embodiments, the electrophile contains a conjugated double bond, such as an α,β-unsaturated carbonyl group or an α,β-unsaturated thiocarbonyl compound.

[0109] As used herein, the terms “optional” or “optionally” mean that the event described below may or may not occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, “optionally substituted aryl” means that the aryl group may be substituted or unsubstituted, and the description includes both substituted aryl groups and unsubstituted aryl groups.

[0110] Unless the context clearly indicates otherwise, the singular forms “a,” “an,” and “the” as used in the specification and claims include plural indicators.

[0111] The term "salt" or "pharmaceutically acceptable salt" refers to a salt derived from a variety of organic and inorganic counterions well known in the art. Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and particularly isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0112] As used herein, the phrase “parenteral administration” means any administration mode that is normally administered by injection other than enteral and topical administration, and includes, but is not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intra-bursal, intraorbital, intracardiac, intradermal, intraperitoneal, tracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal, and intrasternal injections and infusions.

[0113] The phrase “pharmaceutically acceptable” in this article refers to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0114] As used herein, the phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be “acceptable” in the sense of compatibility with the other components of the formulation and not cause harm to the patient. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and corn oil. Oils and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0115] In some implementations, the term “prevention” in relation to a disease or condition may refer to the compound reducing the incidence of the disease or condition in a treated sample relative to an untreated control sample, or delaying the onset of one or more symptoms of the disease or condition or reducing its severity relative to an untreated control sample.

[0116] As used herein, the term “treatment” can include reducing, alleviating or improving symptoms of a disease or condition; preventing additional symptoms; improving or preventing the underlying cause of symptoms; suppressing a disease or condition, for example, preventing the development of a disease or condition, alleviating a disease or condition, causing a disease or condition to subside, alleviating the condition caused by a disease or condition, or stopping the symptoms of a disease or condition in a preventive and / or therapeutic manner.

[0117] As used in this article, the term “G12 mutant” refers to the other KRAS oncogenic allele at amino acid position 12 (i.e., G12X).

[0118] The compounds disclosed herein

[0119] The following is a discussion of the compounds and salts that can be used in the methods disclosed herein.

[0120] In some respects, this disclosure provides a compound represented by the structure of formula (I):

[0121]

[0122] Or its pharmaceutically acceptable salt, wherein:

[0123] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional replacement;

[0124] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0125] Y is selected from bonds, O, S, and NR. 5 ;

[0126] R 2 Selected from hydrogen, -N(R) 21 )2、-LN(R 21 )2、-L-OR 21 Heterocyclic rings, C l -C6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R)21 )2,, -L-NHC(=NH)NH2, -LC(O)N(R 21 )2、-LC l -C6 haloalkyl, -L-OR 21 -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R) 21 )2 or -LC(=O)OC l -C6 alkyl, wherein heterocyclic and -L-NR 5 The aryl moiety of C(O)-aryl and the heterocyclic moiety of -L-heterocyclic and the cycloalkyl moiety of -L-cycloalkyl are separated by one or more R 6 Optional substitution, wherein the aryl or heteroaryl groups of -L-aryl and -L-heteroaryl are replaced by one or more R 7 Optional replacement;

[0127] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents may be optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituents are selected from one or more halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are selected from one or more elements chosen from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0128] Each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 aminoalkyl, C1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles, of which C 3-12 The carbide ring and the 3 to 12-membered heterocycle are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, -NH(C 1-6 alkyl), -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0129] Each R 5 Independently selected from hydrogen and C1-C6 alkyl groups;

[0130] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5 -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 )2、(C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl group of the -C3 alkyl)phenyl group is optionally substituted with one or more substituents selected from -C(O)H and OH, wherein -OC l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0131] Each R 7 Independently selected from halogens, hydroxyl groups, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 )2;

[0132] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0133] Each R 21 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0134] Each Q is independently selected from the bond, S, and O;

[0135] B is selected from heterocycles and carbocycles, wherein the heterocycle and carbocycle are independently selected from halogens, cyano groups, hydroxyl groups, =O, -NO2, C. l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted, and wherein B forms a spirocyclic ring with ring A; and

[0136] Ring A is selected from heterocycles and carbocycles, wherein the heterocycle or carbocycle is composed of one or more rings selected from R. 4 The substituents may be substituted by choice.

[0137] In some implementations, formula (I) is represented by formula (II), formula (II*), or formula (III).

[0138] In some embodiments, for compounds or salts of formula (I), ring A is selected from heterocycles, wherein the heterocycle is composed of one or more elements selected from R. 4 The substituents are optionally substituted. In some cases, ring A contains at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom of ring A is nitrogen, wherein nitrogen is replaced by R. 3 Optional substitution, where R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-N(R) 20 2. C 1-6aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles, of which C 3-12 The carbide ring and the 3 to 12-membered heterocycle are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents in the carbon ring and the 3- to 12-membered heterocycles are optionally substituted. In some cases, the heteroatom of ring A is sulfur, wherein the sulfur is optionally substituted by one or two oxygen atoms. In some cases, the heteroatom of ring A is oxygen.

[0139] In some embodiments, for compounds or salts of formula (I), ring A is selected from a carbide ring, wherein the carbide ring is composed of one or more elements selected from R. 4 The substituents may be substituted by choice.

[0140] In some implementations, for compounds or salts of formula (I), R 2 Selected from -L-NR 21 S(O)2(R 21 ) and -LS(O)2N(R 21 )2.

[0141] In some implementations, for compounds or salts of formula (I), R 2 Selected from -LN(R) 21 )C(O)(OR 21 ) and -L-OC(O)N(R 21 )2.

[0142] In some implementations, for compounds or salts of formula (I), each R 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 The alkyl and oxo substituents are optionally substituted. In some cases, each R... 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles. In some cases, each R...21 Independently selected from hydrogen and C 1-6 alkyl.

[0143] In some implementations, for compounds or salts of formula (I), R 2 Selected from L-bicyclic heterocycles, wherein the bicyclic heterocycle is separated by one or more R 6 Optional replacement.

[0144] In some implementations, for compounds or salts of formula (I), R 2 Selected from L-pyrrolizine, wherein the pyrrolizine is reacted with one or more R 6 Optional replacement.

[0145] In some embodiments, for compounds or salts of formula (I), each L is independently selected from optionally substituted C. l -C4 alkylene; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring, wherein the C3-C6 carbon ring is permeated by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, the optional substituents of L are selected from C. l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are selected from one or more halogens and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0146] In some embodiments, for compounds or salts of formula (I), each L is independently selected from substituted C. l -C4 alkylene, wherein two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, the C3-C6 carbon ring is formed by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0147] In some embodiments, for compounds or salts of formula (I), each L is independently selected from substituted C. l-C4 alkylene, wherein the two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, each L is independently selected from substituted C3 alkylene, wherein the two substituents on the same carbon atom of L together form a C3 carbon ring. In some cases, each L is independently selected from...

[0148] In some implementations, for compounds or salts of formula (I), R 2 Selected from -L-heterocycles, wherein the heterocyclic portion of the -L-heterocycle is separated by one or more R... 6 Optional substitution. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0149] In some implementations, for compounds or salts of formula (I), R 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0150] In some implementations, for compounds or salts of formula (I), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0151] In some implementations, for compounds or salts of formula (I), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0152] In some implementations, for compounds or salts of formula (I), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0153] In some implementations, for compounds or salts of formula (I), R 2 Selected from -L-saturated heterocycles, wherein the saturated heterocyclic portion of the -L-saturated heterocycle is separated by one or more R 6 The substitution is optional, and it contains one nitrogen atom and one sulfur atom. In some cases, YR 2 Selected from The heterocyclic portion is divided by one or more R 6Optional replacement. In some cases, YR 2 Selected from The heterocyclic moiety is optionally substituted by one or more substituents selected from C1-C3 alkyl and oxo groups. In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0154] In some implementations, for compounds or salts of formula (I), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN, C l -C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl groups of the -C3 alkyl)phenyl groups are each optionally substituted with -C(O)H and OH, and the heterocycles of the -CH2 heterocyclic groups are optionally substituted with oxy groups.

[0155] In some implementations, for compounds or salts of formula (I), each R 6 Independently selected from halogens, -OH, C l-C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl.

[0156] In some implementations, for compounds or salts of formula (I), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -N(R) 5 )2 and oxygenation. In some cases, each R 6 Independently selected from -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C1-C3 alkoxy and -N(R 5 2. In some cases, each R 6 Selected independently from C l -C3 alkyl, C1-C3 alkoxy and -N(R 5 )2.

[0157] In some implementations, for compounds or salts of formula (I), R 6 Selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 It is a halogen. In some cases, R 6 C l -C3 alkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 Selected from methyl and fluorine.

[0158] In some implementations, for compounds or salts of formula (I), R 2 Selected from

[0159] In some implementations, for compounds or salts of formula (I), YR 2 Selected from

[0160] In some implementations, for compounds or salts of formula (I), YR 2 Selected from

[0161] In some implementations, for compounds or salts of formula (I), YR 2 for

[0162] In some implementations, for compounds or salts of formula (I), YR 2 Selected from

[0163] In some embodiments, for compounds or salts of formula (I), B is an optionally substituted 5- to 15-membered heterocycle or an optionally substituted C3-C ring. 15 Carbon ring. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C... 15 Carbon ring.

[0164] In some embodiments, for compounds or salts of formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C... 15 Fused carbon ring. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C... 15 Fused carbon rings.

[0165] In some embodiments, for compounds of formula (I) or salts, for B, there is an optional substituted 8- to 15-membered fused heterocycle or an optional substituted C8-C 15 Each of the fused carbocyclic rings is either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings are either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings or optionally substituted C8-C... 15 Each of the fused carbon rings is either a bicyclic or a tricyclic ring.

[0166] In some embodiments, for compounds or salts of formula (I), B, the heterocycle or the carbocyclic ring, is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocyclic ring is bicyclic.

[0167] In some embodiments, for compounds or salts of formula (I), B, the heterocycle or the carbocyclic ring, is independently a tricyclic ring. In some cases, the heterocycle is a tricyclic ring. In some cases, the carbocyclic ring is a tricyclic ring.

[0168] In some embodiments, for compounds or salts of formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C... 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0169] In some embodiments, for compounds of formula (I) or salts, for B, there is an optional substituted 8- to 15-membered fused heterocycle or an optional substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0170] In some embodiments, for compounds of formula (I) or salts, for B, there is an optional substituted 8- to 15-membered fused heterocycle or an optional substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0171] In some embodiments, for compounds or salts of formula (I), for B, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogens, C1-C3 alkyl groups, -B(OR) 20 )2、-OR 20 -C(O)N(R) 20 )2、-N(R 20 )2、=O、-CN、-NHCN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Alkyne group. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR) groups. 20 )2、-OH、-C(O)N(R 20 )2、=O、-CN、C 1-6 Alkoxy and C 2-6 Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy and C 2-6Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbocyclic ring are independently selected each time they appear, from oxo, -NH2, -CN, halogen, and C1-C3 alkyl groups. In some cases, one or more optional substituents of the heterocycle or carbocyclic ring are independently selected, from oxo, -NH2, halogen, and C1-C3 alkyl groups.

[0172] In some implementations, for compounds or salts of formula (I), B is selected from...

[0173] In some embodiments, for compounds or salts of formula (I), for B, one or more optional substituents of the heterocyclic or carbocyclic ring are independently selected from oxo, -NH2, CN, halogen, C1-C3 alkyl.

[0174] In some implementations, for compounds or salts of formula (I), B is selected from...

[0175] In some implementations, for compounds or salts of formula (I), each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen. In some cases, each R... 4 Selected independently from C 1-6 Alkyl, oxo, and halogen.

[0176] In some implementations, for compounds or salts of formula (I), n is selected from 1 and 2. In some cases, n is 0.

[0177] In some implementations, Y is O for compounds or salts of formula (I).

[0178] In some implementations, for compounds or salts of formula (I), R 1 Selected from 5 to 12-membered heterocycles with optional substitution.

[0179] In some implementations, for compounds or salts of formula (I), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 C(O)N(R) 20 )2、-N(R20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 ), CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0180] In some implementations, for compounds or salts of formula (I), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -C(O)N(R) 20 )2、-C(O)NR 20 -OR 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN, C 1-6 aminoalkyl, C 1-6Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0181] In some implementations, for compounds or salts of formula (I), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)OR 20 and -OC(O)N(R 20 The substituents of )2 may be optionally substituted.

[0182] In some implementations, for compounds or salts of formula (I), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0183] In some implementations, for compounds or salts of formula (I), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0184] In some implementations, for compounds or salts of formula (I), R 1 R 20 Selected from hydrogen and C 1-3 alkyl.

[0185] In some implementations, for compounds or salts of formula (I), R 1 The 5- to 12-membered heterocycles are unsaturated heterocycles.

[0186] In some implementations, for compounds or salts of formula (I), R1 The 5- to 12-membered heterocycles are saturated heterocycles.

[0187] In some implementations, for compounds or salts of formula (I), R 1 The 5- to 12-membered heterocycles are bridging heterocycles.

[0188] In some implementations, for compounds or salts of formula (I), R 1 Selected from

[0189]

[0190] Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0191] In some implementations, for compounds or salts of formula (I), R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0192] In some implementations, for compounds or salts of formula (I), R 1 Selected from

[0193] In some embodiments, for compounds or salts of formula (I), L is selected from C1-C4 alkylene groups.

[0194] In some embodiments, for compounds or salts of formula (I), L is selected from unsubstituted C1-C4 alkylene compounds.

[0195] In some implementations, for compounds or salts of formula (I), R 2 It is an L-heterocyclic ring, which is bounded by one or more R... 6 Optional substitution, wherein the heterocyclic portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least one nitrogen atom. In some cases, the bicyclic heterocycle contains at most one nitrogen atom.

[0196] In some implementations, for compounds or salts of formula (I), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0197] In some implementations, for compounds or salts of formula (I), R 2 R 6 Each time it appears, it is independently selected from halogen, hydroxyl, C. l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl.

[0198] In some implementations, for compounds or salts of formula (I), R 2 R 6 Each time it appears, it is independently selected from C1-C3 alkyl groups and halogens.

[0199] In some implementations, for compounds or salts of formula (I), YR 2 Selected from

[0200] In some respects, this disclosure provides a compound represented by the structure of formula (II):

[0201] A compound of formula (II):

[0202]

[0203] Or its pharmaceutically acceptable salt, wherein:

[0204] M is selected from O, S, SO, SO2, and NR. 3 ;

[0205] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-SO2R 20 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional substitution; and where M is NR 3 Y is O, and R 1 When it is piperazine, the piperazine is reacted with one or more R 9 replace;

[0206] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0207] Y is selected from bonds, O, S, and NR. 5 ;

[0208] R 2 Selected from -LN(R) 21 )2、-L-OR 21 Heterocyclic rings, C l -C6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R) 21 )2、-LC l -C6 haloalkyl, -L-OR 21 -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R)21 )2 and -LC(=O)OC l -C6 alkyl, wherein heterocyclic, -L-NR 21 The aryl moiety of the C(O)-aryl group, the heterocyclic moiety of the -L-heterocyclic group, and the cycloalkyl moiety of the -L-cycloalkyl group are each surrounded by one or more R groups. 6 Optional substitution, wherein the aryl moiety of -L-aryl and the heteroaryl moiety of -L-heteroaryl are each replaced by one or more R 7 Optional substitution, where R is a bond, O, or S. 2 Further selected from hydrogen;

[0209] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents may be optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituents are selected from one or more halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are each substituted by one or more elements selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0210] R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyalkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles, of which C 3-12 The carbide ring and the 3 to 12-membered heterocycle are each independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, -N(C1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0211] n is selected from 0 to 2;

[0212] Each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen, C 3-12 Carbocyclic rings and 3 to 12-membered heterocycles, including C1-C6 alkyl groups, ... 3-12 The carbon ring and 3 to 12-membered heterocycles are each independently selected from cyano, halogen, -OR 5 and —N(R) 5 The substituents of )2 may be optionally substituted;

[0213] Each R 5 Independently selected from hydrogen or C1-C6 alkyl;

[0214] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5 -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 )2、(C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5)2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl groups of the -C3 alkyl)phenyl groups are each optionally substituted by one or more substituents selected from -C(O)H and OH, wherein -OC l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0215] Each Q is independently selected from the bond, S, and O;

[0216] Each R 7 Independently selected from halogens, hydroxyl groups, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 )2;

[0217] Each R 9 Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl groups;

[0218] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0219] Each R 21 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3- to 12-membered heterocyclic rings may be optionally substituted; and

[0220] B is selected from heterocycles and carbocycles, wherein the heterocycle and carbocycle are each independently selected from halogens, cyano groups, hydroxyl groups, =O, -NO2, C. l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0221] In some implementations, for compounds or salts of formula (II), R 2 Selected from -L-NR 21 S(O)2(R 21 ) and -LS(O)2N(R 21 )2.

[0222] In some implementations, for compounds or salts of formula (II), R 2 Selected from -LN(R) 21 )C(O)(OR 21 ) and -L-OC(O)N(R 21 )2.

[0223] In some implementations, for compounds or salts of formula (II), each R 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 The alkyl and oxo substituents are optionally substituted. In some cases, each R... 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles. In some cases, each R... 21 Independently selected from hydrogen and C 1-6 alkyl.

[0224] In some implementations, for compounds or salts of formula (II), R 3 Selected from hydrogen and C 1-6 alkyl.

[0225] In some embodiments, for compounds or salts of formula (II), M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe.

[0226] In some embodiments, for compounds or salts of formula (II), B is an optionally substituted 5- to 15-membered heterocycle or an optionally substituted C3-C ring. 15 Carbon ring. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C... 15 Carbocyclic ring. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C8-C... 15 Carbon ring.

[0227] In some embodiments, for compounds or salts of formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C... 15 Fused carbon ring. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C... 15 Fused carbon rings.

[0228] In some embodiments, for compounds of formula (II) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Each of the fused carbocyclic rings is either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings are either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings or optionally substituted C8-C... 15 Each of the fused carbon rings is either a bicyclic or a tricyclic ring.

[0229] In some embodiments, for compounds or salts of formula (II), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0230] In some embodiments, for compounds or salts of formula (II), for B, the heterocycle or carbocyclic ring is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocyclic ring is bicyclic.

[0231] In some embodiments, for compounds or salts of formula (II), for B, the heterocycle or carbocyclic ring is independently a tricyclic ring. In some cases, the heterocycle is a tricyclic ring. In some cases, the carbocyclic ring is a tricyclic ring.

[0232] In some embodiments, for compounds of formula (II) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0233] In some embodiments, for compounds of formula (I) or salts, for B, there is an optional substituted 8- to 15-membered fused heterocycle or an optional substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0234] In some embodiments, for compounds of formula (II) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0235] In some embodiments, for compounds or salts of formula (II), for B, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogens, C1-C3 alkyl groups, -B(OR) 20 )2、-OR 20 -C(O)N(R) 20 )2、-N(R 20 )2、=O、-CN、-NHCN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Alkyne group. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR) groups. 20 )2、-OH、-C(O)N(R 20 )2、=O、-CN、C 1-6 Alkoxy and C 2-6 Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy and C 2-6Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbocyclic ring are independently selected each time they appear, from oxo, -NH2, -CN, halogen, and C1-C3 alkyl groups. In some cases, one or more optional substituents of the heterocycle or carbocyclic ring are independently selected, from oxo, -NH2, halogen, and C1-C3 alkyl groups.

[0236] In some embodiments, for compounds or salts of formula (II), B is selected from...

[0237]

[0238] In some embodiments, for compounds or salts of formula (II), B is selected from...

[0239] In some implementations, for compounds or salts of formula (II), each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen. In some cases, each R... 4 Selected independently from C 1-6 Alkyl, oxo, and halogen.

[0240] In some embodiments, for compounds or salts of formula (II), n is selected from 1 and 2. In some cases, n is 0.

[0241] In some implementations, Y is O for compounds or salts of formula (II).

[0242] In some implementations, for compounds or salts of formula (II), R 1 Selected from 5 to 12-membered heterocycles with optional substitution.

[0243] In some implementations, for compounds or salts of formula (II), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0244] In some implementations, for compounds or salts of formula (II), R 1 Selected from C3-C 12Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 ), CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0245] In some implementations, for compounds or salts of formula (II), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)OR 20 and -OC(O)N(R 20 The substituents of )2 may be optionally substituted.

[0246] In some implementations, for compounds or salts of formula (II), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、C 1-6aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0247] In some implementations, for compounds or salts of formula (II), R 1 R 20 Selected from hydrogen and C 1-3 alkyl.

[0248] In some implementations, for compounds or salts of formula (II), R 1 The 5- to 12-membered heterocycles are unsaturated heterocycles.

[0249] In some implementations, for compounds or salts of formula (II), R 1 The 5- to 12-membered heterocycles are saturated heterocycles.

[0250] In some implementations, for compounds or salts of formula (II), R 1 The 5- to 12-membered heterocycles are bridging heterocycles.

[0251] In some implementations, for compounds or salts of formula (II), R 1 Selected from

[0252] Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0253] In some implementations, for compounds or salts of formula (II), R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0254] In some implementations, for compounds or salts of formula (II), R 1 Selected from

[0255] In some implementations, for compounds or salts of formula (II), R 1 Selected from optionally substituted saturated 6- to 7-membered heterocycles. In some cases, R 1 Selected from saturated 6-membered heterocycles with optional substitution. In some cases, R 1 Selected from It is optionally substituted. In some cases, one or more optional substituents are independently selected from halogens, -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -NHCN and C. 1-6 Alkyl group. In some cases, R 1 Selected from It is selected from one or more of -NHCN and C 1-6 Alkyl substituents. In some cases, R 1 Selected from

[0256] In some implementations, for compounds or salts of formula (II), R 1 Selected from substituted saturated 6-membered heterocycles, wherein the substituted saturated 6-membered heterocycle is substituted with at least one -NHCN and optionally one or more C. 1-6 Alkyl substitution; M is O; n is 0; B is selected from optionally substituted 8- to 15-membered fused heterocycles and optionally substituted C8-C 15 Fused carbocyclic rings, each of which is independently selected from one or more halogens, oxo-, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 The substituents of the alkynyl group can be substituted at will; Y is O; R 2 Selected from -L-heterocycles, wherein the heterocyclic moiety is independently selected from one or more halogens, hydroxyl groups, C... l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 The substituents of )2 are optionally substituted; and L is selected from C l-C4 alkylene. In some cases, R 1 Selected from In some cases, B is selected from

[0257] In some cases, B is selected from In some cases, B is

[0258] In some implementations, for compounds or salts of formula (II), each R 9 Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl groups. In some cases, each R... 9 Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN. In some cases, each R 9 Independently selected from halogens, -SR 20-S(O)2(R 20 -S(O)2N(R) 20 )2、-N(R 20 )2, -NO2, =O and =NO(R 20 In some cases, each R 9 Independently selected from halogens and -N(R) 20 )2.

[0259] In some embodiments, for compounds or salts of formula (II), each L is independently selected from optionally substituted C. l -C4 alkylene; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring, wherein the C3-C6 carbon ring is permeated by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, the optional substituents of L are selected from C. l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are selected from one or more halogens and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0260] In some embodiments, for compounds or salts of formula (II), each L is independently selected from the substituted C. l -C4 alkylene, wherein two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, the C3-C6 carbon ring is formed by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0261] In some embodiments, for compounds or salts of formula (II), each L is independently selected from substituted C. l -C4 alkylene, wherein the two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, each L is independently selected from substituted C3 alkylene, wherein the two substituents on the same carbon atom of L together form a C3 carbon ring. In some cases, each L is independently selected from...

[0262] In some implementations, for compounds or salts of formula (II), R 2 Selected from -L-heterocycles, wherein the heterocyclic portion of the -L-heterocycle is separated by one or more R... 6 Optional substitution. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0263] In some implementations, for compounds or salts of formula (II), R 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0264] In some implementations, for compounds or salts of formula (II), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0265] In some implementations, for compounds or salts of formula (II), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0266] In some implementations, for compounds or salts of formula (II), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0267] In some implementations, for compounds or salts of formula (II), R 2 Selected from -L-saturated heterocycles, wherein the saturated heterocyclic portion of the -L-saturated heterocycle is separated by one or more R 6 The substitution is optional, and it contains one nitrogen atom and one sulfur atom. In some cases, YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement. In some cases, YR 2 Selected from The heterocyclic moiety is optionally substituted by one or more substituents selected from C1-C3 alkyl and oxo groups. In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0268] In some implementations, for compounds or salts of formula (II), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN, C l -C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl groups of the -C3 alkyl)phenyl groups are each optionally substituted with -C(O)H and OH, and the heterocycles of the -CH2 heterocyclic groups are optionally substituted with oxy groups.

[0269] In some implementations, for compounds or salts of formula (II), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl.

[0270] In some implementations, for compounds or salts of formula (II), each R6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -N(R) 5 )2 and oxygenation. In some cases, each R 6 Independently selected from -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C1-C3 alkoxy and -N(R 5 2. In some cases, each R 6 Selected independently from C l -C3 alkyl, C1-C3 alkoxy and -N(R 5 )2.

[0271] In some implementations, for compounds or salts of formula (II), R 6 Selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 It is a halogen. In some cases, R 6 C l -C3 alkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 Selected from methyl and fluorine.

[0272] In some implementations, for compounds or salts of formula (II), R 2 Selected from

[0273] In some implementations, for compounds or salts of formula (II), YR 2 Selected from

[0274] In some implementations, for compounds or salts of formula (II), YR 2 Selected from

[0275] In some implementations, for compounds or salts of formula (II), YR 2 for

[0276] In some implementations, for compounds or salts of formula (II), YR 2 Selected from

[0277] In some embodiments, for compounds or salts of formula (II), L is selected from C1-C4 alkylene groups.

[0278] In some embodiments, for compounds or salts of formula (II), L is selected from unsubstituted C1-C4 alkylene compounds.

[0279] In some implementations, for compounds or salts of formula (II), R 2 It is an L-heterocyclic ring, which is bounded by one or more R... 6 Optional substitution, wherein the heterocyclic portion is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least one nitrogen atom. In some cases, the bicyclic heterocycle contains at most one nitrogen atom.

[0280] In some implementations, for compounds or salts of formula (II), R 2 Selected from L-bicyclic heterocycles, wherein the bicyclic heterocycle is separated by one or more R 6 Optional replacement.

[0281] In some implementations, for compounds or salts of formula (II), R 2 Selected from L-pyrrolizine, wherein the pyrrolizine is reacted with one or more R 6 Optional replacement.

[0282] In some implementations, for compounds or salts of formula (II), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0283] In some implementations, for compounds or salts of formula (II), R 2 R 6 Each time it appears, it is independently selected from halogen, hydroxyl, C. l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl. In some cases, R 2 R 6Each time it appears, it is independently selected from C1-C3 alkyl groups and halogens. In some cases, YR 2 Selected from

[0284] In some embodiments, for compounds or salts of formula (II), M is selected from NR. 3 In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is selected from C. 1-6 Cyanoalkyl. In some cases, M is selected from C2-cyanoalkyl. In some cases, M is selected from NH. In some cases, R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from C 1-6 Alkyl, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from C 2-6 Alkyl, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from C 1-6 Cyanoalkyl, C 1-6 Alkoxyalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 Haloalkyl. In some cases, R 3 Selected from C 1-6 Alkoxyalkyl, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, R 3 for In some cases, R 3 Selected from C 2-6 alkyl.

[0285] In some implementations, for compounds or salts of formula (II), M is NR. 3 B is selected from Each of these is an arbitrary substitution; n is 0; Y is 0; R 2 Selected from L-heterocyclic rings. The heterocyclic ring is composed of one or more R... 6 Optional substitution; R 1 Selected from It is an optional substitution. In some cases, R 1 for It is selected independently by one or more halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20)2、-C(O)NR 20 OR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkynyl group may be optionally substituted. In some cases, R 1 for In some cases, R 1 for In some cases, R 1 for In some cases, R 1 for In some cases, the L-heterocyclic ring is bicyclic. In some cases, the L-heterocyclic ring is monocyclic. In some cases, L is selected from C1-C4 alkylene oxides. In some cases, L is selected from unsubstituted C1-C4 alkylene oxides. In some cases, L is independently selected from substituted C1-C4 alkylene oxides. l -C4 alkylene, wherein two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, B is selected from It is substituted by one or more substituents. In some cases, B is... It is substituted by one or more substituents. In some cases, B is selected from... It is substituted by one or more substituents. In some cases, for B, one or more substituents are independently selected from halogens, oxo groups, -NH2, C1-C3 alkyl groups, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, -OC. l -C3 haloalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkyne group. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine.

[0286] In some cases, B is selected from In some cases, B is selected from It is selected from one or more halogens, -OC l -C3 haloalkyl and C 1-6 Substituents of haloalkyl groups. In some cases, B is... It is substituted with one or more substituents selected from halogens. In some cases, B is selected from... In some cases, B is It is substituted with one or more substituents selected from fluorine. In some cases, B is selected from... In some cases, B is It is substituted with one or more substituents selected from chlorine. In some cases, B is selected from... In some cases, R 3 Selected from hydrogen and C 1-6 Alkyl group. In some cases, R 3 Selected from C 1-6 Alkyl group. In some cases, R 3 It is methyl. In some cases, each R 6 Selected from halogens, oxometalates, and C 1-6 Alkyl groups. In some cases, each R 6 Selected from halogens and C 1-6 Alkyl groups. In some cases, each R 6 Selected from halogens. In some cases, R 1 Selected from In some cases, R 1 for In some cases, B is

[0287] In some respects, this disclosure provides a compound represented by the structure of formula (III):

[0288]

[0289] Or its pharmaceutically acceptable salt, wherein:

[0290] R 1 Selected from C3-C 12 Carbon rings and 5 to 15-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20)2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbon ring and the 5- to 12-membered heterocycle are each independently bound by one or more R 1* Optional replacement;

[0291] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20)2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C3-C 12 Carbon rings;

[0292] R 2 Selected from -L-NR 21 S(O)2(R 21 -LS(O)2N(R) 21 )2、-LN(R 21 )C(O)(OR 21 -L-OC(O)N(R) 21 )2 and L-bicyclic heterocycles, wherein the bicyclic heterocycle is separated by one or more R 6 Optional replacement;

[0293] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring, or 3- to 8-membered heterocyclic substituents may be optionally substituted, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocyclic substituents are selected from one or more halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6The substituents of the haloalkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are each substituted by one or more elements selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0294] n is selected from 0 to 3;

[0295] Each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen, C 3-12 Carbocyclic rings and 3 to 12-membered heterocycles, including C1-C6 alkyl groups, ... 3-12 The carbon ring and 3 to 12-membered heterocycles are each independently selected from cyano, halogen, -OR 5 and —N(R) 5 The substituents of )2 may be optionally substituted;

[0296] B is selected from heterocycles and carbocycles, wherein the heterocycle or carbocycle is independently selected from one or more halogens, cyano groups, hydroxyl groups, =O, -NO2, C l -C4 alkyl, C 1-6 aminoalkyl, -SC l -C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C l -C3 haloalkyl, -OC l -C3 haloalkyl, -SC l -C3 haloalkyl, C1-C3 alkoxy, C l -C3 hydroxyalkyl, -CH2C(=O)N(R) 5 )2、-C3-C4 ynyl group (NR 5 )2、-N(R 5 2. (C1-C3 alkoxy)halogenated C l -C3 alkyl-, C 1-6 Alkyl-N(R) 20 2. C3-C 12 The substituents of the carbocyclic ring and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the C3-C... 12 The carbide ring and the 5- to 12-membered heterocycle are each separated by one or more elements selected from halogens, -OH, -NO2, -NH2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be substituted in any way;

[0297] Y is selected from bonds, O, S, and NR. 5 ;

[0298] Each R 6 Independently selected from halogens, hydroxyl groups, and C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C l -C3 alkyl, C l -C3 aminoalkyl, -N(R) 5 )S(O)2(R 5 -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic, -OC l -C3 alkyl and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl group of the -C3 alkyl)phenyl group is optionally substituted with one or more substituents selected from -C(O)H and OH, wherein -OC lThe alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycles, oxo groups, and hydroxyl groups; and the heterocycle of the -CH2 heterocyclic group is optionally substituted with an oxo group;

[0299] Each Q is independently selected from the bond, S, and O;

[0300] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted;

[0301] Each R 21 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic ring and the 3- to 12-membered heterocyclic rings may be optionally substituted; and

[0302] Each R 5 It is independently selected from hydrogen or C1-C6 alkyl.

[0303] In some implementations, for compounds or salts of formula (III), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -C(O)N(R) 20 )2、-C(O)NR 20 -OR 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)R 20 -N(R)20 )C(O)N(R 20 )2、N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 -CN, -NHCN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0304] In some implementations, for compounds or salts of formula (III), R 2 Selected from -L-NR 21 S(O)2(R 21 ) and -LS(O)2N(R 21 )2.

[0305] In some implementations, for compounds or salts of formula (III), R 2 Selected from -LN(R) 21 )C(O)(OR 21 ) and -L-OC(O)N(R 21 )2.

[0306] In some implementations, for compounds or salts of formula (III), each R 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 The alkyl and oxo substituents are optionally substituted. In some cases, each R... 21 Independently selected from hydrogen; C 1-6 Alkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles. In some cases, each R... 21 Independently selected from hydrogen and C 1-6 alkyl.

[0307] In some implementations, for compounds or salts of formula (III), R 2 Selected from L-bicyclic heterocycles, wherein the bicyclic heterocycle is separated by one or more R 6 Optional replacement.

[0308] In some implementations, for compounds or salts of formula (III), R 2 Selected from L-pyrrolizine, wherein the pyrrolizine is reacted with one or more R 6 Optional replacement.

[0309] In some embodiments, for compounds or salts of formula (III), B is an optionally substituted 5- to 15-membered heterocycle or an optionally substituted C3-C ring. 15 Carbocyclic ring. In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C... 15 Carbon ring. In some cases, B is an optionally substituted C8-C ring. 15 Carbon ring.

[0310] In some embodiments, for compounds or salts of formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C... 15 Fused carbon ring. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted C8-C... 15 Fused carbon rings.

[0311] In some embodiments, for compounds or salts of formula (III), for B, the optionally substituted 8- to 15-membered heterocycle contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocycle contains at least two heteroatoms.

[0312] In some embodiments, for compounds of formula (III) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Each of the fused carbocyclic rings is either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings are either bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic rings or optionally substituted C8-C... 15 Each of the fused carbon rings is either a bicyclic or a tricyclic ring.

[0313] In some embodiments, for compounds or salts of formula (III), for B, the heterocycle or carbocyclic ring is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocyclic ring is bicyclic.

[0314] In some embodiments, for compounds or salts of formula (III), for B, the heterocycle or carbocyclic ring is independently a tricyclic ring. In some cases, the heterocycle is a tricyclic ring. In some cases, the carbocyclic ring is a tricyclic ring.

[0315] In some embodiments, for compounds of formula (III) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0316] In some embodiments, for compounds of formula (III) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0317] In some embodiments, for compounds of formula (III) or salts, for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 Fused carbon rings are selected from Each of them is optionally substituted by one or more substituents.

[0318] In some embodiments, for compounds of formula (III) or salts, for B, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogens, C1-C3 alkyl groups, -B(OR) 20 )2、-OR 20 -C(O)N(R) 20 )2、-N(R 20 )2、=O、-CN、-NHCN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 Alkyne group. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OR) groups. 20 )2、-OH、-C(O)N(R 20)2、=O、-CN、C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbide ring are independently selected each time they appear from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkynyl. In some cases, one or more optional substituents of the heterocycle and carbocyclic ring are independently selected each time they appear, from oxo, -NH2, -CN, halogen, and C1-C3 alkyl groups. In some cases, one or more optional substituents of the heterocycle or carbocyclic ring are independently selected, from oxo, -NH2, halogen, and C1-C3 alkyl groups.

[0319] In some embodiments, for compounds or salts of formula (III), B is selected from...

[0320] In some embodiments, for compounds or salts of formula (III), for B, one or more optional substituents of the heterocyclic or carbocyclic ring are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

[0321] In some embodiments, for compounds or salts of formula (III), B is selected from...

[0322] In some implementations, for compounds or salts of formula (III), each R 4 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, oxo, hydroxyl, halogen. In some cases, each R... 4 Selected independently from C 1-6 Alkyl, oxo, and halogen.

[0323] In some implementations, for compounds or salts of formula (III), n is selected from 1 and 2. In some cases, n is 0.

[0324] In some implementations, Y is O for compounds or salts of formula (III).

[0325] In some implementations, for compounds or salts of formula (III), R 1 Selected from 5 to 12-membered heterocycles with optional substitution.

[0326] In some implementations, for compounds or salts of formula (III), R 1Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 ), CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0327] In some implementations, for compounds or salts of formula (III), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from halogens, -B (OR) rings, and other heterocycles. 20 )2、-OR 20 SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR20 -N(R) 20 )2、-C(O)R 20 C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=NO(R 20 ), CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0328] In some implementations, for compounds or salts of formula (III), R 1 Selected from C3-C 12 Carbon rings and 5 to 12-membered heterocycles, each of which is independently selected from -S(O)2(R 20 -S(O)2N(R) 20 )2、-NR 20 S(O)2R 20 -N(R) 20 )C(O)OR 20 and -OC(O)N(R 20 The substituents of )2 may be optionally substituted.

[0329] In some implementations, for compounds or salts of formula (III), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0330] In some implementations, for compounds or salts of formula (III), R 1 Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently selected from halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0331] In some implementations, for compounds or salts of formula (III), R 1 R 20 Selected from hydrogen and C 1-3 alkyl.

[0332] In some implementations, for compounds or salts of formula (III), R 1 The 5- to 12-membered heterocycles are unsaturated heterocycles.

[0333] In some implementations, for compounds or salts of formula (III), R 1 The 5- to 12-membered heterocycles are saturated heterocycles.

[0334] In some implementations, for compounds or salts of formula (III), R 1 The 5- to 12-membered heterocycles are bridging heterocycles.

[0335] In some implementations, for compounds or salts of formula (III), R 1 Selected from

[0336]

[0337] Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0338] In some implementations, for compounds or salts of formula (III), R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0339] In some implementations, for compounds or salts of formula (III), R 1 Selected from

[0340] In some implementations, for compounds or salts of formula (III), R 1Selected from optionally substituted saturated 6- to 7-membered heterocycles. In some cases, R 1 Selected from saturated 6-membered heterocycles with optional substitution. In some cases, R 1 Selected from It is optionally substituted. In some cases, one or more optional substituents are independently selected from halogens, -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -NHCN and C. 1-6 Alkyl group. In some cases, R 1 Selected from It is selected from one or more of -NHCN and C 1-6 Alkyl substituents. In some cases, R 1 Selected from

[0341] In some implementations, for compounds or salts of formula (III), R 1 Selected from substituted saturated 6-membered heterocycles, wherein the substituted saturated 6-membered heterocycle is substituted with at least one -NHCN and optionally one or more C. 1-6 Alkyl substitution; M is O; n is 0; B is selected from optionally substituted 8- to 15-membered fused heterocycles and optionally substituted C8-C 15 Fused carbocyclic rings, each of which is independently selected from one or more halogens, oxo-, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 The substituents of the alkynyl group can be substituted at will; Y is O; R 2 Selected from -L-bicyclic heterocycles, wherein the bicyclic heterocycle portion is independently selected from one or more halogens, hydroxyl groups, C... l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 The substituents of )2 are optionally substituted; and L is selected from C l -C4 alkylene. In some cases, R 1 Selected from In some cases, B is selected from In some cases, B is selected from In some cases, B is

[0342] In some embodiments, for compounds or salts of formula (III), L is selected from C1-C4 alkylene groups.

[0343] In some embodiments, for compounds or salts of formula (III), each L is independently selected from optionally substituted C. l -C4 alkylene; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring, wherein the C3-C6 carbon ring is permeated by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, the optional substituents of L are selected from C. l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbon ring; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring or a 3- to 8-membered heterocycle, wherein the C3-C6 carbon ring and the 3- to 8-membered heterocycle are selected from one or more halogens and C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0344] In some embodiments, for compounds or salts of formula (III), each L is independently selected from the substituted C. l -C4 alkylene, wherein two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, the C3-C6 carbon ring is formed by one or more substituents selected from halogens, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0345] In some embodiments, for compounds or salts of formula (III), each L is independently selected from substituted C. l -C4 alkylene, wherein the two substituents on the same carbon atom of L together form a C3-C6 carbon ring. In some cases, each L is independently selected from substituted C3 alkylene, wherein the two substituents on the same carbon atom of L together form a C3 carbon ring. In some cases, each L is independently selected from...

[0346] In some implementations, for compounds or salts of formula (III), R 2 Selected from -L-heterocycles, wherein the heterocyclic portion of the -L-heterocycle is separated by one or more R... 6 Optional substitution. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0347] In some implementations, for compounds or salts of formula (III), R 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0348] In some implementations, for compounds or salts of formula (III), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0349] In some implementations, for compounds or salts of formula (III), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0350] In some implementations, for compounds or salts of formula (III), YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0351] In some implementations, for compounds or salts of formula (III), R 2 Selected from -L-saturated heterocycles, wherein the saturated heterocyclic portion of the -L-saturated heterocycle is separated by one or more R 6 The substitution is optional, and it contains one nitrogen atom and one sulfur atom. In some cases, YR 2 Selected from The heterocyclic portion is divided by one or more R 6 Optional replacement. In some cases, YR 2 Selected from The heterocyclic moiety is optionally substituted by one or more substituents selected from C1-C3 alkyl and oxo groups. In some cases, YR 2 Selected from In some cases, YR 2Selected from

[0352] In some implementations, for compounds or salts of formula (III), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN, C l -C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5 2. (C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C l -C3 alkoxy group, -CH2OC(O)N(R) 5 )2、-CH2NHC(O)OC1-C6 alkyl、-CH2NHC(O)N(R 5 )2、-CH2NHC(O)C1-C6 alkyl、-CH2(pyrazolyl)、-CH2NHSO2C1-C6 alkyl、-CH2OC(O) heterocyclic、-OC(O)N(R 5 )2、-OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(C l -C3alkyl)phenyl(C1-C3alkyl)N(CH3)2、-OC(O)NH(C1-C3alkyl)O(C l -C3 alkyl)phenyl, -OC(O) heterocyclic and -CH2 heterocyclic, of which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l The phenyl groups of the -C3 alkyl)phenyl groups are each optionally substituted with -C(O)H and OH, and the heterocycles of the -CH2 heterocyclic groups are optionally substituted with oxy groups.

[0353] In some implementations, for compounds or salts of formula (III), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl.

[0354] In some implementations, for compounds or salts of formula (III), each R 6 Independently selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -N(R) 5 )2 and oxygenation. In some cases, each R 6 Independently selected from -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 aminoalkyl, C1-C3 alkoxy and -N(R 5 2. In some cases, each R 6 Selected independently from C l -C3 alkyl, C1-C3 alkoxy and -N(R 5 )2.

[0355] In some implementations, for compounds or salts of formula (III), R 6 Selected from halogens, -OH, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 It is a halogen. In some cases, R 6 C l -C3 alkyl. In some cases, R 6 Selected from halogens and C l -C3 alkyl. In some cases, R 6 Selected from methyl and fluorine.

[0356] In some implementations, for compounds or salts of formula (III), R 2 Selected from

[0357] In some implementations, for compounds or salts of formula (III), YR 2 Selected from

[0358] In some implementations, for compounds or salts of formula (III), YR 2 Selected from

[0359] In some implementations, for compounds or salts of formula (III), YR 2 for

[0360] In some embodiments, for compounds or salts of formula (III), L is selected from unsubstituted C1-C4 alkylene groups.

[0361] In some implementations, for compounds or salts of formula (III), YR 2 Selected from and The heterocyclic portion is divided by one or more R 6 Optional replacement.

[0362] In some implementations, for compounds or salts of formula (III), R 2 R 6 Each time it appears, it is independently selected from halogen, hydroxyl, C. l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl.

[0363] In some implementations, for compounds or salts of formula (III), R 2 R 6 Each time it appears, it is independently selected from C1-C3 alkyl groups and halogens.

[0364] In some implementations, for compounds or salts of formula (III), YR 2 Selected from

[0365] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The carbon rings are selected from C3-C 12 Carbon rings, C3-C 10 Carbon rings, C3-C9 carbon rings, C3-C8 carbon rings, or C3-C6 carbon rings. In some cases, R... 1 The carbon rings are selected from C3-C 12 Carbon rings, C4-C 12 Carbon rings, C5-C 12 Carbon rings, C6-C 12 Carbon ring, C7-C 12 Carbon rings, C8-C 12 Carbon ring or C9-C 12 Carbon ring.

[0366] In some implementations, for compounds of formula (I), R1 The heterocycles are 5- to 12-membered, 6- to 12-membered, 7- to 12-membered, or 8- to 12-membered heterocycles. In some cases, R... 1 The heterocycles are 5- to 11-membered, 5- to 10-membered, 5- to 9-membered, or 5- to 8-membered heterocycles. In some cases, R... 1 The heterocycles are 6- to 11-membered, 6- to 10-membered, 6- to 9-membered, or 6- to 8-membered heterocycles. In some cases, R... 1 The heterocycles are 7- to 11-membered, 7- to 10-membered, 7- to 9-membered, or 7- to 8-membered heterocycles. In some cases, R... 1 The heterocycle is a 5- to 6-membered heterocycle or a 5- to 9-membered heterocycle. In some cases, R 1 The heterocycle is an 8- to 9-membered heterocycle. In some cases, R 1 The heterocycle is saturated. The heterocycle can be optionally substituted as described elsewhere in this document.

[0367] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The heterocycles are 5- to 12-membered monocyclic heterocycles, 6- to 12-membered monocyclic heterocycles, 7- to 12-membered monocyclic heterocycles, or 8- to 12-membered monocyclic heterocycles. In some cases, R... 1 The heterocycles are 5- to 11-membered monocyclic heterocycles, 5- to 10-membered monocyclic heterocycles, 5- to 9-membered monocyclic heterocycles, or 5- to 8-membered monocyclic heterocycles. In some cases, R... 1 The heterocycles are 6- to 11-membered monocyclic heterocycles, 6- to 10-membered monocyclic heterocycles, 6- to 9-membered monocyclic heterocycles, or 6- to 8-membered monocyclic heterocycles. In some cases, R... 1 The heterocycles are 7- to 11-membered monocyclic heterocycles, 7- to 10-membered monocyclic heterocycles, 7- to 9-membered monocyclic heterocycles, or 7- to 8-membered monocyclic heterocycles. In some cases, R... 1 The heterocycle is a 5- to 6-membered monocyclic heterocycle or a 5- to 9-membered monocyclic heterocycle. In some cases, R 1 The heterocycle is an 8- to 9-membered monocyclic heterocycle. In some cases, R 1 The heterocycle is saturated. The monocyclic heterocycle can be optionally substituted as described elsewhere in this document.

[0368] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The heterocyclic rings are 5- to 12-membered bridged heterocyclic rings, 6- to 12-membered bridged heterocyclic rings, 7- to 12-membered bridged heterocyclic rings, or 8- to 12-membered bridged heterocyclic rings. In some cases, R 1 The heterocyclic rings are 5- to 11-member bridged heterocyclic rings, 5- to 10-member bridged heterocyclic rings, 5- to 9-member bridged heterocyclic rings, or 5- to 8-member bridged heterocyclic rings. In some cases, R 1The heterocyclic rings are 6- to 11-member bridged heterocyclic rings, 6- to 10-member bridged heterocyclic rings, 6- to 9-member bridged heterocyclic rings, or 6- to 8-member bridged heterocyclic rings. In some cases, R 1 The heterocyclic rings are 7- to 11-member bridged heterocyclic rings, 7- to 10-member bridged heterocyclic rings, 7- to 9-member bridged heterocyclic rings, or 7- to 8-member bridged heterocyclic rings. In some cases, R 1 The heterocycles are 5- to 6-membered bridged heterocycles or 5- to 9-membered bridged heterocycles. In some cases, R 1 The heterocycle is an 8- to 9-membered bridging heterocycle. In some implementations, R 1 The heterocycle is saturated. The bridging heterocycle can be optionally substituted, as described elsewhere in this document.

[0369] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 It is a 5- to 9-membered heterocycle, containing at most one nitrogen atom. In some embodiments, R 1 Selected from 5 to 9-membered heterocycles with optional substitution, each of which is optionally substituted.

[0370] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The heterocycle contains at most one nitrogen atom. In some embodiments, R 1 The heterocycle contains at most one heteroatom. In some embodiments, R 1 The heterocycle contains at most two heteroatoms. In some cases, the heteroatoms are selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is selected from... In some cases, heterocycles are selected from... In some cases, bridging heterocyclic elements are selected from... Heterocyclic rings can be substituted as is described elsewhere in this document.

[0371] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The spiroheterocycle contains at most one nitrogen atom. In some embodiments, R 1 The spiroheterocycle contains at most two heteroatoms. In some embodiments, R 1 The spiroheterocycle contains at most three heteroatoms. In some embodiments, R 1 The spiroheterocycle contains at most one heteroatom. In some cases, R 1 The spirocyclic heterocycle contains at least two heteroatoms. In some cases, R 1 The spirocyclic heterocycle contains at least three heteroatoms. In some cases, R 1The spirocyclic heterocycle contains at least four heteroatoms. In some cases, R 1 The spiroheterocycle contains at least two nitrogen atoms. In some embodiments, R 1 The spiroheterocycle contains at most one heteroatom. In some cases, R 1 The spiroheterocycle contains at most one sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 The spiroheterocycles are selected from

[0372] In some implementation schemes, R 1 The spiroheterocycles are selected from Spirohexacyclic rings can be substituted as is described elsewhere in this document.

[0373] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted 7- to 8-membered spiroheterocycles. In some cases, R 1 Selected from optionally substituted 7-membered spiroheterocycles. In some cases, R 1 Selected from arbitrarily substituted 8-membered spiroheterocycles.

[0374] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The fused heterocycles are 6- to 12-membered fused heterocycles, 7- to 12-membered fused heterocycles, or 8- to 12-membered fused heterocycles. In some cases, R 1 The fused heterocycles are 6- to 11-membered fused heterocycles, 6- to 10-membered fused heterocycles, 6- to 9-membered fused heterocycles, or 6- to 8-membered fused heterocycles. In some cases, R 1 The fused heterocycles are 7- to 11-membered fused heterocycles, 7- to 10-membered fused heterocycles, 7- to 9-membered fused heterocycles, or 7- to 8-membered fused heterocycles. In some cases, R 1 The fused heterocycles are 8 to 11-membered fused heterocycles. In some cases, R 1 The fused heterocycle is a 6-membered fused heterocycle. The fused heterocycle can be optionally substituted as described elsewhere in this document.

[0375] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The fused heterocycles are selected from 6-, 9-, 10-, 11-, and 12-membered fused heterocycles. In some cases, R... 1 The fused heterocycles are selected from 9- to 12-membered fused heterocycles. In some cases, R 1 The fused heterocycle is selected from 10 to 12-membered fused heterocycles. The fused heterocycle is composed of one or more elements independently selected from halogens, -OR...20 -N(R) 20 )2、-NO2、=O、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted. The fused heterocycle may be independently selected from one or more halogens, -OR 20 -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0376] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The fused heterocycle contains at most one nitrogen atom. In some embodiments, R 1 The fused heterocycle contains at most one heteroatom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle is... The fused heterocycle can be optionally substituted, as described elsewhere in this document.

[0377] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The components are selected from C6-C7 carbon rings, 5- to 10-membered heterocycles, 7- to 8-membered spiroheterocycles, and 6, 9, 10, 11, and 12-membered fused heterocycles, each of which is optionally substituted.

[0378] In some implementations, for compounds of formula (I), R 1 Selected from C6-C7 carbon rings, 5- to 10-membered heterocycles, 7- to 8-membered spiroheterocycles, and 6, 8- to 12-membered fused heterocycles, each of which is independently selected from halogens, -OR 20 -N(R) 20 )2、-NO2、=O、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0379] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1Selected from C6-C7 carbon rings, 5- to 10-membered heterocycles, 7- to 8-membered spiroheterocycles, and 6, 8- to 12-membered fused heterocycles, each of which is independently selected from halogens, -OR 20 -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0380] In some implementations, for compounds or salts of formula (I), (II), or (III), for R 1 -OR 20 and -N(R) 20 )2 of R 20 Selected from hydrogen and C 1-6 alkyl.

[0381] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from C6-C7 carbon rings and 5- to 10-membered heterocycles, each of which is optionally substituted. In some cases, the heterocycle contains at most one nitrogen atom. In some cases, R 1 Selected from C6-C7 carbon rings, each of which is optionally substituted.

[0382] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 One or more optional substituents are independently selected from halogens, -OR 20 -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, -N(R) 20 )C(O)N(R 20 )2 and C 1-6 alkyl.

[0383] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 One or more optional substituents are independently selected from halogens, -OR 20 -N(R) 20 )2、-NO2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C1-6 Alkyl group. In some cases, R 1 One or more optional substituents are independently selected from -OR 20 -N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents of R1 are independently selected from -OR. 20 -N(R) 20 2. C 1-6 aminoalkyl and C 1-6 Hydroxyalkyl. In some cases, one or more optional substituents of R1 are independently selected from -OR. 20 -N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkyl and C 1-6 Hydroxyalkyl. In some cases, R 1 One or more optional substituents are independently selected from -OR 20 -N(R) 20 )2 and C 1-6 Alkyl group. In some cases, R 1 One or more optional substituents are independently selected from -N(R) 20 )C(O)N(R 20 )2.

[0384] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from C3-C 12 A carbon ring and a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 Further selected from 7-, 8-, 10-, and 11-membered spirochetes and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, wherein C3-C 12 Carbocyclic rings, 5- to 12-membered heterocycles, 7, 8, 10, and 11-membered spirocyclic rings, and 6, 9, 10, 11, and 12-membered fused heterocycles are each independently selected from one or more halogens, -OR 20 -SR 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )2、-C(O)R 20-C(O)OR 20 -OC(O)R 20 -NO2, =O, =N(R) 20 -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0385] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from C3-C 12 A carbon ring and a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle contains at most one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 Further selected from 7-, 8-, 10-, and 11-membered spirochetes and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, wherein C3-C 12 Carbocyclic rings, 5- to 12-membered heterocycles, 7, 8, 10, and 11-membered spirocyclic rings, and 6, 9, 10, 11, and 12-membered fused heterocycles are each independently selected from halogens, -B (OR) 20 )2、-OR 20 -SR 20 -N(R) 20 ), S(O)2(R 20 -C(O)N(R) 20 )2、-N(R 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 , -NO2, =O, =S, =N(R 20 -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0386] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1Selected from 5- to 10-membered heterocycles, 7, 8, 10, 11-membered spiroheterocycles, and 6, 9, 10, 11, and 12-membered fused heterocycles, and each of which is independently selected from halogens, -N(R) 20 2. C 1-6 Alkyl, -OR 20 -N(R) 20 )C(O)N(R 20 2. -B(OR) 20 )2、-N(R 20 )C(O)N(R 20 )2、=O、C 1-6 Hydroxyalkyl, halogen, -N(R) 20 )C(O)R 20 -N(R) 20 )S(O)2(R 20 ) and C 1-6 The substituents of the aminoalkyl group may be optionally substituted.

[0387] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 5- to 10-membered heterocycles, 7, 8, 10, 11-membered spiroheterocycles, and 6, 9, 10, 11, and 12-membered fused heterocycles, and each of which is independently selected from halogens, -N(R) 20 2. C 1-6 Alkyl, -OR 20 -N(R) 20 )C(O)N(R 20 2. -B(OR) 20 2. C 1-6 Cyanoalkyl, -N(R) 20 )C(O)N(R 20 )2、=O、C 1-6 Hydroxyalkyl, halogen, -N(R) 20 )C(O)R 20 -N(R) 20 ), S(O)2(R 20 ) and C 1-6 The substituents of the aminoalkyl group may be optionally substituted. In some cases, R 1 Selected from Each of these is independently selected from one or more halogens, -N(R) 20 2. C 1-6 Alkyl, -OR 20 -N(R) 20 )C(O)N(R 20 2. -B(OR) 20 2. C 1-6 Cyanoalkyl, -N(R)20 )C(O)N(R 20 )2、=O、C 1-6 Hydroxyalkyl, halogen, -N(R) 20 )C(O)R 20 -N(R) 20 )S(O)2(R 20 ) and C 1-6 The substituents of the aminoalkyl group may be optionally substituted.

[0388] In some cases, R 1 Selected from

[0389]

[0390] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 5- to 10-membered heterocycles, wherein the 5- to 10-membered heterocycles are independently selected from -OR 20 -N(R) 20 2. C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)R 20 and -B(OR) 20 The substituents of )2 can be optionally substituted. In some cases, R 1 Selected from Each of these is independently selected from one or more OR 20 -N(R) 20 2. C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 aminoalkyl, -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)R 20 and -B(OR) 20 The substituents of )2 may be optionally substituted.

[0391] In some implementations, for compounds of formula (I), formula (II), or formula (III), R 1 Selected from

[0392] In some implementations, for compounds or salts of formula (I), (II), or (III), R1 Selected from 5- to 10-membered heterocycles, wherein the 5- to 10-membered heterocycles are independently selected from -N(R) 20 )2、-OR 20 and C 1-6 The alkyl substituents may be optionally substituted. In some cases, the 5- to 10-membered heterocycle is independently selected from -OR 20 and C 1-6 The alkyl substituents may be optionally substituted. In some embodiments, for compounds of formula (I), (II), or (III), R 1 Selected from Each of these is independently selected from one or more OR 20 and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from

[0393] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0394] Each of these is an optional substitution.

[0395] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is independently selected from one or more of -OH, -CN, oxo, C 1-6 The substituents of the cyanoalkyl group may be optionally substituted.

[0396] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0397] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is an optional substitution.

[0398] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is an optional substitution.

[0399] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0400] Each of these is an optional substitution.

[0401] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 for It is an optional replacement.

[0402] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0403] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from In some cases, R 1 for In some cases, R 1 for

[0404] In some embodiments, for compounds or salts of formula (I), (II), or (III), wherein R 1 The 5- to 12-membered heterocycles are unsaturated and bridged heterocycles. In some cases, R... 1 Selected from optionally substituted 7- to 8-membered unsaturated and bridged heterocyclic rings. In some cases, R 1 Selected from

[0405] In some implementations, for compounds of formula (I) or formula (II), R 1 Selected from 5- to 10-membered heterocycles, 7, 8, 10, 11-membered spiroheterocycles, and 6, 9, 10, 11, and 12-membered fused heterocycles, and each of which is independently selected from one or more halogens, -N(R) 20 2. C 1-6 Alkyl, -OR 20 -N(R) 20 )C(O)N(R 20 2. -B(OR) 20 2. C 1-6 Cyanoalkyl, -N(R) 20 )C(O)N(R 20 )2、=O、C 1-6 Hydroxyalkyl, halogen, -N(R)20 )C(O)R 20 -N(R) 20 )S(O)2(R 20 ) and C 1-6 The substituents of the aminoalkyl group may be optionally substituted; R 3 Naphthalene is selected from one or more elements independently of halogen, -OH, -NH2, -NO2, =O, C. 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted; R 4 Selected from hydrogen, halogen or C l -C3 alkyl; Y is O; L is independently C l -C4 alkylene; R 2 Selected from -L-heterocycles, wherein the heterocyclic moiety is independently selected from one or more halogens, hydroxyl groups, C... l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 The substituents of )2 are optionally substituted. In some cases, YR 2 Selected from The heterocyclic portion is optionally substituted.

[0406] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The heterocycle is selected from 5- to 12-membered unsaturated heterocycles with optional substitutions, wherein the heterocycle has at most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.

[0407] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 6- to 7-membered heterocycles. In some cases, R 1 Selected from 7-membered heterocycles. In some cases, R 1 Selected from 6-membered heterocycles. In some cases, the 6- to 7-membered heterocycle contains only one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen and sulfur. In some cases, optionally one or more additional heteroatoms are selected from sulfur. In some cases, optionally one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only one nitrogen atom and no additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, R... 1The 6- to 7-membered heterocycles are bonded to formula (I) via only one nitrogen atom. In some cases, R 1 The 6- to 7-membered heterocycles are bonded to formula (II) via only one nitrogen atom. In some cases, R 1 The 6- to 7-membered heterocycles are bonded to formula (III) via only one nitrogen atom. In some cases, R 1 Selected from Each of these is a substitute. In some cases, R 1 Selected from Each of these is a substitute. In some cases, R 1 The substituents are each selected from one or more halogens, -OR 20 -SR 20 -N(R) 20 )2, -NHCN, -NO2, =O, -CN, C 1-6 fluoroalkyl and C 2-6 Alkyne group; and further selected by one or more groups independently from -C(O)N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkenyl group may be optionally substituted. In some cases, R 1 The substituents are each selected from one or more halogens, -OR 20 -N(R) 20 2. -NHCN, =O, -CN and C 2-6 Alkyne group; and further selected by one or more groups independently from -C(O)N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 The substituents are each selected from one or more halogens, -OH, -NHCN, =O, -CN, and C. 2-6 Alkyne group; and further, one or more independently selected from C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from In some cases, R 1 Selected from Each of these is an optional substitution. In some cases, R 1 Selected from Each of these is an optional substitution. In some cases, R 1 Selected from Each of these is an optional substitution. In some cases, R 1 One or more optional substituents are each independently selected from fluorine, -OH, -C(O)NH2, -NH-C(O)-(C 1-6 alkoxy), -NH-C(O)-(C 1-6 hydroxyalkyl), -NH2, -NH(CN), =O, -CN, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -CN, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are each independently selected from halogens, -OH, and -CN. In some cases, R 1 One or more optional substituents are each independently selected from fluorine, -OH, -CN, C 1-6 Cyanoalkyl, C 1-6 Alkyl, oxo and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are each independently selected from fluorine, -OH, -CN, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 Selected from

[0408]

[0409] In some cases, R 1 Selected from

[0410] In some cases, R 1 Selected from

[0411] In some cases, R 1 Selected from

[0412] In some cases, R1 Selected from

[0413] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted unsaturated 6- to 8-membered heterocycles. In some cases, R 1 Selected from optionally substituted unsaturated 6-membered heterocycles. In some cases, R 1 Selected from optionally substituted unsaturated 7-membered heterocycles. In some cases, the heterocycle has 1 or 2 double bonds. In some cases, the heterocycle has only 1 double bond. In some cases, the heterocycle has only 2 double bonds. In some cases, R... 1 Selected from Each of these is independently selected from one or more halogens, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0414] In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 for In some cases, R 1Selected from Each of them is substituted by one or more substituents independently selected from halogens.

[0415] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The unsaturated 6- or 7-membered heterocycle is selected from unsaturated 6- or 7-membered heterocycles, wherein the unsaturated 6- or 7-membered heterocycle is substituted by one or more substituents selected from halogens. In some cases, the unsaturated 6- or 7-membered heterocycle is substituted by at least one halogen. In some cases, the unsaturated 6- or 7-membered heterocycle is substituted by only one halogen. In some cases, R... 1 Selected from unsaturated 6-membered heterocycles, which are substituted with at least one halogen. In some cases, R 1 Selected from unsaturated 7-membered heterocycles, which are substituted with at least one halogen. In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases R 1 Selected from In some cases, R 1 for In some cases, R 1 for In some cases, R 1 for

[0416] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted unsaturated 6- to 8-membered heterocycles. In some cases, R 1 Selected from optionally substituted unsaturated 7-membered heterocycles. In some cases, R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from

[0417] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1Selected from substituted 6-membered heterocycles. In some cases, the 6-membered heterocycle contains only one nitrogen atom. In some cases, R... 1 The 6-membered heterocycle is bonded to formula (I) via only one nitrogen atom. In some cases, R 1 The 6-membered heterocycle is bonded to formula (II) via only one nitrogen atom. In some cases, R 1 The 6-membered heterocycle is bonded to formula (III) via only one nitrogen atom. In some cases, R 1 Selected from Either of them is optional. In some cases, R 1 One or more optional substituents are each independently selected from halogens, -OR 20 -N(R) 20 )2、=O、-CN、C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are each independently selected from fluorine, -OH, -NH2, -NH(CN), =O, -CN, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are each independently selected from fluorine, -OH, -NH2, -NH(CN), =O, -CN, C 1-6 Hydroxyalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, the 6-membered heterocycle is a partially unsaturated or saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is saturated. In some cases, the 6-membered heterocycle is a monocyclic 6-membered heterocycle. In some cases, the 6-membered heterocycle is not a bridged heterocycle. In some cases, R... 1 Selected from

[0418] In some implementations, for compounds of formula (I), formula (II), or formula (III), R 1 Selected from substituted 6-membered unsaturated heterocycles and 6-membered saturated heterocycles.

[0419] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is independently selected from one or more halogens, -OH, -NH2, -NO2, C 1-6aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0420] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is independently selected from halogens and C. 1-6 The substituents of the haloalkyl group may be optionally substituted.

[0421] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0422] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is selected independently from two halogens, -OH, -NH2, -NO2, and C. 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl groups and C 1-6 The alkyl substituents may be optionally substituted.

[0423] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from Each of these is independently selected from two halogens and C. 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, R 1 for

[0424] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 6- to 10-membered heterocycles with optional substitution. In some cases, the 6- to 10-membered heterocycle contains at least one nitrogen atom. In some cases, R 1 Selected from Each of these is independently selected from one or more halogens, =O, -OH, -CN, -NHCN, -C(O)N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6The alkyl substituents are optionally substituted. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, C 3-12 Substituents in the carbocyclic ring and 3- to 12-membered heterocycles may be optionally substituted. In some cases, R 1 Selected from

[0425] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 10-membered heterocycles with optional substitution. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spirocyclic heterocycle. In some cases, the 10-membered heterocycle is a fused heterocycle. In some cases, the 10-membered heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle contains at least one nitrogen atom. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, the 10-membered heterocycle contains at least one sulfur atom. In some cases, R... 1 Selected from Each of these is independently selected from one or more halogens, =O, -OH, -CN, -NHCN, -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from It is selected independently by one or more halogens, -OR 20-SR 20 -N(R) 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted by choice.

[0426] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted unsaturated 9- to 11-membered heterocycles. In some cases, R 1 Selected from optionally substituted unsaturated 10-membered heterocycles. In some cases, R 1 Selected from optionally substituted unsaturated 10-membered fused heterocycles. In some cases, R 1 for It is optionally substituted. In some cases, one or more optional substituents are selected from halogens, -OH, -C(O)N(R) 20 )2、-N(R 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 for It is selected from one or more of -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkynyl group may be optionally substituted. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl and C 3-12 A carbon ring, and each of which is independently selected from one or more halogens, -OH, -CN, -NO2, -NH2, C 1-10 Alkyl, -C1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted.

[0427] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 7- to 11-membered spirochetes. In some cases, R 1 Selected from 10-membered spiroheterocycles. In some cases, the spiroheterocycle has at least 3 nitrogen atoms. In some cases, the spiroheterocycle has at least 1 sulfur atom. In some cases, R... 1 Selected from Each of these is optionally substituted. In some cases, one or more optional substituents are independently selected from halogens, -OH, -N(R) 20 )2, -NO2, =O, -CN, -NHCN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 Alkyne group. In some cases, R 1 Selected from In some cases, R 1 for In some cases, R 1 for In some cases, M is selected from O and NR. 3 In some cases, M is selected from O. In some cases, M is selected from NR. 3 In some cases, R 3 Selected from C 1-6 Alkyl group. In some cases, R 3 Selected from C 1-2 Alkyl group. In some cases, R 3 Selected from methyl.

[0428] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted 8- to 10-membered fused heterocycles. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R... 1Selected from optionally substituted 9-membered fused heterocycles. In some cases, R 1 Selected from 10-membered fused heterocycles with optional substitution. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least one nitrogen atom. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, the 9-membered heterocycle contains at least one nitrogen atom. In some cases, the 9-membered heterocycle contains at least two nitrogen atoms. In some cases, the 9-membered heterocycle contains at least three nitrogen atoms. In some cases, R... 1 Selected from Each of these is optionally substituted by one or more substituents. In some cases, R 1 for It is optionally substituted by one or more substituents. In some cases, R 1 for It is optionally substituted by one or more substituents. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C (=NR) 20 )N(R 20 )2、-C(O)N(R 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group and 5 to 12-membered heterocycles, wherein each of the 5 to 12-membered heterocycles is independently bounded by one or more R groups. 1* Optional substitution. In some cases, R1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, one or more optional substituents are independently selected from halogen, =O, -OH, -CN, -NHCN, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from halogens, =O, C. 1-6 Alkyl-N(R) 20 )2、-S(O)2(R 20 ), -S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)R 20 -C(O)N(R) 20 )2 and -C(O)NR 20 OR 20In some cases, one or more optional substituents are independently selected from halogens, =O, -S(O)2(R). 20 ), -S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)R 20 -C(O)N(R) 20 )2 and -C(O)NR 20 OR 20 In some cases, one or more optional substituents are independently selected from -C(O)R. 20 -C(O)N(R) 20 )2 and -C(O)NR 20 OR 20 In some cases, one or more optional substituents are independently selected from -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 In some cases, one or more optional substituents are independently selected from -S(O)N(R). 20 2. In some cases, one or more optional substituents are independently selected from S(O)2(R 20 In some cases, one or more optional substituents are independently selected from S(O)R. 20 (=NR 20 In some cases, one or more optional substituents are independently selected from -C(O)R. 20 In some cases, one or more optional substituents are independently selected from -C(O)N(R). 20 2. In some cases, one or more optional substituents are independently selected from -C(O)NR. 20 OR 20 In some cases, R 1 Selected from Each of these is further optionally substituted. In some cases, one or more additional optional substituents are selected from halogens, -OH, =O, -CN, C. 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, one or more additional optional substituents are selected from halogens, -CN, C2-alkenyl, and C...1-6 Alkyl group. In some cases, one or more additional optional substituents are selected from halogens and C. 1-6 Alkyl group. In some cases, one or more additional optional substituents are selected from halogens. In some cases, each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl groups and 3 to 12-membered heterocycles. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl groups and 3 to 12-membered saturated heterocycles. In some cases, each R... 20 Independently selected from 5- to 6-membered saturated heterocycles. In some cases, R 20 The heterocycle has at least one nitrogen atom. In some cases, R 20 The heterocycle has at least one sulfur atom. In some cases, R 20 The heterocycle has at least one oxygen atom. In some cases, R 20 The heterocycle contains only one heteroatom. In some cases, R 20 The heterocycle has at least two heteroatoms. In some cases, R 20 The heterocycle contains only two heteroatoms. In some cases, R 1 One or more optional substituents are independently selected from halogens, -CN, C2-alkenyl groups, In some cases, R 1 One or more optional substituents are independently selected from halogens, In some cases, R 1 One or more optional substituents are independently selected from In some cases, R 1 One or more optional substituents are independently selected from halogens, In some cases, R 1 select In some cases, R 1 Selected from

[0429]

[0430] In some cases, R 1 Selected from In some cases, R 1 Selected from

[0431] In some cases, R 1 One or more optional substituents are independently selected from halogens and C. 1-6 Alkyl-N(R) 20 2. In some cases, R 1 One or more optional substituents are independently selected from halogens, In some cases, R 1 Selected from In some cases, each R 20 Independently selected from hydrogen, C 1-6 Alkyl and C 3-6 Carbon rings. In some cases, R 1 Selected from In some cases, R 1 Selected from

[0432] In some cases, R 1 Selected from It is selected independently by one or more halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 The alkynyl group and the substituents of the 5- to 12-membered heterocycle are optionally substituted, wherein the 5- to 12-membered heterocycle is replaced by one or more substituents selected from halogens, -OR20 and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from It is selected independently by one or more halogens and C. 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from

[0433] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from in Selected from 5- to 12-membered heterocycles, wherein the 5- to 12-membered heterocycles are independently separated by one or more R 1* Optional substitution; and R B Selected from hydrogen, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkyne group and -CN. In some cases, R B Selected from hydrogen and halogens. In some cases, R B It is chlorine. In some cases, R B It is hydrogen. In some cases, It has at least 1, 2, 3, or 4 heteroatoms. In some cases, It has at least 1, 2, 3, or 4 nitrogen atoms. In some cases, It has at least one oxygen atom. In some cases, It is a monocyclic heterocyclic ring. In some cases, It is a bicyclic heterocyclic ring. In some cases, Selected from arbitrarily substituted 5-membered heterocycles. In some cases, Selected from substituted 9-membered heterocycles. In some cases, Selected from Each of them is controlled by one or more R 1* Optional substitution. In some cases, Selected from Each of them is controlled by one or more R 1* Optional substitution. In some cases, each R 1* Independently selected from halogens, -OR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens and C 1-6 Alkyl groups. In some cases, Selected from

[0434] In some embodiments, for compounds or salts of formula (I), (II), (II*), or (III), when R 1 -C(O)R 20 When replacing, R 20 Selected from 5- to 12-membered heterocyclic rings, which are optionally substituted. In some cases, R 1 -C(O)R 20 Replacement. In some cases, R 20 Selected from 5 to 12 unsubstituted heterocycles. In some cases, R20 Selected from 5- to 6-membered heterocycles, which are optionally substituted. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has two heteroatoms. In some cases, R 20 The heterocycles are selected from Each of these is an optional substitution. In some cases, R 20 Selected from In some cases, the optional substituents are selected from C. 1-10 Alkyl, oxo, and =NH.

[0435] In some implementations, for compounds or salts of formula (I), (II), (II*), or (III), each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, and =NH substituents may be optionally substituted. In some cases, each R... 20 Independently selected from hydrogen; and unsubstituted C 1-6 Alkyl groups and one or more elements independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C) 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 The alkyl, oxo, and =NH substituents are optionally substituted into 3 to 12-membered heterocycles.

[0436] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 For optional substitution of 12 to 15-membered heterocyclic rings. In some cases, R 1 For optional substituted 12-membered heterocycles. In some cases, R 1 For optional substituted 13-membered heterocycles. In some cases, R 1 For optional substituted 14-membered heterocycles. In some cases, R 1 For optional substituted 15-membered heterocyclic rings. In some cases, R 1 The heterocycle is a tricyclic ring. In some cases, R 1 The heterocycle contains fused heterocycles. In some cases, R 1The heterocycle contains spiroheterocycles. In some cases, R 1 The heterocycles contain fused and spiroheterocycles. In some cases, R 1 The heterocycle is an unsaturated heterocycle. In some cases, R 1 The heterocycle is a non-aromatic heterocycle. In some cases, R 1 The heterocycle has at least one double bond. In some cases, R 1 The heterocyclic ring has at least two double bonds. In some cases, R 1 The heterocycle has at least two heteroatoms. In some cases, R 1 The heterocycle has at least three heteroatoms. In some cases, R 1 The heterocycle has at least four heteroatoms. In some cases, R 1 The heterocycle has at least 5 heteroatoms. In some cases, R 1 The heterocycle has at least six heteroatoms. In some cases, R 1 The heterocycle has at least seven heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, R... 1 The heterocycle has at least 3, 4, or 5 nitrogen atoms and at least 1 sulfur atom. In some cases, R 1 The heterocycle has at least 3, 4, or 5 nitrogen atoms and at least 1 oxygen atom. In some cases, R 1 The heterocycle has 3, 4, or 5 nitrogen atoms. In some cases, R 1 The heterocycle has 3, 4, or 5 nitrogen atoms and no other heteroatoms. In some cases, the heteroatoms are selected from nitrogen and sulfur. In some cases, the heteroatoms are selected from nitrogen and oxygen. In some cases, R... 1 Selected from

[0437] Each of these is optionally substituted by one or more substituents. In some cases, R 1 Selected from

[0438] Each of these is optionally substituted by one or more substituents. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -NHCN, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(O)NHOR 20 -N(R)20 )2、-C(O)R 20 , -NO2, =O, =NH, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -NHCN, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, C 1-6 Alkyl groups and -C(O)N(R) 20 2. In some cases, R 1 Selected from

[0439] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 For optional substitution of 12 to 15-membered heterocyclic rings. In some cases, R 1 for Wherein ring W is an optionally substituted heterocycle, and ring P is an optionally substituted carbocyclic ring or an optionally substituted heterocycle, wherein ring P and ring W form a spirocyclic ring. In some cases, ring W is an optionally substituted fused heterocycle. In some cases, ring P and ring W combine to form a heterocycle having at least 12 atoms and at most 15 atoms. In some cases, ring P and ring W have a total of at least 12 atoms and at most 15 atoms. In some cases, ring W is an optionally substituted 10-membered fused heterocycle. In some cases, R... 1for Where ring P is an optionally substituted carbocyclic ring or an optionally substituted heterocyclic ring. In some cases, R 1 for In some cases, ring P is an optionally substituted carbon ring. In some cases, ring P is an optionally substituted heterocycle. In some cases, ring P forms an optionally substituted C3-C6 carbon ring or an optionally substituted 4- to 6-membered heterocycle. In some cases, ring P forms an optionally substituted C3 carbon ring. In some cases, ring P forms an optionally substituted C4 carbon ring. In some cases, ring P forms an optionally substituted C5 carbon ring. In some cases, ring P forms an optionally substituted 4-membered heterocycle. In some cases, ring P forms an optionally substituted 5-membered heterocycle. In some cases, ring P forms an optionally substituted 5-membered heterocycle. In some cases, ring P has at least 1, 2, or 3 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, ring P has 1 sulfur atom. In some cases, ring P has 1 nitrogen atom. In some cases, ring P has 1 oxygen atom. In some cases, one or more optional substituents of ring P are independently selected from halogens, -OH, -NHCN, =O, =NR. 20 -CN,C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkyne group. In some cases, one or more optional substituents of the ring P are independently selected from halogens, -OH, =O, =NH, -CN, and C. 1-6 Alkyl group. In some cases, one or more optional substituents of the ring W are independently selected from halogens, -OH, -NHCN, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6Alkyne group. In some cases, one or more optional substituents of the ring W are independently selected from halogens, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 and C 1-6 Alkyl group. In some cases, one or more optional substituents of the ring W are independently selected from -C(O)R. 20 In some cases, ring P is substituted. In some cases, ring W is substituted.

[0440] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from

[0441] Each of these is optionally substituted by one or more substituents. In some cases, one or more of the optional substituents are independently selected from halogens, -OH, -N(R) 20 )2、-B(OH)2、-C(O)N(R 20 )2、-NHCN、-NO2、C 1-6 Alkoxy, =O, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 1-6 Haloalkyl. In some cases, R 1 Selected from

[0442]

[0443]

[0444]

[0445] In some implementations, for compounds or salts of formula (I), (II), or (III), R 2Selected from optionally substituted -L-heterocycles. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only one nitrogen atom. In some cases, the heterocycle has only one nitrogen atom and no other heteroatoms. In some cases, YR 2 Selected from The heterocyclic portion is optionally substituted. In some cases, R 2 Selected from The heterocyclic portion is optionally substituted. In some cases, YR 2 Selected from The heterocyclic portion is optionally substituted. In some cases, YR 2 Selected from The heterocyclic moiety is optionally substituted. In some cases, the heterocycle is replaced by one or more elements selected from halogens, hydroxyl groups, and C. l -C3 alkyl, -N(R) 5 )S(O)2(R 5 ), -OC(O)N(R 5 2. Oxygenation, =CH2, =NO-C l -C3 alkyl, -CH2OC(O) heterocyclic, -CH2 heterocyclic, -CH2OC(O)N(R) 5 )2 and -OC l The substituents of the -C3 alkyl group may be optionally substituted, wherein the -OC group is... l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocyclic, oxo, and hydroxyl groups. In some cases, YR 2 Selected from

[0446] In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0447] In some implementations, for compounds or salts of formula (I), (II), or (III), R 2 Selected from -LN(R) 21 2. In some cases, each R 21 Selected from hydrogen and C 1-6 Alkyl groups. In some cases, each R 21 Selected from C 1-6 Alkyl group. In some cases, L is independently selected from substituted C. l-C4 alkylene, wherein the two substituents on the same carbon atom of L together form a C3-C6 carbon ring, wherein the C3-C6 carbon ring is optionally substituted by one or more substituents selected from halogens. In some cases, L is In some cases, R 2 for In some cases, YR 2 for

[0448] In some implementations, for compounds or salts of formula (I), (II), or (III), each R 21 Independently selected from hydrogen. In some cases, each R... 21 Independently selected from hydrogen and C 1-6 Alkyl groups. In some cases, each R 21 Selected independently from C 1-6 Alkyl groups. In some cases, each R 21 Independently selected from hydrogen; and C 3-12 A carbocyclic ring and 3 to 12-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl or oxo substituents may be substituted optionally.

[0449] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from optionally substituted 8- to 10-membered fused heterocycles. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R... 1 Selected from optionally substituted 9-membered fused heterocycles. In some cases, R 1 Selected from 10-membered fused heterocycles with optional substitution. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least one nitrogen atom. In some cases, the 9-membered heterocycle contains at least two nitrogen atoms. In some cases, the 9-membered heterocycle contains at least three nitrogen atoms. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, R...1 Selected from Each of these is optionally substituted by one or more substituents. In some cases, R 1 Selected from Each of these is optionally substituted by one or more substituents. In some cases, R 1 for It is optionally substituted by one or more substituents. In some cases, the one or more optional substituents are independently selected from halogens, =O, -OH, -CN, -NHCN, -C(O)R. 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from halogens, =O, -C(O)R. 20 -C(O)N(R) 20 )2 and -C(O)NR 20 OR 20 In some cases, one or more optional substituents are independently selected from -C(O)R. 20 -C(O)N(R) 20 )2 and -C(O)NR 20 OR 20 In some cases, one or more optional substituents are independently selected from -C(O)R. 20 In some cases, one or more optional substituents are independently selected from -C(O)N(R). 20 2. In some cases, one or more optional substituents are independently selected from -C(O)NR. 20 OR 20 In some cases, each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 Carbon rings and 3 to 12-membered heterocycles. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl groups and 3 to 12-membered heterocycles. In some cases, each R... 20 Independently selected from hydrogen; and C 1-6 Alkyl groups and 3 to 12-membered saturated heterocycles. In some cases, R 1 One or more optional substituents are independently selected from In some cases, R 1 Selected from

[0450] In some cases, R 1 Selected from

[0451] In some cases, R 1 for

[0452] In some implementations, for compounds or salts of formula (I), R 1 Selected from optionally substituted saturated 6- to 7-membered heterocycles. In some cases, R 1 Selected from saturated 6-membered heterocycles with optional substitution. In some cases, R 1 Selected from It is optionally substituted. In some cases, one or more optional substituents are independently selected from halogens, -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C... 1-6 Cyanoalkyl and C 1-6 Alkyl group. In some cases, one or more optional substituents are independently selected from -NHCN and C. 1-6 Alkyl group. In some cases, R 1 Selected from It is selected from one or more of -NHCN and C 1-6 Alkyl substituents. In some cases, R 1 Selected from

[0453] In some implementations, for compounds or salts of formula (I), R 1 Selected from substituted saturated 6-membered heterocycles, wherein the saturated 6-membered heterocycle is coupled with at least one -NHCN and optionally one or more C24-C ... 1-6 Alkyl substitution; B is selected from optionally substituted 8- to 15-membered fused heterocycles and optionally substituted C8-C 15 Fused carbocyclic rings, each of which is independently selected from one or more halogens, oxo-, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 The substituents of the alkynyl group are optional; ring A is selected from optional heterocycles; Y is O; R 2Selected from -L-heterocycles, wherein the heterocyclic moiety is independently selected from one or more halogens, hydroxyl groups, C... l -C4 alkyl, C l -C4 alkoxy group, C l -C4 haloalkyl, C l -C4 hydroxyalkyl or -N(R) 5 The substituents of )2 are optionally substituted; and L is selected from C l -C4 alkylene. In some cases, R 1 Selected from In some cases, B is selected from In some cases, B is selected from In some cases, B is

[0454] In some embodiments, for compounds or salts of formula (I), (II), or (III), B is an optionally substituted 8- to 10-membered fused carbide ring. In some cases, B is a substituted 8- to 10-membered fused carbide ring. In some cases, B is an unsubstituted 8- to 10-membered fused carbide ring. In some cases, B is an optionally substituted 9-membered fused carbide ring. In some cases, B is... It is optionally substituted by one or more substituents. In some cases, B is... It is substituted by one or more substituents. In some cases, for B, one or more substituents are independently selected from halogens, oxo groups, -NH2, C1-C3 alkyl groups, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkynyl group. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selected from... In some cases, B is It is selected from one or more halogens and C 1-6 Substituents of haloalkyl groups. In some cases, B is... It is substituted with one or more substituents selected from halogens. In some cases, B is selected from... In some cases, B is It is substituted with one or more substituents selected from fluorine. In some cases, B is selected from... In some cases, B is It is substituted with one or more substituents selected from chlorine. In some cases, B is selected from... In some cases, B is a substituted 10-membered fused carbide ring. In some cases, for the 10-membered fused carbide ring of B, one or more substituents are independently selected from halogens, -NH2, C1-C3 alkyl groups, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkyne group. In some cases, B is selected from...

[0455] In some cases, for the 10-membered fused carbon ring of B, it is substituted with at least one halogen. In some cases, B is selected from... In some cases, B is an unsubstituted 9- to 10-membered fused carbon ring. In other cases, B is selected from... Each of these is unsubstituted. In some cases, B is... In some cases, B is

[0456] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group, 5 to 12-membered heterocycle, wherein the 5 to 12-membered heterocycle is selected from one or more halogens and C 1-6 The alkyl substituents may be optionally substituted.

[0457] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 for And R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C1-6 Alkyl, C 2-6 Alkyne group and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from halogens, -CN, C 2-6 alkynyl group, -C (=NR) 20 )N(R 20 )2 and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from halogens, -C(=NR) 20 )N(R 20 )2 and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from -C(=NR) 20 )N(R 20 )2 and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, R 1 One or more optional substituents are independently selected from 5-membered and 9-membered heterocycles, each of which is independently substituent for one or more R 1* Optional substitution. In some cases, R 1 It is substituted with at least one halogen and is independently selected from -CN, C 2-6 alkynyl group, -C (=NR) 20 )N(R 20 The substituents of the 2-membered and 5- to 12-membered heterocycles are optionally substituted, wherein the 5- to 12-membered heterocycles are independently substituted by one or more R groups. 1* Optional substitution. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has at least one nitrogen atom and at least one oxygen atom. In some cases, the heterocycle has at least two heteroatoms. In some cases, the heterocycle has at least three heteroatoms. In some cases, the heterocycle has at least four heteroatoms. In some cases, R... 1 The heterocycle with one or more optional substituents is selected from Each of them is controlled by one or more R 1* Optional substitution. In some cases, R 1 The heterocycle with one or more optional substituents is selected from It is controlled by one or more R 1* Optional substitution. In some cases, each R 1* Independently selected from halogens, -OR 20 -S(O)2(R 20 -S(O)2N(R)20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, -OR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens. In some cases, each R... 1* Selected independently from C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from -OR 20 In some cases, each R 1* Independently selected from -OH. In some cases, each R 1* Independently selected from -OMe. In some cases, R 1 The heterocycle with one or more optional substituents is selected from

[0458] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 One or more optional substituents are independently selected from -C(=NR) 20 )N(R 20 )2 and optionally substituted 5- to 12-membered heterocycles. In some cases, R 1One or more optional substituents are independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, the heterocycle is selected from... Each of them is controlled by one or more R 1* Optional substitution. In some cases, R 1 One or more optional substituents are selected from

[0459] In some implementations, for compounds or salts of formula (I), (II), or (III), each R 1* Independently selected from halogens, -OR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, -OR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens and C 1-6 Alkyl groups. In some cases, each R 1* Independently selected from halogens. In some cases, each R... 1* Selected independently from C 1-6 alkyl.

[0460] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1Selected from 5 to 15-membered heterocycles (preferably 8 to 10-membered heterocycles or preferably 10-membered heterocycles), each of which is independently selected from halogen, oxo, -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -SO2R 20 -NHCN, C 1-6 Cyanoalkyl, C 1-6 Alkyl, C 1-6 Alkyl-N(R) 20 2. C 2-6 The substituents of the alkynyl group and the 5- to 12-membered heterocycle (preferably 5- to 9-membered heterocycle) are optionally substituted, wherein each of the 5- to 12-membered heterocycles is independently substituted by one or more R groups. 1* Optional substitution; each R 1* Independently selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl group. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R... 1 Selected from Each of these is an optional substitution. In some cases, R 1 Selected from It is an optional substitution. In some cases, R 1 Selected from

[0461] In some cases, R 1 Selected from In some cases, R 1 for

[0462] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Selected from 5- to 15-membered heterocycles (preferably 8- to 10-membered heterocycles or preferably 10-membered heterocycles), each of which is independently selected from one or more halogens, -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -NHCN, C 1-6 Cyanoalkyl, C1-6 Alkyl, C 2-6 The substituents of the alkynyl group and the 5- to 12-membered heterocycle (preferably 5- to 6-membered heterocycle) are optionally substituted, wherein each of the 5- to 12-membered heterocycles is independently substituted by one or more R groups. 1* Optional substitution; each R 1* Independently selected from halogens, C 1-6 Halogenated alkyl groups and C 1-6 Alkyl group. In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted.

[0463] In some cases, R 1 Selected from Each of these is an optional substitution.

[0464] In some cases, R 1 Selected from It is an optional substitution. In some cases, R 1 Selected from

[0465] In some cases, R 1 Selected from In some cases, M is chosen from O and NMe. In some cases, M is O. In some cases, M is NMe. In some cases, R... 2 Selected from -LN(R) 21 )2 and -L-heterocyclic rings, which are bounded by one or more R 6 Optional replacement. In some cases, YR 2 Selected from In some cases, B is selected from optionally substituted carbocyclic rings. Each of these is an optional substitution. In some cases, B is selected from... In some cases, B is In some cases, B is In some cases, n is 0.

[0466] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 The compounds are selected from the compounds in the Examples section. In some cases, Y is selected from the compounds in the Examples section. In some cases, L is selected from the compounds in the Examples section. In some cases, R... 2 Compounds selected from the Examples section. In some cases, B is selected from the compounds in the Examples section. In some cases, M is selected from the compounds in the Examples section. In some cases, R... 1The optional substituents of the heterocycle are selected from the compounds in the Examples section.

[0467] In some implementations, for compounds or salts of formula (I), (II), or (III), R 2 -LN(R) 21 2. In some cases, R 2 For -L-OR 21 In some cases, R 2 It is a heterocyclic ring. In some cases, R 2 C l -C6 alkyl. In some cases, R 2 It is an L-heterocyclic ring. In some cases, R 2 It is -L-aryl. In some cases, R 2 It is an -L-heteroaryl group. In some cases, R... 2 It is an -L-cycloalkyl group. In some cases, R 2 -LN(R) 21 2. In some cases, R 2 It is -L-NHC(=NH)NH2. In some cases, R 2 -LC(O)N(R) 21 2. In some cases, R 2 For -LC l -C6 haloalkyl. In some cases, R 2 For -L-OR 21 In some cases, R 2 -L-NR 21 C(O)-aryl. In some cases, R 2 It is -L-COOH. In some cases, R 2 -L-NR 21 S(O)2(R 21 In some cases, R 2 -LS(O)2N(R) 21 2. In some cases, R 2 -LN(R) 21 )C(O)(OR 21 In some cases, R 2 -L-OC(O)N(R) 21 2. In some cases, R 2 -LC(=O)OC l -C6 alkyl. In some cases, heterocyclic, -L-NR 21 The aryl moiety of the C(O)-aryl group, the heterocyclic moiety of the -L-heterocyclic group, and the cycloalkyl moiety of the -L-cycloalkyl group are each surrounded by one or more R groups. 6Optional substitution, wherein the aryl moiety of -L-aryl and the heteroaryl moiety of -L-heteroaryl are each replaced by one or more R 7 Optional substitution. In some cases, when Y is a bond, O, or S, R... 2 Further selected from hydrogen.

[0468] In some implementations, equation (I) or equation (II) is represented by equation (II*):

[0469]

[0470] Or its pharmaceutically acceptable salt, wherein:

[0471] M is selected from O and NR 3 ;

[0472] R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Cyanoalkyl;

[0473] R 1 Selected from 7- to 10-membered heterocycles, wherein the 7- to 10-membered heterocycles are independently selected from halogens, -B (OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20-CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 The alkynyl group and the substituents of the 5- to 12-membered heterocycle are optionally substituted, wherein the 5- to 12-membered heterocycle is independently substituted by one or more R groups. 1* Optional replacement;

[0474] Each R 1* Independently selected from halogens, -B(OR) 20 )2、-OR 20 -SR 20 -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -NR 20 S(O)2R 20 -C(O)N(R) 20 )2、-C(O)NR 20 OR 20 -N(R) 20 )C(O)R 20 -N(R) 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 -N(R) 20 )2、-C(O)R 20 -C(O)OR 20 -OC(O)R 20 -OC(O)N(R) 20 )2、-NO2、=O、=N(R 20 =NO(R) 20 -CN, -NHCN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 alkenyl, C2-6 alkynyl and C3-C 12 Carbon rings;

[0475] B is selected from C6-C 15 Carbon rings, where C6-C 15 The carbon ring is independently selected from one or more halogens, C1-C3 alkyl groups, -B(OR) 20 )2、-OR 20 -C(O)N(R) 20 )2、-N(R 20 )2、=O、-CN、-NHCN、C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 alkenyl and C 2-6 The substituents of the alkynyl group may be substituted at will;

[0476] R 2 Selected from -L-heterocycles, wherein the -L-heterocycle is a heterocycle of one or more R 6 Optional replacement;

[0477] L is independently selected from C l -C4 alkylene, where C l -C4 alkylene oxide is selected from one or more hydroxyl groups, C l -C4 hydroxyalkyl, C l The substituents of the -C4 alkyl group are optionally substituted; and optionally, the two substituents on the same carbon atom of L together form a C3-C6 carbon ring;

[0478] Each R 20 Independently selected from hydrogen; and C 1-6 Alkyl, C 3-6 A carbocyclic ring and 3 to 6-membered heterocycles, each of which is independently selected from halogens, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Halogenated alkyl groups, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic ring and the 3 to 12-membered heterocyclic rings may be optionally substituted.

[0479] In some implementations, for compounds or salts of formula (II*), R 1 Selected from optionally substituted 7- to 10-membered spiroheterocycles and optionally substituted 7- to 10-membered fused heterocycles. In some cases, R1 The heterocycle has at least one nitrogen atom. In some cases, R 1 At least one nitrogen atom of the heterocycle is incorporated into formula (II*). In some cases, R 1 Selected from optionally substituted 10-membered spirocyclic heterocycles and optionally substituted 10-membered fused heterocycles. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group, 5 to 12-membered heterocycle, wherein the 5 to 12-membered heterocycle is selected from one or more halogens and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from It is selected independently by one or more halogens, -OH, -S(O)2(R 20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 The alkynyl group or a 5- to 12-membered heterocycle is substituted with one or more substituents selected from halogens and C. 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from In some cases, R 1 Selected from

[0480]

[0481] In some cases, R 1 for In some cases, M is selected from O. In some cases, M is NCH2CH3. In some cases, M is NMe. In some cases, R... 2 The heterocycle is a saturated heterocycle. In some cases, R 2 R 6 Each time it appears, it is independently selected from halogen, =CH2, hydroxyl, C. l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl. In some cases, R 2 L is selected from C1-C4 alkylene groups and In some cases, R 2 Selected from In some cases, B is selected from the optionally substituted C9-C. 10 Fused carbon rings. In some cases, B is selected from... Each of these is optionally substituted. In some cases, B is independently selected from one or more halogens, oxo-, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -OC. l -C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6The substituents of the alkynyl group may be optionally substituted. In some cases, B is optionally substituted by one or more substituents independently selected from halogens. In some cases, B is... In some cases, B is In some cases, B is unsubstituted. In other cases, B is substituted.

[0482] In some implementations, for compounds or salts of formula (II*), R 1 Selected from optionally substituted 7- to 10-membered spiroheterocycles and optionally substituted 7- to 10-membered fused heterocycles. In some cases, R 1 Selected from optionally substituted 10-membered spirocyclic heterocycles and optionally substituted 10-membered fused heterocycles. In some cases, R 1 Selected from arbitrarily substituted 10-membered spiroheterocycles. In some cases, R 1 Selected from arbitrarily substituted 10-membered fused heterocycles. In some cases, R 1 The heterocycle has at least three heteroatoms. In some cases, R 1 One or more optional substituents are independently selected from halogens, -OH, -S(O)2(R 20 ), -S(O)N(R 20 )2、-S(O)2N(R 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkyne group, 5 to 12-membered heterocycle, wherein the 5 to 12-membered heterocycle is selected from one or more halogens and C 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 Selected from It is selected independently by one or more halogens, -OH, -S(O)2(R20 -S(O)2N(R) 20 )2、-S(O)N(R 20 )2、-S(O)R 20 (=NR 20 -C(O)N(R) 20 )2、-C(=NR 20 )N(R 20 )2、-C(O)OR 20 -C(O)NHOR 20 -N(R) 20 )2、-C(O)R 20 -NO2, =O, -CN, C 1-6 Alkyl-N(R) 20 2. C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 The alkynyl group or a 5- to 12-membered heterocycle is substituted with one or more substituents selected from halogens and C. 1-6 The alkyl substituents may be optionally substituted. In some cases, R 1 select

[0483]

[0484] In some cases, R 1 Selected from In some cases, R 1 for In some cases, M is chosen from O. In some cases, M is NMe. In some cases, R 2 The heterocycle is a saturated heterocycle. In some cases, R 2 R 6 Each time it appears, it is independently selected from halogen, =CH2, hydroxyl, C. l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl. In some cases, R 2 L is selected from C1-C4 alkylene groups and In some cases, R 2 Selected from In some cases, B is selected from the optionally substituted C9-C. 10 Fused carbon rings. In some cases, B is selected from... Each of these is optionally substituted. In some cases, B is independently selected from one or more halogens, oxo-, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -OC. l -C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 The substituents of the alkynyl group may be optionally substituted. In some cases, B is optionally substituted by one or more substituents independently selected from halogens. In some cases, B is... In some cases, B is In some cases, B is unsubstituted. In other cases, B is substituted.

[0485] In some implementations, for compounds or salts of formula (I), formula (II), formula (II*), or formula (III), R 1 Heterocyclic or carbocyclic rings are not C 1-6 Cyanoalkyl substitution. In some embodiments, for compounds or salts of formula (I), R 1 Heterocyclic or carbocyclic rings are not C 1-6 Cyanoalkyl substitution. In some embodiments, for compounds or salts of formula (II), R 1 Heterocyclic or carbocyclic rings are not C 1-6 Cyanoalkyl substitution. In some embodiments, for compounds or salts of formula (III), R 1 Heterocyclic or carbocyclic rings are not C 1-6 Cyanoalkyl substitution.

[0486] In some implementations, for compounds or salts of formula (I), (II), (II*), or (III), each R 20 Independently selected from hydrogen and C 1-6 alkyl.

[0487] In some implementations, for compounds or salts of formula (I), formula (II), formula (II*), or formula (III), C is not used. 1-6 Cyanoalkyl substitution.

[0488] In some implementations, for compounds or salts of formula (I), (II), or (III), R 1 Not piperazine. In some cases, R 1 Piperazine that is not substituted.

[0489] In some implementations, for compounds of formula (I), the compound is not a Michael acceptor.

[0490] In some implementations, for compounds of formula (I), the compound or salt does not include an electrophilic substituent.

[0491] In some implementations, the compounds or salts of formula (I), (II), (II*), or (III) do not contain an electrophilic portion.

[0492] In some implementations, the compounds or salts of formula (I), (II), (II*), or (III) do not contain covalent modifiers.

[0493] In some implementations, for compounds or salts of formula (I), formula (II), formula (II*), or formula (III), R 1 One or more optional substituents are not electrophilic.

[0494] This disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts. Compounds of the present invention having sufficient acidity, sufficient basicity, or both functional groups can react with a variety of inorganic bases and any of inorganic and organic acids to form salts. Alternatively, inherently charged compounds, such as those having a quaternary nitrogen, can form salts with suitable counterions (e.g., halides, such as bromides, chlorides, or fluorides, particularly bromides).

[0495] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities can exist in various tautomer forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E, and tautomer forms.

[0496] A "tautomer" is a molecule in which a proton can potentially transfer from one atom of the molecule to another atom of the same molecule. In some embodiments, the compounds presented herein exist as tautomers. Where tautomerism is possible, a chemical equilibrium of tautomers will exist. The exact ratio of tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomer equilibria include:

[0497]

[0498] In some embodiments, the compounds disclosed herein are used in different enriched isotopic forms, for example in 2 H, 3 H, 11 C 13 C and / or 14The compound is enriched in terms of carbon content. In one specific embodiment, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy, thereby increasing the duration of drug action.

[0499] Unless otherwise stated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds where hydrogen is replaced by deuterium or tritium, or carbon is enriched by... 13 C or 14 Compounds having the structure of this invention, other than carbon-enriched carbon substitutions, are within the scope of this disclosure.

[0500] The compounds disclosed herein optionally contain atomic isotopes in non-natural proportions at one or more atoms constituting such compounds. For example, the compounds can be labeled with isotopes such as deuterium (…). 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C). Use 2 H, 11 C 13 C 14 C 15 C 12 N、 13 N、 15 N、 16 N、 16 O、 17 O、 14 F, 15 F, 16 F, 17 F, 18 F, 33 S, 34 S, 35 S, 36 S, 35 Cl、 37 Cl、 79 Br、 81 Br and 125 I. All isotopic substitutions are considered. All isotopic variations of the compounds of this invention, whether or not they are radioactive, are covered within the scope of this invention.

[0501] In some embodiments, some or all of the compounds disclosed herein 1 H atoms are 2H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art, and the following synthetic methods are included only as non-limiting examples.

[0502] Deuterium-substituted compounds are synthesized using various methods, such as those described in: Dean, Dennis C.; ed. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [in Curr., Pharm. Des., 2000; 6(10)] 2000, 110pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0503] Deuterated starting materials are readily available and can be synthesized using the methods described herein to provide deuterium-containing compounds. A wide range of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0504] The compounds of the present invention also include crystalline and amorphous forms of these compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, nonsolventized polymorphs (including anhydrous forms), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0505] In some cases, the compounds described herein exist as diastereomers, enantiomers, or other stereoisomers. Unless otherwise specified in absolute stereochemistry, the compounds presented herein include all diastereomers, enantiomers, and epimers, as well as suitable mixtures thereof. Separation of stereoisomers can be achieved by chromatography or by forming diastereomers and separating them by recrystallization or chromatography, or any combination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley and Sons, Inc., 1981, incorporated herein by reference). Stereoisomers can also be obtained by stereoselective synthesis.

[0506] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds having the same type of activity are also included within the scope of this disclosure. Additionally, the compounds described herein may be in unsolvable forms as well as in solvated forms with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Solvated forms of the compounds proposed herein are also contemplated and disclosed herein.

[0507] In some embodiments, the compound or a salt of a compound may be a prodrug, for example, wherein the hydroxyl group in the parent compound is present as an ester or carbonate, or the carboxylic acid present in the parent compound is present as an ester. The term "prodrug" is intended to cover compounds that are converted into pharmaceutical agents of this disclosure under physiological conditions. One method for preparing a prodrug includes hydrolyzing one or more selected portions under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a host animal, such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonates) are preferred prodrugs of this disclosure.

[0508] The prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce the compounds as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs of another derivative or active compound.

[0509] In some cases, prodrugs are often useful because they can be more easily administered than the parent drug. For example, they may be bioavailable via oral administration, while the parent drug is not. Prodrugs can help enhance the cellular permeability of a compound relative to the parent drug. Prodrugs in pharmaceutical compositions can also have improved solubility relative to the parent drug. Prodrugs can be engineered as reversible drug derivatives to act as modifiers that enhance drug delivery to site-specific tissues or increase drug retention within cells.

[0510] In some implementations, the prodrug design increases the lipophilicity of the agent. In some implementations, the prodrug design increases effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269: G210-218 (1995); McLoed et al., Gastroenterol, 106: 405-413 (1994); Hochhaus et al., Biomed. Chrom., 6: 283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64: 181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, ACSSymposium Series, Vol. 14; and Edward B. Roche, Bioreversible Carriers The disclosure in *Drug Design*, American Pharmaceutical Association and Pergamon Press, 1987, is entirely incorporated herein by reference. According to another embodiment, this disclosure provides a method for producing compounds as defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0511] The synthetic chemical transformations and methods that can be used to synthesize the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T.W. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis, Second Edition (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).

[0512] pharmaceutical preparations

[0513] In some embodiments, this document provides compositions (also referred to herein as “pharmaceuticals”) comprising a therapeutically effective amount of any compound or salt of any of formulas (I), (II), (II*), and (III).

[0514] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of the pharmaceutical agent into a formulation for pharmaceutical use. The appropriate formulation depends on the chosen route of administration. Overviews of pharmaceutical compositions can be found, for example, in: Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, HA and Lachman, L. (eds.), Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins, 1999).

[0515] The compositions and methods disclosed herein can be used to treat individuals in need. In some embodiments, the individual is a mammal, such as a human or a non-human mammal. When administered to an animal (such as a human), the composition or agent is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or media (such as ethylene glycol, glycerin, oils (such as olive oil), or injectable organic esters). In a preferred embodiment, when such pharmaceutical compositions are used for human administration, particularly for invasive routes of administration, such as those bypassing transport or diffusion across the epithelial barrier (such as injection or implantation), the aqueous solution is pyrogen-free or substantially pyrogen-free. For example, the excipient may be selected to achieve delayed release of the agent or selective targeting of one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of dosage units, such as tablets, capsules, granules, lyophiles for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition may also be present in transdermal delivery systems, such as skin patches. The composition may also be present in a solution suitable for surface application, such as eye drops.

[0516] Pharmaceutically acceptable excipients may contain physiologically acceptable agents that, for example, stabilize the compound (such as a pharmaceutical preparation), increase its solubility, or enhance its absorption. Such physiologically acceptable agents include, for example, carbohydrates (such as glucose, sucrose, or dextran), antioxidants (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins, or other stabilizers or excipients. The choice of pharmaceutically acceptable excipients (including physiologically acceptable agents) depends, for example, on the route of administration of the composition. The formulation or pharmaceutical composition may be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (formulation) may also be a liposome or other polymer matrix into which compounds, such as those of the present invention, may be incorporated. For example, liposomes comprising phospholipids or other lipids are relatively simple to manufacture and administer, being non-toxic, physiologically acceptable, and metabolizable carriers.

[0517] Pharmaceutical compositions (formulations) can be administered to a target via a variety of routes of administration, including, for example, oral administration, as an extract (drench) in an aqueous or non-aqueous solution or suspension, tablets, capsules (including sprinkle capsules and gelatin capsules), granules, powders, particles, pastes for application to the tongue; absorption through the oral mucosa, such as sublingually; via the anus, rectum, or vagina, such as vaginal suppositories, creams, or foams; parenteral administration, including intramuscular, intravenous, subcutaneous, or intrathecal administration, such as in a sterile solution or suspension; via the nose; intraperitoneally; subcutaneously; transdermally, such as in a patch for application to the skin; and via the surface, such as in an ointment, cream, or spray for application to the skin, or in eye drops. The compound can also be formulated for inhalation. In some embodiments, the compound can simply be dissolved or suspended in sterile water.

[0518] Pharmaceutical compositions may be sterile aqueous or non-aqueous solutions, suspensions, or emulsions, such as microemulsions. The excipients described herein are examples and are not intended to limit the scope in any way. An effective amount, or therapeutically effective amount, refers to the amount of one or more pharmaceutical agents administered to a subject in a single dose or as part of a series of doses to effectively produce the desired therapeutic effect.

[0519] Treatment efficacy in a subject can typically be monitored using assays and methods appropriate to the condition being treated, assays familiar to those skilled in the art and described herein. Pharmacokinetics of a drug or one or more metabolites administered to a subject can be monitored by determining the levels of the drug or metabolite in biological fluids (e.g., blood, blood fractions (e.g., serum), and / or urine) and / or other biological samples or tissues from the subject. Methods for any assays practiced in the art and described herein can be used to measure the levels of the drug or metabolite during treatment.

[0520] The dosage of the agents described herein for treating diseases or conditions may depend on the subject's condition (i.e., the stage of the disease), the severity of the symptoms caused by the disease, general health status, and age, sex, and weight, as well as other factors readily apparent to a person skilled in the medical field. Pharmaceutical compositions may be administered in a manner appropriate for the disease being treated, as determined by a person skilled in the medical field. In addition to the factors relating to the use of agents for treating diseases or conditions described herein and above, the appropriate duration and frequency of agent administration may be determined or adjusted by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the agent can generally be determined using experimental models and / or clinical trials. The optimal dosage may depend on the subject's constitution, weight, or blood volume. Generally, the minimum dose sufficient to provide effective treatment is preferred. The design and execution of preclinical and clinical studies of the agents described herein (including when administered for preventative benefit) are entirely within the skill of a person skilled in the relevant field. When two or more agents are administered to treat a disease or condition, the optimal dosage of each agent may be different, such as lower than the dosage when either agent is administered alone as a monotherapy. In certain specific embodiments, the two combined agents may act synergistically or additively, and either agent may be used in a smaller amount than that applied alone. The amount of agent that can be administered daily may be, for example, between about 0.01 mg / kg body weight and 100 mg / kg body weight, such as between about 0.1 and 1 mg / kg body weight, between about 1 and 10 mg / kg body weight, between about 10 and 50 mg / kg body weight, or between about 50 and 100 mg / kg body weight. In other embodiments, the amount of agent that can be administered daily may be between about 0.01 mg / kg body weight and 1000 mg / kg body weight, between about 100 and 500 mg / kg body weight, or between about 500 and 1000 mg / kg body weight. The optimal daily or per treatment course may vary depending on the disease or condition being treated and may also vary depending on the route of administration and treatment regimen.

[0521] Pharmaceutical compositions containing pharmaceutical agents can be formulated in a manner suitable for delivery methods using techniques conventionally practiced in the art. The compositions can be in the form of solids (e.g., tablets, capsules), semi-solids (e.g., gels), liquids, or gases (e.g., aerosols). In other embodiments, the pharmaceutical composition is administered via bolus infusion.

[0522] Pharmaceutically acceptable excipients are well known in the pharmaceutical industry and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition, Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc., may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may be used. Generally, the type of excipient is selected based on the method of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized or otherwise formulated into lyophilized products using one or more suitable excipient solutions to dissolve and / or dilute the pharmaceutical agent in the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated in liposomes using techniques known and practiced in the art. In some specific embodiments, the agent is not formulated in liposomes for application to stents used to treat highly (but not entirely) occluded arteries. The pharmaceutical composition may be formulated for any suitable administration method described herein and in the art.

[0523] Pharmaceutical compositions (e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods) may be in liquid form. Liquid pharmaceutical compositions may contain one or more of the following: sterile diluents such as water, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension media, polyethylene glycol, glycerin, propylene glycol, or other solvents; antibacterial agents; antioxidants; chelating agents; buffers; and agents for regulating tension, such as sodium chloride or dextran. Parenteral compositions may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic. The use of physiological saline is preferred, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for the treatment of ophthalmic conditions or diseases, the liquid pharmaceutical composition may be applied to the eye as eye drops. The liquid pharmaceutical composition may be delivered orally.

[0524] For oral formulations, at least one of the pharmaceutical agents described herein may be used alone or in combination with suitable additives to form tablets, powders, granules, or capsules, and, if desired, in combination with diluents, buffers, wetting agents, preservatives, colorants, and flavoring agents. The pharmaceutical agents may be formulated with buffers to provide protection against the low pH of the gastric environment and / or with an enteric coating. The pharmaceutical agents contained in the pharmaceutical composition may be formulated for oral delivery with, for example, flavoring agents in liquid, solid, or semi-solid formulations and / or with an enteric coating.

[0525] Pharmaceutical compositions comprising any of the agents described herein can be formulated for sustained or slow release, also known as timed release or controlled release. Such compositions are typically prepared using well-known techniques and administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain compounds dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlled membrane. Excipients used in such formulations are biocompatible and may also be biodegradable; preferably, the formulation provides a relatively constant level of release of the active ingredient. The amount of agent contained in a sustained-release formulation depends on the implantation site, the rate of release and the intended duration of release, and the nature of the condition, disease, or ailment to be treated or prevented.

[0526] In some embodiments, the pharmaceutical composition comprising the agent is formulated for transdermal, intradermal, or topical application. The composition can be applied using syringes, bandages, transdermal patches, inserts, or syringe-like application devices, in the form of powder / talcum powder or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, or pastes. Preferably, it is in the form of a controlled-release or sustained-release formulation applied topically or injected directly into the skin adjacent to the treatment area or into the skin (e.g., intradermally or subcutaneously) within the area to be treated. The active composition can also be delivered via iontophoresis. Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzyl chloride, benzyl alcohol, hexadecylpyridine chloride, chlorobutanol, phenol, phenethyl alcohol, thimerosal, and combinations thereof.

[0527] Pharmaceutical compositions containing pharmaceutical agents can be formulated as emulsions for surface application. The emulsion contains a liquid distributed within a bulk of a second liquid. The emulsion can be an oil-in-water emulsion or an oil-in-water emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other pharmaceutically approved oily excipients. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for surface application may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or moisturizing agent.

[0528] For example, ointments and creams can be formulated with aqueous or oil-based bases, with the addition of suitable thickeners and / or gelling agents. Lotions can be formulated with aqueous or oil-based bases and typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants. Liquid sprays can be delivered, for example, from pressurized packaging via specially shaped closures. Water-in-oil emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foam emulsion systems.

[0529] In some embodiments, the pharmaceutical agents described herein can be formulated as inhalers. Inhalation methods can deliver the drug directly to the airways. The agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The agents can be formulated with solvents, gases, nitrates, or any combination thereof. The compositions described herein can optionally be formulated for delivery as liquid aerosols or inhalable dry powder. Liquid aerosol formulations are optionally primarily atomized into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosols and inhalable dry powder formulations are preferably delivered via the endobronchial canal to the terminal bronchioles and ultimately to the parenchymal tissue.

[0530] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device, such as an ejector, a vibrating perforated plate, or an ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles with a median mass average diameter primarily between 1 and 5 μm. Furthermore, the formulation preferably has balanced osmotic pressure, ionic strength, and chloride concentration, as well as a minimum aerosol volume capable of delivering an effective dose of the drug. In addition, the aerosolized formulation preferably does not negatively impact airway function or cause undesirable side effects.

[0531] Suitable aerosol atomizing devices for administering the aerosols described herein include, for example, jet atomizers, vibrating perforated plates, ultrasonic atomizers, and electrically powered dry powder inhalers, capable of atomizing formulations into aerosol particles primarily in the range of 1-5 μm in size. Primarily, this application means that at least 70%, but preferably more than 90%, of all generated aerosol particles are in the 1-5 μm range. Jet atomizers operate by breaking down liquid solutions into aerosol droplets using air pressure. Vibrating perforated plate atomizers operate by using an acoustic vacuum generated by rapidly vibrating perforated plates to expel solvent droplets from the perforated plates. Ultrasonic atomizers operate using piezoelectric crystals that shear liquids into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNebTM and AeroDoseTM vibrating perforated plate atomizers (AeroGen, Inc., Sunnyvale, California). Nebulizer (Medic-Aid Ltd., West Sussex, England), Pari and Pari LC Jet atomizers (Pari Respiratory Equipment, Inc., Richmond, Virginia) and Aerosonic TM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and (Omron Healthcare, Inc., Vernon Hills, Illinois) Ultrasonic nebulizer.

[0532] In some embodiments, the agent can be formulated with an oily base or ointment to form a semi-solid composition having the desired shape. In addition to the agent, these semi-solid compositions may also contain a system of dissolved and / or suspended bactericides, preservatives, and / or buffers. The petrolatum component that may be included can be any paraffin wax ranging in viscosity from mineral oils incorporating isobutylene, colloidal silica, or stearates to paraffin wax. The absorbent base can be used with the oily system. Additives may specifically or in combination include cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohol, low HLB (hydrophobic-oleophobic balance) emulsifiers, and a wide variety of ionic and nonionic surfactants.

[0533] Controlled or sustained release transdermal or surface formulations can be achieved by adding time-delayed release additives (such as polymer structures, matrices) available in the art. For example, the composition can be administered using a hot-melt extruded article (such as a bioadhesive hot-melt extruded film). The formulation may include a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent may be present in an amount that provides sufficient adhesion to maintain the system attached to the surface of the target epithelial or endothelial cells for a duration sufficient to achieve the desired release of the compound.

[0534] Inserts, transdermal patches, bandages, or articles may contain mixtures or coatings of polymers that provide the release of a drug at a constant rate over an extended period of time. In some embodiments, the article, transdermal patch, or insert contains a water-soluble pore-forming agent, such as polyethylene glycol (PEG), which can be mixed with a water-insoluble polymer to increase the durability of the insert and prolong the release of the active ingredient.

[0535] Transdermal devices (insertions, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers can be used at sites where release can be influenced by pH variations. These rate-controlling polymers can be applied using a continuous coating film during spraying and drying with the active compound. In one embodiment, a coating formulation is used to coat a pellet containing the active ingredient, the pellet being compressed to form a solid, biodegradable insert.

[0536] Polymer formulations can also be used to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. By way of example, sustained-release gels and compounds can be incorporated into a polymer matrix (such as a hydrophobic polymer matrix). Examples of polymer matrices include microparticles. Microparticles can be microspheres, and the core can be a material different from the polymer shell. Alternatively, the polymer can be cast into sheets or films, produced as powders by grinding or other standard techniques, or as a gel (such as a hydrogel). The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device that facilitates drug delivery. The matrix can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0537] Kits are provided that contain unit doses of one or more of the agents described herein (typically oral or injectable doses). Such kits may include containers containing unit doses, informational inserts describing the use of the drug in treating diseases and associated benefits, and optionally, appliances or devices for delivering the composition.

[0538] Treatment

[0539] In one aspect, this disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method can inhibit KRas G12 mutant activity in cells. In some cases, inhibiting KRas G12 mutant activity in cells may include contacting cells for which KRas G12 mutant activity needs to be inhibited with an effective amount of a compound of formula (I), formula (II), formula (II*), formula (III), or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In some cases, the contact is in vitro. In some cases, the contact is in vivo. As used herein, the term “contact” means bringing the indicated portions together in an in vitro or in vivo system. For example, “contacting” KRas G12D and / or other G12 mutants with the compounds provided herein includes administering the compounds provided herein to an individual or patient (such as a human) having KRas G12D and / or other G12 mutants, and, for example, introducing the compounds provided herein into a sample containing cells containing KRas G12D and / or other G12 mutants or a purified formulation. In some cases, cells requiring inhibition of KRas G12D and / or other G12 mutant activity are contacted with an effective amount of a compound of formula (I), (II), (II*), or (III) or a pharmaceutically acceptable salt thereof to negatively modulate the activity of KRas G12D and / or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and / or other G12 mutants, the methods described herein are designed to inhibit unwanted cell proliferation resulting from enhanced intracellular activity of KRas G12D and / or other G12 mutants. Cells can be contacted in single or multiple doses, depending on the specific treatment regimen, to achieve the desired negative modulation of KRas G12D and / or other G12 mutants. The ability of a compound to bind to KRas G12D and / or other G12 mutants can be monitored in vitro using well-known methods.

[0540] In some implementations, the inhibitory activity of exemplary compounds in cells can be monitored, for example, by measuring the amount of phosphorylated ERK that inhibits the activity of KRas G12D and / or other G12 mutants.

[0541] On the other hand, a method for treating cancer in patients in need is provided, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II*), formula (III), or a pharmaceutically acceptable salt thereof, or providing a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. The compositions and methods provided herein can be used to treat cancer associated with KRas G12D and / or other G12 mutants in patients in need, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II*), formula (III), a pharmaceutically acceptable salt thereof, or providing a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In some cases, cancer associated with KRas G12D and / or other G12 mutants is lung cancer. The compositions and methods provided herein can be used to treat a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic carcinoma, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, oral cancer, ovarian cancer, prostate cancer, thyroid cancer, and sarcoma. More specifically, these compounds can be used to treat: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchial carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma). Sarcoma, leiomyomas, hemangiomas, lipomas, neurofibromas, fibromas; colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyomas); urogenital tract: kidneys (adenocarcinoma, Wilms' tumor, lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminomas, teratomas, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma); liver: hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma;Bone: Osteoblastic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondrofibroma (osteochondroma), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, degeneration) Osteoarthritis (atopic dermatitis), meninges (meningioma, meningiosarcoma, glioma), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal neurofibroma, meningioma, glioma, sarcoma; Gynecology: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia). Cervical dysplasia), ovaries (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, ovarian gonadotropin-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (cancer); Hematology: Myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease Diseases: non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer being treated. Compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be administered co-administered with other antitumor compounds (e.g., chemotherapy) or in combination with other treatments (such as radiation or surgical interventions) as adjuvants before or after surgery.

[0542] This article also provides for the use of compounds of formula (I), formula (II), formula (II*), formula (III) as defined herein in treatment, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0543] This article also provides for the use of compounds of formula (I), (II), (II*), (III) as defined herein in the treatment of cancer, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.

[0544] This article also provides compounds of formula (I), formula (II), formula (II*), formula (III) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for use in inhibiting KRas G12D and / or other G12 mutants.

[0545] This article also provides information on the use of compounds of formula (I), (II), (III) as defined herein, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the treatment of diseases or conditions associated with KRas G12D and / or other G12 mutants.

[0546] This document also provides for the use of compounds of formula (I), formula (II), formula (II*), formula (III) or pharmaceutically acceptable salts thereof, as defined herein, in the manufacture of medicaments for the treatment of cancer.

[0547] This document also provides for the use of compounds of formula (I), formula (II), formula (II*), formula (III) as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of medicaments for inhibiting the activity of KRas G12D and / or other G12 mutants.

[0548] This document also provides for the use of compounds of formula (I), formula (II), formula (III) as defined herein, or pharmaceutically acceptable salts thereof, in the manufacture of medicaments for the treatment of diseases or conditions associated with KRas G12D and / or other G12 mutants.

[0549] In another aspect, this disclosure provides a method for treating cancer in a patient in need, the method comprising (a) determining that the cancer is associated with a KRas G12D mutation and / or other G12 mutants (e.g., cancer associated with KRas G12D and / or other G12 mutants) (e.g., as determined using a regulatory-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II*), formula (III) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0550] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. Furthermore, methods for treating any of the diseases or conditions described herein in a subject requiring such treatment involve administering to the subject a therapeutically effective amount of a pharmaceutical composition containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

[0551] Compositions containing the compounds described herein may be applied to achieve preventive and / or therapeutic treatment. In therapeutic use, the composition is administered to a patient who already has a disease or condition in an amount sufficient to cure or at least partially stop the symptoms of the disease or condition. The effective amount for this purpose will depend on the severity and course of the disease or condition, prior treatment, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician.

[0552] In prophylactic use, a composition containing the compounds described herein is administered to a patient who is susceptible to or otherwise at risk of a particular disease, condition, or illness. Such amounts are defined as “preventative effective amounts or doses.” In this use, the precise amount also depends on the patient’s health status, weight, etc. When used in a patient, the effective amount for this purpose will depend on the severity and duration of the disease, condition, or illness; prior treatment; the patient’s health status and response to the drug; and the judgment of the treating physician.

[0553] If the patient’s condition does not improve, the compound may be administered long-term, i.e., for an extended period of time, including the entire duration of the patient’s life, as appropriate by the physician, in order to improve the patient’s disease or condition or otherwise control or limit their symptoms.

[0554] Once the patient's condition improves, a maintenance dose is administered (if necessary). Subsequently, the dose or frequency of administration, or both, may be reduced to the level that preserves the improvement in the disease, symptom, or condition, depending on the symptoms. However, in the event of any recurrence of symptoms, the patient may require prolonged intermittent treatment.

[0555] The amount of a given agent corresponding to such quantities will vary depending on factors such as the specific compound, the disease or condition and its severity, and the identity (e.g., weight) of the person or host requiring treatment. However, it can still be determined in a manner recognized in the art based on the specific circumstances surrounding the case, including, for example, the specific agent administered, the route of administration, the condition being treated, and the person or host being treated. Generally, however, the dosage used for treatment in adults will typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The required dose can be conveniently provided as a single dose, or in divided doses administered simultaneously (or over a short period of time) or at appropriate intervals (e.g., as sub-dose twice, three, four, or more times per day).

[0556] The pharmaceutical compositions described herein may be in the form of unit dosage forms suitable for precise single-dose administration. In a unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds. The unit dose may be in the form of packaging containing discrete amounts of the formulation. Non-limiting examples include packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-reclosed containers. Alternatively, multi-dose, non-reclosed containers may be used, in which case the composition typically contains a preservative. By way of example only, formulations for parenteral injection may be provided in unit dosage forms, including but not limited to ampoules, or in multi-dose containers with added preservatives.

[0557] The toxicity and efficacy of such treatment regimens can be determined through standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to determining the LD50. 50 (50% lethal dose for the population) and ED 50 (50% of the effective dose for the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, and it can be expressed as LD50. 50 With ED 50 The ratio between [specific values]. Compounds exhibiting a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of doses for human use. The dosage of such compounds is preferably within the range including [specific dosage range]. 50 This is within the range of circulating concentrations where toxicity is minimal. Dosage can vary within this range depending on the dosage form and route of administration used.

[0558] In some embodiments, the present invention provides a method for treating or preventing a disease, state, or condition in a patient in need, comprising administering to the patient an effective amount of a compound of any embodiment of the present invention or a pharmaceutically acceptable salt thereof. The disease, state, or condition may be selected from the group described elsewhere herein.

[0559] Bifunctional compounds

[0560] In some embodiments, the compounds described herein can be used to selectively eliminate overactivated KRas signaling induced by KRas mutations by directly binding to the mutated KRas protein, by stabilizing it in its GDP-bound (inactive) form, or by blocking the interaction between its GTP-bound form and its downstream target proteins. In some implementations, another approach involves hijacking the protein degradation mechanism in the cell and utilizing the substrate specificity of E3 ligases (such as VHL, CRBN, or IAP) through a bifunctional molecule called a proteolytic-targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUGDEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19; 348(6241):1376-81). This bifunctional molecule can bind to both the mutated KRas protein and the E3 ligase, creating an interaction between the two proteins and inducing KRas degradation.

[0561] This document discloses a bifunctional compound comprising a target protein (i.e., KRAS G12D) binding moiety and an E3 ubiquitin ligase binding moiety, which can induce proteasome-mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D) binding moiety and an E3 ubiquitin ligase binding moiety known in the art. In some embodiments, the use of the disclosed compound in degrading a target protein compound by chemical modification of the disclosed compound is disclosed. In some cases, the target protein binding moiety is derived from compounds of formula (I), (II), (II*), or (III).

[0562] Preparation of compounds

[0563] The compounds disclosed herein can generally be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of example, the compounds disclosed herein can be synthesized using the methods described herein, as well as synthetic methods known in the field of synthetic organic chemistry, or variations thereof as understood by those skilled in the art. The compounds disclosed herein can be prepared using the schemes and examples described elsewhere herein.

[0564] The following examples further illustrate the invention, but should not be construed as limiting its scope in any way.

[0565] Example

[0566] The following synthetic schemes are provided for illustrative purposes and not for limiting purposes. The following examples illustrate various methods for preparing the compounds described herein. It should be understood that those skilled in the art can prepare these compounds by similar methods or by combining other methods known to them. It should also be understood that those skilled in the art will be able to prepare them in a similar manner as described below, by using suitable starting materials and changing the synthetic route as needed. Typically, the starting materials and reagents are available from commercial suppliers, or synthesized from sources known to those skilled in the art, or prepared as described herein.

[0567] This disclosure provides a process for preparing the compounds described herein (described in more detail below).

[0568] General Solution

[0569] Solution IA

[0570]

[0571] Treatment of R1 with methyl 2,4-dichloro-6-methylpyrimidin-5-carboxylate in the presence of a base (such as DIEA in DCM) yields IA-a, which can be deprotonated in THF at -78 °C using LDA or LiHMDS. IA-b can be formed by adding a solution of the ketone in THF at -78 °C, with the reaction quenched at -78 °C. The ester IA-b can be reduced to the diol IA-c by DIBAL or LiAlH4, which can then be cyclized to IA-d via the Mitsunobu reaction or in the presence of BuLi and TsCl in THF at -78 °C. Compound I can be prepared via a Pd-mediated coupling reaction or in the presence of a base (such as NaH or LiHMDS).

[0572] Scheme IB

[0573]

[0574] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidin-5-carboxylate can be deprotonated in THF at -78 °C using LDA or LiHMDS. IB-a can be formed by adding a solution of the ketone in THF at -78 °C, and the reaction is quenched at -78 °C. Ester IB-a can be reduced to diol IB-b by DIBAL or LiAlH4, which can then be cyclized to IB-c via photoelectrophoresis or at -78 °C in the presence of BuLi and TsCl in THF. Treatment of R1 with IB-c in the presence of a base (such as DIEA in DCM) yields IB-d, which can be oxidized to sulfone IB-e. Compound I can be prepared via Pd-mediated coupling or in the presence of a base (such as NaH or LiHMDS).

[0575] Solution IIA

[0576]

[0577] Treatment of tert-butylsulfinamide and ketone in the presence of Ti(OEt)4 yields IIA-a. A solution of IIA-a in THF can be added to a solution of IA-a, deprotonated in THF at -78°C with LDA or LiHMDS, and the reaction can be quenched at -78°C to yield IIA-b. Ester IIA-b can be reduced to IIA-c by DIBAL or LiAlH4, which can be cyclized to IIA-d via removal of the sulfinamide in HCl, chlorination of OH, and cyclization in the presence of a base (such as NaOH) (see Garcia, D.; Moreno, B.; Soler, T.; Foubelo, F.; Yus, M. Tetrahedron Lett. 2009, 50, 4710). R3 of IIA-e can be introduced via reductive amination or alkylation. Compound II can be prepared via Pd-mediated coupling or in the presence of a base (such as NaH or LiHMDS).

[0578] Scheme IIB

[0579]

[0580] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidin-5-carboxylate can be deprotonated in THF at -78 °C using LDA or LiHMDS. IIB-a can be formed by adding a solution of IIA-a in THF at -78 °C, and the reaction is quenched at -78 °C. Ester IIB-a can be reduced to diol IIB-b by DIBAL or LiAlH4, which can then be cyclized to IIB-c as described in scheme IIA above. R3 of IIB-d can be introduced via reductive amination or alkylation. Treatment of R1 with IIB-d in the presence of a base (such as DIEA in DCM) yields IIB-e. IIB-e can be oxidized to sulfoxide IIB-f, which can be converted to II in the presence of a base (such as NaH or LiHMDS).

[0581] Example 1: Exemplary synthesis of 4'-(azacycloheptan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 1)

[0582]

[0583] Step 1: At 20 °C, DIPEA (1.17 g, 9.05 mmol, 2.0 equivalent) and azircycloheptadecane (449 mg, 4.52 mmol, 1.0 equivalent) were added to a solution of methyl 2,4-dichloro-6-methylpyrimidin-5-carboxylate (1.0 g, 4.52 mmol, 1.0 equivalent) in ACN (7 mL). The reaction was then stirred at 20 °C for 2 h. TLC showed that the reaction was complete. The reaction was concentrated under vacuum. The residue was poured into water (20 mL). The aqueous phase was extracted with EtOAc (5 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give compound 1a (1.1 g, 3.88 mmol, 85.7% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ3.88(s,3H),3.49-3.52(m,4H),2.36(s,3H),1.75-1.85(m,4H),1.50-1.60(m,4H).

[0584] Step 2: Compound 1a (1.0 g, 3.52 mmol, 1.0 equivalent) was added to a solution of LDA (2 M, 2.11 mL, 1.2 equivalent) in THF (30 mL) at -60 °C. The mixture was stirred at -60 °C for 30 min. 4-Chloro-2,3-dihydro-1H-inden-1-one (587 mg, 3.52 mmol, 1.0 equivalent) was added at -60 °C. The mixture was stirred at -60 °C for 1 h. The reaction mixture was quenched by adding HCl (5%, 50 mL) at 0 °C and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc = 5:1) to give compound 1b (0.5 g, 1.20 mmol, 33.9% yield) as a yellow solid. LCMS: C 22 H 25 Cl2N3O3(M+H) + Calculated value: m / z = 450.1; Measured value: 450.1. 1 H NMR (400MHz, CDCl3) δ7.22(d,J=8.0Hz,1H),7.13(t,J=7.6Hz,1H),7.03(d,J=7.6Hz,1H),6.06(s,1H),3.69(s,3H) ,3.47-3.54(m,4H),3.08-3.11(m,2H),2.76-2.99(m,2H),2.22-2.26(m,2H),1.70-1.80(m,4H),1.45-1.60(m,4H).

[0585] Step 3: At 0°C, DIBAL-H (1M, 3.26mL, 3.0 equivalent) was added to a solution of mixture 1b (490mg, 1.09mmol, 1.0 equivalent) in DCM (5mL). The reaction was then stirred at 0°C for 1h. The reaction mixture was quenched with H2O (20mL) at 25°C. The mixture was extracted with DCM (10mL*2). The combined organic layers were washed with brine (15mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 80 / 1 to 8 / 1) to give compound 1c (200mg, 474µmol, 43.5% yield) as a white solid. LCMS: C 21 H 25 Cl2N3O2(M+H) + Calculated value: m / z = 422.1; Measured value: 422.1. 1H NMR (400MHz, CD3OD) δ7.25(d,J=8.0Hz,1H),7.19(t,J=7.6Hz,1H),7.09(d,J=7.6Hz,1H),4.40-4.44(m,1H),4.29-4.32(m,1H),3.78-3.81( m,4H),3.25-3.26(m,1H),2.96-3.03(m,2H),2.84-2.88(m,1H),2.56- 2.59(m,1H),2.01-2.04(m,1H),1.75-1.90(m,4H),1.55-1.65(m,4H).

[0586] Step 4: PPh3 (149 mg, 568 μmol, 1.2 equivalent) and DIAD (115 mg, 568 μmol, 1.2 equivalent) were added to a solution of compound 1c (200 mg, 474 μmol, 1 equivalent) in THF (10 mL) at 0 °C and N2. The reaction was then stirred at 0 °C and N2 for 2 h. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EtOAc = 20:1) to give compound 1d (100 mg, 247 μmol, 52.2% yield) as a yellow solid. 21 H 23 Cl2N3O(M+H) + m / z = 404.1; Measured value: 404.1. 1 H NMR (400MHz, CDCl3) δ7.31(d,J=8.0Hz,1H),7.17(t,J=7.6Hz,1H),7.12(d,J=7.6Hz,1H),4.65-4.71(m,1H),4.51-4.53(m,1H),3. 50-3.65(m,4H),3.07-3.17(m,3H),2.96-3.00(m,1H),2.36-2.38(m,1H),2.15-2.20(m,1H),1.70-1.75(m,4H),1.50-1.65(m,4H).

[0587] Step 5: At 0°C, NaH (15.8 mg, 396 μmol, 60% purity, 2.0 equivalent) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (37.8 mg, 237 μmol, 1.2 equivalent) in THF (2 mL). The reaction was stirred at 0°C for 30 min. Then, at 0°C, a solution of compound 1d (80 mg, 198 μmol, 1.0 equivalent) in THF (0.5 mL) was added to the above solution. The reaction was continued to be stirred at 60°C for 8 h. LC-MS showed that 11% of the starting material remained and 52.9% of the desired compound was detected. The reaction was quenched with H2O (10 mL) at 0°C. The aqueous phase was extracted with EtOAc (5 mL * 2). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative TLC (SiO₂, DCM:MeOH = 6:1) to give 4'-(azacycloheptan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 1, 11.0 mg, 20.8 μmol, 10.5% yield) as a yellow solid. 29 H 36 ClFN4O2(M+H) + m / z = 526.25; measured value: 527.2. 1 H NMR (400MHz, CDCl3) δ7.10 (d, J = 8.0Hz, 1H), 6.90-7.00 (m, 2H), 5.00-5.40 (m, 1H), 4.50-4.53(m,1H),4.32-4.36(m,1H),3.93-3.95(m,1H),3.79-3.81(m,1H),3.38- 3.41(m,4H),3.05-3.15(m,2H),2.90-3.00(m,2H),2.85-2.87(m,1H),2.70-2.80( m,2H),2.15-2.25(m,1H),1.95-2.10(m,4H),1.50-1.80(m,6H),1.30-1.50(m,6H).

[0588] Example 2.4 Exemplary synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 2)

[0589]

[0590] Step 1.3 Synthesis of (2-chloro-5-methoxycarbonyl-6-methylpyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2a). At 0 °C, a mixture of DIEA (233.88 mg, 1.81 mmol) and 3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (192.08 mg, 0.9 mmol) in DMF (1 mL) was added to a solution of methyl 2,4-dichloro-6-methylpyrimidin-5-carboxylic acid (200.0 mg, 0.9 mmol) in MeCN (4 mL). The reaction mixture was stirred at 0 °C under Ar for 30 min. The solution was diluted with EtOAc (5 mL) and washed with H2O (5 mL x 3) and brine (5 mL). The organic phase was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (eluting with EtOAc:PE = 1:7) to give tert-butyl 3-(2-chloro-5-methoxycarbonyl-6-methylpyrimidin-4-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylate (2a, 280 mg, 0.71 mmol, 78% yield) as a white solid. LCMS (ESI): C 18 H 25 ClN4O4 + Calculated m / z value of H: 397.87; Measured value: 397.2.

[0591] Step 2.3 Synthesis of [2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl-6-methylpyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2b). To a solution of degassed tert-butyl octane-8-carboxylate (2a, 400.0 mg, 1.01 mmol) in toluene (15 mL), [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (332.67 mg, 2.09 mmol), Ruphos (97.5 mg, 0.21 mmol), Pd2(dba)3 (95.71 mg, 0.1 mmol), and Cs2CO3 (851.06 mg, 2.61 mmol) were added. The degassed mixture was stirred at 110 °C under Ar for 16 h. The reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (EtOAc:PE = 1:1 to DCM:MeOH = 10:1) to obtain 3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2b, 460 mg, 0.88 mmol, 88% yield) as a viscous brown solid. LCMS (ESI): C 26 H 38 FN5O5 + Calculated m / z value of H: 520.2; Measured value: 520.2.

[0592] Step 3.3 Synthesis of [6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-methoxycarbonyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1] tert-butyl octane-8-carboxylate (2c). At -70 °C, LDA (0.72 mL, 1.44 mmol in THF) was added dropwise to a solution of tert-butyl octane-8-carboxylate (2b, 150.0 mg, 0.29 mmol) in 15 mL of THF. The reaction mixture was stirred under Ar for 1.5 h between -70 °C and -20 °C. Then, at -70 °C, a solution of 4-chloroindan-1-one (240.47 mg, 1.44 mmol) in 3 mL of...

Claims

1. A compound of formula (II): or a pharmaceutically acceptable salt thereof, in: M is selected from O, S, SO, SO 2 and NR 3 ; R 1 Selected from C 3 -C 12 carbocyclic and 5- to 15-membered heterocyclic rings, each of which is independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-SO 2 R 20 , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein the C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each independently substituted with one or more R 1* optionally substituted; and wherein when M is NR 3 , Y is O, and R 1 When it is piperazine, the piperazine is 9 replace; Each R 1* are independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3 -C 12 Carbon ring; Y is selected from a bond, O, S and NR 5 ; R 2 Selected from -LN(R 21 ) 2 、-L-OR 21 , heterocyclic, C l -C 6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH 2 、-LC(O)N(R 21 ) 2 , -LC l -C 6 Haloalkyl, -L-OR 21 、-L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O) 2 (R 21 )、-LS(O) 2 N(R 21 ) 2 、-LN(R 21 )C(O)(OR 21 )、-L-OC(O)N(R 21 ) 2 and -LC(=O)OC l -C 6 alkyl, wherein the heterocyclic ring, the -L-NR 21 The aryl portion of C(O)-aryl, the heterocyclic portion of the -L-heterocyclic, and the cycloalkyl portion of the -L-cycloalkyl are each substituted by one or more R 6 optionally substituted, and wherein the aryl portion of the -L-aryl and the heteroaryl portion of the -L-heteroaryl are each replaced by one or more R 7 optionally substituted, and wherein when Y is a bond, O or S, R 2 is further selected from hydrogen; Each L is independently selected from C l -C 4 Alkylene, the C l -C 4 The alkylene group is replaced by one or more selected from hydroxyl, C l -C 4 Hydroxyalkyl, C l -C 4 Alkyl, C 3 -C 6 The substituents of the carbocyclic or 3- to 8-membered heterocyclic ring are optionally substituted, wherein the C 3 -C 6 The carbocyclic ring and the 3 to 8 membered heterocyclic ring are substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C 3 -C 6 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; R 3 Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyalkyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, wherein C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently substituted by one or more selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; n is selected from 0 to 2; Each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, hydroxyl, halogen, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, wherein the C 1 -C 6 Alkyl, C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently substituted by one or more radicals selected from cyano, halogen, -OR 5 and—N(R 5 ) 2 The substituents of are optionally substituted; Each R 5 are independently selected from hydrogen or C 1 -C 6 alkyl; Each R 6 are independently selected from halogen, hydroxyl, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, oxo, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano, =CH 2 , =NO-C l -C 3 Alkyl, C l -C 3 Aminoalkyl, -N(R 5 )S(O) 2 (R 5 ), -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, -NHC(O)phenylSO 2 F.C 1 -C 3 Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 -、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)C l -C 3 Alkyl-, (C 1 -C 3 alkyl)C(=O), oxo, (C 1 -C 3 Haloalkyl)C(=O)-, -SO 2 F、(C 1 -C 3 Alkoxy)C l -C 3 Alkoxy, -CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OC 1 -C 6 Alkyl, -CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl), -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC(O) heterocycle, -OC(O)N(R 5 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl), -OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 Alkyl)phenyl (C 1 -C 3 alkyl)N(CH 3 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C 3 Alkyl and -CH 2 Heterocyclic rings, including -NHC(O)phenyl and -OC(O)NH(C 1 -C 3 Alkyl)(C l -C 3 The phenyl groups of the alkyl)phenyl groups are each optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein the -OC l -C 3 The alkyl group of the alkyl group is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein the -CH 2 The heterocyclic ring of the heterocyclyl group is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 7 are independently selected from halogen, hydroxy, HC(=O)-, C l -C 4 Alkyl, C l -C 4 Alkoxy, C l -C 4 Haloalkyl, C l -C 4 Hydroxyalkyl or -N(R 5 ) 2 ; Each R 9 are independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-NR 20 S(O) 2 R 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-NO 2 , =O, =NO(R 20 )、-CN、-NHCN、C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 Haloalkyl; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; and B is selected from heterocyclic and carbocyclic rings, wherein the heterocyclic rings and carbocyclic rings are each independently substituted by one or more selected from halogen, cyano, hydroxyl, =O, -NO 2 , C l -C 4 Alkyl, C 1-6 Aminoalkyl, -SC l -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 2 -C 4 Hydroxyalkynyl, C 1 -C 3 Cyanoalkyl, triazolyl, C l -C 3 Haloalkyl, -OC l -C 3 Halogenated alkyl, -SC l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C l -C 3 Hydroxyalkyl, -CH 2 C(=O)N(R 5 ) 2 , -C 3 -C 4 Alkynyl (NR 5 ) 2 、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)halogenated C l -C 3 Alkyl-, C 1-6 Alkyl-N(R 20 ) 2 , C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each substituted by one or more selected from halogen, -OH, -NO 2 、-NH 2 , =O, =S, -CN, C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents on the haloalkyl group are optionally substituted.

2. The compound or salt of claim 1, wherein R 3 Selected from hydrogen and C 1-6 alkyl.

3. The compound or salt of claim 1 or 2, wherein M is selected from O, NH and NMe.

4. The compound or salt of claim 3, wherein M is O.

5. The compound or salt of claim 1, wherein M is selected from NR 3 .

6. The compound or salt of claim 5, wherein M is selected from NH and NMe.

7. The compound or salt of claim 6, wherein M is NMe.

8. The compound or salt of any one of claims 1 to 7, wherein B is selected from an optionally substituted 5 to 15 membered heterocycle and an optionally substituted C 3 -C 15 Carbon ring.

9. The compound or salt of claim 8, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocyclic ring and an optionally substituted C 8 -C 15 Fused carbocyclic ring.

10. The compound or salt of claim 9, wherein B is an optionally substituted 8- to 15-membered fused heterocyclic ring.

11. The compound or salt of claim 10, wherein B is an optionally substituted unsaturated C 8 -C 15 Fused carbocyclic ring.

12. The compound or salt of any one of claims 9 to 11, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C 8 -C 15 The fused carbocyclic rings are each independently bicyclic or tricyclic.

13. The compound or salt of claim 12, wherein for B, the heterocyclic ring and the carbocyclic ring are each independently bicyclic.

14. The compound or salt of claim 12, wherein for B, the heterocyclic ring and the carbocyclic ring are each independently tricyclic.

15. The compound or salt of any one of claims 9 to 14, wherein B is selected from Each of these is optionally substituted with one or more substituents.

16. The compound or salt of claim 15, wherein B is selected from Each of these is optionally substituted with one or more substituents.

17. The compound or salt of claim 16, wherein B is selected from Each of these is optionally substituted with one or more substituents.

18. A compound or salt as described in any one of claims 8 to 17, wherein for B, the one or more optional substituents are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.

19. The compound or salt of any one of claims 1 to 18, wherein B is selected from 20. A compound or salt as described in any one of claims 8 to 17, wherein for B, the one or more optional substituents of the heterocyclic and carbocyclic rings are independently selected at each occurrence from halogen, C 1 -C 3 Alkyl, -B(OR 20 ) 2 、-OR 20 、-C(O)N(R 20 ) 2 、-N(R 20 ) 2 , =O, -CN, -NHCN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

21. as claimed in any one of claims 8 to 17 compound or salt, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from halogen, oxo, -NH 2 , C 1 -C 3 Alkyl, -B(OH) 2 、-OH、-OC l -C 3 Haloalkyl, -C(O)NH 2 、-NH 2 ,=O,-CN,C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkynyl.

22. A compound or salt as described in any one of claims 8 to 21, wherein B is selected from 23. A compound or salt as described in any one of claims 1 to 22, wherein each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, hydroxy, halogen.

24. The compound or salt of claim 23, wherein each R 4 Independently selected from C 1-6 Alkyl, oxo and halogen.

25. The compound or salt of any one of claims 1 to 24, wherein n is selected from 1 and 2.

26. The compound or salt of any one of claims 1 to 25, wherein n is 0.

27. A compound or salt as described in any one of claims 1 to 26, wherein R 1 is selected from optionally substituted 5- to 12-membered heterocyclic rings.

28. The compound or salt of claim 27, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

29. The compound or salt of claim 28, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

30. The compound or salt of claim 28 or 29, wherein R 20 Selected from hydrogen and C 1-3 alkyl.

31. A compound or salt as described in any one of claims 27 to 29, wherein R 1 The 5- to 12-membered heterocyclic ring is unsaturated.

32. A compound or salt as described in any one of claims 27 to 29, wherein R 1 The 5- to 12-membered heterocyclic ring is saturated.

33. A compound or salt as described in any one of claims 27 to 29, wherein R 1 The 5- to 12-membered heterocyclic ring is a bridged heterocyclic ring.

34. A compound or salt as described in any one of claims 27 to 33, wherein R 1 Selected from Each of which is optionally substituted.

35. The compound or salt of claim 34, wherein the one or more optional substituents are each independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl.

36. The compound or salt of claim 34, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

37. The compound or salt of claim 36, wherein R 1 Selected from 38. A compound or salt as described in any one of claims 27 to 33, wherein R 1 is selected from 6 to 8 membered heterocyclic rings, which are optionally substituted.

39. The compound or salt of claim 38, wherein R 1 is selected from a 7-membered saturated heterocyclic ring, an 8-membered bridged heterocyclic ring, and a 6- to 7-membered unsaturated heterocyclic ring, each of which is optionally substituted.

40. The compound or salt of claim 39, wherein R 1 Selected from Each of which is optionally substituted.

41. The compound or salt of claim 40, wherein the one or more optional substituents are independently selected from -OH, -CN, oxo, C 1-6 Cyanoalkyl.

42. The compound or salt of claim 40 or 41, wherein R 1 Selected from 43. A compound or salt as described in any one of claims 1 to 26, wherein R 1 is selected from an optionally substituted 6- to 7-membered heterocyclic ring.

44. The compound or salt of claim 43, wherein the 6- to 7-membered heterocyclic ring contains only 1 nitrogen atom, and wherein the 6- to 7-membered heterocyclic ring is optionally substituted.

45. The compound or salt of claim 44, wherein R 1 The 6- to 7-membered heterocyclic ring is bonded to formula (II) via only one nitrogen atom.

46. ​​A compound or salt as described in any one of claims 43 to 45, wherein R 1 is selected from an optionally substituted unsaturated 6-membered heterocyclic ring.

47. A compound or salt as described in any one of claims 43 to 45, wherein R 1 is selected from an optionally substituted unsaturated 7-membered heterocyclic ring.

48. A compound or salt as described in any one of claims 43 to 47, wherein R 1 Selected from Any of which is optionally substituted.

49. A compound or salt as described in any one of claims 43 to 48, wherein R 1 Selected from Any of which is optionally substituted.

50. A compound or salt as described in any one of claims 43 to 49, wherein R 1 The one or more optional substituents are each independently selected from halogen, -OR 20 、-N(R 20 ) 2 ,=O,-CN,C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl, -NHCN and C 2-6 Alkynyl.

51. A compound or salt as described in any one of claims 43 to 50, each of which is independently selected from halogen, -OH, -NH 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents on the alkyl group are optionally substituted.

52. A compound or salt as described in any one of claims 43 to 51, wherein R 1 The one or more optional substituents of are each independently selected from halogen.

53. A compound or salt as described in any one of claims 43 to 52, wherein R 1 Selected from 54. A compound or salt as described in any one of claims 43 to 51, wherein R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents on the alkyl group are optionally substituted.

55. The compound or salt of claim 54, wherein R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents on the alkyl group are optionally substituted.

56. The compound or salt of claim 55, wherein R 1 Selected from Each of which is independently selected from halogen and C 1-6 The substituents on the haloalkyl group are optionally substituted.

57. The compound or salt of claim 56, wherein R 1 Selected from 58. A compound or salt as described in any one of claims 43 to 51, wherein R 1 Selected from which are independently selected from halogen, -OH, -NH 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents on the alkyl group are optionally substituted.

59. The compound or salt of claim 58, wherein R 1 Selected from It is optionally substituted with one or more substituents independently selected from halogen.

60. The compound or salt of claim 59, wherein R 1 Selected from 61. The compound or salt of claim 43, wherein R 1 is selected from a 6- to 7-membered heterocyclic ring.

62. The compound or salt of claim 61, wherein the 6- to 7-membered heterocyclic ring contains only 1 nitrogen atom and optionally one or more additional heteroatoms selected from oxygen and sulfur.

63. The compound or salt of claim 62, wherein the optional one or more additional heteroatoms are selected from sulfur.

64. A compound or salt as described in any one of claims 61 to 63, wherein the 6 to 7 membered heterocyclic ring contains only 1 nitrogen atom and does not additionally contain additional heteroatoms.

65. The compound or salt of any one of claims 61 to 64, wherein the 6 to 7 membered heterocycle is a non-aromatic 6 to 7 membered heterocycle.

66. A compound or salt as described in any one of claims 62 to 65, wherein R 1 The 6- to 7-membered heterocyclic ring is bonded to formula (II) via only one nitrogen atom.

67. A compound or salt as described in any one of claims 61 to 66, wherein R 1 Selected from Each of which is optionally substituted.

68. The compound or salt of claim 67, wherein R 1 The one or more optional substituents are each independently selected from halogen, -OH, -CN, C 1-6 Cyanoalkyl, -NHCN, C 1-6 Alkyl, oxo and C 2-6 Alkynyl.

69. The compound or salt of claim 43, wherein R 1 is selected from optionally substituted 6- to 10-membered heterocyclic rings.

70. The compound or salt of claim 69, wherein R 1 Selected from Each of which is optionally substituted.

71. The compound or salt of claim 70, wherein the one or more optional substituents are independently selected from halogen, =O, -OH, -C(O)N(R 20 ) 2 , C 2-6 Alkynyl, -NHCN, -CN, C 1-6 Aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 alkyl.

72. The compound or salt of claim 71, wherein R 1 Selected from 73. The compound or salt of claim 27, wherein R 1 is selected from 7 to 11 membered spiro heterocycles.

74. The compound or salt of claim 73, wherein R 1 is selected from 10-membered spiro heterocycles.

75. The compound or salt of claim 73 or 74, wherein the spiroheterocycle has at least 3 nitrogen atoms.

76. The compound or salt of claim 75, wherein R 1 Selected from Each of which is optionally substituted.

77. The compound or salt of claim 76, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , =O, -CN, -NHCN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Substituents on an alkynyl group are optionally substituted.

78. The compound or salt of claim 77, wherein R 1 Selected from Preferably 79. The compound or salt of claim 27, wherein R 1 is selected from optionally substituted unsaturated 9- to 11-membered heterocyclic rings.

80. The compound or salt of claim 79, wherein R 1 is selected from an optionally substituted unsaturated 10-membered heterocyclic ring.

81. The compound or salt of claim 80, wherein R 1 for It is optionally substituted.

82. The compound or salt of claim 81, wherein R 1 for It is replaced by one or more selected from halogen, -OH, -C(O)N(R 20 ) 2 、-C(O)OR 20 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Substituents on an alkynyl group are optionally substituted.

83. The compound or salt of claim 82, wherein R 1 Selected from Each of which is replaced by one or more selected from halogen, -OH, -N(R 20 ) 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Substituents on an alkynyl group are optionally substituted.

84. The compound or salt of claim 27, wherein R 1 is selected from optionally substituted unsaturated 9- to 11-membered heterocyclic rings.

85. The compound or salt of claim 84, wherein R 1 is selected from an optionally substituted unsaturated 10-membered heterocyclic ring.

86. The compound or salt of claim 85, wherein R 1 for It is optionally substituted.

87. The compound or salt of claim 86, wherein R 1 The one or more optional substituents are independently selected from halogen, -OH, -S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 )、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)OR 20 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkynyl, 5 to 12 membered heterocyclic ring, wherein the 5 to 12 membered heterocyclic ring is substituted by one or more selected from halogen, -OR 20 and C 1-6 The substituents on the alkyl group are optionally substituted.

88. A compound or salt as described in any one of claims 84 to 87, wherein R 1 Selected from Each of which is optionally substituted.

89. A compound or salt as described in any one of claims 84 to 88, wherein R 1 Selected from 90. A compound or salt as described in any one of claims 84 to 87, wherein R 1 The one or more optional substituents are independently selected from halogen, -OH, -N(R 20 ) 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, -C(O)N(R 20 ) 2 , C 1-6 Alkyl and C 2-6 Alkynyl.

91. The compound or salt of claim 90, wherein R 1 The one or more optional substituents are independently selected from halogen and -C(O)N(R 20 ) 2 .

92. The compound or salt of claim 91, wherein R 1 Selected from 93. A compound or salt as described in any one of claims 84 to 87, wherein R 1 The one or more optional substituents are independently selected from halogen, -N(R 20 ) 2 、-CN、C 1-6 Alkyl, C 1-6 Cyanoalkyl, C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Alkyl-SO 2- C 1-6 Alkyl, C 2-6 Alkenyl, -C(O)NR 20 OR 20 、-C(O)N(R 20 ) 2 、-C(O)R 20 and a 5- to 10-membered heterocyclic ring, wherein the 5- to 10-membered heterocyclic ring is independently replaced by one or more R 1* optionally substituted, wherein each R 1* are independently selected from halogen, -OR 20 and C 1-6 alkyl.

94. The compound or salt of claim 93, wherein R 1 The one or more optional substituents are selected from chlorine, -NH 2 、-CN、C 1 Alkyl, C 2 Alkenyl, 95. The compound or salt of claim 94, wherein R 1 Selected from 96. A compound or salt as described in any one of claims 1 to 26, wherein R 1 is an optionally substituted 12- to 15-membered heterocyclic ring.

97. The compound or salt of claim 96, wherein R 1 is an optionally substituted 12-membered heterocyclic ring.

98. The compound or salt of claim 96, wherein R 1 is an optionally substituted 13-membered heterocyclic ring.

99. The compound or salt of claim 96, wherein R 1 is an optionally substituted 14-membered heterocyclic ring.

100. The compound or salt of claim 96, wherein R 1 is an optionally substituted 15-membered heterocyclic ring.

101. A compound or salt as described in any one of claims 96 to 100, wherein R 1 The heterocyclic ring is a tricyclic ring.

102. A compound or salt as described in any one of claims 96 to 101, wherein R 1 The heterocyclic ring contains a condensed heterocyclic ring.

103. A compound or salt as described in any one of claims 96 to 102, wherein R 1 The heterocycle contains a spiro heterocycle.

104. A compound or salt as described in any one of claims 96 to 103, wherein R 1 The heterocycle contains fused and spiro heterocycles.

105. A compound or salt as described in any one of claims 96 to 104, wherein R 1 The heterocyclic ring is an unsaturated heterocyclic ring.

106. A compound or salt as described in any one of claims 96 to 105, wherein R 1 The heterocycle of is a non-aromatic heterocycle.

107. A compound or salt as described in any one of claims 96 to 106, wherein R 1 The heterocyclic ring has at least one double bond.

108. A compound or salt as described in any one of claims 96 to 107, wherein R 1 The heterocyclic ring has at least two double bonds.

109. A compound or salt as described in any one of claims 96 to 108, wherein R 1 The heterocyclic ring has two double bonds.

110. A compound or salt as described in any one of claims 96 to 109, wherein R 1 Selected from Each of these is optionally substituted with one or more substituents.

111. The compound or salt of claim 110, wherein the one or more optional substituents are selected from halogen, -OH, -NHCN, -S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 )、-C(O)N(R 20 ) 2 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkynyl.

112. The compound or salt of claim 111, wherein the one or more optional substituents are selected from halogen, -OH, C 1-6 Alkyl and -C(O)N(R 20 ) 2 .

113. A compound or salt as described in any one of claims 96 to 112, wherein R 1 Selected from 114. The compound or salt of claim 43, wherein R 1 is selected from substituted 6- to 7-membered heterocyclic rings, wherein the 6- to 7-membered heterocyclic ring is substituted with at least one -NHCN and is further substituted with one or more C 1-6 Alkyl groups are optionally substituted.

115. The compound or salt of claim 114, wherein R 1 Selected from 116. A compound or salt as described in any one of claims 1 to 25, wherein R 1 is selected from 8 to 10 membered heterocyclic rings, each of which is replaced by one or more independently selected from halogen, -C(O)N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 , -NHCN, C 1-6 Cyanoalkyl, C 1-6 Alkyl, C 2-6 The substituents of the alkynyl group and the 5- to 12-membered heterocyclic ring (preferably the 5- to 6-membered heterocyclic ring) are optionally substituted, wherein the 5- to 12-membered heterocyclic ring is each independently substituted with one or more R 1* Optionally substituted; each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 alkyl.

117. The compound or salt of claim 116, wherein R 1 Selected from Each of which is optionally substituted.

118. The compound or salt of claim 117, wherein R 1 Selected from It is optionally substituted.

119. The compound or salt of claim 118, wherein R 1 Selected from 120. The compound or salt of claim 117, wherein R 1 Selected from 121. The compound or salt of any one of claims 1 to 120, wherein Y is O.

122. A compound or salt as described in any one of claims 1 to 121, wherein R 2 is -L-heterocyclic ring, which is replaced by one or more R 6 Optional substitution.

123. The compound or salt of claim 122, wherein L is selected from C 1 -C 4 Alkylene.

124. The compound or salt of claim 123, wherein L is selected from unsubstituted C 1 -C 4 Alkylene.

125. The compound or salt of claim 123, wherein each L is independently selected from optionally substituted C l -C 4 and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 A carbon ring wherein the C 3 -C 6 The carbocyclic ring is replaced by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents on the haloalkyl group are optionally substituted.

126. The compound or salt of claim 125, wherein the optional substituents of L are selected from C l -C 4 Hydroxyalkyl, C l -C 4 Alkyl, C 3 -C 6 and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C 3 -C 6 The carbocyclic and 3- to 8-membered heterocyclic rings are replaced by one or more selected from halogen and C 1-6 The substituents on the haloalkyl group are optionally substituted.

127. A compound or salt as described in any one of claims 1 to 126, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

128. The compound or salt of claim 127, wherein R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano and C l -C 3 Aminoalkyl.

129. The compound or salt of claim 128, wherein R 2 R 6 In each occurrence, independently selected from C 1 -C 3 Alkyl and halogen.

130. A compound or salt as described in any one of claims 127 to 129, wherein YR 2 Selected from 131. A compound or salt as described in any one of claims 121 to 125, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

132. The compound or salt of claim 131, wherein R 6 Selected from halogen, -OH, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, oxo, C 1 -C 3 Alkoxy, -CN and C l -C 3 Aminoalkyl.

133. The compound or salt of claim 132, wherein R 6 Selected from halogen and C l -C 3 alkyl.

134. The compound or salt of claim 133, wherein YR 2 Selected from 135. The compound or salt of claim 131, YR 2 Selected from 136. A compound or salt as described in any one of claims 1 to 121, wherein R 2 is selected from -L-heterocycle, wherein the heterocyclic portion of the -L-heterocycle is replaced by one or more R 6 Optional substitution.

137. The compound or salt of claim 136, wherein each L is independently selected from substituted C l -C 4 an alkylene group; and in, The two substituents on the same carbon atom of L together form C 3 -C 6 A carbon ring wherein the C 3 -C 6 The carbocyclic ring is replaced by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents on the haloalkyl group are optionally substituted.

138. The compound or salt of claim 137, wherein each L is independently selected from substituted C l -C 4 Alkylene, and wherein the two substituents on the same carbon atom of L together form a C 3 -C 6 Carbon ring.

139. The compound or salt of claim 138, wherein each L is independently selected from substituted C 3 Alkylene, and wherein the two substituents on the same carbon atom of L together form a C 3 Carbon ring.

140. The compound or salt of claim 139, wherein each L is independently selected from 141. The compound or salt of claim 140, wherein YR 2 for 142. A compound or salt as described in any one of claims 1 to 126, wherein YR 2 Selected from wherein the heterocycle is optionally substituted.

143. The compound or salt of claim 142, wherein the heterocycle is replaced by one or more selected from halogen, hydroxyl, C l -C 3 Alkyl, -N(R 5 )S(O) 2 (R 5 )、-OC(O)N(R 5 ) 2 , =CH 2 , oxo, =NO-C l -C 3 Alkyl, -CH 2 OC(O) heterocycle, -CH 2 Heterocyclic ring, -CH 2 OC(O)N(R 5 ) 2 and-OC l -C 3 The alkyl substituents are optionally substituted, wherein -OC l -C 3 The alkyl group of the alkyl group is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy.

144. The compound or salt of claim 143, wherein YR 2 Selected from 145. A compound or salt as described in any one of claims 1 to 126 or 136 to 140, wherein R 2 Selected from -LN(R 21 ) 2 .

146. The compound or salt of claim 145, wherein L is independently selected from substituted C l -C 4 an alkylene group; and in, The two substituents on the same carbon atom of L together form C 3 -C 6 A carbon ring wherein the C 3 -C 6 The carbocyclic ring is optionally substituted with one or more substituents selected from halogen.

147. The compound or salt of claim 1, 145 or 146, wherein L is 148. A compound or salt as described in any one of claims 1 or 145 to 147, wherein R 2 for 149. A compound or salt as described in any one of claims 1 or 145 to 147, wherein YR 2 for 150. The compound or salt of claim 1, wherein the compound is selected from: or a pharmaceutically acceptable salt thereof.

151. A compound of formula (III): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from C 3 -C 12 carbocyclic and 5- to 15-membered heterocyclic rings, each of which is independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein the C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each independently substituted with one or more R 1* Optional substitution; Each R 1* are independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3 -C 12 Carbon ring; R 2 Selected from -L-NR 21 S(O) 2 (R 21 )、-LS(O) 2 N(R 21 ) 2 、-LN(R 21 )C(O)(OR 21 )、-L-OC(O)N(R 21 ) 2 and L-bicyclic heterocycles, wherein the bicyclic heterocycles are separated by one or more R 6 Optional substitution; Each L is independently selected from C l -C 4 Alkylene, the C l -C 4 The alkylene group is replaced by one or more selected from hydroxyl, C l -C 4 Hydroxyalkyl, C l -C 4 Alkyl, C 3 -C 6 The substituents of the carbocyclic or 3- to 8-membered heterocyclic ring are optionally substituted, wherein the C 3 -C 6 The carbocyclic ring and the 3 to 8 membered heterocyclic ring are substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C 3 -C 6 The carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; n is selected from 0 to 3; Each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, hydroxyl, halogen, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, wherein the C 1 -C 6 Alkyl, C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently substituted by one or more radicals selected from cyano, halogen, -OR 5 and—N(R 5 ) 2 The substituents of are optionally substituted; B is selected from heterocyclic and carbocyclic rings, wherein the heterocyclic ring or carbocyclic ring is substituted by one or more independently selected from halogen, cyano, hydroxyl, =O, -NO 2 , C l -C 4 Alkyl, C 1-6 Aminoalkyl, -SC l -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 2 -C 4 Hydroxyalkynyl, C 1 -C 3 Cyanoalkyl, triazolyl, C l -C 3 Haloalkyl, -OC l -C 3 Halogenated alkyl, -SC l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C l -C 3 Hydroxyalkyl, -CH 2 C(=O)N(R 5 ) 2 , -C 3 -C 4 Alkynyl (NR 5 ) 2 、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)halogenated C l -C 3 Alkyl-, C 1-6 Alkyl-N(R 20 ) 2 , C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each substituted by one or more selected from halogen, -OH, -NO 2 、-NH 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; Y is selected from a bond, O, S and NR 5 ; Each R 6 are independently selected from halogen, hydroxyl, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, oxo, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano, =CH 2 , =NO-C l -C 3 Alkyl, C l -C 3 Aminoalkyl, -N(R 5 )S(O) 2 (R 5 ), -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, -NHC(O)phenylSO 2 F.C 1 -C 3 Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 -、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)C l -C 3 Alkyl-, (C 1 -C 3 alkyl)C(=O), oxo, (C 1 -C 3 Haloalkyl)C(=O)-, -SO 2 F、(C 1 -C 3 Alkoxy)C l -C 3 Alkoxy, -CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OC 1 -C 6 Alkyl, -CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl), -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC(O) heterocycle, -OC(O)N(R 5 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl), -OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 Alkyl)phenyl (C 1 -C 3 alkyl)N(CH 3 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C 3 Alkyl and -CH 2 Heterocyclic rings, including -NHC(O)phenyl and -OC(O)NH(C 1 -C 3 Alkyl)(C l -C 3 The phenyl group of the alkyl)phenyl group is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein -OC l -C 3 The alkyl group of the alkyl group is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein -CH 2 The heterocyclic ring of the heterocyclyl group is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; and Each R 5 are independently selected from hydrogen or C 1 -C 6 alkyl.

152. The compound or salt of claim 151, wherein R 2 is selected from L-pyrrolizine, wherein the pyrrolizine is replaced by one or more R 6 Optional substitution.

153. A compound or salt as described in any one of claims 151 to 152, wherein B is selected from an optionally substituted 5 to 15 membered heterocycle and an optionally substituted C 3 -C 15 Carbon ring.

154. The compound or salt of claim 153, wherein B is selected from an optionally substituted 8 to 15 membered fused heterocycle and an optionally substituted C 8 -C 15 Fused carbocyclic ring.

155. The compound or salt of claim 154, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocyclic ring.

156. The compound or salt of claim 154, wherein B is selected from an optionally substituted unsaturated C 8 -C 15 Fused carbocyclic ring.

157. A compound or salt as described in any one of claims 153 to 156, wherein for B, the optionally substituted 8 to 15 membered fused heterocycle and the optionally substituted C 8 -C 15 Fused carbocyclic rings are each bicyclic and tricyclic.

158. The compound or salt of claim 157, wherein for B, the heterocycle and carbocycle are each independently bicyclic.

159. The compound or salt of claim 157, wherein for B, the heterocycle and carbocycle are each independently tricyclic.

160. A compound or salt as described in any one of claims 151 to 159, wherein B is selected from Each of these is optionally substituted with one or more substituents.

161. The compound or salt of claim 160, wherein B is selected from Each of these is optionally substituted with one or more substituents.

162. The compound or salt of claim 161, wherein B is selected from Each of these is optionally substituted with one or more substituents.

163. as described in any one of claim 151 to 162 compound or salt, wherein for B, described one or more optional substituents of described heterocycle and carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.

164. A compound or salt as described in any one of claims 151 to 163, wherein B is selected from 165. A compound or salt as described in any one of claims 151 to 162, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from halogen, C 1 -C 3 Alkyl, -B(OR 20 ) 2 、-OR 20 、-C(O)N(R 20 ) 2 、-N(R 20 ) 2 , =O, -CN, -NHCN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 Alkynyl.

166. compounds or salts as described in claim 155, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from halogen, oxo, -NH 2 , C 1 -C 3 Alkyl, -B(OH) 2 、-OH、-C(O)NH 2 、-NH 2 ,=O,-CN,C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Alkynyl.

167. A compound or salt as described in any one of claims 165 to 166, wherein B is selected from 168. A compound or salt as described in any one of claims 151 to 167, wherein each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, hydroxy, halogen.

169. The compound or salt of claim 168, wherein each R 4 Independently selected from C 1-6 Alkyl, oxo and halogen.

170. The compound or salt of any one of claims 151 to 169, wherein n is selected from 1 and 2.

171. The compound or salt of any one of claims 151 to 169, wherein n is 0.

172. A compound or salt as described in any one of claims 151 to 171, wherein Y is O.

173. A compound or salt as described in any one of claims 151 to 172, wherein R 1 is selected from optionally substituted 5- to 12-membered heterocyclic rings.

174. The compound or salt of claim 173, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

175. The compound or salt of claim 174, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

176. The compound or salt of claim 174 or 175, wherein R 20 Selected from hydrogen and C 1-3 alkyl.

177. A compound or salt as described in claims 151 to 176, wherein R 1 The 5- to 12-membered heterocyclic ring is unsaturated.

178. A compound or salt as described in claims 151 to 176, wherein R 1 The 5- to 12-membered heterocyclic ring is saturated.

179. A compound or salt as described in claims 151 to 176, wherein R 1 The 5- to 12-membered heterocyclic ring is bridged.

180. The compound or salt of claims 151 to 176, wherein R 1 The 5- to 12-membered heterocycle is a spiroheterocycle.

181. The compound or salt of claims 151 to 180, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

182. The compound or salt of claim 181, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

183. The compound or salt of claim 182, wherein R 1 Selected from 184. The compound or salt of claims 151 to 183, wherein R 2 is -L-heterocyclic ring, which is replaced by one or more R 6 Optional substitution.

185. The compound or salt of claim 184, wherein L is selected from C 1 -C 4 Alkylene.

186. The compound or salt of claim 185, wherein L is selected from unsubstituted C 1 -C 4 Alkylene.

187. A compound or salt as described in any one of claims 184 to 186, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

188. The compound or salt of claim 187, wherein R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano and C l -C 3 Aminoalkyl.

189. The compound or salt of claim 188, wherein R 2 R 6 In each occurrence, independently selected from C 1 -C 3 Alkyl and halogen.

190. The compound or salt of claim 189, wherein YR 2 Selected from 191. A compound of formula (I): or a pharmaceutically acceptable salt thereof, in: R 1 Selected from C 3 -C 12 carbocyclic and 5- to 15-membered heterocyclic rings, each of which is independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein the C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each independently substituted with one or more R 1* Optional substitution; Each R 1* are independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3 -C 12 Carbon ring; Y is selected from a bond, O, S and NR 5 ; R 2 Selected from hydrogen, -N(R 21 ) 2 、-LN(R 21 ) 2 、-L-OR 21 , heterocyclic, C l -C 6 alkyl, -L-heterocyclic, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 21 ) 2、 、-L-NHC(=NH)NH 2 、-LC(O)N(R 21 ) 2 , -LC l -C 6 Haloalkyl, -L-OR 21 、-L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O) 2 (R 21 )、-LS(O) 2 N(R 21 ) 2 、-LN(R 21 )C(O)(OR 21 )、-L-OC(O)N(R 21 ) 2 and -LC(=O)OC l -C 6 Alkyl, wherein the heterocyclic ring and -L-NR 5 The aryl portion of the C(O)-aryl and the heterocyclic portion of the -L-heterocyclic and the cycloalkyl portion of the -L-cycloalkyl may be substituted by one or more R 6 optionally substituted, and wherein the aryl or heteroaryl of said -L-aryl and said -L-heteroaryl may be replaced by one or more R 7 Optional substitution; Each L is independently selected from C l -C 4 Alkylene, the C l -C 4 The alkylene group is replaced by one or more selected from hydroxyl, C l -C 4 Hydroxyalkyl, C l -C 4 Alkyl, C 3 -C 6 The substituents of the carbocyclic or 3- to 8-membered heterocyclic ring are optionally substituted, wherein the C 3 -C 6 The carbocyclic ring and the 3 to 8 membered heterocyclic ring are substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 A carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C 3 -C 6 The carbocyclic ring and the 3 to 8 membered heterocyclic ring are substituted by one or more selected from halogen, -OH, -NO 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl group are optionally substituted; Each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings, wherein C 3-12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are each independently substituted by one or more selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-NH(C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; Each R 5 are independently selected from hydrogen or C 1 -C 6 alkyl; Each R 6 are independently selected from halogen, hydroxyl, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, oxo, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano, =CH 2 , =NO-C l -C 3 Alkyl, C l -C 3 Aminoalkyl, -N(R 5 )S(O) 2 (R 5 ), -Q-phenyl, -Q-phenylSO 2 F, -NHC(O)phenyl, -NHC(O)phenylSO 2 F.C 1 -C 3 Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH 2 -、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)C l -C 3 Alkyl-, (C 1 -C 3 alkyl)C(=O), oxo, (C 1 -C 3 Haloalkyl)C(=O)-, -SO 2 F、(C 1 -C 3 Alkoxy)C l -C 3 Alkoxy, -CH 2 OC(O)N(R 5 ) 2 、-CH 2 NHC(O)OC 1 -C 6 Alkyl, -CH 2 NHC(O)N(R 5 ) 2 、-CH 2 NHC(O)C 1 -C 6 Alkyl, -CH 2 (pyrazolyl), -CH 2 NHSO 2 C 1 -C 6 Alkyl, -CH 2 OC(O) heterocycle, -OC(O)N(R 5 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl), -OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 Alkyl)phenyl (C 1 -C 3 alkyl)N(CH 3 ) 2 、-OC(O)NH(C 1 -C 3 alkyl)O(C l -C 3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C 3 Alkyl and -CH 2 Heterocyclic rings, including -NHC(O)phenyl and -OC(O)NH(C 1 -C 3 Alkyl)(C l -C 3 The phenyl group of the alkyl)phenyl group is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein -OC l -C 3 The alkyl group of the alkyl group is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein -CH 2 The heterocyclic ring of the heterocyclyl group is optionally substituted with oxo; Each R 7 are independently selected from halogen, hydroxy, HC(=O)-, C l -C 4 Alkyl, C l -C 4 Alkoxy, C l -C 4 Haloalkyl, C l -C 4 Hydroxyalkyl or -N(R 5 ) 2 ; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, =NH, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted; each Q is independently selected from a bond, S, and O; B is selected from heterocyclic and carbocyclic rings, wherein the heterocyclic and carbocyclic rings are substituted by one or more independently selected from halogen, cyano, hydroxyl, =O, -NO 2 , C l -C 4 Alkyl, C 1-6 Aminoalkyl, -SC l -C 3 Alkyl, C 2 -C 4 Alkenyl, C 2 -C 4 Alkynyl, C 2 -C 4 Hydroxyalkynyl, C 1 -C 3 Cyanoalkyl, triazolyl, C l -C 3 Haloalkyl, -OC l -C 3 Halogenated alkyl, -SC l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, C l -C 3 Hydroxyalkyl, -CH 2 C(=O)N(R 5 ) 2 , -C 3 -C 4 Alkynyl (NR 5 ) 2 、-N(R 5 ) 2 , (C 1 -C 3 Alkoxy)halogenated C l -C 3 Alkyl-, C 1-6 Alkyl-N(R 20 ) 2 , C 3 -C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein C 3 -C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each substituted by one or more selected from halogen, -OH, -NO 2 、-NH 2 , =O, =S, -CN, C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 The substituents of the haloalkyl are optionally substituted, and wherein B forms a spiro ring with ring A; and Ring A is selected from heterocyclic rings and carbocyclic rings, wherein the heterocyclic ring or carbocyclic ring is surrounded by one or more selected from R 4 The substituents are optionally substituted.

192. The compound or salt of claim 191, wherein B is selected from an optionally substituted 5 to 15 membered heterocycle and an optionally substituted C 3 -C 15 Carbon ring.

193. The compound or salt of claim 192, wherein B is selected from an optionally substituted 8 to 15 membered fused heterocyclic ring and an optionally substituted C 8 -C 15 Fused carbocyclic ring.

194. The compound or salt of claim 193, wherein B is an optionally substituted 8- to 15-membered fused heterocyclic ring.

195. The compound or salt of claim 193, wherein B is an optionally substituted unsaturated C 8 -C 15 Fused carbocyclic ring.

196. A compound or salt as described in any one of claims 191 to 195, wherein for B, the optionally substituted 8 to 15 membered fused heterocycle and the optionally substituted C 8 -C 15 The fused carbocyclic rings are each independently bicyclic or tricyclic.

197. The compound or salt of claim 196, wherein for B, the heterocycle and carbocycle are each independently bicyclic.

198. The compound or salt of claim 196, wherein for B, the heterocycle and carbocycle are each independently tricyclic.

199. A compound or salt as described in any one of claims 191 to 198, wherein B is selected from Each of these is optionally substituted with one or more substituents.

200. The compound or salt of claim 199, wherein B is selected from Each of these is optionally substituted with one or more substituents.

201. The compound or salt of claim 200, wherein B is selected from Each of these is optionally substituted with one or more substituents.

202. compounds or salts as described in any one of claims 191 to 201, wherein for B, the one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, -NH 2 , halogen, C 1 -C 3 alkyl.

203. A compound or salt as described in any one of claims 191 to 202, wherein B is selected from 204. A compound or salt as described in any one of claims 191 to 203, wherein each R 4 Independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, oxo, hydroxy, halogen.

205. The compound or salt of claim 204, wherein each R 4 Independently selected from C 1-6 Alkyl, oxo and halogen.

206. The compound or salt of any one of claims 191 to 205, wherein Y is O.

207. A compound or salt as described in any one of claims 191 to 206, wherein R 1 is selected from optionally substituted 5- to 12-membered heterocyclic rings.

208. The compound or salt of claim 207, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 ,=O,-CN,C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

209. The compound or salt of claim 208, wherein R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is substituted by one or more independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

210. The compound or salt of claims 208 to 209, wherein R 20 Selected from hydrogen and C 1-3 alkyl.

211. A compound or salt as described in any one of claims 191 to 210, wherein R 1 The 5- to 12-membered heterocyclic ring is unsaturated.

212. A compound or salt as described in any one of claims 191 to 210, wherein R 1 The 5- to 12-membered heterocyclic ring is saturated.

213. A compound or salt as described in any one of claims 191 to 210, wherein R 1 The 5- to 12-membered heterocyclic ring is bridged.

214. A compound or salt as described in any one of claims 195 to 210, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

215. The compound or salt of claim 214, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -N(R 20 ) 2 、-NO 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 The substituents on the haloalkyl group are optionally substituted.

216. The compound or salt of claim 215, wherein R 1 Selected from 217. A compound or salt as described in any one of claims 191 to 216, wherein R 2 is -L-heterocyclic ring, which is replaced by one or more R 6 Optional substitution.

218. A compound or salt as described in any one of claims 191 to 217, wherein L is selected from C 1 -C 4 Alkylene.

219. The compound or salt of claim 217 or 218, wherein L is selected from unsubstituted C 1 -C 4 Alkylene.

220. A compound or salt as described in any one of claims 181 to 209, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

221. The compound or salt of claim 220, wherein R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano and C l -C 3 Aminoalkyl.

222. The compound or salt of claim 221, wherein R 2 R 6 In each occurrence, independently selected from C 1 -C 3 Alkyl and halogen.

223. The compound or salt of claim 222, wherein YR 2 Selected from 224. A compound of formula (II*): or a pharmaceutically acceptable salt thereof, in: M is selected from O and NR 3 ; R 3 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Cyanoalkyl; R 1 is selected from a 7- to 10-membered heterocyclic ring, wherein the 7- to 10-membered heterocyclic ring is substituted by one or more independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 5 to 12 membered heterocyclic substituents are optionally substituted, wherein the 5 to 12 membered heterocyclic ring is independently substituted with one or more R 1* Optional substitution; Each R 1* are independently selected from halogen, -B(OR 20 ) 2 、-OR 20 、-SR 20 、-S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 ),-NR 20 S(O) 2 R 20 、-C(O)N(R 20 ) 2 、-C(O)NR 20 OR 20 、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 ) 2 、-N(R 20 )C(O)OR 20 、-N(R 20 ) 2 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 ) 2 、-NO 2 , =O, =N(R 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C 3 -C 12 Carbon ring; B is selected from C 6 -C 15 A carbon ring wherein the C 6 -C 15 The carbocyclic ring is replaced by one or more independently selected from halogen, C 1 -C 3 Alkyl, -B(OR 20 ) 2 、-OR 20 、-C(O)N(R 20 ) 2 、-N(R 20 ) 2 , =O, -CN, -NHCN, C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl and C 2-6 The substituents of the alkynyl group are optionally substituted; R 2 is selected from -L-heterocyclic, wherein the heterocyclic ring of the -L-heterocyclic is replaced by one or more R 6 Optional substitution; L is independently selected from C l -C 4 Alkylene, wherein the C l -C 4 The alkylene group is replaced by one or more selected from hydroxyl, C l -C 4 Hydroxyalkyl, C l -C 4 The substituents of the alkyl group are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form C 3 -C 6 Carbon ring; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-6 carbocyclic and 3 to 6 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO 2 、-NH 2 、-N(C 1-6 alkyl) 2 , C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, =NH, C 3-12 Substituents for the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

225. The compound or salt of claim 224, wherein R 1 is selected from optionally substituted 7- to 10-membered spiro heterocyclic ring and optionally substituted 7- to 10-membered fused heterocyclic ring.

226. The compound or salt of claim 224 or 225, wherein R 1 The heterocyclic ring has at least one nitrogen atom.

227. The compound or salt of claim 226, wherein R 1 The at least one nitrogen of the heterocyclic ring is bound to formula (II*).

228. A compound or salt as described in any one of claims 225 to 227, wherein R 1 is selected from an optionally substituted 10-membered spiro heterocycle and an optionally substituted 10-membered fused heterocycle.

229. A compound or salt as described in any one of claims 225 to 228, wherein R 1 The one or more optional substituents are independently selected from halogen, -OH, -S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 )、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)OR 20 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkynyl, 5 to 12 membered heterocyclic ring, wherein the 5 to 12 membered heterocyclic ring is substituted by one or more selected from halogen and C 1-6 The substituents on the alkyl group are optionally substituted.

230. A compound or salt as described in any one of claims 225 to 229, wherein R 1 The one or more optional substituents are independently selected from halogen, -OH, -S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 )、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)OR 20 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 alkyl, a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is replaced by one or more selected from halogen and C 1-6 The substituents on the alkyl group are optionally substituted.

231. A compound or salt as described in any one of claims 225 to 230, wherein R 1 Selected from It is replaced.

232. A compound or salt as described in any one of claims 225 to 231, wherein R 1 Selected from which are independently selected from halogen, -OH, -S(O) 2 (R 20 )、-S(O) 2 N(R 20 ) 2 、-S(O)N(R 20 ) 2 、-S(O)R 20 (=NR 20 )、-C(O)N(R 20 ) 2 、-C(=NR 20 )N(R 20 ) 2 、-C(O)OR 20 、-C(O)NHOR 20 、-N(R 20 ) 2 、-C(O)R 20 、-NO 2 ,=O,-CN,C 1-6 Alkyl-N(R 20 ) 2 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkynyl, 5 to 12 membered heterocyclic ring substituted with one or more selected from halogen and C 1-6 The substituents on the alkyl group are optionally substituted.

233. A compound or salt as described in any one of claims 225 to 231, wherein R 1 Selected from 234. A compound or salt as described in any one of claims 225 to 232, wherein R 1 Selected from 235. The compound or salt of claim 228, wherein R 1 for 236. The compound or salt of claim 224, wherein M is selected from O.

237. The compound or salt of claim 224, wherein M is selected from NCH 3 and NCH 2 CH 3 .

238. The compound or salt of claim 237, wherein M is NMe.

239. A compound or salt as described in any one of claims 224 to 238, wherein R 2 The heterocyclic ring is a saturated heterocyclic ring.

240. The compound or salt of claim 239, wherein R 2 The heterocyclic ring is a saturated heterocyclic ring.

241. The compound or salt of claim 240, wherein R 2 R 6 is independently selected at each occurrence from halogen, 2 , hydroxyl, C l -C 3 Hydroxyalkyl, C l -C 3 Alkyl, C l -C 3 Haloalkyl, C 1 -C 3 Alkoxy, cyano and C l -C 3 Aminoalkyl.

242. The compound or salt of claim 241, wherein R 2 L is selected from C 1 -C 4 Alkylene and 243. A compound or salt as described in any one of claims 224 to 242, wherein R 2 Selected from 244. A compound or salt as described in any one of claims 224 to 243, wherein B is selected from optionally substituted C 9 -C 10 Fused carbocyclic ring.

245. A compound or salt as described in any one of claims 224 to 244, wherein B is selected from Each of which is optionally substituted.

246. compounds or salts as described in any one of claims 224 to 245, wherein B is independently selected from halogen, oxo, -NH 2 , C 1 -C 3 Alkyl, -B(OH) 2 、-OH、-OC l -C 3 Haloalkyl, -C(O)NH 2 、-NH 2 ,=O,-CN,C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6 Substituents on an alkynyl group are optionally substituted.

247. The compound or salt of claim 246, wherein B is optionally substituted with one or more substituents independently selected from halogen.

248. The compound or salt of claim 246, wherein B is selected from 249. The compound or salt of claim 248, wherein B is 250. The compound or salt of claim 248, wherein B is 251. The compound or salt of claim 224, wherein B is unsubstituted.

252. The compound or salt of claim 224, wherein B is substituted.

253. A pharmaceutical composition comprising a compound or salt as described in any one of claims 1 to 252 and a pharmaceutically acceptable excipient.

254. A method of treating a disease or condition using a compound or salt as described in any one of claims 1 to 252 or a pharmaceutical composition as described in claim 253.

255. A method of inhibiting KRas G12D and / or other G12 mutants using a compound or salt as described in any one of claims 1 to 252 or a pharmaceutical composition as described in claim 253.

256. A method of inhibiting KRas G12D and / or other G12 alleles using a compound or salt as described in any one of claims 1 to 252 or a pharmaceutical composition as described in claim 253.

257. A method of inhibiting KRas G12D and / or other alleles using a compound or salt as described in any one of claims 1 to 252 or a pharmaceutical composition as described in claim 253.

258. Use of the compound of any one of claims 1-252 in the preparation of a target protein degradation compound by using chemical modification of the compound of any one of claims 1-253.

259. A bifunctional compound, which consists of a target protein binding portion and an E3 ubiquitin ligase binding portion, wherein the target protein binding portion is derived from the compound of any one of claims 1-252.

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