Pyrimidine-based modulators and uses thereof

Abstract

Provided herein are compounds, such as compounds of Formula (I), Formula (I-A), Formula (I-B), or pharmaceutically acceptable salts of any one thereof, 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 / 345,794, filed on May 25, 2022; U.S. Provisional Patent Application No. 63 / 380,544, filed on October 21, 2022; and U.S. Provisional Patent Application No. 63 / 486,934, filed on February 24, 2023; the entire contents of each of which are incorporated herein by reference. Background Art

[0003] The small GTPase protein Kirsten rat sarcoma type 2 viral oncogene homolog (KRAS) is a member of the Ras family of cell signaling switches that regulates the growth and survival of normal and cancer cells (e.g., see 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 (e.g., see Stephen, AG et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Although Ras has been recognized as a cancer target for approximately 40 years, Ras-driven cancers remain one of the most difficult to treat cancers due to their insensitivity to available targeted therapies. Ras is encoded by three major genes, KRAS, NRAS, and HRAS, and has the highest mutation frequency of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound 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 the activating codon 12 weaken the ability of small GTPases to hydrolyze GTP. This regulatory weakening is crucial for initiating and maintaining tumor progression.

[0004] Despite extensive efforts, no small molecules have been identified that block effector binding or restore GTPase-activating protein (GAP) sensitivity, although some small molecules are TESs that activate Ras at the plasma membrane. The KRAS G12C mutation, most commonly found in lung adenocarcinoma, has been clinically shown to be more amenable to direct inhibition by covalent modification with small molecule inhibitors, trapping the protein in an inactive GDP-bound state. The KRAS G12D mutation results in a significantly slower intrinsic GTP hydrolysis rate than G12C, leading to more constitutive activation. Therefore, despite the presence of a similar binding pocket in the GDP state, pharmacological targeting of the inactive state is unlikely to achieve similar results for G12D. Furthermore, the presence of a cysteine ​​at the site of the activating mutation itself creates covalent chemistry, while aspartic acid does not offer typical medicinal chemistry approaches for selective covalent modification.

[0005] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a weakness for selective inhibition of cancer cells while preserving normal Ras function, it is attractive for small molecule inhibitors to selectively bind to the GTP state and stabilize a conformation that is unable to interact with oncogenic signaling of effector proteins. In addition, it has been shown that only constitutive activation of Raf, MEK, and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferation signaling (see, for example, 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 effects of Ras in cancer, selective inhibition of KRAS mutants in this pathway is considered a key functional manifestation of the potential clinical benefit of new therapeutic approaches. Therefore, there is a need to develop new inhibitors of KRAS-driven cancers that exhibit inhibition of MAPK signaling via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state.

[0006] Incorporation by reference

[0007] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Summary of the Invention

[0008] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein:

[0011] B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 carbocyclic ring, wherein the 7 to 15 membered heterocyclic ring and C7-C 15 Each of the carbocyclic rings is independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted;

[0012] R 1 is selected from hydrogen and a 5- to 15-membered heterocyclic ring, wherein the 5- to 15-membered heterocyclic ring is replaced by one or more independently selected from halogen, -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 1-6 Alkyl (=NOR 20 )、-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, C 1-6 Alkyl-SO2R 20 、C 1-6 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein the C3-C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each independently substituted by one or more R 1* Optional substitution;

[0013] Each R 1* are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C3-C 12 carbon ring;

[0014] Y is selected from a bond, -O-, -S- and -N(R 5 )-;

[0015] R 2 Selected from heterocyclic, aryl, C l -C6 alkyl, -L-heterocycle, -LN(R 23 )2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 )2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23S(O)2(R 23 )、-LS(O)2N(R 23 )2、-LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of the -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are each replaced by one or more R 6 optionally substituted, and wherein the aryl, -L-NR 23 The aryl portion of the C(O)-aryl, the -L-NR 23 The aryl portion of the C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of the -L-heteroaryl are each substituted by one or more R 7 Optional substitution;

[0016] R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0017] Each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 alkyl halide;

[0018] n is selected from 0, 1, 2, 3 and 4;

[0019] Each R 5 Independently selected from hydrogen and C1-C6 alkyl;

[0020] Each R 6 Independently selected from halogen, hydroxy, 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, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、tert-butyldimethylsilyloxy CH2-、-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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 and -CH2 heterocycle, wherein -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l -C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein the -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of the -CH2 heterocyclyl is optionally substituted with oxo;

[0021] each Q is selected from a bond, S, and O;

[0022] Each R 7 independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2 and -N(R 5 )2;

[0023] Each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is independently selected from one or more halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic and 3 to 8 membered heterocyclic substituents are optionally substituted, wherein said C3-C6 carbocyclic and 3 to 8 membered heterocyclic substituents are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3 to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3 to 8-membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted;

[0024] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0025] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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

[0026] Each R 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NO2, -NH2, -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.

[0027] In one aspect, the present disclosure provides a compound of formula (IA)

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein:

[0030] R 1 is selected from 8 to 10 membered heterocyclic rings, wherein the 8 to 10 membered heterocyclic rings are substituted by one or more independently selected from halogen, -OR 20 、-S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 ,=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 Halogenated alkyl, C 1-6 Alkyl-SO2R 20 、C 1-6 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 Alkynyl and 5- to 12-membered heterocyclic substituents are optionally substituted, wherein the 5- to 12-membered heterocyclic rings are each independently substituted with one or more R 1* Optional substitution;

[0031] Each R 1* are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C3-C 12 carbon ring;

[0032] B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 carbocyclic ring, wherein the 7 to 15 membered heterocyclic ring and C7-C 15 Each of the carbocyclic rings is independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21)C(O)OR 21 、-C(O)R 21 、C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted;

[0033] Y is selected from a bond and -O-;

[0034] R 2 Selected from heterocyclic, aryl, C l -C6 alkyl, -L-heterocycle, -LN(R 23 )2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 )2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2、-LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of the -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are each replaced by one or more R 6 optionally substituted, and wherein the aryl, -L-NR 23 The aryl portion of the C(O)-aryl, the -L-NR 23 The aryl portion of the C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of the -L-heteroaryl are each substituted by one or more R 7 Optional substitution;

[0035] R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0036] Each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 alkyl halide;

[0037] n is selected from 0, 1, 2, 3 and 4;

[0038] Each R5 Independently selected from hydrogen and C1-C6 alkyl;

[0039] Each R 6 Independently selected from halogen, hydroxy, 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, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、tert-butyldimethylsilyloxy CH2-、-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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 20and -CH2 heterocycle, wherein -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l -C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein the -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of the -CH2 heterocyclyl is optionally substituted with oxo;

[0040] each Q is selected from a bond, S, and O;

[0041] Each R 7 independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2 and -N(R 5 )2;

[0042] Each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is independently selected from one or more halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic and 3 to 8 membered heterocyclic substituents are optionally substituted, wherein said C3-C6 carbocyclic and 3 to 8 membered heterocyclic substituents are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3 to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3 to 8-membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted;

[0043] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0044] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0045] Each R 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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.

[0046] In certain embodiments, Formula (IA) is represented by Formula (IB),

[0047]

[0048] or a pharmaceutically acceptable salt thereof, wherein:

[0049] where R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 , =O and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is each independently substituted with one or more R 1* Optional substitution;

[0050] Each R 1* independently selected from halogen, -OR 20 、-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 and C 1-6 alkyl;

[0051] Y is -O-;

[0052] R 2 Selected from -L-heterocycle and -LN(R 23 ) 2, wherein the heterocyclic portion of the -L-heterocycle is replaced by one or more R 6 Optional substitution.

[0053] B is selected from a 7- to 15-membered heterocyclic ring, wherein the 7- to 15-membered heterocyclic ring is substituted by one or more independently selected from halogen, -CN, =O, -N(R 21 )2、-OR 21 、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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkynyl group are optionally substituted;

[0054] R 3 Selected from hydrogen, halogen, -CN, -N(R 20 )2、-OR 20、-C(O)R 20 、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 and C 1-6 alkyl; and

[0055] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl and C 3-12 Carbocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 The alkyl and oxo substituents are optionally substituted.

[0056] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (IA) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (IB) and a pharmaceutically acceptable excipient.

[0057] In certain embodiments, the present disclosure provides a method for treating a disease or condition using a compound or salt of formula (I). In certain embodiments, the present disclosure provides a method for treating a disease or condition using a compound or salt of formula (I) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a method for treating a disease or condition using a pharmaceutical composition comprising a compound or salt of formula (I).

[0058] In certain embodiments, the present disclosure provides a method of treating a disease or condition using a compound or salt of formula (IA). In certain embodiments, the present disclosure provides a method of treating a disease or condition using a compound or salt of formula (IA) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a method of treating a disease or condition using a pharmaceutical composition comprising a compound or salt of formula (IA).

[0059] In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is performed using a compound or salt of formula (I). In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is performed using a compound or salt of formula (I) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants, which is performed using a pharmaceutical composition comprising a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0060] In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of formula (IA). In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of formula (IA) and a pharmaceutically acceptable excipient. In certain embodiments, the present disclosure provides a method for inhibiting KRas G12D and / or other G12 mutants using a pharmaceutical composition comprising a compound or salt of formula (IA) and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION

[0061] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used to implement the present invention. The following claims are intended to define the scope of the invention and thus cover methods and structures within the scope of these claims and their equivalents.

[0062] definition

[0063] Unless defined otherwise, 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 belongs. All patents and publications cited herein are incorporated by reference.

[0064] As used in the specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0065] The term "C x-y " when used in conjunction with a chemical moiety such as an alkyl, alkenyl, or alkynyl group, is intended to include groups containing x to y carbons in the chain. For example, the term "C 1-6 "Alkyl" refers to a saturated hydrocarbon group, including straight-chain and branched-chain alkyl groups containing 1 to 6 carbon atoms. For example, -C1-6 Alkyl- may be selected from methyl, ethyl, propyl, butyl, pentyl and hexyl, any of which are optionally substituted. x-y Alkylene- refers to a substituted or unsubstituted alkylene chain containing x to y carbons in the alkylene chain. For example, –C 1-6 Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any of which are optionally substituted.

[0066] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C 15 In certain embodiments, the alkyl group contains from one to thirteen carbon atoms (i.e., C1-C 13 In certain 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-C 15 In some embodiments, the alkyl group is selected from the group consisting of 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), 1-pentyl (n-pentyl). The alkyl group is attached to the rest of the molecule by a single bond.

[0067] As used herein, "alkenyl" refers to a straight or branched chain hydrocarbon group consisting solely 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 12In 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, for example, ethenyl (vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, pent-1,4-dienyl, and the like.

[0068] As used herein, "alkynyl" refers to a straight or branched chain hydrocarbon group consisting solely 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 In some embodiments, the alkynyl group comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, the alkynyl group comprises two to six carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, the alkynyl group comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl group is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0069] As used herein, the term "C x-y Alkenyl" and "C x-y "Alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to the alkyl groups described above, but containing at least one double or triple bond, respectively. The term -C x-y Alkenylene- refers to a substituted or unsubstituted alkenylene chain containing x to y carbons in the alkenylene chain. For example, –C 2-6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any of which are optionally substituted. The alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. Term—C x-y Alkyne- refers to a substituted or unsubstituted alkynylene chain containing from x to y carbon atoms in the chain. For example, –C 2-6 Alkenylene- can be selected from ethynylene, propynylene, butynylene, pentynylene and hexynylene, any of which are optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0070] "Alkylene" refers to a straight divalent hydrocarbon chain having one to twelve carbon atoms, such as methylene, ethylene, propylene, n-butylene, etc., which is connected to the rest of the molecule by a single bond and to the group by a single bond. The attachment point of the alkylene chain to the rest of the molecule and to the group are respectively through the terminal carbon. In other embodiments, the alkylene group comprises one to five carbon atoms (i.e., C1-C5 alkylene). In other embodiments, the alkylene group comprises one to four carbon atoms (i.e., C1-C4 alkylene). In other embodiments, the alkylene group comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, the alkylene group comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, the alkylene group comprises one carbon atom (i.e., C1 alkylene). In other embodiments, the alkylene group comprises five to eight carbon atoms (i.e., C5-C8 alkylene). In other embodiments, the alkylene group comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, the alkylene group comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless otherwise specifically stated in the specification, the alkylene chain is optionally substituted with one or more substituents, such as those described herein.

[0071] "Alkenylene" refers to a straight divalent hydrocarbon chain having two to twelve carbon atoms and connected to the rest of the molecule, consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond. The alkenylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. The attachment point of the alkenylene chain to the rest of the molecule and to the group are respectively through terminal carbon. In other embodiments, the alkenylene comprises two to five carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, the alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, the alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, the alkenylene comprises two carbon atoms (i.e., C2 alkenylene). In other embodiments, the alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, the alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted with one or more substituents such as those described herein.

[0072] "Alkynylidene" refers to a straight divalent hydrocarbon chain having two to twelve carbon atoms and connected to the rest of the molecule, consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond. The alkynylene chain is attached to the rest of the molecule by a single bond and to the group by a single bond. The attachment point of the alkynylene chain to the rest of the molecule and to the group are respectively through the terminal carbon. In other embodiments, the alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, the alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, the alkynylene comprises two to three carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, the alkynylene comprises two carbon atoms (i.e., C2 alkynylene). In other embodiments, the alkynylene comprises five to eight carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, the alkynylene comprises three to five carbon atoms (i.e., C3-C5 alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted with one or more substituents such as those described herein.

[0073]

[0046] "Halo" or "halogen" as used herein refers to halogen substituents such as bromo, chloro, fluoro, and iodo substituents.

[0074] As used herein, "haloalkyl" 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, and the like. Examples of halogen-substituted alkanes ("haloalkanes") include halogenated methane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), dihalogenated methane and trihalogenated methane (e.g., chloroform, bromomethane, trifluoromethane, iodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, and any other suitable combination of an alkane (or substituted alkane) and a halogen. When an alkyl group is substituted with more than one halogen group, each halogen can be independently selected, such as 1-chloro, 2-bromoethane.

[0075] "Alkoxy" refers to a group of the formula -O-alkyl bonded through an oxygen atom, wherein alkyl is an alkyl chain as defined above.

[0076] "Fluoroalkyl" refers to an alkyl group as defined above substituted with one or more fluoro groups, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0077] "Aminoalkyl" refers to an alkyl group as defined above substituted with one or more amine groups, for example, propan-2-amine, butane-1,2-diamine, pentan-1,2,4-triamine, and the like.

[0078] "Hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxy groups, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0079] "Alkoxyalkyl" refers to an alkyl group as defined above substituted with one or more alkoxy groups, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0080] As used herein, "cyanoalkyl" refers to an alkyl group as defined above substituted with one or more cyano groups, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0081] As used herein, the term "carbocycle" refers to a saturated, unsaturated, or aromatic ring, wherein each atom of the ring is a carbon atom. Carbocycles 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 carbocycle can be selected from a saturated, unsaturated, and aromatic ring. In an exemplary embodiment, an aromatic ring, such as a phenyl group, can be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Where valence permits, bicyclic carbocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings. Bicyclic carbocycles include any combination of ring sizes, such as a 4-5 fused ring system, a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, a 5-7 fused ring system, a 6-7 fused ring system, a 5-8 fused ring system, and a 6-8 fused ring system. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The bicyclic carbocycle can be a fused ring system, a bridged ring system, or a spiro ring system. In some cases, the spirocyclic carbocycle has at least two molecular rings with only one common atom.

[0082] As used herein, "aryl" refers to a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing hydrogen atoms from ring carbon atoms. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon and five to eighteen carbon atoms, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. Ring systems from which aryl groups are derived include, but are not limited to, radicals such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0083] The term "unsaturated carbocycle" refers to a carbocycle having at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0084] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including fused or bridged ring systems, and preferably having three to twelve carbon atoms. In certain embodiments, the cycloalkyl group comprises three to ten carbon atoms. In other embodiments, the cycloalkyl group comprises 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.

[0085] The term "C x-y "Carbocycle" is intended to include groups containing x to y carbon atoms in the ring. For example, the term "C 3-6 "Carbocycle" refers to a saturated, unsaturated, or aromatic ring containing 3 to 6 carbon atoms. For example, -C 3-6 Carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl, any of which are optionally substituted.

[0086] The term "carbocyclylene" refers to a divalent ring that is connected to the rest of the molecule and is composed only of carbon and hydrogen atoms. Carbocyclylene is attached to the rest of the molecule by a single bond and is attached to the group by a single bond. The attachment point of the carbocyclylene to the rest of the molecule and the attachment point to the group are respectively through any two carbon atoms. Carbocyclylene includes arylene and cycloalkylene. Therefore, this term distinguishes carbocyclylene from heterocyclylene, in which the divalent ring includes at least one atom that is different from a carbon atom. Heterocyclylene is attached to the rest of the molecule by a single bond and is attached to the group by a single bond. Where valence permits, the attachment point of the heterocyclylene to the rest of the molecule and the attachment point to the group are respectively through any two atoms. Heterocyclylene includes heteroarylene and heterocycloalkylene. Carbocyclylene and heterocyclylene can each be optionally substituted by one or more substituents (such as, those substituents described herein).

[0087] As used herein, the term "heterocycle" refers to a saturated ring, an unsaturated ring or an aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B and S atoms. Where valence permits, the heterocycle can be attached to the remainder of the molecule by any atom of the heterocycle (such as the carbon or nitrogen atom of the heterocycle). The heterocycle includes 3 to 10 yuan of monocycles, 6 to 12 yuan of bicyclics and 6 to 12 yuan of bridged rings. Where valence permits, the bicyclic heterocycle includes any combination of saturated bicyclics, unsaturated bicyclics and aromatic bicyclics. In an exemplary embodiment, the aromatic ring (e.g., pyridyl) can 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 spiro ring systems. Spiro ring systems can be referred to as "spiroheterocycles, spiroheterocycles, or spiro-heterocycles." In some cases, spiroheterocycles have at least two molecular rings with only one common atom. Spiroheterocycles include one or more heteroatoms.

[0088] "Heteroaryl" or "aromatic heterocycle" refers to a group derived from a heteroaromatic ring group containing one to eleven carbon atoms and at least one heteroatom, wherein each heteroatom can be selected from N, O and S. As used herein, the heteroaryl ring can be selected from a monocyclic or bicyclic and fused or bridged ring system, wherein at least one ring in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2)π-electron system according to the Hückel theory. The heteroatoms in the heteroaryl group can be optionally oxidized. One or more nitrogen atoms (if present) are optionally quaternized. Where valence permits, the heteroaryl group can be attached to the rest of the molecule through any atom of the heteroaryl group (such as, a carbon or nitrogen atom of the heteroaryl group). Examples of heteroaryl groups include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thiophene, benzothiazole and imidazopyridine.

[0089] "X-membered heteroaryl" refers to the number of internal ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 internal ring atoms, for example, triazole, oxazole, thiophene, and the like.

[0090] The term "unsaturated heterocycle" refers to a heterocycle having at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrroles, dihydrofurans, oxazolines, pyrazoline, and dihydropyridines. The heterocycle can be optionally substituted by one or more substituents, such as those described herein.

[0091] "Substituted" refers to a moiety having a substituent that replaces a hydrogen or substitutable heteroatom (e.g., NH or NH2 of a compound) on one or more carbons. It should be understood that "substituted" or "substituted by..." includes implicit prerequisites, i.e., such substitutions conform to the allowed valences 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, elimination, etc. In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, such as replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, it is envisioned that the term "substituted" includes all allowed substituents of an organic compound. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. For appropriate organic compounds, allowed substituents can be one or more and are the same or different.

[0092] As used herein, the term "optional" or "optionally" means that the subsequently described event may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl group may be substituted or unsubstituted, and that the description includes both substituted aryl groups and aryl groups without substitution.

[0093] As used herein, the term "electrophile" or "electrophile moiety" is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge, and / or an excess of electrons, such as an -SH group). Electrophiles typically lack electrons or comprise atoms lacking electrons. In certain embodiments, the electrophile contains a positive charge or a partial positive charge, has a resonance structure containing a positive charge or a partial positive charge, or is a moiety where the delocalization or polarization of electrons results in one or more atoms containing a positive charge or a partial positive charge. In some embodiments, the electrophile comprises a conjugated double bond, for example, an α, β-unsaturated carbonyl or an α, β-unsaturated thiocarbonyl compound.

[0094] In some embodiments, the substituents may include any of the substituents described herein, for example, halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=NH), oximo (=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 (wherein t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl, any of which can be replaced by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=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(Ra )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 (wherein t is 1 or 2) optionally substituted; wherein each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein 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 (wherein t is 1 or 2) is optionally substituted; and wherein each R b are independently selected from a direct bond or a straight or branched alkylene, alkenylene or alkynylene chain, and each R c It will be understood by those skilled in the art that substituents may themselves be substituted where appropriate.

[0095] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0096] As used herein, the phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious 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 carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (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 starch, and maltose. oil 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.

[0097] The terms "subject," "individual," and "patient" are used interchangeably to refer to humans and non-human mammals (e.g., non-human primates, canines, equines, felines, porcine, bovines, ungulates, lagomorphs, etc.). In various embodiments, a subject can be a person (e.g., an adult male, an adult female, an adolescent male, an adolescent female, a male child, a female child) who is under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical setting. In certain embodiments, a subject may not be under the care or prescription of a physician or other health worker.

[0098] As used herein, the phrase "a subject in need thereof" refers to a subject, as described below, who has, or is at risk for, a pathology to be treated prophylactically or therapeutically with a compound or salt described herein.

[0099] The term "administering" is defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, oral, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal administration. In certain embodiments, the composition can be administered using an oral route. The term "administering" a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof.

[0100] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or salt as described herein that is sufficient to affect the intended application (including but not limited to disease treatment), as defined below. The therapeutically effective amount can vary depending on the intended application (in vitro or in vivo) or the subject and the disease condition being treated, such as the weight and age of the subject, the severity of the disease condition, the mode of administration, etc., which can be readily determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a specific response in the target cell, such as reducing the proliferation of the target protein or downregulating its activity. The specific dosage can vary depending on the specific compound selected, the dosing regimen to be followed, whether it is administered in combination with other compounds, the time of administration, the tissue to which it is administered, and the physical delivery system that carries it.

[0101] As used herein, "treatment" or "treatment" refers to a method of obtaining a beneficial or desired result with respect to a disease, disorder or medical condition, including but not limited to therapeutic benefit and / or preventive benefit. In certain embodiments, treatment or treatment comprises administering a compound or composition disclosed herein to a subject. Therapeutic benefit may include eradicating or improving the underlying disorder being treated. In addition, therapeutic benefit may be achieved by eradicating or improving one or more physiological symptoms associated with the underlying disorder, such as observing improvement in the subject, although the subject may still be troubled by the underlying disorder. In certain embodiments, for preventive benefit, a composition is administered to a patient at risk of developing a particular disease or to a patient reporting one or more physiological symptoms of a disease (even if a diagnosis of the disease may not yet have been made). Treatment may include, for example, reducing, delaying or alleviating the severity of one or more symptoms of a disease or condition, or it may include reducing the frequency with which a patient experiences symptoms such as a disease, defect, disorder or adverse condition. Treatment may be used herein to refer to a method that results in some degree of treatment or improvement of a disease or condition, and a range of results for this purpose may be considered, including but not limited to preventing the condition altogether.

[0102] In certain embodiments, the term "prevent" or "prevent" in relation to a disease or condition may refer to a compound that reduces the incidence of the disease or condition in a treated sample relative to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disease or condition relative to an untreated control sample.

[0103] As used herein, the term "therapeutic effect" encompasses therapeutic benefits and / or prophylactic benefits as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, stopping, or reversing the progression of a disease or condition, or any combination thereof.

[0104] As used herein, "sum frequency generation" (SFG) is a nonlinear optical technique in which light of one frequency (Ω1) is mixed with light of another frequency (Ω2) to produce a sum frequency (Ω1 + Ω2) reaction (Shen, 1984, 1989). For example, SFG is particularly useful for detecting molecules at surfaces through their characteristic vibrational transitions, and in this case, it is essentially a surface-selective infrared spectroscopy with Ω1 and Ω2 at visible and infrared frequencies. When the term "SHG" or "second harmonic generation" is used herein, it is understood that SFG and "sum frequency generation" can be substituted and used in place of SHG using methods well known to those skilled in the art.

[0105] As used herein, "second harmonic-active moiety" or "second harmonic-active moiety" refers to a nonlinearly active moiety, particle, or molecule that can be attached (covalently or non-covalently) to a molecule (e.g., a protein such as an enzyme), particle, or phase (e.g., a lipid bilayer) in order to render it more nonlinearly optically active.

[0106] As used herein, a "non-linear active moiety" is a substance that has a hyperpolarizability.

[0107] As used herein, "hyperpolarisability" or "nonlinear susceptibility" refers to a property of a molecule, particle, interface, or phase that allows for the generation of nonlinear light. The terms "hyperpolarisability," "second-order nonlinear susceptibility," and "nonlinear susceptibility" are sometimes used interchangeably.

[0108] As used herein, "allosteric," "allosteric modulator," or "allosteric candidate" refers to a molecule, moiety, or substance that binds primarily to a site other than the active site and causes a conformational change that can be determined by SHG or SFG, thereby exerting its effect via an allosteric mechanism of action.

[0109] The terms "inhibit," "selective inhibition," or "selectively inhibit" when referring to a biologically active agent refer to the ability of the agent to preferentially reduce target signaling activity as compared to off-target signaling activity, either directly or through interaction with the target.

[0110] As used herein, the term "targeted agent" or "targeted therapy" refers to therapy that uses specific drugs to target specific genes, proteins, or active sites involved in the development, survival, and proliferation of cancer cells.

[0111] It is intended that every maximum numerical limitation given throughout this specification include every lower numerical limitation, as if such lower numerical limitations were expressly written herein. It is intended that every minimum numerical limitation given throughout this specification include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. It is intended that every numerical range given throughout this specification include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0112] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0113] Compound

[0114] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):

[0115]

[0116] or a pharmaceutically acceptable salt thereof, wherein:

[0117] B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 Carbocyclic rings, including 7 to 15-membered heterocyclic rings and C7-C 15 Each of the carbocyclic rings is independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted;

[0118] R 1 is selected from hydrogen and a 5- to 15-membered heterocyclic ring, wherein the 5- to 15-membered heterocyclic ring is replaced by one or more independently selected from halogen, -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 1-6 Alkyl (=NOR 20 )、-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, C 1-6Alkyl-SO2R 20 、C 1-6 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein C3-C 12 The carbocyclic ring and the 5- to 12-membered heterocyclic ring are each independently substituted by one or more R 1* Optional substitution;

[0119] Each R 1* are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C3-C 12 carbon ring;

[0120] Y is selected from a bond, -O-, -S- and -N(R 5 )-;

[0121] R 2 Selected from heterocyclic, C l -C6 alkyl, -L-heterocycle, -LN(R 23 )2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 )2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2、-LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle and the cycloalkyl portion of -L-cycloalkyl are each replaced by one or more R 6 optionally substituted, and wherein -L-NR 23 The aryl portion of C(O)-aryl, -L-NR 23 The aryl portion of C(O)-aryl, the aryl of -L-aryl, and the heteroaryl of -L-heteroaryl are each replaced by one or more R 7 Optional substitution;

[0122] R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20)C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0123] Each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 alkyl halide;

[0124] n is selected from 0, 1, 2, 3 and 4;

[0125] Each R 5 Independently selected from hydrogen and C1-C6 alkyl;

[0126] Each R 6 Independently selected from halogen, hydroxy, 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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 and -CH2 heterocycle, wherein -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l -C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2 heterocyclyl is optionally substituted with oxo;

[0127] each Q is selected from a bond, S, and O;

[0128] Each R 7 independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl and -N(R 5 )2;

[0129] Each L is independently selected from C l -C4 alkylene, the C l-C4 alkylene is independently selected from one or more halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are optionally substituted, wherein the C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted;

[0130] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0131] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC1-10 Alkyl, oxo, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted;

[0132] Each R 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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.

[0133] In some embodiments, for the compound or salt of Formula (I), B is selected from an optionally substituted 7- to 15-membered fused heterocycle and an optionally substituted C7-C 15 In some cases, and optionally substituted C7-C 15 In some cases, B is an optionally substituted 7- to 15-membered fused heterocyclic ring. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocyclic ring. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl ring. In some cases, B is selected from an optionally substituted 7- to 15-membered fused heteroaryl ring and an optionally substituted C7-C 15 In some cases, B is an optionally substituted unsaturated C7-C 15 In some cases, B is an optionally substituted 7- to 15-membered fused heterocyclic ring, wherein the fused heterocyclic ring is partially unsaturated. In some cases, B is an optionally substituted 7- to 15-membered fused heterocyclic ring, wherein the fused heterocyclic ring is partially saturated.

[0134] In some embodiments, for the compound or salt of Formula (I), B is selected from an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 In some cases, and optionally substituted C8-C 15 In some cases, B is an optionally substituted 8- to 15-membered fused heterocyclic ring. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocyclic ring. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl ring. In some cases, B is selected from an optionally substituted 8- to 15-membered fused heteroaryl ring and an optionally substituted C8-C 15 In some cases, B is an optionally substituted unsaturated C8-C 15In some cases, B is an optionally substituted 8- to 15-membered fused heterocyclic ring, wherein the fused heterocyclic ring is partially unsaturated. In some cases, B is an optionally substituted 8- to 15-membered fused heterocyclic ring, wherein the fused heterocyclic ring is partially saturated.

[0135] In some embodiments, for compounds of formula (I) or salts, B is selected from optionally substituted 8 to 15 membered fused heterocycles, wherein the fused heterocycles are formed by combining three rings (e.g., tricyclic). In some cases, B is selected from optionally substituted 8 to 15 membered fused heterocycles, wherein the fused heterocycles are formed by combining two rings (e.g., bicyclic). In some cases, for B, optionally substituted 8 to 15 membered fused heterocycles and optionally substituted C8-C 15 Each fused carbocyclic ring is independently bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic ring is bicyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic ring is tricyclic.

[0136] In some embodiments, for compounds or salts of Formula (I), the heterocyclic or carbocyclic ring of B is bicyclic. In some cases, the heterocyclic or carbocyclic ring of B is tricyclic. In some cases, tricyclic heterocycles contain three rings of atoms connected to each other.

[0137] In some embodiments, for compounds or salts of formula (I), for B, heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, heterocycle and carbocycle are each independently tricyclic. In some cases, for B, heterocycle and carbocycle are each independently bicyclic.

[0138] In some embodiments, for the compound or salt of formula (I), for B, the optionally substituted 8- to 15-membered fused heterocyclic ring and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from Each of which is optionally substituted by one or more substituents. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from Each of which is optionally substituted with one or more substituents. In some cases, B is selected from Each of which is optionally substituted with one or more substituents. In some cases, B is selected from Each of which is optionally substituted with one or more substituents. In some cases, B is selected from Each of which is optionally substituted with one or more substituents.

[0139] In some embodiments, for compounds or salts of Formula (I), B is selected from Each of which is optionally substituted with one or more substituents. In some cases, B is selected from Each of which is optionally substituted with one or more substituents.

[0140] In some embodiments, for compounds or salts of formula (I), for B, the optional substituents of the heterocyclic and carbocyclic rings are each independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 In some cases, the optional substituents of the heterocycle and the carbocycle are each independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2, -OH, -SR 21 、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 In some cases, for B, one or more optional substituents of heterocycle and carbocycle are independently selected at each occurrence from halogen, 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 In some cases, the optional substituents of the heterocyclic and carbocyclic rings are each independently selected from halogen, -CN, =O, -NH2, -N(C 1-6alkyl)HN(C 1-6 Alkyl)2, -OH, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 In some cases, one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3 alkyl. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from In some cases, B is selected from In some cases, B is selected from

[0141]

[0142] In some cases, B is selected from

[0143] In some embodiments, for the compound or salt of Formula (I), B is selected from an optionally substituted 7- to 12-membered fused heterocyclic ring and an optionally substituted C 9-10 In some cases, the heterocyclic ring of B has at least one sulfur atom. In some cases, the heterocyclic ring of B has one or more sulfur atoms. In some cases, the heterocyclic ring of B has at least one nitrogen atom. In some cases, B is selected from Each of which is optionally substituted. In some cases, one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 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 Halogenated alkyl, C 2-6 Alkenyl and C 2-6In some cases, one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =O, and -CN. In some cases, B is selected from

[0144] In some embodiments, for compounds or salts of formula (I), B is selected from an optionally substituted 8- to 10-membered fused heterocyclic ring having at least one sulfur atom. In some cases, B is selected from Each of which is optionally substituted. In some cases, one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -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 Halogenated alkyl, C 2-6 Alkenyl and C 2-6 In some cases, the one or more optional substituents of B are independently selected from halogen, C1-C3 alkyl, -NH2 and -CN at each occurrence. In some cases, B is substituted. In some cases, B is substituted with at least one -NH2.

[0145] In some cases, B is selected from In some cases, B is substituted with at least one -NH2 or at least one -CN.

[0146] In some cases, B is selected from

[0147] In some embodiments, for compounds or salts of formula (I), B is an optionally substituted 7- to 11-membered fused heterocyclic ring. In some cases, B is an optionally substituted 8- to 10-membered fused heterocyclic ring. In some cases, B is an optionally substituted 7-membered fused heterocyclic ring. In some cases, B is an optionally substituted 8-membered fused heterocyclic ring. In some cases, B is an optionally substituted 9-membered fused heterocyclic ring. In some cases, B is an optionally substituted 10-membered fused heterocyclic ring. In some cases, B's heterocyclic ring is an unsaturated heterocyclic ring. In some cases, B's heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, B has at least one sulfur atom. In some cases, B has at least two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 heteroatom. In some cases, B has at least 2 heteroatoms. In some cases, B is selected from Each of which is optionally substituted. In some cases, B is selected from Each of which is optionally substituted. In some cases, B is selected from Each of which is optionally substituted. In some cases, one or more optional substituents of B are independently selected at each occurrence from halogen, 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 In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is selected from

[0148] In some embodiments, for compounds or salts of Formula (I), R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 20 )2、-OR 20 、-SR 20 、-S(O)2(R20 )、-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 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 In some cases, R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 20 )2、-OR 20 、-SR 20 、-C(O)N(R 20 )2、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 In some cases, R 3 Selected from hydrogen, halogen, -CN, -NO2, -NH2, -N(C 1-6 alkyl)HN(C 1-6 Alkyl)2, -OH, -C(O)N(R 20 )2、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、C 1-6 aminoalkyl, C1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 In some cases, R 3 Selected from hydrogen, -CN, -C(O)R 20 、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, R 3 Selected from hydrogen, -CN, -C(O)R 20 、C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 3 Selected from hydrogen, -CN, -C(O)H, C1 hydroxyalkyl and C 1-6 In some cases, R 3 is selected from hydrogen, fluorine and -CN. In some cases, R 3 is selected from fluorine. In some cases, R 3 is selected from hydrogen. In some cases, R 3 Selected from -CN.

[0149] In some embodiments, for compounds or salts of Formula (I), Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R 5 )-.

[0150] In some embodiments, for compounds or salts of formula (I), L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, L is selected from unsubstituted C1 alkylene. In some cases, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6The substituents of haloalkyl are optionally substituted. In some cases, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3 to 8 membered heterocycle. In some cases, two substituents on the same carbon atom of L together form a C3-C6 carbocycle. In some embodiments, for compounds of formula (I) or salts, L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, each L is independently selected from optionally substituted C l -C4 alkylene; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3 to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3 to 8-membered heterocyclic ring are each substituted by one or more substituents 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 are optionally substituted. In some cases, the optional substituents of L are selected from C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocycle; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3 to 8-membered heterocycle, wherein the C3-C6 carbocycle and the 3 to 8-membered heterocycle are substituted by one or more halogens and C 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, L is selected from In some cases, L is selected from In some cases, each L is independently selected from substituted C l -C4 alkylene, and wherein the two substituents on the same carbon atom of L together form a C3-C6 carbocyclic 3 to 5 membered heterocyclic ring. In some cases, each L is independently selected from substituted C 2-3 alkylene, and wherein the two substituents on the same carbon atom of L together form a C3 carbocycle or a 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each L is independently selected from In some cases, each L is independently selected from In some cases, each L is independently selected from In some cases, each L is independently selected from C l -C4 alkylene, which is substituted by one or more independently selected from halogen and C l -C4 alkyl is optionally substituted. In some cases, L is selected from

[0151] In some embodiments, for compounds or salts of Formula (I), each L is independently selected from unsubstituted Cl -C4 alkylene. In some cases, L is selected from In some cases, L is selected from

[0152] In some embodiments, for compounds or salts of Formula (I), R 2 Selected from heterocyclic, C l -C6 alkyl, -L-heterocycle, -LN(R 23 )2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 23 )2, -L-NHC(=NH)NH2, -LC(O)N(R 23 )2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2、-LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle and the cycloalkyl portion of -L-cycloalkyl are each replaced by one or more R 6 optionally substituted, and wherein -L-NR 23 The aryl portion of C(O)-aryl, -L-NR 23 The aryl portion of C(O)-aryl, the aryl of -L-aryl, and the heteroaryl of -L-heteroaryl are each replaced by one or more R 7 Optional substitution.

[0153] In some embodiments, for compounds or salts of Formula (I), R 2 is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl and -LN(R 23 ) 2, wherein the heterocyclic ring and the heterocyclic ring of -L-heterocyclic ring are each replaced by one or more R 6 optionally substituted, and wherein the aryl of -L-aryl and the heteroaryl of -L-heteroaryl are each replaced by one or more R 7 Optional substitution.

[0154] In some embodiments, for compounds or salts of Formula (I), R 2 is -L-heterocycle, wherein the heterocycle portion is optionally substituted. 2is -L-heterocycle, wherein the heterocycle moiety is a bicyclic heterocycle. In some cases, R 2 is -L-heterocycle, wherein the heterocycle moiety is a monocyclic heterocycle. In some cases, R 2 is -L-heterocycle, wherein the heterocycle moiety is a saturated heterocycle. In some cases, R 2 is selected from -L-5 to 10 membered heterocyclic ring. In some cases, R 2 is selected from -(C1-C2 alkylene)-5 to 10 membered heterocycle. In some cases, R 2 is selected from -L-5 to 8 membered heterocyclic ring. In some cases, R 2 is selected from -L-5 to 8 membered saturated heterocyclic ring. In some cases, R 2 In some cases, R 2 In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains at most one nitrogen atom. In some cases, the heterocycle contains one nitrogen atom. In some cases, the bicyclic heterocycle contains at least one nitrogen atom. In some cases, the bicyclic heterocycle contains at most one nitrogen atom. In some cases, the bicyclic heterocycle contains one nitrogen atom. In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted. In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted. In some cases, the heterocyclic moiety is substituted by one or more halogens, hydroxyls, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, -CN and C l -C3 aminoalkyl is optionally substituted. In some cases, the heterocyclic moiety is replaced by one or more selected from halogen, hydroxy, -CN, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy and C l -C3 aminoalkyl is optionally substituted. In some cases, the heterocyclic moiety is optionally substituted with one or more substituents selected from C1-C3 alkyl and halogen. In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 for

[0155] In some embodiments, for compounds or salts of Formula (I), R 2 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 wherein the heterocyclic moiety is optionally substituted. In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted. In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted. In some cases, YR 2 Selected from Wherein the heterocyclic moiety is optionally substituted. In some cases, the heterocyclic ring is replaced by one or more selected from halogen, hydroxyl, C l -C3 alkyl, -N(R 5 )S(O)2(R 5 )、-OC(O)N(R 5 )2, oxo, =CH2, =NO-C l -C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R 5 )2 and -OC l -C3 alkyl is optionally substituted, wherein -OC l -C3 alkyl is optionally substituted by a substituent selected from heterocycle, oxo and hydroxy. In some cases, the heterocycle is substituted by at least one halogen. In some cases, the heterocycle is substituted by at least one =CH2. In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0156] In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0157] In some embodiments, for compounds or salts of Formula (I), R 2-L-heteroaryl, wherein the heteroaryl portion is replaced by one or more R 7 In some cases, the heteroaryl group is selected from a 5- to 6-membered heteroaryl group, wherein the heteroaryl portion is replaced by one or more R 7 Optional substitution.

[0158] In some cases, the heteroaryl group is selected from a 5-membered heteroaryl group, wherein the heteroaryl portion is separated by one or more R 7 In some cases, the heteroaryl group has at least one nitrogen atom. In some cases, the heteroaryl group has two nitrogen atoms. In some cases, the heteroaryl group has three nitrogen atoms. In some cases, the heteroaryl group is selected from It is optionally substituted. In some cases, the heteroaryl group is It is optionally substituted. In some cases, YR 2 Selected from wherein the heteroaryl portion is replaced by one or more R 7 Optionally substituted. In some cases, each R 7 Independently selected from C l -C4 alkyl, halogen and C1-C4 haloalkyl. In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0159] In some embodiments, for compounds or salts of Formula (I), R 2 is -L-aryl, which is replaced by one or more R 7 In some cases, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 7 In some cases, YR 2 Selected from

[0160] In some embodiments, for compounds or salts of Formula (I), R 2 -LN(R 23 )2. In some cases, YR 2 Selected from

[0161] In some embodiments, for compounds or salts of Formula (I), R 2 is a heterocyclic ring, which is surrounded by one or more R 6Optionally substituted. In some cases, R 2 The heterocyclic ring is It is optionally substituted. In some cases, R 2 The heterocyclic ring is In some cases, YR 2 for

[0162] In some embodiments, for compounds or salts of Formula (I), R 2 is selected from heterocycle, -L-heterocycle, wherein the heterocycle and the heterocyclic portion of -L-heterocycle are each separated by one or more R 6 Optionally substituted; -L-aryl and -L-heteroaryl, wherein the aryl of the -L-aryl and the heteroaryl of the -L-heteroaryl are each replaced by one or more R 7 optionally substituted; and -LN(R 23 )2. In some cases, R 2 The heterocyclic ring is selected from where R 2 The heterocyclic ring is replaced by one or more R 6 Optionally substituted; wherein R 2 The aryl and heteroaryl groups are selected from wherein aryl and heteroaryl are each replaced by one or more R 7 optionally substituted; and In some cases, R 2 The heterocyclic ring is selected from wherein the heterocyclic ring is replaced by one or more R 6 Optionally substituted; wherein R 2 The aryl and heteroaryl groups are selected from wherein aryl and heteroaryl are each replaced by one or more R 7 optionally substituted; and In some cases, each R 6 Independently selected from halogen, hydroxy, C l -C3 alkyl, C l -C3 haloalkyl, -N(R 5 )S(O)2(R 5 )、-OC(O)N(R 5 )2、=CH2、oxo、=NO-C l -C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R 5 )2 and -OC l -C3 alkyl, wherein -OC l-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein each R 7 Selected from C l -C3 alkyl, halogen and C l -C3 haloalkyl. In some cases, R 2 Heterocyclic ring, R 2 The aryl and heteroaryl groups, and R 2 -N(R 20 )2Selected

[0163] In some cases, YR 2 Selected from wherein the heterocycle and the heterocycle portion of -L-heterocycle are each separated by one or more R 6 Optional substitution; wherein the aryl of -L-aryl and the heteroaryl of -L-heteroaryl are each replaced by one or more R 7 optionally substituted; and In some cases, YR 2 Selected from

[0164] In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0165]

[0166] In some embodiments, for compounds or salts of Formula (I), L is independently selected from C l -C4 alkylene, which is independently selected from hydroxy, C l -C4 hydroxyalkyl and C l -C4 alkyl is optionally substituted. In some cases, L is independently selected from C l -C4 alkylene, which is independently selected from C l -C4 alkyl is optionally substituted. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene. In some cases, L is In some cases, L is

[0167] In some embodiments, for compounds or salts of Formula (I), each L is independently selected from optionally substituted C l -C4 alkylene; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is substituted by one or more substituents 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 are optionally substituted. In some cases, the optional substituents of L are selected from C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocycle; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3 to 8-membered heterocycle, wherein the C3-C6 carbocycle and the 3 to 8-membered heterocycle are substituted by one or more halogens and C 1-6 The substituents on the haloalkyl group are optionally substituted.

[0168] 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 carbocyclic ring. In some cases, the C3-C6 carbocyclic ring is replaced by one or more substituents 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 on the haloalkyl group are optionally substituted.

[0169] In some embodiments, for compounds or salts of Formula (I), each L is independently selected from substituted C l -C4 alkylene, and the two substituents on the same carbon atom of L together form a C3-C6 carbocycle. In some cases, each L is independently selected from substituted C3 alkylene, and wherein the two substituents on the same carbon atom of L together form a C3 carbocycle. In some cases, each L is independently selected from

[0170] In some embodiments, for compounds or salts of Formula (I), R 2 is selected from -L-heterocycle, wherein the heterocyclic portion of the -L-heterocycle is replaced by one or more R 6 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.

[0171] In some embodiments, for compounds or salts of Formula (I), R 2 Selected from wherein the heterocyclic portion is replaced by one or more R 6 Optional substitution.

[0172] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from wherein the heterocyclic portion is replaced by one or more R 6 Optional substitution.

[0173] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from wherein the heterocyclic portion is replaced by one or more R 6 Optional substitution.

[0174] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from wherein the heterocyclic portion is replaced by one or more R 6 Optional substitution.

[0175] In some embodiments, for compounds or salts of Formula (I), R 2 is selected from -L-saturated heterocycle, wherein the saturated heterocyclic ring portion of the -L-saturated heterocycle is replaced by one or more R 6 is optionally substituted and contains one nitrogen atom and one sulfur atom. 2 Selected from wherein the heterocyclic portion is replaced by one or more R 6 In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted by one or more substituents selected from C1-C3 alkyl and oxo. 2 Selected from In some cases, YR 2 Selected from

[0176] In some embodiments, for compounds or salts of Formula (I), Y is a bond. 2 is selected from optionally substituted heteroaryl and optionally substituted aryl. 2In some cases, the heteroaryl group has at least one nitrogen atom. In some cases, the heteroaryl group has at least two nitrogen atoms. In some cases, the heteroaryl group contains only nitrogen atoms. In some cases, the heteroaryl group is a 6-membered heteroaryl group. In some cases, the heteroaryl group is a 5-membered heteroaryl group. In some cases, the heteroaryl group is selected from Each of which is optionally substituted. In some cases, the heteroaryl group is selected from Each of which is optionally substituted. In some cases, R 2 In some cases, the heteroaryl group is replaced by one or more R 6 optionally substituted, wherein each R 6 Selected from halogen, hydroxyl, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano, -CH2 heterocycle, -C1-C3 alkyl-N(R 5 )2 and -C(O)N(R 5 )2. In some cases, R 6 Selected from C l -C3 alkyl, -CH2 heterocycle and -C(O)N(R 5 )2. In some cases, the aryl group is replaced by one or more R 7 In some cases, YR 2 Selected from In some cases, YR 2 Selected from

[0177] In some embodiments, for the compound or salt of Formula (I), Y is -O- and R 2 In some cases, the heteroaryl group has at least one nitrogen atom. In some cases, the heteroaryl group has at least two nitrogen atoms. In some cases, the heteroaryl group has three nitrogen atoms. In some cases, L is selected from an optionally substituted C1-C4 alkylene group. In some cases, L is independently selected from an optionally substituted C l -C4 alkylene; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3 to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3 to 8-membered heterocyclic ring are each substituted by one or more substituents selected from halogen, -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. In some cases, L is selected from In some cases, L is selected from In some cases, the heteroaryl group is replaced by one or more R 7 Optionally substituted. In some cases, each R 7 Selected from halogen, C l -C4 alkyl and C l -C4 haloalkyl. In some cases, YR 2 Selected from

[0178] In some embodiments, for compounds or salts of Formula (I), each R 6 independently selected from halogen, -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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle and -CH2heterocycle, among which -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C l wherein the phenyl group of the -C3 alkyl)phenyl group is optionally substituted by -C(O)H and OH, and wherein the heterocycle of the -CH2 heterocyclyl group is optionally substituted by oxo.

[0179] In some embodiments, for compounds or salts of Formula (I), each R 6 independently selected from halogen, -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, each R 6 independently selected from halogen, C l -C3 alkyl and C1-C3 haloalkyl.

[0180] In some embodiments, for compounds or salts of Formula (I), each R 6 independently selected from halogen, -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 oxo. 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 Independently selected from C l -C3 alkyl, C1-C3 alkoxy and -N(R 5 )2. In some cases, each R 6 Independently selected from halogen, hydroxy, C l -C3 alkyl, C l -C3 haloalkyl, -N(R 5 )S(O)2(R 5 )、-OC(O)N(R 5 )2、=CH2、oxo、=NO-C l -C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R 5 )2 and -OC l -C3 alkyl, wherein -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein each R 7 Selected from C l -C3 alkyl, halogen and C l -C3 haloalkyl.

[0181] In some embodiments, for compounds or salts of Formula (I), R 6 Selected from halogen, -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 halogen and C l -C3 alkyl. In some cases, R 6 In some cases, R 6 C l -C3 alkyl. In some cases, R 6 Selected from halogen and C l -C3 alkyl. In some cases, R 6 Selected from methyl and fluoro.

[0182] In some embodiments, for compounds or salts of Formula (I), R 2 Selected from

[0183] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from

[0184] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from

[0185] In some embodiments, for a compound or salt of formula (I), YR 2 for

[0186] In some embodiments, for the compound or salt of Formula (I), L is selected from unsubstituted C1-C4 alkylene.

[0187] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

[0188] In some embodiments, for compounds or salts of Formula (I), R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l-C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl.

[0189] In some embodiments, for compounds or salts of Formula (I), R 2 R 6 is independently selected at each occurrence from C1-C3 alkyl and halogen.

[0190] In some embodiments, for compounds or salts of Formula (I), YR 2 Selected from

[0191] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 5- to 12-membered heterocyclic ring. 1 The heterocycle of R is selected from a 5- to 12-membered heterocycle, a 6- to 12-membered heterocycle, a 7- to 12-membered heterocycle, and an 8- to 12-membered heterocycle. 1 The heterocycle of is selected from 5 to 11 membered heterocycle, 5 to 10 membered heterocycle, 5 to 9 membered heterocycle, and 5 to 8 membered heterocycle. 1 The heterocycle of R is selected from a 6- to 11-membered heterocycle, a 6- to 10-membered heterocycle, a 6- to 9-membered heterocycle, and a 6- to 8-membered heterocycle. 1 The heterocycle of R is selected from a 7- to 11-membered heterocycle, a 7- to 10-membered heterocycle, a 7- to 9-membered heterocycle, and a 7- to 8-membered heterocycle. 1 The heterocycle of is selected from 5- to 6-membered heterocycles and 5- to 9-membered heterocycles. 1 The heterocycle is selected from an 8- to 9-membered heterocycle. 1 is selected from an optionally substituted 5- to 7-membered heterocyclic ring. 1 is selected from an optionally substituted 6- to 7-membered heterocyclic ring. 1 is selected from an optionally substituted 7-membered heterocycle. 1 The 5- to 12-membered heterocycle of is a bridged heterocycle. 1 The 5- to 12-membered heterocycle of is not a bridged heterocycle. 1 The heterocyclic ring is saturated. 1 The heterocyclic ring is unsaturated. 1 The heterocycle of R is a non-bridged heterocycle. 1 The heterocycle is optionally substituted as described elsewhere herein.

[0192] In some embodiments, for compounds or salts of Formula (I), R 1 The heterocyclic ring contains up to 1 nitrogen atom. In some embodiments, R1 The heterocycle of contains up to 1 heteroatom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 The heterocycle contains up to 2 heteroatoms. 1 The heterocyclic ring contains 1 nitrogen atom. In some cases, R 1 The heterocyclic ring contains only one nitrogen atom. In some cases, R 1 The heterocyclic ring contains only 1 nitrogen atom and no other heteroatoms.

[0193] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from 5 to 12 membered heterocyclic rings, wherein the 5 to 12 membered heterocyclic rings are substituted by one or more independently selected from halogen, -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 are optionally substituted. In some cases, R 1 The 5- to 12-membered heterocyclic ring of is an unsaturated heterocyclic ring. 1 The 5- to 12-membered heterocyclic ring is selected from a saturated heterocyclic ring and an unsaturated heterocyclic ring. 1 The 5- to 12-membered heterocyclic ring of is a saturated heterocyclic ring. 1 The 5- to 12-membered heterocyclic ring is an unsaturated heterocyclic ring.

[0194] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 5- to 15-membered heterocyclic ring, wherein the 5- to 15-membered heterocyclic ring is optionally substituted. 1 is selected from an optionally substituted 6- to 15-membered heterocycle. In some cases, the heterocycle is a spiro heterocycle. In some cases, the heterocycle is a fused heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is an unsaturated heterocycle.

[0195] In some embodiments, for compounds or salts of Formula (I), R 1 is a 6- to 12-membered fused heterocyclic ring, which is optionally substituted.

[0196] In some embodiments, for compounds or salts of Formula (I), R 1 is a 6- to 12-membered spiroheterocyclic ring, which is optionally substituted. 1 is selected from optionally substituted 7- to 8-membered spiroheterocycles.

[0197] In some embodiments, for compounds or salts of Formula (I), R 1The heterocycle of is a 5- to 12-membered heterocycle, a 6- to 12-membered heterocycle, a 7- to 12-membered heterocycle, or an 8- to 12-membered heterocycle. 1 The heterocycle of is a 5- to 11-membered heterocycle, a 5- to 10-membered heterocycle, a 5- to 9-membered heterocycle, or a 5- to 8-membered heterocycle. 1 The heterocycle of is 6 to 11 membered heterocycle, 6 to 10 membered heterocycle, 6 to 9 membered heterocycle or 6 to 8 membered heterocycle. 1 The heterocycle of is 7 to 11 membered heterocycle, 7 to 10 membered heterocycle, 7 to 9 membered heterocycle or 7 to 8 membered heterocycle. 1 The heterocycle of is a 5- to 6-membered heterocycle or a 5- to 9-membered heterocycle. 1 The heterocycle is an 8- to 9-membered heterocycle. 1 The heterocycle is saturated. The heterocycle is optionally substituted as described elsewhere herein.

[0198] In some embodiments, for compounds or salts of Formula (I), R 1 is a 5- to 12-membered monocyclic heterocyclic ring. 1 The heterocycle is a 5- to 12-membered monocyclic heterocycle, a 6- to 12-membered monocyclic heterocycle, a 7- to 12-membered monocyclic heterocycle, or an 8- to 12-membered monocyclic heterocycle. 1 The heterocycle is a 5- to 11-membered monocyclic heterocycle, a 5- to 10-membered monocyclic heterocycle, a 5- to 9-membered monocyclic heterocycle, or a 5- to 8-membered monocyclic heterocycle. 1 The heterocycle is a 6- to 11-membered monocyclic heterocycle, a 6- to 10-membered monocyclic heterocycle, a 6- to 9-membered monocyclic heterocycle, or a 6- to 8-membered monocyclic heterocycle. 1 The heterocycle is a 7- to 11-membered monocyclic heterocycle, a 7- to 10-membered monocyclic heterocycle, a 7- to 9-membered monocyclic heterocycle, or a 7- to 8-membered monocyclic heterocycle. 1 The heterocycle is a 5- to 6-membered monocyclic heterocycle or a 5- to 9-membered monocyclic heterocycle. 1 The heterocycle is an 8- to 9-membered monocyclic heterocycle. 1 The heterocycle is saturated. The monocyclic heterocycle is optionally substituted as described elsewhere herein.

[0199] In some embodiments, for compounds or salts of Formula (I), R 1 is a bridged heterocycle. In some cases, R 1 The heterocycle is a 5- to 12-membered bridged heterocycle, a 6- to 12-membered bridged heterocycle, a 7- to 12-membered bridged heterocycle, or an 8- to 12-membered bridged heterocycle. 1 The heterocycle is a 5- to 11-membered bridged heterocycle, a 5- to 10-membered bridged heterocycle, a 5- to 9-membered bridged heterocycle, or a 5- to 8-membered bridged heterocycle. 1The heterocycle of is a 6- to 11-membered bridged heterocycle, a 6- to 10-membered bridged heterocycle, a 6- to 9-membered bridged heterocycle, or a 6- to 8-membered bridged heterocycle. 1 The heterocycle is a 7- to 11-membered bridged heterocycle, a 7- to 10-membered bridged heterocycle, a 7- to 9-membered bridged heterocycle, or a 7- to 8-membered bridged heterocycle. 1 The heterocycle is a 5- to 6-membered bridged heterocycle or a 5- to 9-membered bridged heterocycle. 1 The heterocycle is an 8- to 9-membered bridged heterocycle. 1 The heterocycle is saturated. In some cases, the bridged heterocycle is selected from In some cases, the bridged heterocycle is selected from Each bridged heterocycle is optionally substituted as described elsewhere herein.

[0200] In some embodiments, for compounds or salts of Formula (I), R 1 is a spiro heterocycle. 1 The spiroheterocycle is a 7- to 12-membered spiroheterocycle, a 7- to 12-membered spiroheterocycle, or an 8- to 12-membered spiroheterocycle. 1 The spiroheterocycle is a 7- to 11-membered spiroheterocycle, a 7- to 10-membered spiroheterocycle, a 7- to 9-membered spiroheterocycle, or a 7- to 8-membered spiroheterocycle. 1 The spiroheterocycle is a 7- to 11-membered spiroheterocycle, a 7- to 10-membered spiroheterocycle, a 7- to 9-membered spiroheterocycle, or a 7- to 8-membered spiroheterocycle. 1 The spiroheterocycle of is a 7- to 11-membered spiroheterocycle. 1 The spiroheterocycle of is a 7-membered spiroheterocycle. In some cases, R 1 The spiroheterocycle of is an 8-membered spiroheterocycle. 1 The spiroheterocycle of is a 9-membered spiroheterocycle. 1 The spiroheterocycle of is a 10-membered spiroheterocycle. In some cases, R 1 The spiro heterocycle contains up to 1 nitrogen atom. In some cases, R 1 The spiro heterocycle contains only 1 nitrogen atom. In some cases, R 1 The spiro heterocycle contains up to 2 heteroatoms. 1 The spiro heterocycle contains at least 2 heteroatoms. 1 The spiro heterocycle contains at least 3 heteroatoms. In some cases, the heteroatoms are selected from nitrogen, oxygen, and sulfur. In some cases, R 1 The spiro heterocyclic ring of is bound to the formula via a nitrogen atom. In some embodiments, R 1 The spiroheterocycle is selected from

[0201] In some cases, R 1 The spiroheterocycle is selected from Each spiroheterocycle is optionally substituted as described elsewhere herein.

[0202] In some embodiments, for compounds or salts of Formula (I), R 1 is a fused heterocyclic ring. In some cases, R 1 The fused heterocycle of is a 6- to 12-membered fused heterocycle, a 6- to 12-membered fused heterocycle, a 7- to 12-membered fused heterocycle, or an 8- to 12-membered fused heterocycle. 1 The fused heterocycle of is a 6- to 11-membered fused heterocycle, a 6- to 10-membered fused heterocycle, a 6- to 9-membered fused heterocycle, or a 6- to 8-membered fused heterocycle. 1 The fused heterocycle of is a 7- to 11-membered fused heterocycle, a 7- to 10-membered fused heterocycle, a 7- to 9-membered fused heterocycle, or a 7- to 8-membered fused heterocycle. 1 The fused heterocyclic ring of is an 8- to 11-membered fused heterocyclic ring. 1 The fused heterocycle of is a 9-membered fused heterocycle. 1 The fused heterocycle of is a 10-membered fused heterocycle. In some cases, R 1 The fused heterocycle of is an 11-membered fused heterocycle. In some cases, R 1 The fused heterocycle of is a 6-membered fused heterocycle. 1 The fused heterocycle of is a 7-membered fused heterocycle. In some cases, R 1 The fused heterocycle is a 10-membered fused heterocycle. In some cases, the fused heterocycle is selected from Each fused heterocyclic ring is optionally substituted as described elsewhere herein.

[0203] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 8- to 10-membered fused heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is an unsaturated heterocyclic ring. In some cases, the 8- to 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, R 1 is selected from an optionally substituted 9-membered fused heterocyclic ring. 1is selected from an optionally substituted 10-membered fused heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 9-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the fused heterocyclic ring has one saturated ring and one aromatic ring. In some cases, the fused heterocyclic ring has one saturated ring and one unsaturated ring. In some cases, the fused heterocyclic ring has two saturated rings. In some cases, the 10-membered heterocyclic ring contains at least 1 nitrogen atom. In some cases, the 10-membered heterocyclic ring contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least 3 nitrogen atoms. In some cases, the 9-membered heterocyclic ring contains at least 1 nitrogen atom. In some cases, the 9-membered heterocyclic ring contains at least 2 nitrogen atoms. In some cases, the 9-membered heterocyclic ring contains at least 3 nitrogen atoms. In some cases, R 1 Selected from Each of which is optionally substituted with one or more substituents. 1 for It is optionally substituted with one or more substituents. 1 for It is optionally substituted with one or more substituents. 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkynyl and 5 to 12 membered heterocyclic rings, wherein the 5 to 12 membered heterocyclic rings are each independently substituted by one or more R 1* Optionally substituted. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -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(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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 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 In some cases, one or more optional substituents are independently selected from halogen, =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 20 In some cases, one or more optional substituents are independently selected from halogen, =O, -S(O)2(R 20 )、-S(O)N(R20 )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 which is further optionally substituted. In some cases, the additional one or more optional substituents are selected from halogen, -OH, =O, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, the additional one or more optional substituents are selected from halogen, -CN, C2 alkenyl and C 1-6 In some cases, the additional one or more optional substituents are selected from halogen and C 1-6In some cases, each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings. In some cases, each R 20 are independently selected from hydrogen; and C 1-6 alkyl and a 3- to 12-membered heterocyclic ring. In some cases, each R 20 are independently selected from hydrogen; and C 1-6 alkyl and a 3- to 12-membered saturated heterocyclic ring. In some cases, each R 20 is independently selected from a 5- to 6-membered saturated heterocyclic ring. 20 The heterocyclic ring has at least one nitrogen atom. 20 The heterocyclic ring has at least one sulfur atom. 20 The heterocyclic ring has at least one oxygen atom. 20 The heterocycle contains only 1 heteroatom. In some cases, R 20 The heterocycle has at least two heteroatoms. 20 The heterocycle contains only 2 heteroatoms. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -CN, C2 alkenyl, In some cases, R 1 The one or more optional substituents are independently selected from halogen,

[0204] In some cases, R 1 The one or more optional substituents are independently selected from In some cases, R 1 The one or more optional substituents are independently selected from 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 The one or more optional substituents are independently selected from halogen and C 1-6 Alkyl-N(R 20 )2. In some cases, R 1 The one or more optional substituents are independently selected from halogen, In some cases, R 1 Selected from In some cases, each R 20 are independently selected from hydrogen, C 1-6 Alkyl and C 3-6 In some cases, R 1 Selected from In some cases, R 1 Selected from

[0205] In some cases, R 1 Selected from which are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkynyl, 5 to 12 membered heterocyclic ring substituents are optionally substituted, wherein the 5 to 12 membered heterocyclic ring is replaced by one or more selected from halogen, -OR 20 and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from which are independently selected from halogen and C 1-6The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from

[0206] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from in is selected from 5- to 12-membered heterocyclic rings, wherein the 5- to 12-membered heterocyclic rings are independently replaced by one or more R 1* optionally substituted; and R B Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkynyl and -CN. In some cases, R B is selected from hydrogen and halogen. In some cases, R B In some cases, R B is hydrogen. In some cases, has at least 1, 2, 3, or 4 heteroatoms. has at least 1, 2, 3, or 4 nitrogen atoms. has at least 1 oxygen atom. In some cases, Is a monocyclic heterocycle. In some cases, Is a bicyclic heterocycle. In some cases, is selected from an optionally substituted 5-membered heterocycle. is selected from an optionally substituted 9-membered heterocycle. Selected from Each of which is represented by one or more R 1* Optional substitution.

[0207] In some cases, Selected from Each of which is represented by one or more R 1* Optionally substituted. In some cases, each R 1* independently selected from halogen, -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 OR20 、-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 and C 1-6 In some cases, each R 1* independently selected from halogen, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen and C 1-6 In some cases, Selected from

[0208] In some embodiments, for compounds or salts of formula (I), when R 1 -C(O)R 20 When substituted, R 20 is selected from a 5- to 12-membered heterocyclic ring, which is optionally substituted. 1 -C(O)R 20 In some cases, R 20 is selected from a 5- to 12-membered unsubstituted heterocyclic ring. 20is selected from a 5- to 6-membered heterocyclic ring, which is optionally substituted. In some cases, the heterocyclic ring has at least one nitrogen atom. In some cases, the heterocyclic ring has at least one sulfur atom. In some cases, the heterocyclic ring has at least one oxygen atom. In some cases, the heterocyclic ring has two heteroatoms. In some cases, R 20 The heterocyclic ring is selected from Each of which is optionally substituted. In some cases, R 20 Selected from In some cases, the optional substituents are selected from C 1-10 Alkyl, oxo and =NH.

[0209] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, and =NH substituents are optionally substituted. In some cases, each R 20 are independently selected from hydrogen; and unsubstituted C 1-6 Alkyl and one or more independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Substituents for alkyl, oxo and =NH are optionally substituted 3- to 12-membered heterocyclic rings.

[0210] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, and =NH substituents are optionally substituted. In some cases, each R 21 are independently selected from hydrogen; and unsubstituted C 1-6 Alkyl and one or more independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Substituents for alkyl, oxo and =NH are optionally substituted 3- to 12-membered heterocyclic rings.

[0211] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, and =NH substituents are optionally substituted. In some cases, each R 20 are independently selected from hydrogen; and unsubstituted C 1-6 Alkyl and one or more independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Substituents for alkyl, oxo and =NH are optionally substituted 3- to 12-membered heterocyclic rings.

[0212] In some embodiments, for compounds or salts of Formula (I), each R 23 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, and =NH substituents are optionally substituted. In some cases, each R 20 are independently selected from hydrogen; and unsubstituted C 1-6 Alkyl and one or more independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Substituents for alkyl, oxo and =NH are optionally substituted 3- to 12-membered heterocyclic rings.

[0213] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is optionally substituted by one or more substituents. In some cases, one or more optional substituents are independently selected from halogen, -CN, -NO2, =O, -N(R 20 )2、-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 、-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 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 In some cases, one or more optional substituents are independently selected from halogen, -OH, -N(R 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 In some cases, one or more optional substituents are independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 20 Selected from hydrogen and C 1-3 alkyl.

[0214] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a saturated 5- to 12-membered heterocyclic ring, which is optionally substituted with one or more substituents. 1 The 5- to 12-membered heterocyclic ring is bridged. 1 The 5- to 12-membered heterocyclic ring is not bridged. In some cases, the 5- to 12-membered heterocyclic ring is selected from Each of which is optionally substituted with one or more substituents.

[0215] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from

[0216] Each of which is optionally substituted by one or more substituents. In some cases, one or more of the optional substituents are independently selected from halogen, -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 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 1 Selected from

[0217]

[0218]

[0219]

[0220] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocyclic ring, wherein the heterocyclic ring has at most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocyclic ring has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocyclic ring has at most one nitrogen atom.

[0221] In some embodiments, for compounds or salts of Formula (I), R 1The heterocycle contains only one nitrogen atom and optionally one or more heteroatoms selected from oxygen and sulfur. In some cases, the heterocycle is a fused heterocycle or a bridged heterocycle. 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 Heterocycles are optionally substituted as described elsewhere herein.

[0222] In some embodiments, for compounds or salts of Formula (I), R 1 The heterocyclic ring has up to 1 nitrogen atom. In some cases, R 1 The heterocyclic ring has only 1 nitrogen atom and optionally one or more other heteroatoms selected from oxygen and sulfur. 1 The heterocycle has only 1 nitrogen atom and no other heteroatoms.

[0223] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from optionally substituted 5 to 12 membered saturated heterocycles, wherein the heterocycle has at most one nitrogen atom. In some cases, the 5 to 12 membered unsaturated heterocycles have at least one nitrogen atom. In some cases, the 5 to 12 membered unsaturated heterocycles have only one nitrogen atom and 0-2 other heteroatoms selected from nitrogen, oxygen and sulfur. In some cases, the 5 to 12 membered unsaturated heterocycles have only one nitrogen atom and no additional heteroatoms. In some cases, the 5 to 12 membered unsaturated heterocycles have three nitrogen atoms and no additional heteroatoms.

[0224] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 5- to 12-membered unsaturated heterocycle, 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 only one nitrogen atom and does not contain additional heteroatoms.

[0225] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 6- to 7-membered heterocyclic ring. 1 is selected from a 7-membered heterocyclic ring. In some cases, R 1 In some cases, the 6- to 7-membered heterocyclic ring 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 heterocyclic ring contains only one nitrogen atom and no additional additional heteroatoms. In some cases, the 6- to 7-membered heterocyclic ring is a non-aromatic 6- to 7-membered heterocyclic ring. In some cases, R 1The 6- to 7-membered heterocyclic ring is bound to Formula (I) via only one nitrogen atom. 1 Selected from Each of which is substituted. In some cases, R 1 Selected from Each of which is substituted. In some cases, R 1 The substituents are each selected from one or more halogen, -OR 20 、-SR 20 、-N(R 20 )2, -NHCN, -NO2, =O, -CN, C 1-6 Fluoroalkyl and C 2-6 Alkynyl; and further independently selected from one or more -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 are optionally substituted. 1 The substituents are each selected from one or more halogen, -OR 20 、-N(R 20 )2, -NHCN, =O, -CN and C 2-6 Alkynyl; and further independently selected from one or more -C(O)N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 The substituents are each selected from one or more halogen, -OH, -NHCN, =O, -CN and C 2-6 Alkynyl; and further one or more independently selected from C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from

[0226] In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 The 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 In some cases, R 1 The one or more optional substituents are each independently selected from halogen, -OH, -CN, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 In some cases, R 1 The one or more optional substituents of are each independently selected from halogen, -OH and -CN. In some cases, R 1 The 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 In some cases, R 1 The 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 In some cases, R 1 Selected from

[0227]

[0228] 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

[0229] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from Each of which is optionally substituted by one or more substituents. In some cases, one or more of the optional substituents are independently selected from halogen, -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 In some cases, R 1 Selected from

[0230]

[0231]

[0232]

[0233] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocyclic ring. 1 is selected from an optionally substituted unsaturated 6-membered heterocyclic ring. 1 is selected from an optionally substituted unsaturated 7-membered heterocycle. 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 which is replaced by one or more independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH2, -NO2, 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.

[0234] 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 Selected from Each of which is substituted with one or more substituents independently selected from halogen.

[0235] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an unsaturated 6- to 7-membered heterocyclic ring, wherein the unsaturated 6- to 7-membered heterocyclic ring is substituted by one or more substituents selected from halogen. In some cases, the unsaturated 6- to 7-membered heterocyclic ring is substituted by at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocyclic ring is substituted by only one halogen. In some cases, the unsaturated 7-membered heterocyclic ring is substituted by one fluorine. In some cases, R 1 is selected from an unsaturated 6-membered heterocyclic ring substituted with at least one halogen. 1 is selected from an unsaturated 7-membered heterocyclic ring substituted with at least one halogen. 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

[0236] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocyclic ring. 1 is selected from an optionally substituted unsaturated 7-membered heterocycle. 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from

[0237] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 6-membered heterocyclic ring. In some cases, the 6-membered heterocyclic ring contains only one nitrogen atom. In some cases, R 1 The 6-membered heterocyclic ring is bound to Formula (I) via only one nitrogen atom. 1 Selected from Any of which is optionally substituted. In some cases, 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 and C 2-6 In some cases, R 1 The 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 In some cases, R 1 The 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 In some cases, the 6-membered heterocycle is a partially unsaturated 6-membered heterocycle or a saturated 6-membered heterocycle. In some cases, the 6-membered heterocycle is partially unsaturated. In some cases, the 6-membered heterocycle is a saturated 6-membered heterocycle. 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, R1 Selected from

[0238] In some embodiments, for compounds of formula (I), R 1 is selected from an optionally substituted 6-membered unsaturated heterocyclic ring and a 6-membered saturated heterocyclic ring.

[0239] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -OH, -NH2, -NO2, 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.

[0240] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from wherein each is replaced by one or more independently selected from halogen and C 1-6 The substituents on the haloalkyl group are optionally substituted.

[0241] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from

[0242] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from Each of which is replaced by two independently selected from halogen, -OH, -NH2, -NO2, 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.

[0243] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from Each of which is replaced by two independently selected from halogen and C 1-6 The substituents of the haloalkyl group are optionally substituted. In some cases, R 1 for

[0244] In some embodiments, for compounds or salts of Formula (I), R 1is selected from an optionally substituted 6- to 10-membered heterocyclic ring. In some cases, the 6- to 10-membered heterocyclic ring contains at least one nitrogen atom. In some cases, R 1 Selected from Each of which is replaced by one or more independently selected from halogen, =O, -OH, -CN, -NHCN, -C(O)N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, 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, -NO2, -NH2, -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. 1 Selected from

[0245] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 6- to 7-membered heterocyclic ring. 1 is selected from a 7-membered heterocyclic ring. In some cases, R 1 In some cases, the 6- to 7-membered heterocyclic ring 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 heterocyclic ring contains only one nitrogen atom and no additional additional heteroatoms. In some cases, the 6- to 7-membered heterocyclic ring is a non-aromatic 6- to 7-membered heterocyclic ring. In some cases, R 1 The 6- to 7-membered heterocyclic ring is bound to Formula (I) via only one nitrogen atom. 1 Selected from Each of which is substituted. In some cases, R 1 Selected from Each of which is substituted. In some cases, R 1 The substituents are each selected from one or more halogen, -OR 20、-SR 20 、-N(R 20 )2, -NHCN, -NO2, =O, -CN, C 1-6 Fluoroalkyl and C 2-6 Alkynyl; and further independently selected from one or more -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 are optionally substituted. 1 The substituents are each selected from one or more halogen, -OR 20 、-N(R 20 )2, -NHCN, =O, -CN and C 2-6 Alkynyl; and further independently selected from one or more -C(O)N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 The substituents are each selected from one or more halogen, -OH, -NHCN, =O, -CN and C 2-6 Alkynyl; and further one or more independently selected from C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, R 1 Selected from

[0246] In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 The 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 C2-6 In some cases, R 1 The one or more optional substituents are independently selected from halogen, -OH, -CN, C 1-6 Cyanoalkyl, C 1-6 Alkyl and C 2-6 In some cases, R 1 The one or more optional substituents of are each independently selected from halogen, -OH and -CN. In some cases, R 1 The 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 In some cases, R 1 The 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 In some cases, R 1 Selected from

[0247] In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 Selected from

[0248] In some cases, R 1 Selected from

[0249] In some embodiments, for compounds or salts of Formula (I), R 1 The 5- to 12-membered heterocyclic ring of is unsaturated and bridged. 1 is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. 1 Selected from

[0250] In some embodiments, for compounds or salts of Formula (I), R 1is selected from 5- to 10-membered heterocyclic rings, 7-, 8-, 10-, 11-membered spiro heterocyclic rings, and 6-, 9-, 10-, 11-, or 12-membered fused heterocyclic rings, and each of which is independently selected from halogen, -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 are optionally substituted. In some cases, R 1 Selected from wherein each is replaced by one or more independently selected from halogen, -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 on the aminoalkyl group are optionally substituted.

[0251] In some cases, R 1 Selected from

[0252]

[0253] In some embodiments, for compounds or salts of Formula (I), R 1is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro 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 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom. In some cases, R 1 Selected from Each of which is replaced by one or more independently selected from halogen, =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 substituents of the alkyl group are 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 which are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substituents are optionally substituted.

[0254] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocyclic ring. 1 is selected from an optionally substituted unsaturated 10-membered heterocycle. 1 is selected from an optionally substituted unsaturated 10-membered fused heterocyclic ring.1 for It is optionally substituted. In some cases, one or more optional substituents are selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, R 1 for which 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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkynyl group are optionally substituted. In some cases, each R 20 are independently selected from hydrogen; and C 1-6 Alkyl and C 3-12 carbocyclic ring, and each of which is independently selected from one or more halogen, -OH, -CN, -NO2, -NH2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-12 The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

[0255] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 7- to 11-membered spiroheterocyclic ring. 1 is selected from a 10-membered spiro heterocycle. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, one or more optional substituents are independently selected from halogen, -OH, -N(R 20 )2, -NO2, =O, -CN, -NHCN, C 1-6 aminoalkyl, C1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 In some cases, R 1 Selected from In some cases, R 1 for In some cases, R 1 for

[0256] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 8- to 10-membered fused heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is an unsaturated heterocyclic ring. In some cases, the 8- to 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, R 1 is selected from an optionally substituted 10-membered fused heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the fused heterocyclic ring has one saturated ring and one aromatic ring. In some cases, the fused heterocyclic ring has one saturated ring and one unsaturated ring. In some cases, the fused heterocyclic ring has two saturated rings. In some cases, the 10-membered heterocyclic ring contains at least 1 nitrogen atom. In some cases, the 10-membered heterocyclic ring contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least 3 nitrogen atoms. In some cases, R 1 Selected from Each of which is optionally substituted with one or more substituents. 1 Selected from Each of which is optionally substituted with one or more substituents. 1 for It is optionally substituted with one or more substituents. 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 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 In some cases, one or more optional substituents are independently selected from halogen, =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 20 In some cases, one or more optional substituents are independently selected from halogen, =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 20In 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 which is further optionally substituted. In some cases, the additional one or more optional substituents are selected from halogen, -OH, =O, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, the additional one or more optional substituents are selected from halogen and C 1-6 In some cases, each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings. In some cases, each R 20 are independently selected from hydrogen; and C 1-6 alkyl and a 3- to 12-membered heterocyclic ring. In some cases, each R 20are independently selected from hydrogen; and C 1-6 alkyl and a 3- to 12-membered saturated heterocyclic ring. In some cases, each R 20 is independently selected from a 5- to 6-membered saturated heterocyclic ring. 20 The heterocyclic ring has at least one nitrogen atom. 20 The heterocyclic ring has at least one sulfur atom. 20 The heterocyclic ring has at least one oxygen atom. 20 The heterocycle contains only 1 heteroatom. In some cases, R 20 The heterocycle has at least two heteroatoms. 20 The heterocycle contains only 2 heteroatoms. In some cases, R 1 The one or more optional substituents are independently selected from halogen, In some cases, R 1 The one or more optional substituents are independently selected from In some cases, R 1 Selected from In some cases, R 1 Selected from In some cases, R 1 The one or more optional substituents are independently selected from halogen and C 1-6 Alkyl-N(R 20 )2. In some cases, R 1 The one or more optional substituents are independently selected from halogen, In some cases, R 1 Selected from In some cases, each R 20 are independently selected from hydrogen, C 1-6 Alkyl and C 3-6 In some cases, R 1 Selected from In some cases, R 1 Selected from

[0257] In some embodiments, for compounds or salts of formula (I), when R 1 -C(O)R 20 When substituted, R 20 is selected from a 5- to 12-membered heterocyclic ring.

[0258] In some embodiments, for compounds or salts of Formula (I), Formula (II), or Formula (III), R 1 for And R 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 alkynyl and optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C1-6 Alkyl, C 2-6 alkynyl and optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -CN, C 2-6 Alkynyl, -C(=NR 20 )N(R 20 )2 and an optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -C(=NR 20 )N(R 20 )2 and an optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1 The one or more optional substituents are independently selected from -C(=NR 20 )N(R 20 )2 and an optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1 The one or more optional substituents of are independently selected from an optionally substituted 5- to 12-membered heterocyclic ring. 1 The one or more optional substituents are independently selected from 5-membered heterocyclic rings and 9-membered heterocyclic rings, each of which is independently replaced by one or more R 1* Optionally substituted. In some cases, R 1 is substituted by at least one halogen, and is substituted by one or more independently selected from -CN, C 2-6 Alkynyl, -C(=NR 20 )N(R 20 )2 and 5 to 12 membered heterocyclic rings are optionally substituted, wherein the 5 to 12 membered heterocyclic rings are independently substituted with one or more R 1* 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 one or more optional substituents of the heterocyclic ring are selected from

[0259] Each of which is represented by one or more R 1* Optionally substituted. In some cases, R 1 The one or more optional substituents of the heterocyclic ring are selected from It is represented by one or more R 1* Optionally substituted. In some cases, each R 1* independently selected from halogen, -OR 20 、-S(O)2(R20 )、-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 and C 1-6 In some cases, each R 1* independently selected from halogen, -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(R20 )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 and C 1-6 In some cases, each R 1* independently selected from halogen, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen and C 1-6 In some cases, each R 1* is independently selected from halogen. In some cases, each R 1* Independently selected from C 1-6 In some cases, each R 1* Independently selected from -OR 20 In some cases, each R 1* is independently selected from -OH. In some cases, each R 1* is independently selected from -OMe. In some cases, R 1 The one or more optional substituents of the heterocyclic ring are selected from

[0260] In some embodiments, for compounds or salts of Formula (I), Formula (II), or Formula (III), R 1 The one or more optional substituents are independently selected from -C(=NR 20 )N(R 20 )2 and an optionally substituted 5- to 12-membered heterocyclic ring. In some cases, R 1The one or more optional substituents of are independently selected from an optionally substituted 5- to 12-membered heterocyclic ring. In some cases, the heterocyclic ring is selected from

[0261] Each of which is represented by one or more R 1* Optionally substituted. In some cases, R 1 The one or more optional substituents are selected from

[0262] In some embodiments, for compounds or salts of Formula (I), Formula (II), or Formula (III), each R 1* independently selected from halogen, -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 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen, -OR 20 、-S(O)2(R 20 )、-S(O)2N(R20 )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 and C 1-6 In some cases, each R 1* independently selected from halogen, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 In some cases, each R 1* independently selected from halogen and C 1-6 In some cases, each R 1* is independently selected from halogen. In some cases, each R 1* Independently selected from C 1-6 alkyl.

[0263] In some embodiments, for compounds or salts of Formula (I), R1 is selected from a 5- to 15-membered heterocycle (preferably an 8- to 10-membered heterocycle or preferably a 10-membered heterocycle), each of which is replaced by one or more 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 Alkynyl and 5- to 12-membered heterocyclic rings (preferably 5- to 9-membered heterocyclic rings) are optionally substituted, wherein the 5- to 12-membered heterocyclic rings are 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 In some cases, the 8- to 10-membered heterocyclic ring is bicyclic. In some cases, the 10-membered heterocyclic ring is substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from It is optionally substituted. 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 Selected from

[0264] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from 5 to 15 membered heterocycles (preferably 8 to 10 membered heterocycles or preferably 10 membered heterocycles or preferably 8 membered heterocycles), 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、C1-6 Cyanoalkyl, C 1-6 Alkyl, C 2-6 Alkynyl and 5- to 12-membered heterocyclic rings (preferably 5- to 6-membered heterocyclic rings) are optionally substituted, wherein the 5- to 12-membered heterocyclic rings are 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 In some cases, the 8- to 10-membered heterocyclic ring is bicyclic. In some cases, the 10-membered heterocyclic ring is substituted. In some cases, R 1 Selected from Each of which is optionally substituted. In some cases, R 1 Selected from It is optionally substituted. In some cases, R 1 Selected from In some cases, R 1 Selected from

[0265] In some embodiments, for compounds or salts of Formula (I), R 1 Selected from

[0266] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 7- to 10-membered spiroheterocycle and an optionally substituted 7- to 10-membered fused heterocycle. 1 The heterocyclic ring has at least one nitrogen atom. 1 At least one nitrogen atom of the heterocyclic ring of is bound to Formula (I). 1 is selected from an optionally substituted 10-membered spiroheterocycle and an optionally substituted 10-membered fused heterocycle. 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkynyl, 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 of the alkyl group are optionally substituted. In some cases, R 1 Selected from which are independently selected from halogen, -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 Halogenated alkyl, 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 of the alkyl group are optionally substituted. In some cases, R 1 Selected from In some cases, R 1 Selected from

[0267]

[0268] In some embodiments, for compounds or salts of Formula (I), R 1is selected from an optionally substituted 6- to 11-membered heterocyclic ring, wherein the 6- to 11-membered heterocyclic ring has at least one nitrogen atom. In some cases, R 1 One or more optional substituents are selected from halogen, -OR 20 、-C(O)N(R 20 )2、-C(O)R 20 、-S(O)2R 20 ,=O,-C 1-6 Alkyl (=NOR 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 alkyl and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is independently replaced by one or more R 1* optionally substituted; and wherein each R 1* independently selected from halogen and C 1-6 In some embodiments, R 1 Selected from

[0269] In some cases, R 1 Selected from hydrogen,

[0270] In some cases, R 1 Selected from hydrogen,

[0271]

[0272] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from hydrogen and an optionally substituted 5- to 15-membered heterocyclic ring. 1 Selected from Each of which is optionally substituted. In some cases, R 1 One or more optional substituents are selected from -OH, =NO(R 20 ), -NHCN and C 1-6 In some cases, R 1 Selected from hydrogen,

[0273] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from hydrogen and an optionally substituted 7- to 10-membered heterocyclic ring. 1 Selected from hydrogen Each of which is optionally substituted. In some cases, R 1 The one or more optional substituents are independently selected from halogen, -NH2, -S(O)2(R 20 ),-C(O)R 20 、-C(O)N(R 20 )2、=O、=NO(R 20 )、-CN、-NHCN、C 1-6 alkyl and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is independently replaced by one or more R 1* optionally substituted; and wherein each R 1* independently selected from halogen and C 1-6 In some cases, R 1 Selected from hydrogen,

[0274]

[0275] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 8- to 10-membered heterocycle. In some cases, the heterocycle is bicyclic. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, Each of which is optionally substituted. In some cases, R 1 The one or more optional substituents are independently selected from halogen Oxygen, and 5- to 9-membered heteroaryl, wherein the 5- to 9-membered heteroaryl is surrounded by at least one R 1* Substituted, where R 1* Selected from halogen and C 1-6 In some cases, R 1 The one or more optional substituents are independently selected from chlorine Oxygen, In some cases, R 1 Selected from

[0276]

[0277] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted bridged 8- to 9-membered heterocycle. 1 The heterocyclic ring is selected from Each of which is optionally substituted. In some cases, R 1One or more substituents are selected from halogen, C 1-6 Alkyl, -N(R 20 )2 and C 1-6 Aminoalkyl.

[0278] In some cases, R 1 Selected from

[0279] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted bridged 8-membered heterocyclic ring, wherein the heterocyclic ring contains a heteroatom selected from nitrogen. In some cases, R 1 One or more substituents are selected from C 1-6 Alkyl, -N(R 20 )2 and C 1-6 In some cases, R 1 The heterocyclic ring is selected from Each of which is optionally substituted. In some cases, R 1 Selected from In some cases, R 1 for In some cases, R 1 for

[0280] In some embodiments, for compounds or salts of Formula (I), R 1 For hydrogen.

[0281] In some embodiments, for compounds or salts of Formula (I), R 1 is an optionally substituted 12- to 15-membered heterocyclic ring. 1 is an optionally substituted 12-membered heterocycle. 1 is an optionally substituted 13-membered heterocycle. 1 is an optionally substituted 14-membered heterocycle. 1 is an optionally substituted 15-membered heterocycle. 1 The heterocycle is tricyclic. In some cases, R 1 The heterocycle of contains a fused heterocycle. In some cases, R 1 The heterocycle of contains a spiro heterocycle. In some cases, R 1 The heterocycle contains fused and spiro heterocycles. In some cases, R 1 The heterocycle of is an unsaturated heterocycle. In some cases, R 1 The heterocycle of is a non-aromatic heterocycle. In some cases, R 1 The heterocyclic ring has at least one double bond. 1 The heterocyclic ring has at least two double bonds.1 The heterocycle has at least 2 heteroatoms. 1 The heterocycle has at least 3 heteroatoms. 1 The heterocycle has at least 4 heteroatoms. 1 The heterocycle has at least 5 heteroatoms. 1 The heterocycle has at least 6 heteroatoms. 1 The heterocycle has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, R 1 The heterocyclic ring has at least 3, 4, or 5 nitrogen atoms and at least 1 sulfur atom. 1 The heterocyclic ring has at least 3, 4, or 5 nitrogen atoms and at least 1 oxygen atom. 1 The heterocyclic ring has 3, 4, or 5 nitrogen atoms. 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 Each of which is optionally substituted with one or more substituents. 1 Selected from Each of which is optionally substituted with one or more substituents. 1 The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, R 1The one or more optional substituents are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, R 1 The one or more optional substituents are independently selected from halogen, -OH, C 1-6 Alkyl and -C(O)N(R 20 )2.

[0282] In some cases, R 1 Selected from

[0283]

[0284] In some embodiments, for compounds or salts of Formula (I), R 1 is an optionally substituted 12- to 15-membered heterocyclic ring. 1 for Wherein ring W is an optionally substituted heterocycle, and ring P is an optionally substituted carbocycle or an optionally substituted heterocycle, wherein ring P forms a spirocycle with ring W. 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 1 for wherein Ring P is an optionally substituted carbocycle or an optionally substituted heterocycle. 1 for In some cases, Ring P is an optionally substituted carbocycle. In some cases, Ring P is an optionally substituted heterocycle. In some cases, Ring P forms an optionally substituted C3-C6 carbocycle or an optionally substituted 4 to 6-membered heterocycle. In some cases, Ring P forms an optionally substituted C3 carbocycle. In some cases, Ring P forms an optionally substituted C4 carbocycle. In some cases, Ring P forms an optionally substituted C5 carbocycle. 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 halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, one or more optional substituents of ring P are independently selected from halogen, -OH, =O, =NH, -CN and C 1-6 In some cases, one or more optional substituents of ring W are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 In some cases, one or more optional substituents of Ring W are independently selected from halogen, -S(O)2(R 20 )、-S(O)2N(R 20 )2、-S(O)N(R20 )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 In some cases, one or more optional substituents of Ring W are independently selected from -C(O)R 20 In some cases, Ring P is substituted. In some cases, Ring W is substituted.

[0285] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from a 5- to 12-membered bridged heterocycle, which is optionally substituted with one or more substituents. 1 is selected from an 8-membered bridged heterocycle, which is optionally substituted with one or more substituents. In some cases, the bridged heterocycle has at least 1 heteroatom. In some cases, the bridged heterocycle has at least 2 heteroatoms. In some cases, the bridged heterocycle has at least 1 nitrogen atom. In some cases, the bridged heterocycle has at least 2 nitrogen atoms. In some cases, the bridged heterocycle has 2 nitrogen atoms. In some cases, R 1 Selected from Each of which is optionally substituted with one or more substituents. 1 Selected from It is optionally substituted with one or more substituents.

[0286] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an unsaturated 5- to 12-membered heterocyclic ring, which is optionally substituted with one or more substituents. In some cases, the unsaturated 5- to 12-membered heterocyclic ring is selected from Each of which is optionally substituted with one or more substituents.

[0287] In some embodiments, for the compound or salt of formula (I), wherein R 1 The 5- to 12-membered heterocyclic ring of is unsaturated and bridged. 1 is selected from an optionally substituted 7- to 8-membered unsaturated and bridged heterocycle. 1 Selected from

[0288] In some embodiments, for compounds or salts of Formula (I), R 1is selected from an optionally substituted 10-membered heterocycle. In some cases, the 10-membered heterocycle is a bicyclic heterocycle. In some cases, the 10-membered heterocycle is a spiro 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 1 nitrogen atom. In some cases, the 10-membered heterocycle contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocycle contains at least 1 sulfur atom. In some cases, R 1 Selected from Each of which is replaced by one or more independently selected from halogen, =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 substituents of the alkyl group are 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 which are independently selected from halogen, -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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C 2-6 Alkynyl substituents are optionally substituted.

[0289] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 8- to 10-membered fused heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 8- to 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, R 1is selected from an optionally substituted 10-membered fused heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the fused heterocyclic ring has one saturated ring and one aromatic ring. In some cases, the fused heterocyclic ring has one saturated ring and one unsaturated ring. In some cases, the fused heterocyclic ring has two saturated rings. In some cases, the 10-membered heterocyclic ring contains at least 1 nitrogen atom. In some cases, the 10-membered heterocyclic ring contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least 3 nitrogen atoms. In some cases, R 1 Selected from Each of which is optionally substituted with one or more substituents. 1 for It is optionally substituted with one or more substituents. In some cases, the one or more optional substituents are independently selected from halogen, =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 In some cases, one or more optional substituents are independently selected from halogen, ═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 are independently selected from hydrogen; and C 1-6 Alkyl, C 3-12 carbocyclic and 3- to 12-membered heterocyclic rings. In some cases, each R 20 are independently selected from hydrogen; and C 1-6alkyl and a 3- to 12-membered heterocyclic ring. In some cases, each R 20 are independently selected from hydrogen; and C 1-6 alkyl and a 3- to 12-membered saturated heterocyclic ring. In some cases, R 1 The one or more optional substituents are independently selected from In some cases, R 1 Selected from In some cases, R 1 Selected from

[0290]

[0291] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted saturated 6- to 7-membered heterocyclic ring. 1 is selected from an optionally substituted saturated 6-membered heterocycle. 1 Selected from It is optionally substituted. In some cases, one or more optional substituents are independently selected from halogen, -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 In some cases, one or more optional substituents are independently selected from -CN, -NHCN, C 1-6 Cyanoalkyl and C 1-6 In some cases, one or more optional substituents are independently selected from -NHCN and C 1-6 In some cases, R 1 Selected from It is one or more selected from -NHCN and C 1-6 In some cases, R 1 Selected from

[0292] In some embodiments, for compounds or salts of Formula (I), R 3 is -CN, and R 1 Selected from and B is an optionally substituted 8- to 9-membered fused heterocyclic ring, wherein the 8- to 9-membered fused heterocyclic ring has at least one sulfur atom. In some cases, R 3 is -CN, and R 1 Selected from And B is selected from In some cases, R 3 is -CN, and R 1 Selected from In some cases, R 3 is -CN, and R 1 Selected from In some cases, R 3 is -CN, and R 1 Selected from In some cases, R 3 is -CN, B is And R 1 Selected from In some cases, R 3 is -CN, B is And R 1 Selected from In some cases, R 3 is -CN, B is And R 1 Selected from In some cases, R 3 is -CN, and R 1 Selected from B is an optionally substituted 8- to 9-membered fused heterocyclic ring having at least one sulfur atom; and YR 2 is selected from -OL-heterocycle, wherein the heterocyclic portion of -OL-heterocycle is replaced by one or more R 6 Optional substitution.

[0293] In some embodiments, for compounds or salts of Formula (I), B is an optionally substituted 8- to 10-membered fused carbocyclic ring. In some cases, B is an optionally substituted 8- to 10-membered fused carbocyclic ring. In some cases, B is an optionally substituted 9-membered fused carbocyclic ring. In some cases, B is a substituted 9-membered fused carbocyclic ring. In some cases, B is It is optionally substituted with 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 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 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 which is replaced by one or more selected from halogen and C 1-6 In some cases, B is It is substituted by one or more substituents selected from halogen. 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.

[0294] In some cases, B is selected from

[0295] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted unsaturated 10-membered fused heterocyclic ring. 1 for It is optionally substituted. In some cases, R 1 The 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 In some cases, B is an optionally substituted 8- to 10-membered fused heterocyclic ring containing one sulfur atom. In some cases, B is selected from Each of which is optionally substituted. In some cases, for B, one or more optional substituents of heterocycle and carbocycle are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -OC l -C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 2-6In some cases, YR 2 Selected from wherein the heterocyclic moiety is optionally substituted. In some cases, n is 0. In some cases, R 3 Selected from hydrogen, halogen, -CN, -N(R 20 )2、-OH、-S(O)2(R 20 ),-C(O)R 20 、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 and C 1-6 In some cases, R 3 is selected from hydrogen, halogen and -CN.

[0296] In some embodiments, for compounds or salts of Formula (I), R 1 is selected from an optionally substituted 11-membered fused heterocyclic ring. 1 is selected from an optionally substituted unsaturated 11-membered fused heterocyclic ring. In some cases, the heterocyclic ring contains at least one sulfur atom. In some cases, the heterocyclic ring contains at least one nitrogen atom. In some cases, the heterocyclic ring contains 3 heteroatoms. In some cases, the heterocyclic ring is It is optionally substituted. In some cases, R 1 for

[0297] In some embodiments, for compounds or salts of Formula (I), R 1 The one or more optional substituents are each independently selected from halogen, -CN, -NO2, =O, -N(R 20 )2、-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 、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl and C2-6 In some cases, one or more optional substituents are independently selected from halogen, -OH, -N(R 20 )2、-NO2、=O、-CN、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 1 The optional substituents are each independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 1 The optional substituents are each independently selected from halogen, -CN, -OH, -NH2, C 1-6 aminoalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl and C 1-6 In some cases, R 1 The optional substituents are each independently selected from -OH and -NH2. In some cases, R 20 Selected from hydrogen and C 1-3 alkyl.

[0298] In some embodiments, for the compound or salt of Formula (I), n is selected from 0 to 4. In some cases, n is selected from 0 to 3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0299] In some embodiments, for compounds or salts of Formula (I), each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 1-6 Cyanoalkyl and C 1-6 In some cases, R 4 Independently selected from halogen, =O, -CN, C 1-6 Cyanoalkyl, C 2-6 Alkynyl, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 In some cases, R 4Independently selected from halogen, =O, -CN, C 1-6 Cyanoalkyl, C 2-6 Alkynyl and C 1-6 In some cases, R 4 Independently selected from -CN, C 1-6 Cyanoalkyl and C 2-6 In some cases, each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl.

[0300] In some embodiments, for compounds or salts of Formula (I), Q is a bond. In some cases, Q is S. In some cases, Q is O.

[0301] In some embodiments, for compounds or salts of Formula (I), each R 7 independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl and -N(R 5 )2. In some cases, each R 7 Independently selected from halogen, hydroxy, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl and C l -C4 hydroxyalkyl.

[0302] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -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. 20 independently selected from hydrogen and C 1-6 In some cases, each R 20 Independently selected from C1-6 alkyl.

[0303] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -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. 21 independently selected from hydrogen and C 1-6 In some cases, each R 21 Independently selected from C 1-6 alkyl.

[0304] In some embodiments, for compounds or salts of Formula (I), 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, -NO2, -NH2, -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. 20 independently selected from hydrogen and C 1-6 In some cases, each R 20 Independently selected from C 1-6 alkyl.

[0305] In some embodiments, for compounds or salts of Formula (I), each R 23 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12The substituents of the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted. 23 independently selected from hydrogen and C 1-6 In some cases, each R 23 Independently selected from C 1-6 alkyl.

[0306] In one aspect, the present disclosure provides a compound of formula (IA)

[0307]

[0308] or a pharmaceutically acceptable salt thereof, wherein:

[0309] R 1 is selected from 8 to 10 membered heterocyclic rings, wherein the 8 to 10 membered heterocyclic rings are substituted by one or more independently selected from halogen, -OR 20 、-S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 =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 Halogenated alkyl, C 1-6 Alkyl-SO2R 20 、C 1-6 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 Alkynyl and 5- to 12-membered heterocyclic substituents are optionally substituted, wherein the 5- to 12-membered heterocyclic rings are each independently substituted with one or more R 1* Optional substitution;

[0310] Each R 1* are independently selected from halogen, -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)NR20 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, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and C3-C 12 carbon ring;

[0311] B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 Carbocyclic rings, including 7 to 15-membered heterocyclic rings and C7-C 15 Each of the carbocyclic rings is independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、C(O)OR 21、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted;

[0312] Y is selected from a bond, -O-, -S- and -N(R 5 )-;

[0313] R 2 Selected from heterocyclic, aryl, C l -C6 alkyl, -L-heterocycle, -LN(R 23 )2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 )2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2、-LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle and the cycloalkyl portion of -L-cycloalkyl are each replaced by one or more R 6 optionally substituted, and wherein aryl, -L-NR 23 The aryl portion of C(O)-aryl, -L-NR 23 The aryl portion of C(O)-aryl, the aryl of -L-aryl, and the heteroaryl of -L-heteroaryl are each replaced by one or more R 7 Optional substitution;

[0314] R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R20 )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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0315] Each R 4 Independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 alkyl halide;

[0316] n is selected from 0, 1, 2, 3 and 4;

[0317] Each R 5 Independently selected from hydrogen and C1-C6 alkyl;

[0318] Each R 6 Independently selected from halogen, hydroxy, 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, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、tert-butyldimethylsilyloxy CH2-、-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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 and -CH2 heterocycle, wherein -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l-C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2 heterocyclyl is optionally substituted with oxo;

[0319] each Q is selected from a bond, S, and O;

[0320] Each R 7 independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2 and -N(R 5 )2;

[0321] Each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene is independently selected from one or more halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are optionally substituted, wherein the C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted;

[0322] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0323] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0324] Each R 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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.

[0325] In some embodiments, Formula (I) or Formula (IA) is represented by Formula (IB),

[0326]

[0327] or a pharmaceutically acceptable salt thereof, wherein:

[0328] where R 1 Selected from Each of which is replaced by one or more independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 , =O and a 5- to 12-membered heterocyclic ring optionally substituted, wherein the 5- to 12-membered heterocyclic ring is each independently substituted with one or more R 1* Optional substitution;

[0329] Each R 1* independently selected from halogen, -OR 20 、-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 and C 1-6 alkyl;

[0330] Y is -O-;

[0331] R 2 Selected from -L-heterocycle, -LN(R 23 )2, wherein the heterocyclic portion of -L-heterocycle is replaced by one or more R 6 Optional substitution.

[0332] B is selected from a 7- to 15-membered heterocyclic ring, wherein the 7- to 15-membered heterocyclic ring is replaced by one or more independently selected from halogen, -CN, =O, -N(R 21 )2、-OR 21 、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 Halogenated alkyl, C 1-6 Alkyl and C 2-6 The substituents of the alkynyl group are optionally substituted;

[0333] R 3 Selected from hydrogen, halogen, -CN, -N(R 20 )2、-OR 20 、-C(O)R 20 、C 1-6 Alkyl-N(R 20 )2、C1-6 aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 alkyl; and

[0334] Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl and C 3-12 Carbocyclic rings, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 The alkyl and oxo substituents are optionally substituted.

[0335] In some embodiments, the compound or salt of Formula (I), Formula (IA), or Formula (IB), R 1 Selected from in is independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 , =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently substituted with one or more R 1* optionally substituted; and

[0336] Each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 alkyl.

[0337] In some embodiments, in the compound or salt of Formula (I), Formula (IA), or Formula (IB), Y is -O-.

[0338] In some embodiments, the compound or salt of Formula (I), Formula (IA), or Formula (IB), R 2 is selected from optionally substituted -L-heterocycle and -LN(R 23 )2. In some cases, R 2 is selected from optionally substituted -L-5 to 8 membered heterocycle and -LN(R 23 )2. In some cases, R 2 is selected from an optionally substituted -L-heterocycle. 2 Selected from -LN(R23 )2. In some cases, the heterocycle contains at least one nitrogen atom. In some cases, the heterocycle contains at least one sulfur atom. In some cases, the heterocycle contains at least one oxygen atom. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is a saturated heterocycle. In some cases, each R 6 Independently selected from halogen, hydroxy, 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, C1-C3 alkyl-substituted pyrazolyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、-N(R 5 )2、(C1-C3 alkoxy)C l -C3 alkyl-, (C1-C3 alkyl) C(=O), oxo, -OC l -C3 alkyl. In some cases, each R 6 Independently selected from halogen, hydroxy, C l -C3 hydroxyalkyl, C l -C3 alkyl, oxo, =CH2 and -OC l -C3 alkyl. In some cases, when R 2 When it is a heteroaryl group, R 6 Selected from halogen and C l -C3 haloalkyl, C l -C3 alkyl. In some cases, when R 2 When it is a heteroaryl group, R 6 In some cases, R 23 Selected from hydrogen and C l -C3 alkyl. In some cases, each R 23 Selected from C l -C3 alkyl. In some cases, each R 23 In some cases, each L is independently selected from C l -C4 alkylene, the C l -C4 alkylene is replaced by one or more independently selected from halogen and C l -C4 alkyl is optionally substituted with a substituent; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and the 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen. In some cases, each L is selected from In some cases, L is selected from In some cases, R 2 Selected from

[0339] In some embodiments, the compound or salt of Formula (I), Formula (IA), or Formula (IB), YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 Selected from In some cases, YR 2 for In some cases, YR 2 for

[0340] In some embodiments, in the compound or salt of Formula (I), Formula (IA) or Formula (IB), B is selected from an 8- to 10-membered heterocyclic ring, wherein the 8- to 10-membered heterocyclic ring is replaced by one or more independently selected from halogen, -CN, -NH2 and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, the heterocycle of B is selected from In some cases, B is selected from Each of which is replaced by one or more independently selected from halogen, -CN, -NH2 and C 1-6 The substituents of the alkyl group are optionally substituted. In some cases, B is selected from

[0341] In some embodiments, the compound or salt of Formula (I), Formula (IA), or Formula (IB), R 3 In some cases, R 3 is hydrogen. In some cases, R 3 In some cases, R 3 For fluorine.

[0342] In some embodiments, the compound or salt of Formula (I), Formula (IA), or Formula (IB), R1 for In some cases, R 1 for In some cases, R 1 for In some cases, R 1 for It is optionally substituted with one or more substituents. In some cases, the one or more optional substituents are independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic rings are each independently replaced by one or more R 1* In some cases, one or more optional substituents are independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 , =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently replaced by one or more R 1* In some cases, one or more optional substituents are independently selected from halogen, -C(O)N(R 20 )2. -C 1-6 Alkyl (=NOR 20 ),-C(O)R 20 and 5- to 9-membered heterocyclic rings, wherein the 5- to 9-membered heterocyclic rings are each independently replaced by one or more R 1* Optionally substituted. In some cases, R 1 for It is substituted with at least one substituent. In some cases, R 1 for

[0343] In some cases, R 1 for In some cases, each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 alkyl.

[0344] In some embodiments, for the compound or salt of Formula (I), Formula (IA), or Formula (IB), no electrophile moiety is present.

[0345] In some embodiments, for compounds or salts of Formula (I), Formula (IA), or Formula (IB), R 1 One or more optional substituents of is not an electrophile.

[0346] In some embodiments, for compounds or salts of Formula (I), R 1 In some cases, B is selected from the compounds in the Examples. In some cases, Y is selected from the compounds in the Examples. In some cases, R 2 In some cases, R 3 A compound selected from the examples.

[0347] In some embodiments, for compounds or salts of Formula (I), each R 20 Selected from hydrogen and C 1-3 In some cases, each R 20 is selected from hydrogen and C1 alkyl.

[0348] In one aspect, the present disclosure provides a compound of formula (II):

[0349]

[0350] or a pharmaceutically acceptable salt thereof, wherein:

[0351] A is selected from C5-C8 carbocyclic ring, wherein the C5-C8 carbocyclic ring is replaced by one or more independently selected R 94 The substituents are optionally substituted;

[0352] R 91 Selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0353] R 92 Selected from hydrogen, halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0354] R 93 Selected from hydrogen, -C(O)OR 21 、-C(O)R 21 and-SO2R 21 ;

[0355] Each R 94 independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings; and

[0356] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -N(C 1-6 Alkyl)2, C1-10 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;

[0357] In some embodiments, for the compound or salt of formula (II), A is selected from an optionally substituted C5-C7 carbocycle. In some cases, A is selected from an optionally substituted unsaturated C5-C7 carbocycle. In some cases, A is selected from an optionally substituted C5 carbocycle. In some cases, A is selected from an optionally substituted C6 carbocycle. In some cases, A is selected from an optionally substituted C7 carbocycle. In some cases, the C7 carbocycle of A is a monocyclic ring. In some cases, the C7 carbocycle of A is a bicyclic ring. In some cases, A is selected from In some cases, A is selected from In some cases, each R 94 independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, each R 94 independently selected from halogen, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, each R 94 Independently selected from C 1-6 In some cases, each R 94 are independently selected from methyl.

[0358] In some embodiments, formula (II) is represented by formula (II-A)

[0359]

[0360] or a pharmaceutically acceptable salt;

[0361] wherein n is selected from 0, 1 and 2.

[0362] In some embodiments, formula (II) is represented by formula (II-B)

[0363]

[0364] or a pharmaceutically acceptable salt;

[0365] wherein n is selected from 0, 1 and 2.

[0366] In some embodiments, formula (II) is represented by formula (II-C)

[0367]

[0368] or a pharmaceutically acceptable salt;

[0369] wherein n is selected from 0, 1 and 2.

[0370] In some embodiments, for the compound or salt of formula (II), A is an optionally substituted fused C6-C7 carbocyclic ring. In some cases, A is selected from an optionally substituted fused C6-C7 unsaturated carbocyclic ring. In some cases, A is selected from In some cases, A is selected from

[0371] In some embodiments, Formula (II) is represented by Formula (II-D).

[0372]

[0373] or a pharmaceutically acceptable salt;

[0374] wherein n is selected from 0, 1 and 2.

[0375] In some embodiments, for a compound or salt of Formula (II), Formula (II-A), Formula (II-B), Formula (II-C), or Formula (II-D), R 91 Selected from halogen, -CN, -NO2, -N(R 21 )2、-OR 21 、-C(O)R 21 、C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Halogenated alkyl, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, R 91 Selected from -CN.

[0376] In some embodiments, for a compound or salt of Formula (II), Formula (II-A), Formula (II-B), Formula (II-C), or Formula (II-D), R 92 Selected from hydrogen, halogen, -CN, -NO2, -N(R 21 )2、-OR 21 、-SR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, R 92 Selected from hydrogen, halogen, -CN and -N(R 21 )2. In some cases, R 92 Selected from -N(R 21 )2. In some cases, R 92 is selected from -NH2. In some cases, R 92 -N(R 21 )C(O)R 21 In some cases, R 92 -N(H)C(O)C 1-6 In some cases, R 92 It is -N(H)C(O)tert-butyl.

[0377] In some embodiments, for a compound or salt of Formula (II), Formula (II-A), Formula (II-B), Formula (II-C), or Formula (II-D), R 93 is selected from hydrogen. In some cases, R 93 Selected from -C(O)OR 21 In some cases, R 93 Selected from hydrogen and -C(O)OR21 In some cases, R 93 In some cases, R 93 Selected from -C(O)OC 1-6 alkyl.

[0378] In some embodiments, for a compound or salt of Formula (II-A), Formula (II-B), Formula (II-C), or Formula (II-D), each R 94 independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, each R 94 independently selected from halogen, C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 In some cases, each R 94 Independently selected from C 1-6 In some cases, each R 94 are independently selected from methyl.

[0379] In one aspect, the present disclosure provides a method for preparing a compound or salt of formula (II).

[0380] In one aspect, the present disclosure provides a compound of formula (III):

[0381]

[0382] or a pharmaceutically acceptable salt thereof, wherein:

[0383] B is selected from a 5- to 8-membered heterocyclic ring, wherein the 5- to 8-membered heterocyclic ring is replaced by one or more independently selected from halogen, -CN, -NO2, =O, -N(R21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted;

[0384] R 91 Selected from fluorine, iodine, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0385] R 92 Selected from hydrogen, halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2、-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2、-NR 21 S(O)2R 21 、-C(O)N(R 21 )2、-C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 )2、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 Halogenated alkyl, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings;

[0386] R 93 Selected from hydrogen, -C(O)OR 21 、-C(O)R 21 and-SO2R 21 ;and

[0387] Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 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, -NO2, -NH2, -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;

[0388] In some embodiments, for compounds or salts of formula (III), B is selected from an optionally substituted 5- to 7-membered heterocyclic ring. In some cases, B is selected from an optionally substituted unsaturated 5- to 7-membered heterocyclic ring. In some cases, B is selected from an optionally substituted 5-membered heterocyclic ring. In some cases, the heterocyclic ring of B has at least one sulfur atom. In some cases, the heterocyclic ring of B has one sulfur atom.

[0389] In some embodiments, Formula (III) is represented by Formula (III-A).

[0390]

[0391] or a pharmaceutically acceptable salt.

[0392] In some embodiments, for compounds or salts of Formula (III) and Formula (III-A), R 91 Selected from halogen, -CN, -NO2, -N(R 21 )2、-OR 21 、-C(O)R 21 、C 1-6 Alkyl-N(R 20 )2、C 1-6 aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C1-6 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, R 91 Selected from -CN.

[0393] In some embodiments, for compounds or salts of Formula (III) and Formula (III-A), R 92 Selected from hydrogen, halogen, -CN, -NO2, -N(R 21 )2、-OR 21 、-SR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、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 Halogenated alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 carbocyclic and 5- to 12-membered heterocyclic rings. In some cases, R 92 Selected from hydrogen, halogen, -CN and -N(R 21 )2. In some cases, R 92 Selected from -N(R 21 )2. In some cases, R 92 is -NH2. In some cases, R 92 -N(R 21 )C(O)R 21 In some cases, R 92 -N(H)C(O)C 1-6 In some cases, R 92 It is -N(H)C(O)tert-butyl.

[0394] In some embodiments, for compounds or salts of Formula (III) and Formula (III-A), R 93 is selected from hydrogen. In some cases, R 93 Selected from -C(O)OR 21 In some cases, R 93 Selected from hydrogen and -C(O)OR 21 In some cases, R93 In some cases, R 93 Selected from -C(O)OC 1-6 alkyl.

[0395] In one aspect, the present disclosure provides a method of preparing a compound or salt of any one of formula (III).

[0396] Although preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Many variations, changes, and substitutions will now occur to those skilled in the art without departing from the present invention. It should be understood that various alternatives to the embodiments of the invention described herein may be used to implement the present invention. The following claims are intended to define the scope of the invention and thus cover methods and structures within the scope of these claims and their equivalents.

[0397] Chemical entities with carbon-carbon double bonds or carbon-nitrogen double bonds can exist in Z or E form (or cis or trans form). In addition, some chemical entities can exist in various tautomeric forms. Unless otherwise indicated, compounds or salts of formula (I) are intended to also include all Z, E and tautomeric forms.

[0398] "Isomers" are different compounds with the same molecular formula. "Stereoisomers" are isomers that differ in the way their atoms are arranged in space. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to refer to a racemic mixture where appropriate. "Diastereomers" or "diastereoisomers" refer to stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be designated by R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-), depending on the direction (right- or left-handed) that they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomeric forms, whose asymmetric centers can be defined as (R)- or (S)- in terms of absolute stereochemistry. The chemical entities, pharmaceutical compositions, and methods of the present invention are intended to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. The optical activity of the compounds can be analyzed by any suitable method, including but not limited to chiral chromatography and optical rotation, and the degree of dominance of one stereoisomer over another can be determined.

[0399] In some cases, the compound or salt of formula (I) herein may exist as a diastereomer, enantiomer or other stereoisomeric form. The compound proposed herein includes all diastereomers, enantiomers and epimer forms as well as racemates, mixtures of diastereomers and their other mixtures, as long as they can be prepared by conventional experiments by those of ordinary skill in the art. The separation of stereoisomers can be carried out by chromatography or by forming diastereomers and separating 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 for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis. In addition, a mixture of two enantiomers enriched in one of them can be purified to provide the main enantiomer in a further optically enriched form by recrystallization and / or grinding.

[0400] "Tautomers" refer to molecules in which a proton can be transferred from one atom of the molecule to another atom of the same molecule. In certain embodiments, the compounds or salts of Formula (I) exist as tautomers. Where tautomerism is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non-limiting examples of tautomeric equilibria include:

[0401]

[0402] In some embodiments, the compounds disclosed herein are used in different isotopically enriched forms, for example in 2 H. 3 H. 11 C. 13 C and / or 14 In one 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.

[0403] Unless otherwise indicated, the compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, except for the replacement of hydrogen by deuterium or tritium or the replacement of carbon by 13 C or 14 Compounds having the present structures other than C-enriched carbon substitutions are within the scope of this disclosure.

[0404] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labeled with an isotope, 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 All isotopic substitutions are contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0405] In certain embodiments, some or all of the compounds disclosed herein 1 H atoms are 2 H atom substitution. Methods for synthesizing deuterium-containing compounds are known in the art and include the following synthetic methods by way of non-limiting example only.

[0406] Deuterium substituted compounds are synthesized using various methods such as those described in: Dean, Dennis C.; Editor. 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.

[0407] Deuterated starting materials are readily available and amenable to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A large number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0408] 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, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0409] In some cases, the compounds described herein exist as diastereomers, enantiomers or other stereoisomers. In the absence of a specified absolute stereochemistry, the compounds presented herein include all diastereoisomers, enantiomers and epimeric forms and suitable mixtures thereof. The separation of stereoisomers can be carried out 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 for this disclosure). Stereoisomers can also be obtained by stereoselective synthesis.

[0410] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Likewise, 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 exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. It is also contemplated that solvated forms of the compounds presented herein are disclosed herein.

[0411] In certain embodiments, the compound or the salt of the compound can be a prodrug, for example, wherein the hydroxyl group in the parent compound exists as an ester or carbonate, or the carboxylic acid present in the parent compound exists as an ester. The term "prodrug" is intended to encompass compounds that are converted into the medicament of the present disclosure under physiological conditions. A method for preparing a prodrug is to include one or more selected parts that are hydrolyzed 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 a specific target cell in a host animal). For example, esters or carbonates (for example, esters of alcohol or carboxylic acid or carbonates and esters of phosphonic acid) are preferred prodrugs of the present disclosure.

[0412] Prodrug forms of the compounds described herein (wherein the prodrug is metabolized in vivo to produce a compound as described herein) are included within the scope of the claims. In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0413] In some cases, prodrugs are often useful because they can be more easily administered than the parent drug. For example, they can be bioavailable by oral administration, whereas the parent drug is not. Prodrugs can help enhance the cell permeability of the compound relative to the parent drug. Prodrugs can also have improved solubility relative to the parent drug in pharmaceutical compositions. Prodrugs can be designed as reversible drug derivatives, used as modifiers to enhance drug transport to site-specific tissues or to increase drug retention within cells.

[0414] In some embodiments, the design of the prodrug increases the lipophilicity of the agent. In some embodiments, the design of the prodrug increases the effective water solubility. See, e.g., 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, ACS Symposium Series Vol. 14; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, which is incorporated herein in its entirety for such disclosures. According to another embodiment, the present disclosure provides a method for producing the compounds defined above. The compounds can be synthesized using conventional techniques. Advantageously, these compounds can be conveniently synthesized from readily available starting materials.

[0415] Synthetic chemistry transformations and methods useful for synthesizing 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 PGM Wuts, Protective Groups in Organic Synthesis, 2nd ed. (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).

[0416] pharmaceutical preparations

[0417] In certain embodiments, provided herein are compositions (also referred to herein as "agents") comprising a therapeutically effective amount of any compound or salt of Formula (I), Formula (IA), or Formula (IB).

[0418] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers (including excipients and adjuvants that aid in processing the medicament into a pharmaceutically useful preparation). Appropriate formulations depend on the chosen route of administration. An overview of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, 19th ed. (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 ed. (Lippincott Williams & Wilkins, 1999).

[0419] The compositions and methods of the present disclosure can be used to treat individuals in need. In certain embodiments, the individual is a mammal, such as a human or non-human mammal. When applied to an animal (such as a human), the composition or medicament is preferably administered in the form of a pharmaceutical composition comprising, for example, a medicament 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 vehicles (such as ethylene glycol, glycerol, oil (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 bypassing the transport or diffusion pathway (such as injection or implantation) through the epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. For example, an excipient can be selected to achieve delayed release or selective targeting of one or more cells, tissues or organs of an agent. The pharmaceutical composition can be in dosage unit form, such as tablets, capsules, granules, lyophiles for reconstitution, powders, solutions, syrups, suppositories, injections, etc. The composition can also be present in a transdermal delivery system, such as a skin patch. The composition may also be presented in a solution suitable for topical administration, such as eye drops.

[0420] Pharmaceutically acceptable excipients can contain physiologically acceptable agents, which play an effect such as stabilizing a compound (such as a medicament), increasing its solubility or increasing 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 selection of pharmaceutically acceptable excipients (including physiologically acceptable agents) depends on, for example, the route of administration of the composition. Preparations or pharmaceutical compositions can be self-emulsifying drug delivery systems or self-microemulsifying drug delivery systems. Pharmaceutical compositions (preparations) can also be liposomes or other polymer matrices, into which compounds of the present invention can be incorporated. For example, liposomes comprising phospholipids or other lipids are relatively simple nontoxic, physiologically acceptable and metabolizable carriers for manufacture and administration.

[0421] The pharmaceutical composition (preparation) can be administered to a subject by a variety of routes of administration, including, for example, oral administration, such as a drench in an aqueous or non-aqueous solution or suspension, a tablet, a capsule (including a sprinkle capsule and a gelatin capsule), a bolus, a powder, a granule, a paste for application to the tongue; absorption through the oral mucosa, such as sublingually; anally, rectally or vaginally, such as in the form of a vaginal suppository, a cream or a foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally, such as in the form of a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, such as in the form of a patch applied to the skin; and topically, such as in the form of a cream, ointment or spray applied to the skin, or in the form of eye drops. The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water.

[0422] The pharmaceutical composition can be a sterile aqueous or non-aqueous solution, suspension or emulsion, such as a microemulsion. The excipients described herein are exemplary and not limiting in any way. An effective amount or therapeutically effective amount refers to the amount of one or more agents administered to a subject in a single dose or as part of a series of doses that is effective to produce the desired therapeutic effect.

[0423] Typically, the therapeutic effect of a subject can be monitored using assays and methods suitable for the condition being treated, which are familiar to those of ordinary skill in the art and described herein. The pharmacokinetics of a medicament or one or more metabolites thereof administered to a subject can be monitored by determining the level of the medicament or metabolites in a biological fluid (e.g., blood, blood fractions (e.g., serum) and / or urine) and / or other biological samples or biological tissues from the subject. The methods of any detection agent practiced in the art and described herein can be used to measure the level of the medicament or metabolite during the course of treatment.

[0424] The dosage of the agents described herein for treating a disease or condition 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, and age, sex, and weight, as well as other factors apparent to those skilled in the medical field. The pharmaceutical composition may be administered as determined by those skilled in the medical field in a manner suitable for the disease being treated. In addition to factors related to the use of the agents for treating a disease or condition described herein and above, the appropriate duration and frequency of administration of the agent may also 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 dose of an agent can typically be determined using experimental models and / or clinical trials. The optimal dose may depend on the subject's constitution, weight, or blood volume. It is generally preferred to use the minimum dose sufficient to provide effective treatment. The design and execution of preclinical and clinical studies of the agents described herein (including when administered for preventive benefit) are fully within the skill of those skilled in the relevant art. When two or more agents are administered to treat a disease or condition, the optimal dose of each agent may be different, such as lower than the dose when any one agent is administered alone as a monotherapy. In some specific embodiments, two kinds of medicaments of combination can work synergistically or additively, and any agent can be used with the amount less than being used alone.The amount of the medicament that can be used every day can be for example between about 0.01mg / kg body weight and 100mg / kg body weight, for example, between about 0.1 to 1mg / kg body weight, between about 1 to 10mg / kg body weight, between about 10-50mg / kg body weight, between about 50-100mg / kg body weight.In other embodiments, the amount of the medicament that can be used every day is between about 0.01mg / kg body weight and 1000mg / kg body weight, between about 100-500mg / kg body weight or between about 500-1000mg / kg body weight.Every day or each treatment time course optimum dose can be different because of the disease or illness being treated, and can also change because of route of administration and therapeutic regimen.

[0425] The pharmaceutical composition comprising the medicament can be formulated in a manner suitable for the delivery method using techniques conventionally practiced in the art. The composition can be in the form of a solid (e.g., tablet, capsule), semisolid (e.g., gel), liquid, or gas (e.g., aerosol). In other embodiments, the pharmaceutical composition is administered by bolus infusion.

[0426] Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed., Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. Generally, the type of excipient is selected based on the mode of administration and the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as a lyophilizate. The compositions described herein may be lyophilized or otherwise formulated into a lyophilized product using one or more appropriate excipient solutions to dissolve and / or dilute the agent of the composition upon administration. In other embodiments, the agent may be encapsulated within liposomes using techniques known and practiced in the art. In certain specific embodiments, the agent is not formulated within a liposome for application in a stent for treating a highly (but not totally) occluded artery.The pharmaceutical composition may be formulated for any suitable mode of administration as described herein and in the art.

[0427] Pharmaceutical compositions (e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other methods) can be in the form of liquid. Liquid pharmaceutical compositions can include, for example, one or more of the following: sterile diluents, such as water, saline solution (preferably normal saline), Ringer's solution, isotonic sodium chloride, fixed oils that can be used as solvents or suspension media, polyethylene glycol, glycerol, propylene glycol or other solvents; antibacterial agents; antioxidants; chelating agents; buffers; and agents for regulating tension, such as sodium chloride or dextrose. Parenteral compositions can be packaged in ampoules, disposable syringes or multidose vials made of glass or plastic. It is preferred to use normal saline, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for treating ophthalmic conditions or diseases, liquid pharmaceutical compositions can be applied to eyes in the form of eye drops. Liquid pharmaceutical compositions can be delivered orally.

[0428] For oral formulations, at least one of medicament as herein described can be used alone, or used in combination with suitable additives to make tablets, powders, granules or capsules, and if necessary, used in combination with diluents, buffers, wetting agents, preservatives, coloring agents and flavorings. Medicament can be formulated with a buffer to provide protection and / or enteric coatings that protect the compound from the low pH impact of the gastric environment. The medicament included in the pharmaceutical composition can be formulated for oral delivery together with, for example, the flavorings in liquid, solid or semisolid formulations and / or with enteric coatings.

[0429] The pharmaceutical composition comprising any of the agents described herein can be formulated for sustained or slow release, also referred to as timed release or controlled release. Such compositions can generally be prepared using well-known techniques and can be administered by, for example, oral, rectal, intradermal or subcutaneous implantation, or by implantation in the desired target site. Sustained-release formulations can contain compounds dispersed in a carrier matrix and / or contained in a reservoir surrounded by a rate-controlling membrane. The excipients used in such formulations are biocompatible and can also be biodegradable; preferably, the formulation provides a relatively constant level of active ingredient release. The amount of the medicament contained in the sustained-release formulation depends on the location of implantation, the rate of release, and the expected duration, as well as the nature of the condition, disease, or illness to be treated or prevented.

[0430] In certain embodiments, the pharmaceutical composition comprising the medicament is formulated for transdermal, intradermal or topical administration. A syringe, bandage, transdermal patch, insert or syringe-like application device can be used to apply the composition in the form of powder / talcum powder or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, pastes. Preferably, it is in the form of a controlled release formulation or sustained release formulation through topical administration or direct injection into the skin adjacent to the treatment area or in the area to be treated (e.g., intradermal or subcutaneous). 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, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal and combinations thereof.

[0431] Pharmaceutical compositions comprising medicaments can be formulated as emulsions for topical application. Emulsions contain a liquid distributed in a bulk of a second liquid. Emulsions can be oil-in-water emulsions or water-in-oil emulsions. Either or both of the oil phase and the aqueous phase can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase can 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 topical application can also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or moisturizer.

[0432] For example, ointments and creams can be prepared with aqueous or oily bases, adding suitable thickeners and / or gelling agents. Lotions can be prepared with aqueous or oily bases and usually also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. Liquid sprays can, for example, be delivered from pressurized packaging via a closure of a special shape. Water-in-oil emulsions can also be used in compositions, patches, bandages and products. These systems are semisolid emulsions, microemulsions or foam emulsion systems.

[0433] In some embodiments, the agents described herein can be formulated as inhalants. Inhalation methods can deliver drugs 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 powders. Liquid aerosol formulations are optionally atomized primarily into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered to the terminal bronchioles through the endobronchial tree and ultimately to the parenchymal tissue.

[0434] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device, such as an ejector, a vibrating porous plate, or an ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having a mass median average diameter primarily between 1 and 5 μm. In addition, the formulation preferably has a balanced osmotic pressure, ionic strength, and chloride concentration, and a minimum aerosolized volume capable of delivering an effective dose of the medicament. Furthermore, the aerosolized formulation preferably does not negatively affect the function of the airways nor cause undesirable side effects.

[0435] Aerosol devices suitable for administering the aerosols described herein include, for example, ejectors, vibrating porous plates, ultrasonic nebulizers, and powered dry powder inhalers, which are capable of atomizing the formulation into aerosol particles having a particle size primarily in the range of 1-5 μm. Primarily in this application means that at least 70%, but preferably more than 90%, of all generated aerosol particles are within the range of 1-5 μm. Jet nebulizers work by breaking up liquid solutions into aerosol droplets through air pressure. Vibrating porous plate nebulizers work by squeezing solvent droplets out of a porous plate using a sonic vacuum generated by a rapidly vibrating porous plate. Ultrasonic nebulizers work by piezoelectric crystals that shear the liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Nebulizer (Medic-Aid Ltd., West Sussex, England), Pari and Pari LC Jet nebulizer (Pari Respiratory Equipment, Inc., Richmond, Virginia) and AerosonicTM (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizer.

[0436] In some embodiments, medicament can be formulated with oily base or ointment to form semisolid composition with desired shape.In addition to medicament, these semisolid compositions can also contain dissolved and / or suspended bactericide, preservative and / or buffer system.The petrolatum component that can be included can be any paraffin (paraffin) with viscosity range of mineral oil to paraffin (paraffin waxes) mixed with isobutylene, colloidal silica or stearate.The absorption base can be used together with oily system.Additive can include cholesterol, lanolin (lanolin derivative), beeswax, fatty alcohol, wool wax alcohol (wool wax alcohol), low HLB (hydrophobic lipophobic balance) emulsifier and various ionic and nonionic surfactants in particular or in combination.

[0437] The transdermal or topical formulations of control or sustained release can be achieved by adding a time-delayed release additive (such as a polymer structure, matrix) available in the art. For example, compositions can be applied by using a hot melt extruded article (such as a bioadhesive hot melt extruded film). The preparation can include a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent can exist in an amount sufficient to provide enough adhesion to maintain the system attached to the target epithelium or endothelial cell surface, to last for a period of time sufficient to achieve the desired compound release.

[0438] The insert, transdermal patch, bandage, or article of manufacture may comprise a mixture or coating of polymers that provides for release of the pharmaceutical agent at a constant rate over an extended period of time. In some embodiments, the article of manufacture, transdermal patch, or insert comprises a water-soluble pore former, such as polyethylene glycol (PEG), which may be mixed with a water-insoluble polymer to increase the durability of the insert and prolong the release of the active ingredient.

[0439] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers can be used for application to sites where pH changes can be used to affect release. These rate-controlling polymers can be applied using a continuous coating film during spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid, biodegradable insert.

[0440] Polymer formulations can also be used to provide controlled release 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. The microparticles can be microspheres, and the core can be a material different from the polymer shell. Alternatively, the polymer can be cast into a thin sheet or film, a powder or gel (such as a hydrogel) produced by grinding or other standard techniques. The polymer can also be in the form of a coating or a part of a bandage, stent, catheter, vascular graft or other device that is conducive to drug delivery. The matrix can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0441] Kits are provided having unit doses of one or more of the agents described herein (typically oral or injectable doses). Such kits may include a container containing the unit dose, an informational package insert describing the use of the drug in treating the disease and the attendant benefits, and optionally an implement or device for delivering the composition.

[0442] Treatment

[0443] In one aspect, the present disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method can inhibit the activity of KRas G12 mutants in cells. In some cases, inhibiting the activity of KRas G12 mutants in cells can include contacting cells in which the activity of KRas G12 mutants needs to be inhibited with an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing a compound or salt of Formula (I), Formula (IA) or Formula (IB) and a pharmaceutically acceptable excipient. In some cases, the contact is in vitro contact. In some cases, the contact is in vivo contact. As used herein, the term "contacting" refers to bringing the indicated parts together in an in vitro system or an in vivo system. For example, "contacting" KRas G12D and / or other G12 mutants with a compound provided herein includes administering a compound provided herein to an individual or patient (such as a human) having KRas G12D and / or other G12 mutants, and, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing KRas G12D and / or other G12 mutants. In some cases, cells in which the activity of KRas G12D and / or other G12 mutants is to be inhibited are contacted with an effective amount of a compound of Formula (I) or a salt thereof, or a pharmaceutical composition thereof, to negatively regulate the activity of KRas G12D and / or other G12 mutants. In some cases, by negatively regulating the activity of KRas G12D and / or other G12 mutants, the methods described herein are designed to inhibit unwanted cell proliferation caused by enhanced intracellular activity of KRas G12D and / or other G12 mutants. Cells can be contacted in a single dose or multiple doses, depending on the specific treatment regimen, to achieve the desired negative regulation 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.

[0444] In some embodiments, the inhibitory activity of exemplary compounds can be monitored in cells, for example, by measuring the inhibition of KRas G12D and / or other G12 mutant activity by the amount of phosphorylated ERK.

[0445] In another aspect, a method of treating cancer in a patient in need thereof is provided, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. The compositions and methods provided herein can be used to treat cancers associated with KRas G12D and / or other G12 mutants in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In some cases, the 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, and the like. 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, and thyroid cancer, as well as sarcomas. More specifically, these compounds are useful in the treatment of: Heart: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma; Lung: bronchogenic carcinoma (squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma), Genitourinary tract: Kidney (adenocarcinoma, Wilms' tumor (Nephroblastoma), lymphoma, leukemia); bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma); prostate (adenocarcinoma, sarcoma); testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: Hepatocellular carcinoma, bile duct carcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma;Bone: osteoblastic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma sarcoma), malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondrofibroma (osteocartilaginous exostosis), benign enchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; Nervous system: skull (osteomas, hemangiomas, granulomas, xanthomas, and osteitis deformans); meninges (meningiomas, meningiosarcoma, and gliomatosis); brain (astrocytomas, medulloblastomas, gliomas, ependymomas, germ cell tumors (pinealomas), glioblastomas multiforme, oligodendrogliomas, schwannomas, retinoblastomas, and congenital tumors); spinal neurofibromas, meningiomas, gliomas, and sarcomas; Gynecological: uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia) dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumor, Sertoli-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 tube (carcinoma); Hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease disease), 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 gland: 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 to be treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions comprising such compounds and salts can also be co-administered with other anti-tumor compounds (e.g., chemotherapy), or used in combination with other treatments (such as radiation or surgical intervention) as adjuvants before or after surgery. ;

[0446] Also provided herein are compounds of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in therapy.

[0447] Also provided herein are compounds of Formula (I), Formula (IA), or Formula (IB), or pharmaceutically acceptable salts of any one thereof, or pharmaceutical compositions of any one thereof, for use in treating cancer.

[0448] Also provided herein are compounds of Formula (I), Formula (IA), or Formula (IB), or pharmaceutically acceptable salts of any one thereof, or pharmaceutical compositions of any one thereof, for use in inhibiting KRas G12D and / or other G12 mutants.

[0449] Also provided herein are compounds of formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof for use in treating diseases or conditions associated with KRas G12D and / or other G12 mutants.

[0450] Also provided herein is the use of a compound of Formula (I), Formula (IA) or Formula (IB) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating cancer.

[0451] Also provided herein is the use of a compound of Formula (I), Formula (IA) or Formula (IB) or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for inhibiting the activity of KRas G12D and / or other G12 mutants.

[0452] Also provided herein is the use of a compound of Formula (I), Formula (IA), or Formula (IB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for treating a disease or condition associated with KRas G12D and / or other G12 mutants.

[0453] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, comprising (a) determining that the cancer is associated with KRas G12D mutations and / or other G12 mutants (e.g., KRas G12D and / or other G12 mutant-associated cancer) (e.g., as determined using a regulatory agency-approved (e.g., FDA-approved) assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0454] The compounds described herein can be used in the preparation of a medicament for preventing or treating a disease or condition. In addition, methods for treating any of the diseases or conditions described herein in a subject in need of 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.

[0455] The compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health, weight, and response to the drugs, and the judgment of the treating physician.

[0456] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." 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 use will depend on the severity and course of the disease, disorder, or condition; previous therapy; the patient's health status and response to the drugs; and the judgment of the treating physician.

[0457] In cases where the patient's condition does not improve, at the physician's discretion, administration of the compound may be chronic, i.e., for an extended period of time, including for the entire duration of the patient's life, in order to ameliorate the patient's disease or condition or otherwise control or limit its symptoms.

[0458] Once the patient's condition improves, a maintenance dose (if necessary) is administered. Subsequently, the dosage or frequency of administration, or both, may be reduced to a level that retains the improved disease, disorder, or condition, depending on the symptoms. However, upon any recurrence of symptoms, the patient may require intermittent treatment for an extended period of time.

[0459] The amount of a given dose corresponding to such an amount will vary according to factors such as the specific compound, the disease or condition and its severity, the identity of the subject or host to be treated (e.g., body weight), but 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 to be treated, and the subject or host to be treated. However, in general, the dosage adopted for adult treatment will typically be in the range of about 0.02 to about 5000 mg per day, in some embodiments, in the range of about 1 to about 1500 mg per day. The desired dosage can be conveniently provided in a single dose, or in divided doses administered simultaneously (or in a short period of time) or at appropriate intervals (e.g., twice, three times, four times or more sub-doses per day).

[0460] The pharmaceutical compositions described herein may be in the form of unit dosage forms suitable for single administration of precise doses. 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 a package containing discrete amounts of the formulation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions may be packaged in single-dose, non-reclosable containers. Alternatively, multi-dose, non-reclosable containers may be used, in which case a preservative is typically included in the composition. By way of example only, formulations for parenteral injection may be provided in unit dosage form, including but not limited to ampoules, or in multi-dose containers to which a preservative is added.

[0461] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the LD 50 (50% lethal dose for a population) and ED 50 (50% therapeutically effective dose in the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as LD 50 With ED 50 Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used in formulating a range of doses for use in humans. Dosages of such compounds are preferably in the range that includes the ED 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0462] In certain embodiments, the present invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof, 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.

[0463] Bifunctional compounds

[0464] In some embodiments, the compounds herein can be used to selectively eliminate hyperactivated KRas signaling induced by KRas mutations by directly binding to the mutant KRas protein, by stabilizing its GDP-bound form (inactive form), or by blocking the interaction between the GTP-bound form and its downstream target proteins. In some embodiments, another approach is to hijack the protein degradation machinery in the cell and exploit the substrate specificity of E3 ligases (such as VHL, CRBN or IAP) through bifunctional molecules called proteolysis targeting chimeras (PROTACs) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science. 2015 Jun 19; 348(6241): 1376-81), which can bind to mutant KRas proteins and E3 ligases, generating an interaction between the two proteins and inducing KRas degradation.

[0465] Disclosed herein is a bifunctional compound consisting of a target protein (i.e., KRAS G12D) binding portion and an E3 ubiquitin ligase binding portion, which can induce proteasome-mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D) binding portion and an E3 ubiquitin ligase binding portion known in the art. In some embodiments, disclosed herein is the use of compounds disclosed herein in degrading target protein compounds by chemical modification using compounds disclosed herein. In some cases, the target protein binding portion is derived from a compound of formula (I), formula (IA), or formula (IB).

[0466] Preparation of compounds

[0467] The compounds of the present disclosure 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 of the present disclosure can be synthesized using methods described herein and synthetic methods known in the art of synthetic organic chemistry or variations thereof as understood by those skilled in the art.

[0468] The compounds of the present disclosure can be prepared as described in the Schemes and Examples elsewhere herein.

[0469] Example

[0470] The following examples further illustrate the present invention but, of course, should not be construed as limiting its scope in any way.

[0471] The following synthetic schemes are provided for illustrative purposes only, 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 those skilled in the art. 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 appropriate raw materials and changing the synthetic pathways as needed. Typically, raw materials and reagents can be obtained from commercial suppliers, or synthesized from sources known to those skilled in the art, or prepared as described herein.

[0472] The present disclosure provides processes for preparing the compounds described herein (described in more detail below). Certain compounds in the Tables herein can be prepared using appropriate reagents as described in the Schemes herein.

[0473] Synthesis of intermediates

[0474] Intermediate 1. 3-Chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -Synthesis of 2-formamide.

[0475]

[0476] Step 1. Synthesis of 2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1a). A solution of propan-2-yl-1-amine (1.87 mL, 29.1 mmol) and N,N-diisopropylethylamine (10.15 mL, 58.3 mmol) in DCM (100 mL) was cooled to 0 ° C. 2-nitrobenzenesulfonyl chloride (6.46 g, 29.15 mmol) was added in batches. The solution was then warmed to rt and further stirred for 1 hour. The mixture was washed with water and brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (eluted with 20% to 50% EtOAc in petroleum ether) to obtain 2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1a, 5.98 g, 24.9 mmol, 85.4% yield) as a yellow solid. LCMS: C9H9N2O4S (M+H) + Calcd. for m / z = 241.0; found, 241.0.

[0477] Step 2. (3-chloropropyl) -2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1b) synthesis. To 2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1a, 1.0g, 4.16mmol) and cesium carbonate (6.764g, 20.81mmol) in acetone (30mL) solution, dropwise add pure 1-bromo-3-chloro-propane (6.05mL, 61.19mmol). After addition, reaction mixture was stirred at rt for 2 hours. The mixture was concentrated, then washed with water and salt water, through Na SO Drying, concentrated. The crude product was purified by silica gel chromatography (eluting with 20% to 50% EtOAc in petroleum ether). (3-Chloropropyl)-2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1b, 2.43 g, 7.67 mmol, 92.1% yield) was obtained as a yellow oil. LCMS: C 12 H 14 ClN2O4S(M+H) + Calcd. for m / z = 317.0; found, 317.0.

[0478] Step 3. 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-ethyl formate (Int-1c) Synthesis. To a solution of (3-chloropropyl)-2-nitro-prop-2-ynyl-benzenesulfonamide (Int-1b, 10.0 g, 31.6 mmol) and ethyl 2-diazoacetate (5.4 g, 47.3 mmol) in chlorobenzene (80 mL) was added N,N-diisopropylethylamine (5.5 mL, 31.57 mmol). It was then heated at 140 ° C for 1.5 hours. Cesium carbonate (12.3 g, 37.9 mmol) was subsequently added and then heated at 140 ° C for 30 minutes. The solvent was concentrated and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (eluting with 20% to 90% EtOAc in petroleum ether) and then triturated in EtOAc to afford 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine as a yellow solid. -2-Ethyl carboxylate (Int-1c, 5.80 g, 14.7 mmol, 46.6% yield). LCMS: C 16 H 19 N4O6S(M+H) + Calcd. for m / z = 395.1; found, 395.0.

[0479] Step 4. 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Synthesis of ethyl 2-formate (Int-1d). At 25 °C, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine was added. -2-ethyl formate (Int-1c, 12.6 g, 31.95 mmol) was added to a solution of THF (100 mL) and methanol (25 mL) with 1 M LiOH (128 mL, 128 mmol). The mixture was stirred at 55 ° C for 2 h. The mixture was acidified to pH = 6 with HCl (1 mol / L in H2O), and the crude product was ground in water and filtered. 5- (2-nitrophenyl) sulfonyl -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepine was obtained as a yellow solid. -2-carboxylic acid (Int-1d, 11.5 g, 31.1 mmol, 97.3% yield). LCMS: C 14 H 14 N4O6S(M+H) + Calcd. for m / z = 367.1; found, 367.0.

[0480] Step 5. N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Synthesis of -2-formamide (Int-1e). At 30 ° C, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-formic acid (Int-1d, 9.6 mg, 26.2 mmol), DIEA (18.3 mL, 104.8 mmol) and HATU (14.95 g, 39.3 mmol) in DMF (90 mL) was added 2M methylmethylamine (20 mL, 39.3 mmol) in THF. The mixture was stirred at 30 ° C for 2 h. The mixture was diluted with DCM (300 x 2 mL), washed with water (400 mL) and brine (400 x 2 mL), dried over Na2SO4 and concentrated to give the crude product N, N-dimethyl-5- (2-nitrophenyl) sulfonyl -4,6,7,8-tetrahydropyrazolo [1,5-a] [1,4] diazepine as a yellow oil. -2-formamide (Int-1e, 10.1 g, 24.4 mmol, 93.1% yield). LCMS: C 16 H 20 N4O3S(M+H) +Calcd. value, m / z = 394.1; found, 394.2.

[0481] Step 6. 3-Chloro-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Synthesis of -2-formamide (Int-1f). At 0°C under argon, N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine was added to -2-formamide (Int-1e, 10g, 25.67mmol) in DMF (100mL) was added chlorosuccinimide (3.428g, 25.67mmol). The mixture was stirred at 45 ° C for 1h. The mixture was concentrated to give a crude product. The crude product was ground in water and filtered to give 3-chloro-N, N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine as a crude yellow solid. -2-formamide (Int-1f, 10.2 g, 23.4 mmol, 91.0% yield). LCMS: C 16 H 17 ClN4O6S(M+H) + Calcd. for m / z = 428.1; found, 428.0.

[0482] Step 7. 3-Chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-formamide (Intermediate 1) Synthesis. To 3-chloro-N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-formamide (Int-1f, 10.2g, 23.84mmol), 4-methoxybenzenethiol (8.8mL, 71.52mmol) and Cs2CO3 (31067.73mg, 95.36mmol) in acetonitrile (100mL). The mixture was stirred at 25 ° C for 2h. The mixture was concentrated and the crude product was purified by silica gel chromatography (eluting with 3% to 10% MeOH in DCM) to obtain 3-chloro-N, N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine as a yellow solid. -2-formamide (Intermediate 1, 3.2 g, 13.2 mmol, 55.3% yield). LCMS: C 10 H 15ClN4O(M+H) + Calculated value, m / z = 243.1; found, 243.0

[0483] Alternative synthesis of intermediate 1. 3-Chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -Synthesis of 2-formamide.

[0484]

[0485] Step 1. Synthesis of 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (Int-1g). To a solution of 1H-pyrazole-3,5-dicarboxylic acid diethyl ester (20g, 94.25mmol) in acetic acid (360mL) was added dropwise NaClO (264mL, 1980mmol). After stirring at 25°C for 3h, the remaining mixture was diluted with water, and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated to obtain a light yellow solid, which was dissolved in petroleum ether (160mL) and EtOAc (20mL), then filtered and the solid was collected to obtain 4-chloro-1H-pyrazole-3,5-dicarboxylic acid diethyl ester (Int-1g, 15.20g, 61.6mmol, 65.38% yield) and mother liquor 7g as a white solid. LCMS: C9H 12 ClN2O4(M+H) + Calculated value, m / z = 247.6; found, 247. 1 H NMR (400MHz, CD3OD) δ4.44–4.36 (m, 4H), 1.39 (t, J = 7.1Hz, 6H).

[0486] Step 2. Synthesis of diethyl 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-pyrazole-3,5-dicarboxylate (Int-1h). To a solution of diethyl 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-pyrazole-3,5-dicarboxylate (Int-1g, 24.7g, 24.46mmol, 39.70% yield) in DMF (150mL) were added tert-butyl N-(3-bromopropyl)carbamate (16141.77mg, 67.79mmol), potassium iodide (204.6mg, 1.23mmol), Cs2CO3 (40157.83mg, 123.25mmol), and the mixture was stirred at rt for 16h. The reaction was quenched with water, extracted three times with EtOAc, the organic phases were combined, washed three times with water, dried and filtered, the filtrate was collected and concentrated to give diethyl 1-[3-(tert-butoxycarbonylamino)propyl]-4-chloro-pyrazole-3,5-dicarboxylate (Int-1h, 24.70 g, 24.5 mmol, 39.70% yield) as a reddish brown oil. LCMS: C 17 H 27 ClN3O6(M+H) + Calcd. for m / z = 404.8; found, 304.1 (M+H-Boc).

[0487] Step 3. Synthesis of 1-(3-aminopropyl)-4-chloro-pyrazole-3,5-dicarboxylic acid diethyl ester; hydrochloride (Int-1i). To a solution of 1-(3-aminopropyl)-4-chloro-pyrazole-3,5-dicarboxylic acid diethyl ester; hydrochloride (Int-1h, 25.5 g, 23.99 mmol, 98.05% yield) in 1,4-dioxane (50 mL) was added HCl / dioxane (150 mL, 600 mmol), and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated to give 1-(3-aminopropyl)-4-chloro-pyrazole-3,5-dicarboxylic acid diethyl ester; hydrochloride (Int-1i, 25.50 g, 24.0 mmol, 98.05% yield) as a yellow oil, which was used in the next step. LCMS: C 12 H 19 ClN3O4(M+H) + Calcd. value, m / z = 304.1; found, 304.3.

[0488] Step 4. 3-Chloro-4-oxo-5,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-Ethyl formate (Int-1j). To a solution of diethyl 1-(3-aminopropyl)-4-chloro-pyrazole-3,5-dicarboxylate; hydrochloride (Int-1i, 25.5 g, 23.99 mmol) in methanol (500 mL) was added Et3N (16.74 mL, 119.93 mmol) and the mixture was stirred at 80 ° C overnight. The reaction was concentrated to a volume of 20 mL, the resulting white solid was filtered, then diluted with MeOH, stirred for 10 min, and filtered. The solid was then washed three times with water and extracted three times with DCM to give 3-chloro-4-oxo-5,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-Ethyl carboxylate (Int-1j, 4.80 g, 18.6 mmol, 77.66% yield). LCMS: C 10 H 13 ClN3O3(M+H) + Calculated value, m / z = 258.67; found, 258.1.

[0489] Step 5. 3-Chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Synthesis of ethyl 2-formate (Int-1k). Under N2, 3-chloro-4-oxo-5,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine To a solution of ethyl 2-formate (Int-1j, 4.8 g, 18.63 mmol) in THF (60 mL) was added borane-methyl sulfide complex (27.94 mL, 55.89 mmol). The reaction was stirred at rt for 2 h and then at 45 ° C for 32 h. MeOH was added to quench the reaction at 0 ° C, and the mixture was then concentrated to give 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-Ethyl carboxylate (Int-1k, 4.50 g, 18.5 mmol). LCMS: C 10 H 15 ClN3O2(M+H) + Calculated value, m / z = 244.7; found, 244.3.

[0490] Step 6. O5-tert-Butyl-O2-ethyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Synthesis of 3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine To a solution of ethyl-2-carboxylate (Int-1k, 4.5 g, 18.47 mmol) in DCM (60 mL) was added Et3N (7.73 mL, 55.4 mmol) and DMAP (225.6 mg, 1.85 mmol), then the mixture was stirred at rt for 10 min, Boc2O (8.87 g, 40.63 mmol) was added, and the mixture was stirred at 25°C for 4 h. The mixture was concentrated and purified by flash column chromatography (silica gel, eluted with 0% to 6% EtOAc / DCM) to give O5-tert-butyl-O2ethyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2,5-dicarboxylate (Int-11, 4.10 g, 9.54 mmol, 51.66% yield). LCMS: C 15 H 23 ClN3O4(M+H) + Calcd. value, m / z = 344.8; found, 344.1.

[0491] Step 7. 5-tert-Butyloxycarbonyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-carboxylic acid (Int-1m) synthesis. At 25 ° C, to O5-tert-butyl-O2ethyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2,5-dicarboxylic acid ester (Int-11, 4.1g, 9.54mmol) in a solution of THF (36mL) and methanol (9mL) was added to lithium hydroxide (913.95mg, 38.16mmol) in water (38.16mL). The mixture was stirred at 55 ° C for 2h. The mixture was concentrated and acidified to pH = 1 with HCl (1mol / L in H2O), and the crude product was ground in water and filtered. 5-tert-butoxycarbonyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine was obtained as a white solid. -2-carboxylic acid (Int-1m, 2.4 g, 7.60 mmol, 79.67% yield). LCMS: C 13 H 19 ClN3O4(M+H) + Calculated value, m / z = 316.7; found, 316.1.

[0492] Step 8. 3-Chloro-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Synthesis of tert-butyl-5-carboxylate (Int-1n). At 0°C, 5-tert-butoxycarbonyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-formic acid (Int-1m, 100mg, 0.32mmol) in a mixture of DCM (1mL) was added oxalyl chloride (0.32mL, 0.63mmol), the mixture was stirred at 0 ° C for 0.5h and at rt for 0.5h. The mixture was then concentrated, diluted with DCM (1mL), and it was dropped into dimethylamine (0.63mL, 1.27mmol) (2M in THF), and the mixture was then stirred at rt for 1h. The mixture was quenched with NH4Cl aqueous solution, extracted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated to give the crude product 3-chloro-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine as a yellow oil. -tert-Butyl 5-formate (Int-1n, 108 mg, 0.315 mmol). LCMS: C 15 H 24 ClN4O3(M+H) + Calculated value, m / z = 343.8; found, 343.2. 1 H NMR (400MHz, DMSO) δ4.45-4.58(m,2H),4.33-4.43(m,2H),3.69-3.78(m,2H),3.09(s,6H),1.92-2.01(m,2H),1.44(s,9H).

[0493] Step 9. 3-Chloro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine -2-formamide (Intermediate 1) Synthesis. To 3-chloro-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -5-tert-butyl carboxylate (108 mg, 0.32 mmol), 3-chloro-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -tert-Butyl 5-carboxylate (199 mg, 0.58 mmol) and 3-chloro-2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -5- tert-Butyl formate (9.96g, 27.6mmol) in 1,4- dioxane (50mL) solution was added HCl / dioxane (150mL, 600mmol). The mixture was stirred at 20 ° C for 2h. The mixture was concentrated and the crude product was purified by preparative HPLC (mobile phase: H2O (0.1% NH4HCO3) / MeCN on a C18 column (5uM, 50x 150mm); flow rate: 35mL / min) to obtain 3- chloro-N, N- dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo [1,5-a] [1,4] diazepine as a white solid. -2-formamide (6.18 g, 25.46 mmol, 89.36% yield). LCMS: C 10 H 15 ClN4O(M+H) + Calculated value, m / z = 243.1; found, 243.1. 1 H NMR (400MHz, DMSO) δ4.24-4.38(m,2H), 3.26-3.37(m,2H), 3.00-3.05(m,2H), 2.98(d,J=15.2Hz,6H), 1.66-1.77(m,2H).

[0494] Intermediate 2

[0495]

[0496] Step 1. Synthesis of tert-butyl 2-amino-3-cyano-spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-2a). To a solution of malononitrile (219.93 mg, 3.33 mmol) and tert-butyl 5-oxo-2-azaspiro[3.4]octane-2-carboxylate (500 mg, 2.22 mmol) in DMF (5 mL) at 25°C under N2 was added L-proline (255 mg, 2.22 mmol) and sulfur (113.5 mg, 3.33 mmol). The mixture was then stirred at 60°C for 4 h. The mixture was filtered to obtain a crude solution. The reaction mixture was purified by preparative HPLC (eluting with 5.0% to 95% CH3CN in H2O) to give tert-butyl 2-amino-3-cyano-spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-2a, 380 mg, 1.244 mmol, 56.1% yield) as a yellow solid. LCMS: C 15 H 19 N3O2S(M+H) +Calcd. for m / z = 306.1; found, 306.1. 1 H NMR (400MHz, CD3OD) δ4.19 (s, 2H), 3.95 (d, J = 8.1Hz, 2H), 2.76-2.69 (m, 2H), 2.69-2.61 (m, 2H), 1.45 (s, 9H).

[0497] Step 2. Synthesis of 2-aminospiro [5,6-dihydrocyclopenta [b] thiophene -4,3'-azetidine] -3-carbonitrile (intermediate 2). At 25 ° C, under N2, TFA (1.91 mL, 24.89 mmol) was added to a solution of 2-amino-3-cyano-spiro [5,6-dihydrocyclopenta [b] thiophene -4,3'-azetidine] -1'- tert-butyl carboxylate (Int-2a, 380 mg, 1.24 mmol) in DCM (5 mL). The mixture was then stirred at 20 ° C for 1 h. The mixture was concentrated, and the crude product 2-aminospiro [5,6-dihydrocyclopenta [b] thiophene -4,3'-azetidine] -3-carbonitrile (intermediate 2, 380 mg, 0.678 mmol, 54.5% yield) was used directly in the next step. LCMS: C 10 H 11 N3S(M+H) + Calculated value, m / z = 206.2; found, 206.1.

[0498] Intermediate 3.

[0499]

[0500] Intermediate 3 was prepared from 5-oxo-2-azaspiro[3.5]nonane in a similar manner to Intermediate 2 (refer to Angew. Chem. Int. Ed. 2021, 60, 7360-7365). LCMS: C 11 H 13 N3S(M+H) + Calculated value, m / z = 220.1; found, 220.1.

[0501] Intermediate 4. 2-Aminospiro[5,6,7,8-tetrahydrocycloheptatrieno[b]thiophene-4,3'-azetidine]-3-carbonitrile

[0502]

[0503] Intermediate 4 was prepared in a similar manner to Intermediate 2. LCMS: C 12 H 15 N3S(M+H) +Calcd. for m / z = 234.1; found, 234.1.

[0504] Intermediate 5.1-(3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Synthesis of 2-methyl-1-ethyl ketone

[0505]

[0506] Step 1. 2-[Methoxy(methyl)carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Preparation of tert-butyl-5-carboxylate (Int-5b). At 25°C, 5-tert-butoxycarbonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -2-formic acid (Int5a was prepared in a similar manner to Int-1m, 500 mg, 1.78 mmol), DIEA (1.24 mL, 7.11 mmol) and HATU (1013.76 mg, 2.67 mmol) were added to a solution of DMF (10 mL) with N, O-dimethylhydroxylamine hydrochloride (260.05 mg, 2.67 mmol). The mixture was stirred at 25 ° C for 1 h. The mixture was diluted with EtOAC (50x2 mL), washed with water (50 mL) and brine (50 ml), dried over Na2SO4, and concentrated. The crude product was purified by silica gel chromatography (eluted with 10% to 90% EtOAc in petroleum ether). 2- [methoxy (methyl) carbamoyl] -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepine was obtained as a white solid. -tert-Butyl 5-formate (Int-5b, 300 mg, 0.925 mmol, 52.03% yield). LCMS: C 15 H 24 N4O4(M+H) + Calculated value, m / z = 325.2; found, 325.1. 1 HNMR (400MHz, CDCl3) δ6.63 (s, 1H), 4.47 (dd, J = 14.7, 9.4Hz, 4H), 3.74 (s, 5H), 3.42 (s, 3H), 1.94 (s, 2H), 1.41 (s, 9H).

[0507] Step 2. 3-Chloro-2-[methoxy(methyl)carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Preparation of tert-butyl-5-carboxylate (Int-5c). At 60°C, 2-[methoxy(methyl)carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine To a solution of tert-butyl-5-carboxylate (Int-5b, 400 mg, 1.23 mmol) in acetic acid (1 mL) was added NCS (246.99 mg, 1.85 mmol). The mixture was stirred at 60 ° C for 3 h. The mixture was concentrated to give the crude product and used without further purification. 3-Chloro-2-[methoxy(methyl)carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -tert-Butyl 5-carboxylate (Int-5c, 300 mg, 67.80% yield). LCMS: C 15 H 24 ClN4O4(M+H) + Calcd. value, m / z = 359.82; found, 359.2.

[0508] Step 3. 2-Acetyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine Preparation of tert-butyl-5-carboxylate (Int-5d). At -20 °C, 3-chloro-2-[methoxy(methyl)carbamoyl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine was added. -5- tert-butyl formate (Int-5c, 240mg, 0.67mmol) in THF (1mL) solution is added chloro (methyl) magnesium (0.67mL, 2.01mmol). The resulting mixture is allowed to reach rt and stirred for 16h. Saturated NH4Cl aqueous solution (30mL) is added to the reaction mixture and extracted with EtOAc (2x 30mL), and the combined organic layer is dried over Na2SO4 and concentrated in vacuo to obtain a residue. The crude product is purified by flash chromatography (eluting with 10% to 90% EtOAc in petroleum ether). 2-acetyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine is obtained as a white solid. -tert-Butyl 5-formate (Int-5d, 140 mg, 0.446 mmol, 66.71% yield). LCMS: C 14 H 20 ClN3O3(M+H) + Calcd. value, m / z = 314.1; found, 314.2.

[0509] Step 4. 1-(3-Chloro-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Preparation of 2-acetyl-3-chloro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine -5- tert-Butyl formate (Int-5d, 140 mg, 0.45 mmol) in HCl (56 mL, 224 mmol) in dioxane. The mixture was stirred at 25 ° C. The mixture was concentrated to give a crude product and used without further purification. 1- (3-chloro-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] [1,4] diazepine was obtained as a white solid. -2-yl)ethanone (Intermediate 5, 150 mg). LCMS: C9H 13 ClN3O(M+H) + Calculated value, m / z = 214.66; found, 214.2.

[0510] Intermediate 6. Synthesis of 2-amino-6-methyl-spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile.

[0511]

[0512] Step 1. Preparation of tert-butyl 7-methyl-5-oxo-2-azaspiro [3.4] octane-2-formate (Int-6b). At -68 ° C, 1.6M butyllithium in hexane (4.12 mL, 6.59 mmol) was added to a solution of THF (4 mL). The mixture was stirred at -68 ° C for 10 min. Then, a solution of tert-butyl 3-cyano-3-(3-iodo-2-methyl-propyl)azetidine-1-formate (Int-6a, CN 11257408, 800 mg, 2.2 mmol) in THF (4 mL) was added at -68 ° C. The mixture was stirred at -68 ° C for 3 h. The mixture was quenched with acetic acid (5 mL) at -40 ° C and extracted with methyl tert-butyl ether (60 x 2 mL) and water (60 mL). The solution was washed with NaHCO (60 mL), NaSO (20% in 60 mL) and brine (60 mL), dried over NaSO and concentrated. The crude product was purified by silica gel chromatography (eluting with 0% to 5% EtOAc in petroleum ether). tert-Butyl 7-methyl-5-oxo-2-azaspiro[3.4]octane-2-carboxylate (Int-6b, 110 mg, 0.45 mmol, 20.93% yield) was obtained as a yellow oil.

[0513] Step 2. Preparation of tert-butyl 2-amino-3-cyano-6-methyl-spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-6c). To a solution of malononitrile (45.55 mg, 0.69 mmol) and tert-butyl 7-methyl-5-oxo-2-azaspiro[3.4]octane-2-carboxylate (Int-6b, 110 mg, 0.46 mmol) in DMF (1 mL) at 25°C under N2 was added L-proline (52.92 mg, 0.46 mmol) and sulfur (23.5 mg, 0.69 mmol). The mixture was then stirred at 60°C for 6 h. The mixture was filtered to give a crude solution. The reaction mixture was purified by flash chromatography (eluting with 40% to 60% CH3CN in HO). tert-Butyl 2-amino-3-cyano-6-methyl-spiro[5,6-dihydrocyclopenta[b]thiophene-4,3′-azetidine]-1′-carboxylate (Int-6c, 30 mg, 0.094 mmol, 20.43% yield) was obtained as a yellow solid. LCMS: C 16 H 21 N3O2S(M+Na) + Calcd. for m / z = 342.1; found, 342.1.

[0514] Step 3. Preparation of 2-amino-6-methyl-spiro [5,6-dihydrocyclopenta [b] thiophene-4,3'-azetidine] -3-carbonitrile (intermediate 6). At rt, TFA (0.14mL, 1.8mmol) was added to a solution of 2-amino-3-cyano-6-methyl-spiro [5,6-dihydrocyclopenta [b] thiophene-4,3'-azetidine] -1'-tert-butyl carboxylate (Int-6c, 30mg, 0.09mmol) in DCM (1mL). The reaction mixture was then stirred at 25°C for 30min. The mixture was concentrated to give a crude product. The crude product 2-amino-6-methyl-spiro [5,6-dihydrocyclopenta [b] thiophene-4,3'-azetidine] -3-carbonitrile (intermediate 6, 30mg) was used without purification. LCMS: C 11 H 13 N3S(M+H) + Calculated value, m / z = 220.1; found, 220.1.

[0515] Intermediate 7. 3-Methyl-5-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Synthesis of 2-amino-1,2,4-oxadiazole

[0516]

[0517] 3-Methyl-5-(5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine Preparation of -2-yl)-1,2,4-oxadiazole. To N-hydroxyacetamidine (375.66 mg, 5.07 mmol) and To a solution of molecular sieves in THF (5 mL) was added NaH (76.06 mg, 3.17 mmol). The mixture was stirred at RT for 15 min. 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine was added. -2-Ethyl formate (Int-1c, 500 mg, 1.27 mmol) was added to the mixture. The mixture was stirred at 25 ° C for 3 h. The mixture was filtered through celite and concentrated. The crude product was purified by flash chromatography (eluted with 5.0% to 95% CH3CN in H2O). The product 3-methy...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 The 7- to 15-membered heterocyclic ring and the C7-C 15 The carbocyclic rings are each independently substituted by one or more selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted; R 1 is selected from hydrogen and a 5- to 15-membered heterocyclic ring, wherein the 5- to 15-membered heterocyclic ring is replaced by one or more independently selected from halogen, -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 1-6 Alkyl (=NOR 20 )、-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 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted, wherein the C3-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)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 ring; Y is selected from a bond, -O-, -S- and -N(R 5 )-; R 2 Selected from heterocyclic, aryl, C l -C6 alkyl, -L-heterocyclic, -LN(R 23 2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2. -LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of the -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are each substituted by one or more R 6 optionally substituted, and wherein the aryl group, the -L-NR 23 The aryl portion of C(O)-aryl, the -L-NR 23 The aryl portion of the C(O)-aryl, the aryl of the -L-aryl and the heteroaryl of the -L-heteroaryl are each substituted by one or more R 7 Optional substitution; R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; Each R 4 independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 Haloalkyl; n is selected from 0, 1, 2, 3 and 4; Each R 5 Independently selected from hydrogen and C1-C6 alkyl; Each R 6 are independently selected from halogen, hydroxyl, 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, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 and -CH2 heterocycles, among which -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l The phenyl group of -C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein the -OC l The alkyl group of -C3 alkyl is optionally substituted by a substituent selected from heterocycle, oxo and hydroxy; and the heterocycle of the -CH2 heterocyclyl is optionally substituted by oxo; each Q is selected from a bond, S, and O; Each R 7 are independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2 and -N(R 5 )2; Each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is one or more independently selected from halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are optionally substituted, wherein the C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -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 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Substituents for the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

2. The compound or salt of claim 1, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 Fused carbocyclic ring.

3. The compound or salt of claim 1 or 2, wherein B is an optionally substituted 8- to 15-membered fused heterocyclic ring.

4. The compound or salt of claim 1 or 2, wherein B is an optionally substituted C8-C 15 Fused carbocyclic ring.

5. The compound or salt of any one of claims 1 to 3, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C8-C 15 The fused carbocyclic rings are each independently bicyclic or tricyclic.

6. The compound or salt of any one of claims 1 to 5, wherein the heterocyclic or carbocyclic ring of B is a bicyclic ring.

7. The compound or salt of any one of claims 1 to 5, wherein the heterocyclic or carbocyclic ring of B is a tricyclic ring.

8. The compound or salt of any one of claims 1 to 7, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from Each of these is optionally substituted with one or more substituents.

9. The compound or salt of claim 8, wherein for B, the optionally substituted 8- to 15-membered fused heterocyclic ring and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from Each of these is optionally substituted with one or more substituents.

10. A compound or salt as described in any one of claims 1 to 9, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen and C1-C3 alkyl.

11. The compound or salt of any one of claims 1 to 10, wherein for B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C8-C 15 The fused carbocyclic ring is selected from 12. 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 C3-C 15 Carbon ring.

13. The compound or salt of claim 12, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 Fused carbocyclic ring.

14. The compound or salt of claim 13, wherein B is an optionally substituted 8- to 15-membered fused heterocyclic ring.

15. The compound or salt of claim 13, wherein B is an optionally substituted unsaturated C8-C 15 Fused carbocyclic ring.

16. The compound or salt of any one of claims 12 to 15, wherein for B, the heterocyclic ring and the carbocyclic ring are each independently bicyclic or tricyclic.

17. The compound or salt of claim 16, wherein for B, the heterocyclic ring and the carbocyclic ring are each independently bicyclic.

18. The compound or salt of claim 16, wherein for B, the heterocyclic ring and the carbocyclic ring are each independently tricyclic.

19. The compound or salt of any one of claims 12 to 18, wherein B is selected from Each of these is optionally substituted with one or more substituents.

20. The compound or salt of claim 19, wherein B is selected from Each of these is optionally substituted with one or more substituents.

21. The compound or salt of claim 20, wherein B is selected from Each of these is optionally substituted with one or more substituents.

22. A compound or salt as described in any one of claims 12 to 21, wherein for B, the one or more optional substituents are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

23. The compound or salt of claim 22, wherein B is selected from 24. A compound or salt as described in any one of claims 1 to 21, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected from halogen, C1-C3 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.

25. Compounds or salts as claimed in claim 24, wherein for B, the one or more optional substituents of the heterocycle and carbocycle are independently selected at each occurrence from halogen, 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 Alkynyl.

26. The compound or salt of claim 24 or 25, wherein B is selected from 27. The compound or salt of any one of claims 1 to 7, wherein B is an optionally substituted 7- to 12-membered fused heterocyclic ring.

28. The compound or salt of any one of claims 1 to 7, wherein B is an optionally substituted 7- to 11-membered fused heterocyclic ring.

29. The compound or salt of claim 27 or 28, wherein B is an optionally substituted 8- to 10-membered fused heterocyclic ring.

30. The compound or salt of claim 29, wherein B is an optionally substituted 8- to 9-membered fused heterocyclic ring.

31. The compound or salt of claim 27 or 28, wherein the heterocycle is an unsaturated heterocycle.

32. A compound or salt as described in any one of claims 27 to 31, wherein B has at least one sulfur atom.

33. A compound or salt as described in any one of claims 27 to 32, wherein B has at least one sulfur atom and at least one nitrogen atom.

34. A compound or salt as described in any one of claims 27 to 32, wherein B has at least one sulfur atom and at least one oxygen atom.

35. A compound or salt as described in any one of claims 27 to 32, wherein B has at least two sulfur atoms.

36. A compound or salt as described in any one of claims 27 to 35, wherein B is selected from Each of which is optionally substituted.

37. The compound or salt of claim 36, wherein B is selected from Each of which is optionally substituted.

38. The compound or salt of claim 37, wherein B is selected from Each of which is optionally substituted.

39. as claimed in any one of claims 27 to 38 compound or salt, wherein the one or more optional substituents of B are independently selected from halogen, 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 Alkynyl.

40. The compound or salt of claim 39, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2 and -CN.

41. A compound or salt as described in any one of claims 27 to 37, wherein B is selected from 42. A compound or salt as described in any one of claims 1 to 7, wherein B is selected from an optionally substituted 7 to 12 membered fused heterocycle and an optionally substituted C 9-10 Fused carbocyclic ring.

43. The compound or salt of claim 42, wherein the heterocyclic ring of B has at least one sulfur atom.

44. A compound or salt as claimed in claim 42 or 43, wherein the heterocyclic ring of B has one or two sulfur atoms.

45. The compound or salt of claim 44, wherein the heterocyclic ring of B has at least one nitrogen atom.

46. ​​A compound or salt as described in any one of claims 42 to 45, wherein B is selected from Each of which is optionally substituted.

47. A compound or salt as described in any one of claims 42 to 46, wherein the one or more optional substituents of B are independently selected from halogen, C1-C3 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.

48. A compound or salt as described in any one of claims 42 to 46, wherein the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, -NH2, =O and -CN.

49. The compound or salt of claim 47, wherein B is selected from 50. The compound or salt of any one of claims 1 to 7, wherein B is selected from an optionally substituted 8 to 10 membered fused heterocyclic ring having at least one sulfur atom.

51. The compound or salt of claim 50, wherein B is selected from Each of which is optionally substituted.

52. A compound or salt as described in claim 50 or 51, wherein the one or more optional substituents of B are independently selected from halogen, C1-C3 alkyl, -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.

53. A compound or salt as described in claim 52, wherein the one or more optional substituents of B are independently selected from halogen, C1-C3 alkyl, -NH2 and -CN at each occurrence.

54. A compound or salt as described in any one of claims 50 to 53, wherein B is substituted.

55. A compound or salt as described in any one of claims 50 to 53, wherein B is substituted with at least one -NH2.

56. A compound or salt as described in any one of claims 50 to 54, wherein B is selected from 57. A compound or salt as described in any one of claims 50 to 55, wherein B is substituted with at least one -NH2 and / or at least one -CN.

58. The compound or salt of claim 57, wherein B is selected from 59. A compound or salt as described in any one of claims 1 to 58, wherein R 3 Selected from hydrogen, halogen, -CN, -C(O)R 22 , C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl and C 1-6 alkyl.

60. The compound or salt of claim 59, wherein R 3 Selected from hydrogen, fluorine, -CN, -C(O)H, C1 hydroxyalkyl and C 1-6 alkyl.

61. The compound or salt of claim 59 or 60, wherein R 3 is selected from hydrogen, fluorine and -CN.

62. The compound or salt of claim 61, wherein R 3 Selected from fluorine.

63. The compound or salt of claim 61, wherein R 3 Selected from hydrogen.

64. The compound or salt of claim 61, wherein R 3 Selected from -CN.

65. The compound or salt of any one of claims 1 to 64, wherein Y is -O-.

66. A compound or salt as described in any one of claims 1 to 65, wherein L is selected from C1-C4 alkylene.

67. The compound or salt of claim 66, wherein L is selected from unsubstituted C1-C4 alkylene.

68. The compound or salt of claim 66, wherein each L is independently selected from optionally substituted C l -C4 alkylene; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each substituted by one or more 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 on the haloalkyl group are optionally substituted.

69. The compound or salt of claim 68, wherein the optional substituent of L is selected from C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocycle; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3 to 8-membered heterocycle, wherein the C3-C6 carbocycle and the 3 to 8-membered heterocycle are substituted by one or more selected from halogen and C 1-6 The substituents on the haloalkyl group are optionally substituted.

70. A compound or salt as described in any one of claims 65 to 69, wherein L is selected from 71. The compound or salt of claim 70, wherein L is selected from 72. A compound or salt as described in claim 68 or 69, wherein 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 carbocyclic ring or a 3- to 5-membered heterocyclic ring.

73. The compound or salt of claim 72, wherein each L is independently selected from substituted C 2-3 Alkylene, and wherein two substituents on the same carbon atom of L together form a C3 carbocyclic ring or a 4-membered heterocyclic ring, wherein the C3 carbocyclic ring is optionally substituted by one or more substituents selected from halogen.

74. The compound or salt of claim 73, wherein each L is independently selected from 75. The compound or salt of claim 74, wherein each L is independently selected from 76. The compound or salt of claim 75, wherein each L is independently selected from 77. The compound or salt of claim 66, wherein each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is one or more independently selected from halogen and C l The substituents of the -C4 alkyl group are optionally substituted.

78. The compound or salt of claim 77, wherein L is selected from 79. The compound or salt of claim 66, wherein each L is independently selected from unsubstituted C1-C4 alkylene.

80. The compound or salt of claim 79, wherein L is selected from 81. The compound or salt of claim 80, wherein L is selected from 82. A compound or salt as described in any one of claims 1 to 81, wherein R 2 is selected from heterocyclic, -L-heterocyclic, -L-aryl, -L-heteroaryl and -LN(R 23 ) 2, wherein the heterocyclic ring and the heterocyclic ring portion of the -L-heterocyclic ring are each replaced by one or more R 6 optionally substituted, and wherein the aryl of the -L-aryl and the heteroaryl of the -L-heteroaryl are each replaced by one or more R 7 Optional substitution.

83. The compound or salt of claim 82, wherein R 2 is -L-heterocyclic, wherein R 2 The heterocyclic moiety of is an optionally substituted heterocyclic ring.

84. A compound or salt as described in claim 82 or 83, wherein R 2 is -L-heterocyclic ring, which is replaced by one or more R 6 Optional substitution.

85. A compound or salt as described in any one of claims 1 to 84, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

86. A compound or salt as described in any one of claims 82 to 85, wherein R 2 The heterocyclic moiety is substituted by one or more selected from halogen, hydroxyl, -CN, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C l -C3 alkoxy and C l The substituents of the -C3 aminoalkyl group are optionally substituted heterocyclic rings.

87. The compound or salt of claim 86, wherein R 2 The heterocyclic moiety of is a heterocyclic ring optionally substituted by one or more substituents selected from C1-C3 alkyl and halogen.

88. A compound or salt as described in any one of claims 1 to 88, wherein YR 2 Selected from 89. A compound or salt as described in any one of claims 1 to 85, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

90. The compound or salt of claim 89, wherein R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C l -C3 hydroxyalkyl, C l -C3 alkyl, C l -C3 haloalkyl, C1-C3 alkoxy, cyano and C l -C3 aminoalkyl.

91. The compound or salt of claim 90, wherein R 2 R 6 is independently selected at each occurrence from C1-C3 alkyl and halogen.

92. The compound or salt of claim 91, wherein YR 2 Selected from 93. A compound or salt as described in any one of claims 1 to 82, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 6 Optional substitution.

94. The compound or salt of claim 93, wherein YR 2 Selected from 95. The compound or salt of claim 94, wherein YR 2 Selected from wherein the heterocycle is optionally substituted.

96. The compound or salt of claim 95, wherein the heterocycle is replaced by one or more selected from halogen, hydroxyl, C l -C3 alkyl, -N(R 5 )S(O)2(R 5 )、-OC(O)N(R 5 )2, =CH2, oxo, =NO-C l -C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R 5 )2 and -OC l -C3 alkyl is optionally substituted with a substituent, wherein the -OC l The alkyl group of the -C3 alkyl group is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy.

97. The compound or salt of claims 1 or 95-96, wherein YR 2 Selected from 98. The compound or salt of claim 82, wherein R 2 is -L-heteroaryl, wherein the heteroaryl portion is replaced by one or more R 7 Optional substitution.

99. The compound or salt of claim 98, wherein each R 7 independently selected from halogen and C l -C4 haloalkyl.

100. The compound or salt of claim 99, wherein YR 2 Selected from 101. The compound or salt of claim 82, wherein R 2 is -L-aryl, which is 7 Optional substitution.

102. The compound or salt of claim 101, wherein YR 2 Selected from wherein the heterocyclic moiety is replaced by one or more R 7 Optional substitution.

103. The compound or salt of claim 102, wherein YR 2 Selected from 104. The compound or salt of claim 82, wherein R 2 is -L-heteroaryl, which is replaced by one or more R 7 Optional substitution.

105. The compound or salt of claim 104, wherein YR 2 Selected from wherein the heteroaryl moiety is replaced by one or more R 7 Optional substitution.

106. The compound or salt of claim 104 or 105, wherein YR 2 Selected from 107. The compound or salt of claim 82, wherein R 2 -LN(R 23 )2.

108. The compound or salt of claim 107, wherein YR 2 Selected from 109. The compound or salt of claim 108, wherein R 2 is a heterocyclic ring, which is surrounded by one or more R 6 Optional substitution.

110. The compound or salt of claim 109, wherein YR 2 for 111. The compound or salt of claim 82, wherein YR 2 for 112. A compound or salt as described in any one of claims 1 to 81, wherein R 2 is selected from heterocycle, -L-heterocycle, wherein the heterocycle and the heterocyclic portion of the -L-heterocycle are each separated by one or more R 6 Optionally substituted; -L-aryl and -L-heteroaryl, wherein the aryl of the -L-aryl and the heteroaryl of the -L-heteroaryl are each substituted by one or more R 7 optionally substituted; and -LN(R 23 )2.

113. The compound or salt of claim 112, wherein R 2 The heterocyclic ring is selected from Where R 2 The heterocyclic ring is replaced by one or more R 6 Optionally substituted; wherein R 2 The aryl and heteroaryl groups are selected from wherein the aryl group and the heteroaryl group are each replaced by one or more R 7 optionally substituted; and 114. The compound or salt of claim 113, wherein R 2 The heterocyclic ring is selected from wherein the heterocyclic ring is replaced by one or more R 6 Optionally substituted; wherein R 2 The aryl and heteroaryl groups are selected from wherein the aryl group and the heteroaryl group are each replaced by one or more R 7 optionally substituted; and 115. A compound or salt as described in any one of claims 112 to 114, wherein each R 6 are independently selected from halogen, hydroxyl, C l -C3 alkyl, C l -C3 haloalkyl, -N(R 5 )S(O)2(R 5 )、-OC(O)N(R 5 )2, =CH2, oxo, =NO-C l -C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R 5 )2 and -OC l -C3 alkyl, wherein the -OC l -C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; and wherein each R 7 Selected from C l -C3 alkyl, halogen and C l -C3 haloalkyl.

116. A compound or salt as described in any one of claims 112-115, wherein R 2 The heterocyclic ring, R 2 The aryl and heteroaryl groups and R 2 -N(R 20 )2Selected from 117. A compound or salt as described in any one of claims 1 to 116, wherein YR 2 Selected from wherein the heterocycle and the heterocyclic portion of the -L-heterocycle are each separated by one or more R 6 Optional substitution; wherein the aryl group of the -L-aryl group and the heteroaryl group of the -L-heteroaryl group are each replaced by one or more R 7 optionally substituted; and 118. A compound or salt as described in any one of claims 112-117, wherein YR 2 Selected from 119. The compound or salt of any one of claims 1-118, wherein YR 2 Selected from 120. A compound or salt as described in any one of claims 1-119, wherein Y is -O- and R 2 is selected from L-5 membered heteroaryl, wherein L is selected from optionally substituted C1-C4 alkylene, and wherein the heteroaryl is replaced by one or more R 7 optionally substituted, wherein each R 7 Preferably selected from halogen, C l -C4 alkyl and C l -C4 haloalkyl.

121. A compound or salt as described in any one of claims 1-120, wherein YR 2 Selected from 122. A compound or salt as described in any one of claims 1 to 119, 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, -NO2, =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.

123. The compound or salt of claim 120, 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, -NO2, 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.

124. A compound or salt as described in any one of claims 1 to 122, wherein R 1 is an optionally substituted 5- to 12-membered heterocyclic ring.

125. The compound or salt of claim 124, wherein R 1 The 5- to 12-membered heterocyclic ring is unsaturated.

126. The compound or salt of claim 124, wherein R 1 The 5- to 12-membered heterocyclic ring is saturated.

127. The compound or salt of claim 124, wherein R 1 The 5- to 12-membered heterocyclic ring is bridged.

128. The compound or salt of claim 124, wherein R 1 The 5- to 12-membered heterocycle is a spiroheterocycle.

129. The compound or salt of claim 124, wherein R 1 The 5- to 12-membered heterocyclic ring is non-aromatic.

130. A compound or salt as described in any one of claims 1 to 129, wherein R 1 Selected from Each of which is optionally substituted.

131. The compound of claim 130, wherein the one or more optional substituents are each independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1-6 Aminoalkyl, C 1-6 Alkoxy, =O, -CN, C 1-6 Hydroxyalkyl and C 1-6 Halogenated alkyl.

132. The compound or salt of claim 131, wherein R 1 Selected from Each of which is independently selected from halogen, -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 on the haloalkyl group are optionally substituted.

133. The compound or salt of claim 1, wherein R 1 Selected from 134. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from 6 to 8 membered heterocyclic rings, which are optionally substituted.

135. The compound or salt of claim 134, 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.

136. The compound or salt of claim 135, wherein R 1 Selected from Each of which is optionally substituted.

137. The compound or salt of claim 136, wherein the one or more optional substituents are independently selected from -OH, -CN, oxo, C 1-6 Cyanoalkyl.

138. The compound or salt of claim 136 or 137, wherein R 1 Selected from 139. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from an optionally substituted 6- to 7-membered heterocyclic ring.

140. The compound or salt of claim 139, 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.

141. The compound or salt of claim 140, wherein R 1 The 6- to 7-membered heterocyclic ring is bonded to formula (I) via the 1 nitrogen atom only.

142. A compound or salt as described in any one of claims 139 to 141, wherein R 1 is selected from an optionally substituted unsaturated 6-membered heterocyclic ring.

143. A compound or salt as described in any one of claims 139 to 142, wherein R 1 is selected from an optionally substituted unsaturated 7-membered heterocyclic ring.

144. A compound or salt as described in any one of claims 139 to 143, wherein R 1 Selected from Any of which is optionally substituted.

145. A compound or salt as described in any one of claims 139 to 144, wherein R 1 Selected from Any of which is optionally substituted.

146. A compound or salt as described in any one of claims 139 to 145, 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.

147. A compound or salt as described in any one of claims 139 to 146, each of which is independently selected from halogen, -OH, -NH2, -NO2, 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.

148. A compound or salt as described in any one of claims 139 to 147, wherein R 1 The one or more optional substituents of are each independently selected from halogen.

149. A compound or salt as described in any one of claims 139 to 148, wherein R 1 Selected from 150. A compound or salt as described in any one of claims 139 to 145, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -NH2, -NO2, 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.

151. The compound or salt of claim 150, wherein R 1 Selected from Each of which is independently selected from halogen, -OH, -NH2, -NO2, 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.

152. The compound or salt of claim 151, 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.

153. The compound or salt of claim 152, wherein R 1 Selected from 154. The compound or salt of claim 145, wherein R 1 Selected from which are independently selected from halogen, -OH, -NH2, -NO2, C 1-6 Cyanoalkyl, 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.

155. The compound or salt of claim 154, wherein R 1 Selected from It is optionally substituted with one or more substituents independently selected from halogen.

156. The compound or salt of claim 155, wherein R 1 Selected from 157. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from an optionally substituted 6- to 7-membered heterocyclic ring.

158. The compound or salt of claim 157, 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.

159. The compound or salt of claim 158, wherein the optional one or more additional heteroatoms are selected from sulfur.

160. A compound or salt as described in any one of claims 157 to 159, wherein the 6 to 7 membered heterocyclic ring contains only 1 nitrogen atom and does not otherwise contain additional heteroatoms.

161. The compound or salt of any one of claims 157 to 160, wherein the 6 to 7 membered heterocycle is a non-aromatic 6 to 7 membered heterocycle.

162. A compound or salt as described in any one of claims 157 to 161, wherein R 1 The 6- to 7-membered heterocyclic ring is bonded to formula (I) via the 1 nitrogen atom only.

163. A compound or salt as described in any one of claims 157 to 162, wherein R 1 Selected from Each of which is optionally substituted.

164. A compound or salt as described in any one of claims 157 to 163, 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.

165. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from optionally substituted 6- to 10-membered heterocyclic rings.

166. The compound or salt of claim 165, wherein R 1 Selected from Each of which is optionally substituted.

167. The compound or salt of claim 166, 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.

168. The compound or salt of claim 166 or 167, wherein R 1 Selected from 169. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from 7- to 11-membered spiro heterocycles.

170. The compound or salt of claim 169, wherein R 1 is selected from 10-membered spiro heterocycles.

171. The compound or salt of claim 169 or 170, wherein the spiroheterocycle has at least 3 nitrogen atoms.

172. The compound or salt of claim 171, wherein R 1 Selected from Each of which is optionally substituted.

173. The compound or salt of claim 172, wherein R 1 Selected from Each of which is independently selected from halogen, -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 Substituents on an alkynyl group are optionally substituted.

174. The compound or salt of claim 173, wherein R 1 Selected from 175. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from optionally substituted unsaturated 9- to 11-membered heterocyclic rings.

176. The compound or salt of claim 175, wherein R 1 is selected from an optionally substituted unsaturated 10-membered heterocyclic ring.

177. The compound or salt of claim 175 or 176, wherein R 1 for It is optionally substituted.

178. The compound or salt of claim 177, wherein R 1 for It is replaced by one or more selected from halogen, -OH, -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 Substituents on an alkynyl group are optionally substituted.

179. The compound or salt of claim 178, 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 Alkynyl substituents are further optionally substituted.

180. A compound or salt as described in any one of claims 175 to 177, wherein R 1 The one or more optional substituents are independently selected from halogen, -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 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl and C 2-6 Alkynyl.

181. The compound or salt of claim 177 or 180, wherein R 1 Selected from Each of which is optionally substituted.

182. The compound or salt of claim 181, wherein R 1 Selected from 183. The compound or salt of claim 177, 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.

184. The compound or salt of claim 183, wherein R 1 The one or more optional substituents are independently selected from halogen and -C(O)N(R 20 )2.

185. The compound or salt of claim 184, wherein R 1 Selected from 186. The compound or salt of claim 185, wherein R 1 for 187. The compound or salt of claim 185, wherein R 1 for 188. The compound or salt of claim 177, wherein R 1 The one or more optional substituents are independently selected from halogen, C 1-6 Alkyl, C 1-6 Alkyl-N(R 20 )2. -C(O)NR 20 OR 20 、-C(O)N(R 20 )2 and -C(O)R 20 .

189. The compound or salt of claim 188, wherein R 1 The one or more optional substituents are selected from chlorine, 190. The compound or salt of claim 189, wherein R 1 Selected from 191. A compound or salt as described in any one of claims 175 to 177, 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.

192. The compound or salt of claim 177 or 191, wherein R 1 The one or more optional substituents are selected from chlorine, -NH2, -CN, C1 alkyl, C2 alkenyl, 193. The compound or salt of claim 192, wherein R 1 Selected from 194. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from an optionally substituted 6- to 11-membered heterocyclic ring, wherein the 6- to 11-membered heterocyclic ring has at least one nitrogen atom.

195. The compound or salt of claim 194, wherein R 1 The one or more optional substituents are selected from halogen, -OR 20 、-C(O)N(R 20 )2. -C(O)R 20 、-S(O)2R 20 , =O, -C 1-6 Alkyl (=NOR 20 ), = NO(R 20 )、-CN、-NHCN、C 1-6 alkyl and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is independently replaced by one or more R 1* optionally substituted; and wherein each R 1* independently selected from halogen and C 1-6 alkyl.

196. The compound or salt of claim 194, wherein R 1 Selected from 197. The compound or salt of claim 1, wherein R 1 Selected from hydrogen, 198. The compound or salt of claim 1, wherein R 1 Selected from hydrogen, 199. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from hydrogen and an optionally substituted 5- to 15-membered heterocyclic ring.

200. The compound or salt of claim 199, wherein R 1 Selected from Each of which is optionally substituted.

201. The compound or salt of claim 200, wherein R 1 The one or more optional substituents are selected from -OH, =NO(R 20 ), -NHCN and C 1-6 alkyl.

202. A compound or salt as described in any one of claims 199 to 201, wherein R 1 Selected from hydrogen, 203. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from hydrogen and an optionally substituted 7- to 10-membered heterocyclic ring.

204. The compound or salt of claim 203, wherein R 1 Selected from hydrogen, Each of which is optionally substituted.

205. The compound or salt of claim 203 or 204, wherein R 1 The one or more optional substituents are independently selected from halogen, -NH2, -S(O)2(R 20 )、-C(O)R 20 、-C(O)N(R 20 )2、=O、=NO(R 20 )、-CN、-NHCN、C 1-6 alkyl and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is independently replaced by one or more R 1* optionally substituted; and wherein each R 1* independently selected from halogen and C 1-6 alkyl.

206. A compound or salt as described in any one of claims 203 to 205, wherein R 1 Selected from hydrogen, 207. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from optionally substituted 8- to 10-membered heterocyclic rings.

208. The compound or salt of claim 207, wherein the heterocycle is bicyclic.

209. The compound or salt of claim 207 or 208, wherein the heterocyclic ring has at least one nitrogen atom.

210. The compound or salt of claim 207 or 208, wherein the heterocyclic ring has at least two nitrogen atoms.

211. A compound or salt as described in any one of claims 207 to 210, Each of which is optionally substituted.

212. A compound or salt as described in any one of claims 207 to 211, wherein R 1 The one or more optional substituents are independently selected from halogen, Oxygen and 5 to 9 membered heteroaryl, wherein the 5 to 9 membered heteroaryl is replaced by at least one R 1* Substituted, wherein R 1* Selected from halogen and C 1-6 alkyl.

213. A compound or salt as described in any one of claims 207 to 212, wherein R 1 The one or more optional substituents are independently selected from chlorine, Oxygen 214. A compound or salt as described in any one of claims 207 to 213, 215. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is an optionally substituted 12- to 15-membered heterocyclic ring.

216. The compound or salt of claim 215, wherein R 1 is an optionally substituted 12-membered heterocyclic ring.

217. The compound or salt of claim 216, wherein R 1 is an optionally substituted 13-membered heterocyclic ring.

218. The compound or salt of claim 217, wherein R 1 is an optionally substituted 14-membered heterocyclic ring.

219. The compound or salt of claim 218, wherein R 1 is an optionally substituted 15-membered heterocyclic ring.

220. A compound or salt as described in any one of claims 215 to 219, wherein R 1 The heterocyclic ring is a tricyclic ring.

221. A compound or salt as described in any one of claims 215 to 220, wherein R 1 The heterocyclic ring contains a condensed heterocyclic ring.

222. A compound or salt as described in any one of claims 215 to 221, wherein R 1 The heterocycle contains a spiro heterocycle.

223. A compound or salt as described in any one of claims 215 to 222, wherein R 1 The heterocycle contains fused and spiro heterocycles.

224. A compound or salt as described in any one of claims 215 to 223, wherein R 1 The heterocyclic ring is an unsaturated heterocyclic ring.

225. A compound or salt as described in any one of claims 215 to 223, wherein R 1 The heterocycle of is a non-aromatic heterocycle.

226. A compound or salt as described in any one of claims 215 to 225, wherein R 1 The heterocyclic ring has at least one double bond.

227. A compound or salt as described in any one of claims 215 to 226, wherein R 1 The heterocyclic ring has at least two double bonds.

228. A compound or salt as described in any one of claims 215 to 227, wherein R 1 The heterocyclic ring has two double bonds.

229. A compound or salt as described in any one of claims 215 to 228, wherein R 1 Selected from Each of these is optionally substituted with one or more substituents.

230. The compound or salt of claim 229, wherein the one or more optional substituents are selected from halogen, -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 Alkynyl.

231. The compound or salt of claim 230, wherein the one or more optional substituents are selected from halogen, -OH, C 1-6 Alkyl and -C(O)N(R 20 )2.

232. A compound or salt as described in any one of claims 215 to 231, wherein R 1 Selected from 233. A compound or salt as described in any one of claims 1 to 129, 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.

234. The compound or salt of claim 233, wherein R 1 Selected from 235. A compound or salt as described in any one of claims 1 to 129, wherein R 1 is selected from an optionally substituted bridged 8- to 9-membered heterocyclic ring.

236. The compound or salt of claim 235, wherein R 1 The heterocyclic ring is selected from Each of which is optionally substituted.

237. The compound or salt of claim 235 or 236, wherein R 1 The one or more substituents are selected from halogen, C 1-6 Alkyl, -N(R 20 )2 and C 1-6 Aminoalkyl.

238. A compound or salt as described in any one of claims 235 to 237, wherein R 1 Selected from 239. The compound or salt of claim 235, wherein R 1 is selected from an optionally substituted bridged 8-membered heterocyclic ring, wherein the heterocyclic ring contains a heteroatom selected from nitrogen.

240. The compound or salt of claim 239, wherein R 1 The one or more substituents are selected from C 1-6 Alkyl, -N(R 20 )2 and C 1-6 Aminoalkyl.

241. The compound or salt of claim 240, wherein R 1 The heterocyclic ring is selected from Each of which is optionally substituted.

242. A compound or salt as described in any one of claims 239 to 241, wherein R 1 Selected from 243. A compound or salt as described in claims 1 to 129 or 242, wherein R 1 Selected from 244. A compound or salt as described in any one of claims 1 to 124, wherein R 1 For hydrogen.

245. The compound or salt of any one of claims 1 to 244, wherein n is 0.

246. A compound of formula (IA) or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from 8 to 10 membered heterocyclic rings, wherein the 8 to 10 membered heterocyclic rings are substituted by one or more independently selected from halogen, -OR 20 、-S(O)2(R 20 )、-C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 , =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 1-6 Alkyl-SO2R 20 , C 1-6 Alkoxyalkyl, C 1-6 Alkyl, C 2-6 The substituents of the alkynyl group and the 5- to 12-membered heterocyclic ring are optionally substituted, wherein the 5- to 12-membered heterocyclic ring is 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)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 ring; B is selected from 7 to 15 membered heterocyclic ring and C7-C 15 The 7- to 15-membered heterocyclic ring and the C7-C 15 The carbocyclic rings are each independently substituted by one or more selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted; Y is selected from a bond and -O-; R 2 Selected from heterocyclic, aryl, C l -C6 alkyl, -L-heterocyclic, -LN(R 23 2. -L-OR 23 , -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 23 2. -LC l -C6 haloalkyl, -L-OR 23 、-L-NR 23 C(O)-aryl, -L-COOH, -L-NR 23 S(O)2(R 23 )、-LS(O)2N(R 23 )2. -LN(R 23 )C(O)(OR 23 )、-L-OC(O)N(R 23 )2 and -LC(=O)OC l -C6 alkyl, wherein the heterocycle, the heterocycle portion of the -L-heterocycle and the cycloalkyl portion of the -L-cycloalkyl are each substituted by one or more R 6 optionally substituted, and wherein the aryl, -L-NR 23 The aryl portion of C(O)-aryl, the -L-NR 23 The aryl portion of the C(O)-aryl, the aryl of the -L-aryl and the heteroaryl of the -L-heteroaryl are each substituted by one or more R 7 Optional substitution; R 3 Selected from hydrogen, halogen, -CN, -NO2, -N(R 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、-N(R 20 )C(O)R 20 、-N(R 20 )C(O)N(R 20 )2、-N(R 20 )C(O)OR 20 、-C(O)R 20 、-C(O)OR 20 、-OC(O)R 20 、-OC(O)N(R 20 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; Each R 4 independently selected from halogen, -NO2, =O, =S, -CN, C 1-6 Alkyl, C 2-6 Alkynyl, C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Cyanoalkyl, C 1-6 Hydroxyalkyl and C 1-6 Haloalkyl; n is selected from 0, 1, 2, 3 and 4; Each R 5 Independently selected from hydrogen and C1-C6 alkyl; Each R 6 are independently selected from halogen, hydroxyl, 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, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2、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, -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)heterocycle, -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 -C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(C l -C3 alkyl)phenyl, -OC(O)heterocycle, -OC l -C3 alkyl, -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 and -CH2 heterocyclic ring, wherein the -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(C l The phenyl group of -C3 alkyl)phenyl is optionally substituted by one or more substituents selected from -C(O)H and OH, and wherein the -OC l The alkyl group of -C3 alkyl is optionally substituted by a substituent selected from heterocycle, oxo and hydroxy; and the heterocycle of the -CH2 heterocyclyl is optionally substituted by oxo; each Q is selected from a bond, S, and O; Each R 7 are independently selected from halogen, hydroxy, HC(=O)-, C l -C4 alkyl, C l -C4 alkoxy, C l -C4 haloalkyl, C l -C4 hydroxyalkyl, -C1-C3 alkyl-N(R 5 )2、-C(O)N(R 5 )2 and -N(R 5 )2; Each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is one or more independently selected from halogen, hydroxyl, C 1-6 Alkoxy, C l -C4 hydroxyalkyl, C l -C4 alkyl, C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are optionally substituted, wherein the C3-C6 carbocyclic ring and 3 to 8 membered heterocyclic ring are each substituted by one or more independently selected from halogen, -OH, -NO2, =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 are optionally substituted; and optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, wherein the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are each independently selected from halogen, -OH, -NO2, =O, =S, -CN, C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxy, C 1-6 Hydroxyalkyl and C 1-6 The substituents of the haloalkyl group are optionally substituted; Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -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 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -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 23 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Substituents for the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

247. The compound or salt of claim 246, wherein formula (IA) is represented by formula (IB), or a pharmaceutically acceptable salt thereof, wherein: Where R 1 Selected from Each of which is independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 , =O and a 5- to 12-membered heterocyclic ring, wherein the 5- to 12-membered heterocyclic ring is each independently substituted with one or more R 1* Optional substitution; Each R 1* are independently selected from halogen, -OR 20 、-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 and C 1-6 alkyl; Y is -O-; R 2 is selected from -L-heterocycle and -LN(R 23 ) 2, wherein the heterocyclic portion of the -L-heterocyclic ring is replaced by one or more R 6 Optional substitution. B is selected from a 7- to 15-membered heterocyclic ring, wherein the 7- to 15-membered heterocyclic ring is substituted by one or more independently selected from halogen, -CN, =O, -N(R 21 )2.-OR 21 , 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 are optionally substituted; R 3 is selected from hydrogen, halogen, -CN, -N(R 20 )2.-OR 20 、-C(O)R 20 , 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 and C 1-6 Alkyl; and Each R 20 are independently selected from hydrogen; and C 1-6 Alkyl and C 3-12 carbocyclic ring, each of which is substituted by one or more independently selected from halogen, -OH, -CN, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 The alkyl and oxo substituents are optionally substituted.

248. The compound or salt of claim 246 or 247, wherein R 1 Selected from in is one or more independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 , =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently substituted with one or more R 1* optionally substituted; and Each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 alkyl.

249. The compound or salt of any one of claims 246 to 248, wherein Y is -O-.

250. A compound or salt as described in any one of claims 246 to 249, wherein each L is independently selected from C l -C4 alkylene, said C l -C4 alkylene is one or more independently selected from halogen and C l -C4 alkyl substituents are optionally substituted; and wherein optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 4- to 6-membered heterocycle, wherein the C3-C6 carbocycle and the 3- to 6-membered heterocycle are each optionally substituted by one or more substituents independently selected from halogen.

251. A compound or salt as described in any one of claims 246 to 250, wherein each L is selected from Or L is selected from R 2 Selected from 252. A compound or salt as described in any one of claims 246 to 251, wherein YR 2 Selected from 253. The compound or salt of any one of claims 246 to 252, wherein B is selected from an optionally substituted 8 to 10 membered heterocycle.

254. The compound or salt of claim 253, wherein the 8 to 10 membered heterocyclic ring is substituted by one or more independently selected from halogen, -CN, -NH2 and C 1-6 The substituents on the alkyl group are optionally substituted.

255. A compound or salt as described in any one of claims 246 to 254, wherein the heterocycle of B is selected from 256. A compound or salt as described in any one of claims 246 to 255, wherein Each of which is independently selected from halogen, -CN, -NH2 and C 1-6 The substituents on the alkyl group are optionally substituted.

257. A compound or salt as described in any one of claims 246 to 256, wherein B is selected from 258. A compound or salt as described in any one of claims 246 to 257, wherein R 3 It is -CN.

259. A compound or salt as described in any one of claims 246 to 258, wherein R 1 for It is optionally substituted with one or more substituents.

260. A compound or salt as described in any one of claims 246 to 258, wherein R 1 for 261. A compound or salt as described in any one of claims 246 to 258, wherein R 1 for 262. A compound or salt as described in any one of claims 246 to 258, wherein R 1 for 263. A compound or salt as described in any one of claims 246 to 262, wherein R 1 The one or more optional substituents are independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently replaced by one or more R 1* Optional substitution.

264. A compound or salt as described in any one of claims 246 to 262, wherein R 1 The one or more optional substituents are independently selected from halogen, -S(O)2(R 20 )、-C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 , =O and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently replaced by one or more R 1* Optional substitution.

265. A compound or salt as described in any one of claims 246 to 262, wherein R 1 The one or more optional substituents are independently selected from halogen, -C(O)N(R 20 2. -C 1-6 Alkyl (=NOR 20 )、-C(O)R 20 and a 5- to 9-membered heterocyclic ring, wherein the 5- to 9-membered heterocyclic ring is each independently replaced by one or more R 1* Optional substitution.

266. The compound or salt of claim 265, wherein each R 1* independently selected from halogen, C 1-6 Haloalkyl and C 1-6 alkyl.

267. A compound or salt as described in any one of claims 246 to 259, wherein R 1 for It is substituted with at least one substituent.

268. A compound or salt as described in any one of claims 246 to 259, wherein R 1 for 269. A compound or salt as described in any one of claims 246 to 259, wherein R 1 for 270. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 269 and a pharmaceutically acceptable excipient.

271. A method of treating a disease or condition using a compound or salt as described in any one of claims 1 to 269 or a pharmaceutical composition as described in claim 270.

272. 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 269 or a pharmaceutical composition as described in claim 270.

273. 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 269 or a pharmaceutical composition as described in claim 270.

274. 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 269 or a pharmaceutical composition as described in claim 270.

275. A method of inhibiting KRas G12D and / or other alleles using a compound or salt as described in any one of claims 1 to 269 or a pharmaceutical composition as described in claim 270.

276. Use of a compound as described in any one of claims 1 to 269 in the preparation of a target protein degradation compound by using chemical modification of a compound as described in any one of claims 1 to 269.

277. 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 a compound as described in any one of claims 1 to 269.

278. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: A is selected from C5-C8 carbocyclic ring, wherein the C5-C8 carbocyclic ring is replaced by one or more independently selected from R 94 The substituents of are optionally substituted; R 91 Selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; R 92 is selected from hydrogen, halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; R 93 Selected from hydrogen, -C(O)OR 21 、-C(O)R 21 and-SO2R 21 ; Each R 94 independently selected from hydrogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic rings and 5- to 12-membered heterocyclic rings; and Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Substituents for the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

279. The compound or salt of claim 278, wherein A is selected from an optionally substituted C5-C7 carbocycle.

280. The compound or salt of claim 279, wherein A is selected from an optionally substituted unsaturated C5-C7 carbocycle.

281. The compound or salt of any one of claims 278 to 280, wherein A is selected from an optionally substituted C5 carbocycle.

282. The compound or salt of any one of claims 278 to 280, wherein A is selected from an optionally substituted C6 carbocycle.

283. The compound or salt of any one of claims 278 to 280, wherein A is selected from an optionally substituted C7 carbocycle.

284. The compound or salt of any one of claims 278 to 280, wherein the C7 carbocycle of A is a monocyclic ring.

285. The compound or salt of any one of claims 278 to 280, wherein the C7 carbocycle of A is a bicyclic ring.

286. A compound or salt as described in any one of claims 278 to 280, wherein A is selected from 287. A compound or salt as described in any one of claims 278 to 280, wherein A is selected from 288. A compound or salt as described in any one of claims 278 to 287, wherein formula (II) is represented by formula (II-A) or a pharmaceutically acceptable salt; wherein n is selected from 0, 1 and 2.

289. A compound or salt as described in any one of claims 278 to 287, wherein formula (II) is represented by formula (II-B) or a pharmaceutically acceptable salt; wherein n is selected from 0, 1 and 2.

290. A compound or salt as described in any one of claims 278 to 287, wherein formula (II) is represented by formula (II-C) or a pharmaceutically acceptable salt; wherein n is selected from 0, 1 and 2.

291. The compound or salt of any one of claims 278 to 287, wherein A is an optionally substituted fused C6-C7 carbocycle.

292. The compound or salt of any one of claims 278 to 287, wherein A is selected from an optionally substituted fused C6-C7 unsaturated carbocyclic ring.

293. The compound or salt of claim 292, wherein A is selected from 294. The compound or salt of claim 293, wherein A is selected from 295. The compound or salt of claim 293 or 294, wherein formula (II) is represented by formula (II-D) or a pharmaceutically acceptable salt; wherein n is selected from 0, 1 and 2.

296. A compound or salt as described in any one of claims 278 to 295, wherein R 91 Selected from halogen, -CN, -NO2, -N(R 21 )2.-OR 21 、-C(O)R 21 , C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings.

297. The compound or salt of claim 296, wherein R 91 Selected from -CN.

298. A compound or salt as described in any one of claims 278 to 297, wherein R 92 Selected from hydrogen, halogen, -CN, -NO2, -N(R 21 )2.-OR 21 、-SR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 , 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings.

299. The compound or salt of claim 298, wherein R 92 is selected from hydrogen, halogen, -CN and -N(R 21 )2.

300. The compound or salt of claim 299, wherein R 92 Selected from -N(R 21 )2.

301. A compound or salt as described in any one of claims 278 to 300, wherein R 93 Selected from hydrogen.

302. A process for preparing a compound or salt as described in any one of claims 278 to 301.

303. A compound of formula (III): B is selected from a 5- to 8-membered heterocyclic ring, wherein the 5- to 8-membered heterocyclic ring is substituted by one or more independently selected from halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 The substituents of the carbocyclic and 5- to 12-membered heterocyclic rings are optionally substituted; R 91 Selected from fluorine, iodine, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; R 92 is selected from hydrogen, halogen, -CN, -NO2, =O, -N(R 21 )2、-B(OR 21 )2.-OR 21 、-SR 21 、-S(O)2(R 21 )、-S(O)2N(R 21 )2.-NR 21 S(O)2R 21 、-C(O)N(R 21 )2. -C(O)NR 21 OR 21 、-N(R 21 )C(O)R 21 、-N(R 21 )C(O)N(R 21 )2、-N(R 21 )C(O)OR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 、-OC(O)N(R 21 2. 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings; R 93 Selected from hydrogen, -C(O)OR 21 、-C(O)R 21 and-SO2R 21 ;and Each R 21 are independently selected from hydrogen; and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-12 Carbocyclic and 3 to 12 membered heterocyclic rings, each of which is independently substituted by one or more selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1-6 Alkyl)2, C 1-10 Alkyl, -C 1-10 Haloalkyl, -OC 1-10 Alkyl, oxo, C 3-12 Substituents for the carbocyclic and 3- to 12-membered heterocyclic rings are optionally substituted.

304. The compound or salt of claim 303, wherein B is selected from an optionally substituted 5- to 7-membered heterocycle.

305. The compound or salt of claim 304, wherein B is selected from an optionally substituted unsaturated 5- to 7-membered heterocyclic ring.

306. The compound or salt of claim 280, wherein B is selected from an optionally substituted 5-membered heterocycle.

307. The compound or salt of any one of claims 303 to 306, wherein the heterocyclic ring of B has at least one sulfur atom.

308. The compound or salt of claim 307, wherein formula (III) is represented by formula (III-A) or a pharmaceutically acceptable salt.

309. A compound or salt as described in any one of claims 303 to 308, wherein R 91 Selected from halogen, -CN, -NO2, -N(R 21 )2.-OR 21 、-C(O)R 21 , C 1-6 Alkyl-N(R 20 2. C 1-6 Aminoalkyl, C 1-6 Alkoxyalkyl, C 1-6 Hydroxyalkyl, C 1-6 Cyanoalkyl, C 1-6 Haloalkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings.

310. A compound or salt as described in any one of claims 303 to 309, wherein R 91 Selected from -CN.

311. A compound or salt as described in any one of claims 303 to 310, wherein R 92 Selected from hydrogen, halogen, -CN, -NO2, -N(R 21 )2.-OR 21 、-SR 21 、-C(O)R 21 、-C(O)OR 21 、-OC(O)R 21 , 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 Alkenyl, C 2-6 Alkynyl, C3-C 12 Carbocyclic and 5- to 12-membered heterocyclic rings.

312. The compound or salt of claim 311, wherein R 92 is selected from hydrogen, halogen, -CN and -N(R 21 )2.

313. The compound or salt of claim 312, wherein R 92 Selected from -N(R 21 )2.

314. The compound or salt of claim 313, wherein R 93 Selected from hydrogen.

315. A process for preparing a compound or salt as claimed in any one of claims 303 to 314.

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