KRAS Modulators and Uses Thereof

Abstract

Provided herein is a KRAS modulating compound selected from fused pyrimidines, such as compounds of formula (II), or any of the above pharmaceutically acceptable salts, solvates, stereoisomers, labeling atoms or tautomers, useful for modulating KRAS GD12 and / or other G12 mutants.The present disclosure relates to formula (I) or formula (II) or formula (III), including its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts, and its use in, for example, inhibiting KRas G12D and / or other G12 mutants. JPEG2025508696000570.jpg2739

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Patent Application Nos. 63 / 308,424, filed February 9, 2022; 63 / 368,584, filed July 15, 2022; 63 / 373,302, filed August 23, 2022; 63 / 378,843, filed October 7, 2022; and 63 / 384,374, filed November 18, 2022; the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] Background of the Invention The small GTPase protein Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is a member of the Ras family of cell signaling switches and regulates the growth and survival of normal and cancer cells (see, e.g., Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): pp. 1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by dysregulating the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (see, e.g., Stephen, AG, et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): pp. 272-81). Ras has been recognized as a target in cancer for approximately 40 years, but Ras-driven cancers remain some of the most difficult to treat due to their insensitivity to available targeted therapies. Ras, encoded by three major genes KRAS, NRAS, and HRAS, has the highest frequency of mutations of any oncogene. All oncogenic Ras mutations trigger a switch that accumulates in an active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (see, e.g., The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): pp. 818-831. Dataset Version 4). Activating mutations at codon 12 impair the ability of small GTPases to perform their role of hydrolyzing GTP. This regulatory dysfunction is fundamental to initiating and maintaining tumor progression.

[0003] Despite significant efforts, no small molecules have been identified that block effector binding or restore GTPase-activating protein (GAP) sensitivity, although several have been found that block the interaction between Ras and SOS, a guanine nucleotide exchange factor (GEF) that activates Ras at the cell membrane. The KRAS G12C mutation, the most common in lung adenocarcinoma, has been clinically shown to be sensitive to direct inhibition by covalent modification with small molecule inhibitors that trap the protein in an inactive GDP-bound state. The KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Therefore, pharmacological targeting of the inactive state is unlikely to achieve similar results to G12D, despite the presence of a similar binding pocket in the GDP state. Additionally, the cysteine ​​present at the site of the activating mutation is accessible for covalent chemistry, whereas the aspartate does not offer a typical medicinal chemistry approach for selective covalent modification.

[0004] To achieve selective inhibition of cancer cells while preserving normal Ras function, it is attractive for small molecule inhibitors to selectively bind to the GTP-bound state and stabilize a conformation incompetent for oncogenic signaling interactions with effector proteins, potentially exploiting the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability. Furthermore, it has been shown that constitutive activation of Raf, MEK, and ERK kinases alone in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (see, e.g., Drosten, M., et al., Genetic analysis of Ras signaling pathways in cell proliferation, migration, and survival. EMBO J, 2010. 29(6): pp. 1091-104). Because all evidence indicates that MAPK signaling is essential for the growth effects of Ras in cancer, selective inhibition of KRAS mutants in this pathway is considered an important functional readout for the potential clinical benefit of novel therapeutic approaches. Summary of the Invention There is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signaling through a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p. 1292-1292 e1 [Non-patent document 2] Stephen, AG, et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81 [Non-patent document 3] The AACR Project GENIE Consortium. Cancer Discovery, 2017. 7(8): p. 818-831. Dataset Version 4 [Non-patent document 4] Drosten, M., et al., Genetic analysis of Ras signaling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104 Summary of the Invention [Means for solving the problem]

[0006] The present disclosure relates to compounds of Formula (I) or Formula (II) or Formula (III), including stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts thereof, and their uses, for example, in inhibiting KRas G12D and / or other G12 mutants.

[0007] In some embodiments, the present disclosure provides a compound represented by the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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(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, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently and optionally substituted with; Each R 1* is 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 (=NR20 ), -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 independently selected from: Y is a bond, O, S, or NR 5 Selected from; R 2 is hydrogen, -N(R 21 )2, -LN(R 21 )2, -L-OR 21 , heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 21 )2, -L-C1-C6 haloalkyl, -L-OR 21 , -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 ), -LS(O)2N(R 21)2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, and -LC(=O)OC1-C6 alkyl; heterocycle; and -L-NR 5 The aryl portion of C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl can be one or more R 6 and the aryl or heteroaryl in -L-aryl and -L-heteroaryl is optionally substituted with one or more R 7 , substituted as needed; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 3~12independently selected from carbocycles, and 3- to 12-membered heterocycles; 3~12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with halogen, -OH, -CN, -NO2, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, C 3~12 each optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 5 are independently selected from hydrogen or C1-C6 alkyl; Each R 6 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; Each R 7 is halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 independently selected; Each R 20 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, =NH, C 3~12 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 3~12C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from heterocycles and carbocycles, and heterocycles and carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO, C1-C4 alkyl, C 1~6 Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl, and B forms a spiro ring with ring A; Ring A is selected from heterocycles and carbocycles, and the heterocycle or carbocycle is selected from R 4 and optionally substituted with one or more substituents selected from to provide.

[0008] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a salt, and a pharmaceutically acceptable excipient.

[0009] In certain embodiments, the present disclosure provides methods of treating a disease or disorder using a compound or salt of formula (I). In certain embodiments, the present disclosure provides methods of treating a disease or disorder using a compound or salt of formula (I) and a pharmaceutically acceptable excipient.

[0010] In certain embodiments, the present disclosure provides methods for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of Formula (I). In certain embodiments, the present disclosure provides methods for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of Formula (I) and a pharmaceutically acceptable excipient.

[0011] In some embodiments, the present disclosure provides a compound represented by the structure of formula (II): [ka] or a pharmaceutically acceptable salt thereof [In the formula, M is O, S, SO, SO2, and NR 3 Selected from; R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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(O)NR 20 OR 20 , -N(R 20 )C(O)R20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =N(R 20 ), =NO(R 20 ), -CN, -NHCN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl-SO2R 20 , C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently optionally substituted by; M is NR 3 and Y is O and R 1 is a piperazine, the piperazine may be one or more R 9 is replaced by; Each R 1* is 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 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C3-C 12 independently selected from: Y is a bond, O, S, or NR 5 Selected from; R 2 is -LN(R 21 )2, -L-OR 21 , heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 21 ) 2、 -L-NHC(=NH)NH2, -LC(O)N(R 21 )2, -L-C1-C6 haloalkyl, -L-OR 21 , -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 ), -LS(O)2N(R 21 )2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21)2, or -LC(=O)OC1-C6 alkyl; 21 The aryl portion of C(O)-aryl, the heterocyclic portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl may be one or more R 6 and the aryl portion of -L-aryl and the heteroaryl portion of -L-heteroaryl are each optionally substituted by one or more R 7 and when Y is a bond, O, or S, R 2 is further selected from hydrogen; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6Haloalkyl, C 1~6 Alkoxyalkyl, C 3~12 selected from carbocyclic rings and 3- to 12-membered heterocyclic rings, 3~12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with 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 each optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 12-membered heterocycle; n is selected from 0 to 2; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, oxo, hydroxyl, halogen, C 3~12 independently selected from carbocycle, and 3- to 12-membered heterocycle; C1-C6 alkyl, C 3~12 Carbocycles and 3- to 12-membered heterocycles are substituted with cyano, halogen, -OR 5 , and -N(R 5 ) each optionally substituted with one or more substituents independently selected from: Each R 5 are independently selected from hydrogen or C1-C6 alkyl; Each R 6 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is each optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 7 is halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 independently selected; Each R 9 is halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -NO2, =O, =NO(R 20 ), -CN, -NHCN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 independently selected from haloalkyl; Each R 20 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, =NH, C 3~12 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; B is selected from heterocycles and carbocycles, and heterocycles and carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO, C1-C4 alkyl, C 1~6Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12 each optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle, and 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl, each optionally substituted with one or more substituents selected from to provide.

[0012] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (II) and a pharmaceutically acceptable excipient.

[0013] In certain embodiments, the present disclosure provides a method of treating a disease or disorder using a compound or salt of formula (II). In certain embodiments, the present disclosure provides a method of treating a disease or disorder using a compound or salt of formula (II) and a pharmaceutically acceptable excipient.

[0014] 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 (II). 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 (II) and a pharmaceutically acceptable excipient.

[0015] In some embodiments, the present disclosure provides a compound represented by the structure of formula (III): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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(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, C1~6 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, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently and optionally substituted with; Each R 1* is 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 1~6Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C3-C 12 independently selected from: R 2 -L-NR 21 S(O)2(R 21 ), -LS(O)2N(R 21 )2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, and L-bicyclic heterocycles, wherein the bicyclic heterocycle is selected from one or more R 6 , substituted as needed; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; n is selected from 0 to 3; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, oxo, hydroxyl, halogen, C 3~12 independently selected from carbocycle, and 3- to 12-membered heterocycle; C1-C6 alkyl, C 3~12 Carbocycles and 3- to 12-membered heterocycles are substituted with cyano, halogen, -OR 5 , and -N(R 5 ) each optionally substituted with one or more substituents independently selected from: B is selected from heterocycles and carbocycles, and the heterocycles or carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO2, C1-C4 alkyl, C 1~6 Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; Y is a bond, O, S, or NR 5 Selected from; Each R 6is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 20 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 5 are independently selected from hydrogen or C1-C6 alkyl. to provide.

[0016] In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound or salt of formula (III) and a pharmaceutically acceptable excipient.

[0017] In certain embodiments, the present disclosure provides a method of treating a disease or disorder using a compound or salt of formula (III). In certain embodiments, the present disclosure provides a method of treating a disease or disorder using a compound or salt of formula (III) and a pharmaceutically acceptable excipient.

[0018] In certain embodiments, the present disclosure provides methods for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of formula (III). In certain embodiments, the present disclosure provides methods for inhibiting KRas G12D and / or other G12 mutants using a compound or salt of formula (III) and a pharmaceutically acceptable excipient. Incorporation by Reference

[0019] 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. DETAILED DESCRIPTION OF THE INVENTION

[0020] Detailed Description of the Invention The following description sets forth numerous example configurations, methods, parameters, etc. However, it should be recognized that such description is not intended as a limitation on the scope of the present disclosure, but is instead provided as a description of example embodiments.

[0021] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments of the present disclosure. However, it will be understood by those skilled in the art that the present disclosure may be practiced without these details. definition

[0022] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications mentioned herein are incorporated herein by reference.

[0023] "Alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, consisting solely of carbon and hydrogen atoms, preferably having 1 to 15 carbon atoms (i.e., C1 to C 15In certain embodiments, alkyl comprises 1 to 13 carbon atoms (i.e., C1-C 13 In certain embodiments, alkyl contains 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains 1 to 2 carbon atoms (i.e., C1-C2 alkyl). In other embodiments, alkyl contains 1 carbon atom (i.e., C1 alkyl). In other embodiments, alkyl contains 5 to 15 carbon atoms (i.e., C5-C6 alkyl). 15 In other embodiments, an alkyl contains 5 to 8 carbon atoms (i.e., a C5-C8 alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (i.e., a C2-C5 alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (i.e., a C3-C5 alkyl). In certain embodiments, an alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). An alkyl is attached to the remainder of the molecule by a single bond.

[0024] "C x~y The term "C" when used in conjunction with a chemical moiety, e.g., alkyl, alkenyl, or alkynyl, is meant to include groups containing x to y carbons in the chain. For example, "C 1~6 The term "alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain or branched alkyl groups, containing 1 to 6 carbons. x~y The term alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, -C 1~6Alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0025] "Alkoxy" refers to a radical attached through an oxygen atom of the formula --O-alkyl, where alkyl is an alkyl chain as defined above.

[0026] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms containing at least one carbon-carbon double bond, preferably having from 2 to 12 carbon atoms (i.e., C2-C 12 alkenyl). In certain embodiments, an alkenyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). In other embodiments, an alkenyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). An alkenyl is attached to the remainder of the molecule by a single bond, such as ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0027] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group, consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, preferably having from 2 to 12 carbon atoms (i.e., C2-C 12 alkynyl). In certain embodiments, alkynyl contains 2 to 8 carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, alkynyl contains 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). In other embodiments, alkynyl contains 2 to 4 carbon atoms (i.e., C2-C4 alkynyl). Alkynyl is attached to the remainder of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0028] "C x~yalkenyl" and "C x~y The term "alkynyl" refers to a substituted or unsubstituted unsaturated aliphatic group analogous in length and possible substitution to alkyl, but containing at least one double or triple bond, respectively. x~y The term alkenylene- refers to a substituted or unsubstituted alkenylene chain having x to y carbon atoms in the chain. For example, -C 2~6 Alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain may have one double bond or two or more double bonds in the alkenylene chain. -C x~y The term alkynylene- refers to a substituted or unsubstituted alkynylene chain having x to y carbon atoms in the alkynylene chain. For example, -C 2~6 Alkenylene- can be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. The alkynylene chain can have one triple bond or more than one triple bond in the alkynylene chain.

[0029] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain, containing no unsaturation, consisting solely of carbon and hydrogen, that connects the rest of the molecule to a radical group, preferably having 1 to 12 carbon atoms, such as methylene, ethylene, propylene, n-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkylene contains 1 to 10 carbon atoms (i.e., C1-C8 alkylene). In certain embodiments, alkylene contains 1 to 8 carbon atoms (i.e., C1-C8 alkylene). In other embodiments, alkylene contains 1 to 5 carbon atoms (i.e., C1-C5 alkylene). In other embodiments, alkylene contains 1 to 4 carbon atoms (i.e., C1-C4 alkylene). In other embodiments, alkylene contains 1 to 3 carbon atoms (i.e., C1-C3 alkylene). In other embodiments, alkylene contains 1 to 2 carbon atoms (i.e., C1-C2 alkylene). In other embodiments, alkylene contains 1 carbon atom (i.e., C1 alkylene). In other embodiments, alkylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkylene). In other embodiments, alkylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkylene). In other embodiments, alkylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkylene).

[0030] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, linking the rest of the molecule to a radical group, preferably having 2 to 12 carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkenylene contains 2 to 10 carbon atoms (i.e., C2 to C6). 10alkenylene). In certain embodiments, alkenylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkenylene). In other embodiments, alkenylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkenylene). In other embodiments, alkenylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, alkenylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, alkenylene contains 2 carbon atoms (i.e., C2 alkenylene). In other embodiments, alkenylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, alkenylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkenylene).

[0031] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, linking the rest of the molecule to a radical group, preferably having 2 to 12 carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain. In certain embodiments, alkynylene contains 2 to 10 carbon atoms (i.e., C2 to C6). 10 alkynylene). In certain embodiments, alkynylene contains 2 to 8 carbon atoms (i.e., C2-C8 alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (i.e., C2-C3 alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (i.e., C2 alkynylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (i.e., C5-C8 alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (i.e., C3-C5 alkynylene).

[0032] "Aryl" refers to a radical derived from an aromatic monocyclic or aromatic polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic polycyclic hydrocarbon ring system contains only hydrogen and carbon and contains 5 to 18 carbon atoms, where at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel's rule. Ring systems from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0033] "Aralkyl" is a group of the formula -R c -aryl (wherein R c refers to a radical of an alkylene chain as defined above, e.g., methylene, ethylene, etc.

[0034] "Aralkenyl" refers to a group of the formula -R d -aryl (wherein R d is an alkenylene chain as defined above. "Aralkynyl" refers to a radical of the formula -R e -aryl (wherein R e refers to a radical of the group ##STR00002## which is an alkynylene chain as defined above.

[0035] "Carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles can include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of carbocycle, if valence permits. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles can be fused, bridged, or spirocyclic ring systems. In some cases, spirocyclic carbocycles have at least two rings with only one common atom.

[0036] The term "unsaturated carbocycle" refers to a carbocycle having at least one degree of unsaturation and excludes aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0037] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, including fused or bridged ring systems, preferably having 3 to 12 carbon atoms. In certain embodiments, cycloalkyls contain 3 to 10 carbon atoms. In other embodiments, cycloalkyls contain 5 to 7 carbon atoms. A cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0038] "Cycloalkenyl" refers to an unsaturated, non-aromatic, monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, preferably having 3 to 12 carbon atoms, including fused or bridged ring systems containing at least one double bond. In certain embodiments, a cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, a cycloalkenyl contains 5 to 7 carbon atoms. A cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0039] "Cycloalkylalkyl" refers to a group of the formula -R c -cycloalkyl (wherein R c refers to a radical of the formula (which is an alkylene chain as described above).

[0040] "Cycloalkylalkoxy" refers to a group of the formula -OR c -cycloalkyl (wherein R c refers to a radical attached through an oxygen atom of an alkylene chain, as described above.

[0041] "Halo" or "halogen" refers to a halogen substituent, eg, bromo, chloro, fluoro, and iodo substituent.

[0042] As used herein, the term "haloalkyl" or "haloalkane" refers to an alkyl radical, as defined above, that is substituted with one or more halogen radicals, e.g., trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. In some embodiments, the alkyl portion of the fluoroalkyl radical is optionally further substituted. Examples of halogen-substituted alkanes ("haloalkanes") include halomethanes (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di- and trihalomethanes (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2-dihaloethane, 1-halopropane, 2-halopropane, 3-halopropane, 1,2-dihalopropane, 1,3-dihalopropane, 2,3-dihalopropane, 1,2,3-trihalopropane, and any other suitable combination of an alkane (or substituted alkane) and a halogen (e.g., Cl, Br, F, I, etc.). When an alkyl group is substituted with two or more halogen radicals, each halogen can be independently selected and can be, for example, 1-chloro, 2-fluoroethane.

[0043] "Fluoroalkyl" refers to an alkyl radical as defined above that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0044] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine, and the like.

[0045] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0046] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, e.g., methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0047] "Cyanoalkyl," as used herein, refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, e.g., acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, and the like.

[0048] As used herein, a "heterocycle" refers to a saturated, unsaturated, or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. A heterocycle may be attached to the remainder of the molecule through any atom of the heterocycle, e.g., a carbon atom or nitrogen atom of the heterocycle, where valence allows. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Bicyclic heterocycles include any combination of saturated, unsaturated, and aromatic bicyclic rings, where valence allows. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to 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, bridged, or spiro ring systems. Spiro ring systems can be referred to as "spiroheterocycles," "spiro heterocycles," or "spiro-heterocycles." In some cases, spiro-heterocycles, spiro heterocycles, or spiro-heterocycles have at least two rings with only one common atom. A spiro-heterocycle, spiro heterocycle, or spiroheterocycle contains one or more heteroatoms.

[0049] "Heterocyclene" refers to a divalent heterocycle that links the rest of the molecule to a radical group.

[0050] "Heteroaryl" or "heteroaromatic ring" refers to a radical derived from a heteroaromatic ring radical containing 1 to 11 carbon atoms and at least one heteroatom, where each heteroatom may be selected from N, O, and S. As used herein, heteroaryl rings may be selected from monocyclic or bicyclic rings and fused or bridged ring systems, where at least one ring in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n+2) π-electron system according to Hückel's rule. Heteroatoms in a heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the remainder of the molecule through any atom of the heteroaryl, e.g., a carbon atom or nitrogen atom of the heteroaryl, where valence allows. Examples of heteroaryl include, but are not limited to, pyridine, pyrimidine, oxazole, furan, pyran, thiophene, isoxazole, benzimidazole, benzthiazole, and imidazopyridine.

[0051] An "X-membered heteroaryl" refers to the number of ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered heteroaromatic ring has 5 ring atoms, e.g., triazole, oxazole, thiophene, etc.

[0052] The term "unsaturated heterocycle" refers to a heterocycle having at least one degree of unsaturation, excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle may be optionally substituted with one or more substituents, for example, the substituents described herein.

[0053] The term "substituted" refers to a moiety having a substituent replacing a hydrogen on one or more carbon or substitutable heteroatoms, e.g., NH, of the structure. It will be understood that "substituted" or "substituted with" includes the implicit proviso that such substitution is subject to the permissible valences of the substituted atom and substituent, and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformation, such as rearrangement, cyclization, elimination, and the like. In certain embodiments, substituted refers to a moiety having a substituent replacing two hydrogen atoms on the same carbon atom, e.g., replacing two hydrogen atoms on a single carbon with an oxo, imino, or thioxo group. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.

[0054] In some embodiments, a substituent may be any substituent described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO), imino (=NH), oximo (=N-OH), hydrazino (=N-NH), -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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein 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, and heterocycle, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, 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(Ra )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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); each R a are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each R a is, when valence allows, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, 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 -ORc -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 (wherein t is 1 or 2), -R b -S(O) t R a (wherein t is 1 or 2), -R b -S(O) t OR a (wherein t is 1 or 2) and -R b -S(O) t N(R a )2 (wherein t is 1 or 2); each R b are independently selected from a direct bond, or a straight or branched alkylene, alkenylene, or alkynylene chain, and each R c is a straight or branched alkylene, alkenylene or alkynylene chain.

[0055] As used herein, the term "electrophile" or "electrophilic moiety" refers to any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge, and / or an excess of electrons, e.g., an -SH group). Electrophiles typically contain an atom that is electron-deficient. In certain embodiments, electrophiles contain a positive or partial positive charge, have a resonance structure containing a positive or partial positive charge, or are moieties in which electron delocalization or polarization results in one or more atoms containing a positive or partial positive charge. In some embodiments, electrophiles contain conjugated double bonds, e.g., α,β-unsaturated carbonyl compounds or α,β-unsaturated thiocarbonyl compounds.

[0056] As used herein, the term "optionally" or "optionally" means that the subsequently described circumstance event may or may not occur, and that the description includes instances in which the event or circumstance occurs as well as instances in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and that the description includes both substituted aryl groups and aryl groups having no substituents.

[0057] As used in this specification and claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0058] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salts are selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0059] The phrases "parenteral administration" and "administered parenterally", as used herein, mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

[0060] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that 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.

[0061] The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier," as used herein, refers to 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 harmful to the patient. Some examples of materials that can serve 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 wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and the like. and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, 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) ethyl alcohol; (20) phosphate buffer; and (21) other non-toxic, compatible substances used in pharmaceutical formulations.

[0062] In certain embodiments, the term "prevent" or "preventing," when related to a disease or disorder, may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of or reduces the severity of one or more symptoms of the disorder or condition compared to an untreated control sample.

[0063] The terms "treat," "treating," or "treatment," as used herein, can include alleviating, attenuating, or relieving the symptoms of a disease or condition, preventing additional symptoms, alleviating or preventing the underlying cause of the symptoms, inhibiting the disease or condition, e.g., halting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, alleviating conditions caused by the disease or condition, or arresting the symptoms of the disease or condition prophylactically and / or therapeutically.

[0064] The term "G12 mutant," as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (ie, G12X). Compounds of the Disclosure

[0065] Below is a discussion of compounds and salts thereof that may be used in the methods of the present disclosure.

[0066] In some aspects, the present disclosure provides a compound represented by the structure of formula (I): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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(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, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently and optionally substituted with; Each R 1* is halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -S(O)N(R20 )2, -S(O)R 20 (=NR 20 ), -NR 20 S(O)2R 20 , -C(O)N(R 20 )2, -C(O)NR 20 OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =N(R 20 ), =NO(R 20 ), -CN, -NHCN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C3-C 12 independently selected from: Y is a bond, O, S, or NR 5 Selected from; R 2 is hydrogen, -N(R 21 )2, -LN(R 21 )2, -L-OR 21 , heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -LN(R 21 )2, -L-NHC(=NH)NH2, -LC(O)N(R 21 )2, -L-C1-C6 haloalkyl, -L-OR 21 , -L-NR 21 C(O)-aryl, -L-COOH, -L-NR21 S(O)2(R 21 ), -LS(O)2N(R 21 )2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, or -LC(=O)OC1-C6 alkyl; heterocycle; and -L-NR 5 The aryl portion of C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl can be one or more R 6 and the aryl or heteroaryl in -L-aryl and -L-heteroaryl is optionally substituted with one or more R 7 , substituted as needed; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 3~12 independently selected from carbocycles, and 3- to 12-membered heterocycles; 3~12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with halogen, -OH, -CN, -NO2, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, C 3~12 each optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 5 are independently selected from hydrogen and C1-C6 alkyl; Each R 6 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; Each R 7 is halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 independently selected; Each R 20 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, =NH, C 3~12 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 3~12C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from heterocycles and carbocycles, and heterocycles and carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO, C1-C4 alkyl, C 1~6 Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl, and B forms a spiro ring with ring A; Ring A is selected from heterocycles and carbocycles, and the heterocycle or carbocycle is selected from R 4 and optionally substituted with one or more substituents selected from to provide.

[0067] In some embodiments, Formula (I) can be represented by Formula (II), Formula (II * ), or represented by formula (III):

[0068] In some embodiments, for compounds or salts of Formula (I), ring A is selected from heterocycles, and the heterocycles are selected from R 4 In some cases, ring A contains at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom in ring A is nitrogen, and the nitrogen is optionally substituted with one or more substituents selected from R 3 , substituted as necessary by R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 3~12 selected from carbocyclic rings and 3- to 12-membered heterocyclic rings, 3~12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with 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 A heteroatom in ring A is optionally substituted with one or more substituents independently selected from a carbocycle, a 3- to 12-membered heterocycle, and a 3- to 12-membered heterocycle. In some cases, the heteroatom in ring A is sulfur, which is optionally substituted with one or two oxygen atoms. In some cases, the heteroatom in ring A is oxygen.

[0069] In some embodiments, for compounds or salts of Formula (I), ring A is selected from a carbocycle, and the carbocycle is selected from R 4 and optionally substituted with one or more substituents selected from:

[0070] In some embodiments, for a compound or salt of Formula (I), R 2-L-NR 21 S(O)2(R 21 ) and -LS(O)N(R 21 )2 is selected.

[0071] In some embodiments, for a compound or salt of Formula (I), R 2 is -LN(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 )2 is selected.

[0072] In some embodiments, for a compound or salt of Formula (I), each R 21 are hydrogen; each of which is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 C optionally substituted with one or more substituents independently selected from alkyl, and oxo 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen; C 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen and C 1~6 alkyl.

[0073] In some embodiments, for a compound or salt of Formula (I), R 2 is selected from an L-bicyclic heterocycle, wherein the bicyclic heterocycle is selected from one or more R 6 has been substituted as necessary.

[0074] In some embodiments, for a compound or salt of Formula (I), R 2 is selected from L-pyrrolidine, wherein pyrrolidine is selected from one or more R 6 has been substituted as necessary.

[0075] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from optionally substituted C1-C4 alkylene; and optionally, two substituents on the same carbon atom of L, taken together, form a C3-C6 carbocyclic ring, wherein the C3-C6 carbocyclic ring is selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 In some cases, the optional substituents on L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, and C3-C6 carbocycle; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3-8 membered heterocycle, and the C3-C6 carbocycle and the 3-8 membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0076] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from substituted C1-C4 alkylene, and 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 selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0077] In some embodiments, for a compound or salt of Formula (I), each L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L are joined together to form a C3-C6 carbocyclic ring. In some cases, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L are joined together to form a C3 carbocyclic ring. In some cases, each L is independently selected from: [ka] are independently selected from

[0078] In some embodiments, for a compound or salt of Formula (I), R 2 is selected from -L-heterocycle, the heterocyclic portion of which is selected from 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.

[0079] In some embodiments, for a compound or salt of Formula (I), R 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0080] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0081] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0082] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0083] In some embodiments, for a compound or salt of Formula (I), R 2 is selected from -L-saturated heterocycle, and the saturated heterocycle portion of the -L-saturated heterocycle is selected from one or more R 6 and contains one nitrogen atom and one sulfur atom. In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. 2 teeth, [ka] In some cases, YR 2 teeth, [ka] is selected from.

[0084] In some embodiments, for a compound or salt of Formula (I), each R 6 is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5 )2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with —C(O)H and OH, respectively, and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo.

[0085] In some embodiments, for a compound or salt of Formula (I), each R 6 are independently selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl.

[0086] In some embodiments, for a compound or salt of Formula (I), each R 6 is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo. In some instances, each R 6 is -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R 5 )2. In some cases, each R 6 is C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2 are independently selected.

[0087] In some embodiments, for a compound or salt of Formula (I), R 6 is selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl. 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is a halogen. In some cases, R 6 is C1-C3 alkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is selected from methyl and fluorine.

[0088] In some embodiments, for a compound or salt of Formula (I), R 2 teeth, [ka] is selected from.

[0089] In some embodiments, for a compound or salt of Formula (I), YR2 teeth, [ka] is selected from.

[0090] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] is selected from.

[0091] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] is.

[0092] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] is selected from.

[0093] In some embodiments, for the compound or salt of Formula (I), B is an optionally substituted 5-15 membered heterocycle or an optionally substituted C3-C 15 In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C 15 It is a carbocyclic ring.

[0094] In some embodiments, for the compound or salt of Formula (I), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 In some cases, B is an optionally substituted 8- to 15-membered fused carbocyclic ring. In some cases, B is an optionally substituted C8-C 15 It is a fused carbocyclic ring.

[0095] In some embodiments, for the compound or salt of Formula (I), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocycles are bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle is bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C 15 Each fused carbocycle is bicyclic or tricyclic.

[0096] In some embodiments, for compounds or salts of Formula (I), each heterocycle or carbocycle of B is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0097] In some embodiments, for the compound or salt of Formula (I), each heterocycle or carbocycle of B is independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0098] In some embodiments, for a compound or salt of Formula (I), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0099] In some embodiments, for the compound or salt of Formula (I), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0100] In some embodiments, for the compound or salt of Formula (I), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0101] In some embodiments, for compounds or salts of Formula (I), for B, one or more optional substituents on the heterocycle and carbocycle are selected from, at each occurrence, 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 In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OR 20 )2, -OH, -C(O)N(R 20 )2, =O, -CN, C 1~6 Alkoxy, and C 2~6 In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —C(O)NH, —NH, ═O, —CN, C 1~6 Alkoxy, and C 2~6In some cases, the one or more optional substituents on the heterocycle and carbocycle, at each occurrence, are independently selected from oxo, -NH, -CN, halogen, and C-C alkyl. In some cases, the one or more optional substituents on the heterocycle or carbocycle are independently selected from oxo, -NH, halogen, and C-C alkyl.

[0102] In some embodiments, for the compound or salt of Formula (I), B is [ka] is selected from.

[0103] In some embodiments, for a compound or salt of Formula (I), for B, one or more optional substituents of the heterocycle or carbocycle are independently selected from oxo, —NH, CN, halogen, and C-C alkyl.

[0104] In some embodiments, for the compound or salt of Formula (I), B is [ka] is selected from.

[0105] In some embodiments, for a compound or salt of Formula (I), each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 In some instances, each R is independently selected from alkynyl, oxo, hydroxyl, and halogen. 4 is C 1~6 is independently selected from alkyl, oxo, and halogen.

[0106] In some embodiments, for a compound or salt of Formula (I), n is selected from 1 and 2. In some instances, n is 0.

[0107] In some embodiments, for compounds or salts of Formula (I), Y is O.

[0108] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from optionally substituted 5- to 12-membered heterocycles.

[0109] In some embodiments, for a compound or salt of Formula (I), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , S.R. 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0110] In some embodiments, for a compound or salt of Formula (I), R 1 is C3~C 12carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -C(O)N(R 20 )2, -C(O)NR 20 -OR 20 , -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), -CN, -NHCN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0111] In some embodiments, for a compound or salt of Formula (I), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)OR 20 , and -OC(O)N(R 20 ) optionally substituted with one or more substituents independently selected from

[0112] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0113] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0114] In some embodiments, for a compound or salt of Formula (I), R 1 R 20 is hydrogen and C 1~3 alkyl.

[0115] In some embodiments, for a compound or salt of Formula (I), R 1 The 5- to 12-membered heterocyclic ring is an unsaturated heterocyclic ring.

[0116] In some embodiments, for a compound or salt of Formula (I), R 1 The 5- to 12-membered heterocycle is a saturated heterocycle.

[0117] In some embodiments, for a compound or salt of Formula (I), R 1 The 5- to 12-membered heterocycle is a bridged heterocycle.

[0118] In some embodiments, for a compound or salt of Formula (I), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0119] In some embodiments, for a compound or salt of Formula (I), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0120] In some embodiments, for a compound or salt of Formula (I), R 1 teeth, [ka] is selected from.

[0121] In some embodiments, for the compound or salt of Formula (I), L is selected from C1-C4 alkylene.

[0122] In some embodiments, for the compound or salt of Formula (I), L is selected from unsubstituted C1-C4 alkylene.

[0123] In some embodiments, for a compound or salt of Formula (I), R 2 is one or more R 6 and the heterocyclic moiety is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least one nitrogen atom. In some cases, the bicyclic heterocycle contains at most one nitrogen atom.

[0124] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0125] In some embodiments, for a compound or salt of Formula (I), R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.

[0126] In some embodiments, for a compound or salt of Formula (I), R 2 R 6 is, at each occurrence, independently selected from C1-C3 alkyl and halogen.

[0127] In some embodiments, for a compound or salt of Formula (I), YR 2 teeth, [ka] is selected from.

[0128] In some aspects, the present disclosure provides a compound represented by the structure of formula (II):

[0129] Compounds of formula (II): [ka] or a pharmaceutically acceptable salt thereof [In the formula, M is O, S, SO, SO2, and NR 3 Selected from; R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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(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 , C1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently optionally substituted by; M is NR 3 and Y is O and R 1 is a piperazine, the piperazine may be one or more R 9 is replaced by; Each R 1* is 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, C1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, and C3-C 12 independently selected from: Y is a bond, O, S, or NR 5 Selected from; R 2 is -LN(R 21 )2, -L-OR 21 , heterocycle, C1-C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -LC(O)N(R 21 )2, -L-C1-C6 haloalkyl, -L-OR 21 , -L-NR 21 C(O)-aryl, -L-COOH, -L-NR 21 S(O)2(R 21 ), -LS(O)2N(R 21 )2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, and -LC(=O)OC1-C6 alkyl; 21 The aryl portion of C(O)-aryl, the heterocyclic portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl may be one or more R 6 and the aryl portion of -L-aryl and the heteroaryl portion of -L-heteroaryl are each optionally substituted by one or more R 7 and when Y is a bond, O, or S, R 2 is further selected from hydrogen; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkoxyalkyl, C 3~12 selected from carbocyclic rings and 3- to 12-membered heterocyclic rings, 3~12 Carbocyclic and 3- to 12-membered heterocyclic rings are not substituted with 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 each optionally substituted with one or more substituents independently selected from a carbocycle, and a 3- to 12-membered heterocycle; n is selected from 0 to 2; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, oxo, hydroxyl, halogen, C 3~12 independently selected from carbocycle, and 3- to 12-membered heterocycle; C1-C6 alkyl, C 3~12Carbocycles and 3- to 12-membered heterocycles are substituted with cyano, halogen, -OR 5 , and -N(R 5 ) each optionally substituted with one or more substituents independently selected from: Each R 5 are independently selected from hydrogen or C1-C6 alkyl; Each R 6 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is each optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 7 is halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 independently selected; Each R 9 is halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -NO2, =O, =NO(R 20 ), -CN, -NHCN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 independently selected from haloalkyl; Each R 20 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, =NH, C 3~12 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; B is selected from heterocycles and carbocycles, and heterocycles and carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO, C1-C4 alkyl, C 1~6 Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12each optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle, and 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl], each optionally substituted with one or more substituents selected from:

[0130] In some embodiments, for a compound or salt of Formula (II), R 2 -L-NR 21 S(O)2(R 21 ) and -LS(O)N(R 21 )2 is selected.

[0131] In some embodiments, for a compound or salt of Formula (II), R 2 is -LN(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 )2 is selected.

[0132] In some embodiments, for a compound or salt of Formula (II), each R 21 are hydrogen; each of which is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 C optionally substituted with one or more substituents independently selected from alkyl, and oxo 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen; C 1~6 Alkyl, C 3~12carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen and C 1~6 alkyl.

[0133] In some embodiments, for a compound or salt of Formula (II), R 3 is hydrogen and C 1~6 alkyl.

[0134] In some embodiments, for the compound or salt of Formula (II), M is selected from O, NH, and NMe. In some cases, M is O. In some cases, M is selected from NH and NMe.

[0135] In some embodiments, for the compound or salt of Formula (II), B is an optionally substituted 5-15 membered heterocycle or an optionally substituted C3-C 15 In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C 15 In some cases, B is an optionally substituted 8-15 membered heterocycle. In some cases, B is an optionally substituted C8-C 15 It is a carbocyclic ring.

[0136] In some embodiments, for the compound or salt of Formula (II), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 In some cases, B is an optionally substituted 8- to 15-membered fused carbocyclic ring. In some cases, B is an optionally substituted C8-C 15 It is a fused carbocyclic ring.

[0137] In some embodiments, for the compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15The fused carbocycles are bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle is bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C 15 Each fused carbocycle is bicyclic or tricyclic.

[0138] In some embodiments, for the compound or salt of Formula (II), for B, the optionally substituted 8- to 15-membered heterocyclic ring contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at least two heteroatoms.

[0139] In some embodiments, for the compound or salt of Formula (II), each heterocycle or carbocycle of B is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0140] In some embodiments, for the compound or salt of Formula (II), each heterocycle or carbocycle of B is independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0141] In some embodiments, for a compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0142] In some embodiments, for the compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0143] In some embodiments, for the compound or salt of Formula (II), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0144] In some embodiments, for compounds or salts of Formula (II), for B, one or more optional substituents on the heterocycle and carbocycle are selected from the group consisting of 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 In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OR 20 )2, -OH, -C(O)N(R 20 )2, =O, -CN, C 1~6 Alkoxy, and C 2~6In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —C(O)NH, —NH, ═O, —CN, C 1~6 Alkoxy, and C 2~6 In some cases, the one or more optional substituents on the heterocycle and carbocycle, at each occurrence, are independently selected from oxo, -NH, -CN, halogen, and C-C alkyl. In some cases, the one or more optional substituents on the heterocycle or carbocycle are independently selected from oxo, -NH, halogen, and C-C alkyl.

[0145] In some embodiments, for the compound or salt of Formula (II), B is [ka] is selected from.

[0146] In some embodiments, for the compound or salt of Formula (II), B is [ka] is selected from.

[0147] In some embodiments, for a compound or salt of Formula (II), each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 In some instances, each R is independently selected from alkynyl, oxo, hydroxyl, and halogen. 4 is C 1~6 is independently selected from alkyl, oxo, and halogen.

[0148] In some embodiments, for the compound or salt of Formula (II), n is selected from 1 and 2. In some instances, n is 0.

[0149] In some embodiments, for compounds or salts of Formula (II), Y is O.

[0150] In some embodiments, for a compound or salt of Formula (II), R 1 is selected from optionally substituted 5- to 12-membered heterocycles.

[0151] In some embodiments, for a compound or salt of Formula (II), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0152] In some embodiments, for a compound or salt of Formula (II), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , S.R. 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), CN, C 1~6Aminoalkyl, 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 Optionally substituted with one or more substituents independently selected from alkynyl.

[0153] In some embodiments, for a compound or salt of Formula (II), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)OR 20 , and -OC(O)N(R 20 ) optionally substituted with one or more substituents independently selected from

[0154] In some embodiments, for a compound or salt of Formula (II), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0155] In some embodiments, for a compound or salt of Formula (II), R 1 R 20 is hydrogen and C 1~3 alkyl.

[0156] In some embodiments, for a compound or salt of Formula (II), R 1The 5- to 12-membered heterocyclic ring is an unsaturated heterocyclic ring.

[0157] In some embodiments, for a compound or salt of Formula (II), R 1 The 5- to 12-membered heterocycle is a saturated heterocycle.

[0158] In some embodiments, for a compound or salt of Formula (II), R 1 The 5- to 12-membered heterocycle is a bridged heterocycle.

[0159] In some embodiments, for a compound or salt of Formula (II), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl. In some embodiments, for a compound or salt of Formula (II), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0160] In some embodiments, for a compound or salt of Formula (II), R 1 teeth, [ka] is selected from.

[0161] In some embodiments, for a compound or salt of Formula (II), R 1 is selected from optionally substituted saturated 6- to 7-membered heterocycles. 1 is selected from optionally substituted saturated 6-membered heterocycles. 1 teeth, [ka] In some cases, the optional substituents are selected from halogen, —CN, —NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -NHCN, and C 1~6 alkyl. In some instances, R 1 teeth, [ka] -NHCN, and C 1~6 In some cases, R is substituted with one or more substituents selected from alkyl. 1 teeth, [ka] is selected from.

[0162] In some embodiments, for a compound or salt of Formula (II), R 1is selected from substituted saturated 6-membered heterocycles, the saturated 6-membered heterocycles containing at least one -NHCN and, optionally, one or more C 1~6 M is O; n is 0; B is an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 fused carbocycles, each of which is selected from halogen, oxo, -NH, C-C alkyl, -OH, -C(O)NH, -NH, =O, -CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 alkynyl; Y is O; and R 2 is selected from -L-heterocycle, wherein the heterocycle moiety is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2; and L is selected from C1-C4 alkylene. In some instances, R 1 teeth, [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] is.

[0163] In some embodiments, for a compound or salt of Formula (II), each R 9 is halogen, -B(OR 20 )2, -OR 20 , -SR20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -NO2, =O, =NO(R 20 ), -CN, -NHCN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 haloalkyl. In some instances, each R 9 is halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -NO2, =O, =NO(R 20 ), —CN, and —NHCN. In some instances, each R 9 is halogen, -SR 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -N(R 20 )2, -NO2, =O, and =NO(R 20 ) are independently selected from 9 is halogen, and -N(R 20 )2 are independently selected.

[0164] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from optionally substituted C1-C4 alkylene; and optionally, two substituents on the same carbon atom of L, taken together, form a C3-C6 carbocyclic ring, wherein the C3-C6 carbocyclic ring is selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 In some cases, the optional substituents on L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, and C3-C6 carbocycle; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3-8 membered heterocycle, and the C3-C6 carbocycle and the 3-8 membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0165] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from substituted C1-C4 alkylene, and 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 selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0166] In some embodiments, for a compound or salt of Formula (II), each L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L are joined together to form a C3-C6 carbocyclic ring. In some cases, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L are joined together to form a C3 carbocyclic ring. In some cases, each L is independently selected from: [ka] are independently selected from

[0167] In some embodiments, for a compound or salt of Formula (II), R 2 is selected from -L-heterocycle, the heterocyclic portion of which is selected from 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.

[0168] In some embodiments, for a compound or salt of Formula (II), R 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0169] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0170] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0171] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0172] In some embodiments, for a compound or salt of Formula (II), R 2 is selected from -L-saturated heterocycle, and the saturated heterocycle portion of the -L-saturated heterocycle is selected from one or more R 6 and contains one nitrogen atom and one sulfur atom. In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. 2 teeth, [ka] In some cases, YR 2 teeth, [ka] is selected from.

[0173] In some embodiments, for a compound or salt of Formula (II), each R 6is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5 )2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with —C(O)H and OH, respectively, and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo.

[0174] In some embodiments, for a compound or salt of Formula (II), each R 6 are independently selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl.

[0175] In some embodiments, for a compound or salt of Formula (II), each R 6is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo. In some instances, each R 6 is -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R 5 )2. In some cases, each R 6 is C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2 are independently selected.

[0176] In some embodiments, for a compound or salt of Formula (II), R 6 is selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl. 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is a halogen. In some cases, R 6 is C1-C3 alkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is selected from methyl and fluorine.

[0177] In some embodiments, for a compound or salt of Formula (II), R 2 teeth, [ka] is selected from.

[0178] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] is selected from.

[0179] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] is selected from.

[0180] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] is.

[0181] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] is selected from.

[0182] In some embodiments, for the compound or salt of Formula (II), L is selected from C1-C4 alkylene.

[0183] In some embodiments, for the compound or salt of Formula (II), L is selected from unsubstituted C1-C4 alkylene.

[0184] In some embodiments, for a compound or salt of Formula (II), R 2 is one or more R 6 and the heterocyclic moiety is a bicyclic heterocycle. In some cases, the bicyclic heterocycle contains at least one nitrogen atom. In some cases, the bicyclic heterocycle contains at most one nitrogen atom.

[0185] In some embodiments, for a compound or salt of Formula (II), R 2 is selected from an L-bicyclic heterocycle, wherein the bicyclic heterocycle is selected from one or more R6 has been substituted as necessary.

[0186] In some embodiments, for a compound or salt of Formula (II), R 2 is selected from L-pyrrolidine, wherein pyrrolidine is selected from one or more R 6 has been substituted as necessary.

[0187] In some embodiments, for a compound or salt of Formula (II), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0188] In some embodiments, for a compound or salt of Formula (II), R 2 R 6 is, at each occurrence, independently selected from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 2 R 6 is, at each occurrence, independently selected from C1-C3 alkyl and halogen. In some instances, YR 2 teeth, [ka] is selected from.

[0189] In some embodiments, for the compound or salt of Formula (II), M is NR 3 In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is C 1~6In some cases, M is selected from C cyanoalkyl. In some cases, M is selected from NH. In some cases, R 3 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is hydrogen, C 1~6 Alkyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is C 1~6 Alkyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is C 2~6 Alkyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6In some instances, R is selected from haloalkyl. 3 is C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is C 1~6 Cyanoalkyl, C 1~6 Alkoxyalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is hydrogen, C 1~6 Alkyl, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, and C 1~6 In some instances, R is selected from haloalkyl. 3 is C 1~6 Alkoxyalkyl, C 1~6 Cyanoalkyl, and C 1~6 In some cases, R 3 teeth, [ka] In some cases, R 3 is C 2~6 alkyl.

[0190] In some embodiments, for the compound or salt of Formula (II), M is NR 3 and B is [ka] each of which is optionally substituted; n is 0; Y is O; R 2is selected from an L-heterocycle, the heterocycle being selected from one or more R 6 substituted as needed with ;R 1 teeth, [ka] In some cases, R 1 teeth, [ka] which is a 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)NR 20 OR 20 , -N(R 20 )2, -C(O)R 20 , -NO2, =O, -CN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Alkoxyalkyl, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, and C 2~6 alkynyl, optionally substituted with one or more substituents independently selected from: 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, the heterocycle of the L-heterocycle is bicyclic. In some cases, the heterocycle of the L-heterocycle is monocyclic. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from unsubstituted C1-C4 alkylene. In some cases, L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring. In some cases, YR 2 teeth, [ka] In some cases, YR 2 teeth, [ka] In some cases, B is selected from [ka] In some cases, B is selected from: [ka] which is substituted with one or more substituents. In some cases, B is [ka] In some cases, for B, one or more substituents are selected from halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —C(O)NH, —NH, ═O, —CN, —O-C-C haloalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C2~6 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 [ka] In some cases, B is selected from [ka] is selected from halogen, —O—C1-C3 haloalkyl, and C 1~6 In some instances, B is substituted with one or more substituents selected from: haloalkyl. [ka] which is substituted with one or more substituents selected from halogen. In some cases, B is [ka] In some cases, B is selected from [ka] which is substituted with one or more substituents selected from fluorine. In some cases, B is [ka] In some cases, B is selected from [ka] which is substituted with one or more substituents selected from chlorine. In some cases, B is [ka] In some cases, R 3is hydrogen and C 1~6 In some cases, R 3 is C 1~6 In some cases, R 3 is methyl. In some cases, each R 6 is halogen, oxo, and C 1~6 In some cases, each R 6 is a halogen, and C 1~6 In some cases, each R 6 is selected from halogen. 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, B is [ka] is.

[0191] In some aspects, the present disclosure provides a compound represented by the structure of formula (III): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is C3~C 12 carbocycle and 5- to 15-membered heterocycle, each of which is 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 20S(O)2R 20 , -C(O)N(R 20 )2, -C(=NR 20 )N(R 20 )2, -C(O)NR 20 OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =N(R 20 ), =NO(R 20 ), -CN, -NHCN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3-C 12 optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles may be formed by one or more R 1* each independently and optionally substituted with; Each R 1* is 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(R20 )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 independently selected from: R 2 -L-NR 21 S(O)2(R 21 ), -LS(O)2N(R 21 )2, -LN(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, and L-bicyclic heterocycles, wherein the bicyclic heterocycle is selected from one or more R 6 , substituted as needed; Each L is independently selected from C1-C4 alkylene optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle, or 3-8 membered heterocycle, wherein C3-C6 carbocycle and 3-8 membered heterocycle are selected from halogen, -OH, -NO2, ═O, ═S, -CN, C 1~6 Aminoalkyl, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 optionally substituted with one or more substituents selected from haloalkyl; optionally, two substituents on the same carbon atom of L taken together form a C3-C6 carbocyclic or 3-8 membered heterocyclic ring, and C3-C6 carbocyclic and 3-8 membered heterocyclic rings are selected from halogen, -OH, -NO2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; n is selected from 0 to 3; Each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, oxo, hydroxyl, halogen, C 3~12 independently selected from carbocycle, and 3- to 12-membered heterocycle; C1-C6 alkyl, C 3~12 Carbocycles and 3- to 12-membered heterocycles are substituted with cyano, halogen, -OR 5 , and -N(R 5 ) each optionally substituted with one or more substituents independently selected from: B is selected from heterocycles and carbocycles, and the heterocycles or carbocycles are selected from halogen, cyano, hydroxy, ═O, —NO2, C1-C4 alkyl, C 1~6 Aminoalkyl, -S-C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C2-C4 hydroxyalkynyl, C1-C3 cyanoalkyl, triazolyl, C1-C3 haloalkyl, -O-C1-C3 haloalkyl, -S-C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CH2C(=O)N(R 5 )2, -C3-C4 alkynyl (NR 5 )2, -N(R 5 )2, (C1-C3 alkoxy)haloC1-C3 alkyl-, C 1~6 Alkyl-N(R 20 )2, C3~C 12optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, 12 Carbocycles and 5- to 12-membered heterocycles are not affected by halogen, -OH, -NO2, -NH2, =O, =S, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 haloalkyl; Y is a bond, O, S, or NR 5 Selected from; Each R 6 is halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, oxo, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-C1-C3 alkyl, C1-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)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, —O—C1-C3 alkyl, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with one or more substituents selected from —C(O)H and OH, and the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R 20 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 21 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 independently selected from a carbocycle, and a 3- to 12-membered heterocycle; Each R 5are independently selected from hydrogen or C1-C6 alkyl. to provide.

[0192] In some embodiments, for a compound or salt of Formula (III), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -S(O)2(R 20 ), -C(O)N(R 20 )2, -C(O)NR 20 -OR 20 , -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), -CN, -NHCN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0193] In some embodiments, for a compound or salt of Formula (III), R 2 -L-NR 21 S(O)2(R 21 ) and -LS(O)N(R 21 )2 is selected.

[0194] In some embodiments, for a compound or salt of Formula (III), R 2 is -LN(R 21 )C(O)(OR 21 ), and -L-OC(O)N(R 21 )2 is selected.

[0195] In some embodiments, for a compound or salt of Formula (III), each R 21 are hydrogen; each of which is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 C optionally substituted with one or more substituents independently selected from alkyl, and oxo 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen; C 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 21 is hydrogen and C 1~6 alkyl.

[0196] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from an L-bicyclic heterocycle, wherein the bicyclic heterocycle is selected from one or more R 6 has been substituted as necessary.

[0197] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from L-pyrrolidine, wherein pyrrolidine is selected from one or more R 6 has been substituted as necessary.

[0198] In some embodiments, for the compound or salt of Formula (III), B is an optionally substituted 5-15 membered heterocycle or an optionally substituted C3-C 15 In some cases, B is an optionally substituted 5- to 15-membered heterocycle. In some cases, B is an optionally substituted 8- to 15-membered heterocycle. In some cases, B is an optionally substituted C3-C 15 In some cases, B is an optionally substituted C-C 15 It is a carbocyclic ring.

[0199] In some embodiments, for the compound or salt of Formula (III), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 In some cases, B is an optionally substituted 8- to 15-membered fused carbocyclic ring. In some cases, B is an optionally substituted C8-C 15 It is a fused carbocyclic ring.

[0200] In some embodiments, for the compound or salt of Formula (III), for B, the optionally substituted 8- to 15-membered heterocyclic ring contains at least one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at least one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at most one nitrogen atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at most one sulfur atom. In some cases, the optionally substituted 8- to 15-membered heterocyclic ring contains at least two heteroatoms.

[0201] In some embodiments, for the compound or salt of Formula (III), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15The fused carbocycles are bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle is bicyclic or tricyclic, respectively. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle or optionally substituted C8-C 15 Each fused carbocycle is bicyclic or tricyclic.

[0202] In some embodiments, for the compound or salt of Formula (III), each heterocycle or carbocycle of B is independently bicyclic. In some cases, the heterocycle is bicyclic. In some cases, the carbocycle is bicyclic.

[0203] In some embodiments, for the compound or salt of Formula (III), each heterocycle or carbocycle of B is independently tricyclic. In some cases, the heterocycle is tricyclic. In some cases, the carbocycle is tricyclic.

[0204] In some embodiments, for a compound or salt of Formula (III), B is an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0205] In some embodiments, for the compound or salt of Formula (III), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0206] In some embodiments, for the compound or salt of Formula (III), B is an optionally substituted 8-15 membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic ring is [ka] each of which is optionally substituted with one or more substituents.

[0207] In some embodiments, for compounds or salts of Formula (III), for B, one or more optional substituents on the heterocycle and carbocycle are selected from the group consisting of 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 In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OR 20 )2, -OH, -C(O)N(R 20 )2, =O, -CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 In some cases, one or more optional substituents on the heterocycle and carbocycle are independently selected from, at each occurrence, halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —C(O)NH, —NH, ═O, —CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6In some cases, the one or more optional substituents on the heterocycle and carbocycle, at each occurrence, are independently selected from oxo, -NH, -CN, halogen, and C-C alkyl. In some cases, the one or more optional substituents on the heterocycle or carbocycle are independently selected from oxo, -NH, halogen, and C-C alkyl.

[0208] In some embodiments, for the compound or salt of Formula (III), B is [ka] is selected from.

[0209] In some embodiments, for a compound or salt of Formula (III), for B, one or more optional substituents on the heterocycle or carbocycle are independently selected from oxo, —NH, halogen, and C-C alkyl.

[0210] In some embodiments, for the compound or salt of Formula (III), B is [ka] is selected from.

[0211] In some embodiments, for a compound or salt of Formula (III), each R 4 is C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 In some instances, each R is independently selected from alkynyl, oxo, hydroxyl, and halogen. 4 is C 1~6 is independently selected from alkyl, oxo, and halogen.

[0212] In some embodiments, for the compound or salt of Formula (III), n is selected from 1 and 2. In some instances, n is 0.

[0213] In some embodiments, for the compound or salt of Formula (III), Y is O.

[0214] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from optionally substituted 5- to 12-membered heterocycles.

[0215] In some embodiments, for a compound or salt of Formula (III), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , S.R. 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0216] In some embodiments, for a compound or salt of Formula (III), R 1 is C3~C12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from halogen, -B(OR 20 )2, -OR 20 , S.R. 20 , -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =NO(R 20 ), CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0217] In some embodiments, for a compound or salt of Formula (III), R 1 is C3~C 12 carbocycle and 5- to 12-membered heterocycle, each of which is selected from -S(O)2(R 20 ), -S(O)2N(R 20 )2, -NR 20 S(O)2R 20 , -N(R 20 )C(O)OR 20 , and -OC(O)N(R 20 ) optionally substituted with one or more substituents independently selected from

[0218] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0219] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0220] In some embodiments, for a compound or salt of Formula (III), R 1 R 20 is hydrogen and C 1~3 alkyl.

[0221] In some embodiments, for a compound or salt of Formula (III), R 1 The 5- to 12-membered heterocyclic ring is an unsaturated heterocyclic ring.

[0222] In some embodiments, for a compound or salt of Formula (III), R 1 The 5- to 12-membered heterocycle is a saturated heterocycle.

[0223] In some embodiments, for a compound or salt of Formula (III), R 1 The 5- to 12-membered heterocycle is a bridged heterocycle.

[0224] In some embodiments, for a compound or salt of Formula (III), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0225] In some embodiments, for a compound or salt of Formula (III), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0226] In some embodiments, for a compound or salt of Formula (III), R 1 teeth, [ka] is selected from.

[0227] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from optionally substituted saturated 6- to 7-membered heterocycles. 1 is selected from optionally substituted saturated 6-membered heterocycles. 1 teeth, [ka] In some cases, the optional substituents are selected from halogen, —CN, —NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -NHCN, and C 1~6 alkyl. In some instances, R 1 teeth, [ka] -NHCN, and C 1~6 In some cases, R is substituted with one or more substituents selected from alkyl. 1 teeth, [ka] is selected from.

[0228] In some embodiments, for a compound or salt of Formula (III), R 1 is selected from substituted saturated 6-membered heterocycles, the saturated 6-membered heterocycles containing at least one -NHCN and, optionally, one or more C 1~6 M is O; n is 0; B is an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 fused carbocycles, each of which is selected from halogen, oxo, -NH, C-C alkyl, -OH, -C(O)NH, -NH, =O, -CN, C 1~6 Alkoxy, C1~6 Hydroxyalkyl, and C 2~6 alkynyl; Y is O; and R 2 is selected from -L-bicyclic heterocycle, wherein the bicyclic heterocycle moiety is selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2; and L is selected from C1-C4 alkylene. In some instances, R 1 teeth, [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] is.

[0229] In some embodiments, for the compound or salt of Formula (III), L is selected from C1-C4 alkylene.

[0230] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from optionally substituted C1-C4 alkylene; and optionally, two substituents on the same carbon atom of L, taken together, form a C3-C6 carbocyclic ring, wherein the C3-C6 carbocyclic ring is selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6In some cases, the optional substituents on L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, and C3-C6 carbocycle; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3-8 membered heterocycle, and the C3-C6 carbocycle and the 3-8 membered heterocycle are optionally substituted with one or more substituents selected from halogen and C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0231] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from substituted C1-C4 alkylene, and 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 selected from halogen, —OH, —NO2, ═O, ═S, —CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 and optionally substituted with one or more substituents selected from haloalkyl.

[0232] In some embodiments, for a compound or salt of Formula (III), each L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L are joined to form a C3-C6 carbocyclic ring. In some cases, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L are joined to form a C3 carbocyclic ring. In some cases, each L is independently selected from: [ka] are independently selected from

[0233] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from -L-heterocycle, the heterocyclic portion of which is selected from one or more R 6In 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.

[0234] In some embodiments, for a compound or salt of Formula (III), R 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0235] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0236] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0237] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] [ka] and the heterocyclic moiety is selected from one or more R 6has been substituted as necessary.

[0238] In some embodiments, for a compound or salt of Formula (III), R 2 is selected from -L-saturated heterocycle, and the saturated heterocycle portion of the -L-saturated heterocycle is selected from one or more R 6 and contains one nitrogen atom and one sulfur atom. In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is optionally substituted with one or more substituents selected from C1-C3 alkyl and oxo. 2 teeth, [ka] In some cases, YR 2 teeth, [ka] is selected from.

[0239] In some embodiments, for a compound or salt of Formula (III), each R 6 is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, C1-C3 aminoalkyl, -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3 alkyl-substituted pyrazolyl, -N(R 5)2, (C1-C3 alkoxy)C1-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)C1-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(C1-C3 alkyl), —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl(C1-C3 alkyl)N(CH3)2, —OC(O)NH(C1-C3 alkyl)O(C1-C3 alkyl)phenyl, —OC(O)heterocycle, and —CH2heterocycle, wherein the phenyl in —NHC(O)phenyl and —OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with —C(O)H and OH, respectively, and the heterocycle in —CH2heterocyclyl is optionally substituted with oxo.

[0240] In some embodiments, for a compound or salt of Formula (III), each R 6 are independently selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl.

[0241] In some embodiments, for a compound or salt of Formula (III), each R 6 is halogen, -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -N(R 5 )2, and oxo. In some instances, each R 6 is -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5 )2. In some cases, each R 6 is C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2 are independently selected.

[0242] In some embodiments, for a compound or salt of Formula (III), R 6 is selected from halogen, —OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, —CN, and C1-C3 aminoalkyl. 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is a halogen. In some cases, R 6 is C1-C3 alkyl. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is selected from methyl and fluorine.

[0243] In some embodiments, for a compound or salt of Formula (III), R 2 teeth, [ka] is selected from.

[0244] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] is selected from.

[0245] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] is selected from.

[0246] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] is.

[0247] In some embodiments, for the compound or salt of Formula (III), L is selected from unsubstituted C1-C4 alkylene.

[0248] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] and the heterocyclic moiety is selected from one or more R 6 has been substituted as necessary.

[0249] In some embodiments, for a compound or salt of Formula (III), R 2 R 6 is independently selected at each occurrence from halogen, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl.

[0250] In some embodiments, for a compound or salt of Formula (III), R 2 R 6 is, at each occurrence, independently selected from C1-C3 alkyl and halogen.

[0251] In some embodiments, for a compound or salt of Formula (III), YR 2 teeth, [ka] is selected from.

[0252] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The carbocyclic ring is C3 to C 12 Carbocycle, C3~C 10 carbocycle, C3-C9 carbocycle, C3-C8 carbocycle, or C3-C6 carbocycle. 1 The carbocyclic ring is C3 to C 12 Carbocycle, C4~C 12 Carbocycle, C5~C 12 Carbocycle, C6~C 12 Carbocycle, C7~C 12 Carbocyclic, C8~C 12 Carbocyclic or C9-C 12 Carbocycles are selected from:

[0253] In some embodiments, for compounds of Formula (I), R 1 The heterocycle of R 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 R 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 R is a 6- to 11-membered heterocycle, a 6- to 10-membered heterocycle, a 6- to 9-membered heterocycle, or a 6- to 8-membered heterocycle. 1 The heterocycle of R is a 7- to 11-membered heterocycle, a 7- to 10-membered heterocycle, a 7- to 9-membered heterocycle, or a 7- to 8-membered heterocycle. 1 The heterocycle of R is a 5- to 6-membered heterocycle or a 5- to 9-membered heterocycle. 1 The heterocycle of R is an 8- to 9-membered heterocycle. 1 The heterocycle of is saturated. The heterocycle may be optionally substituted as described elsewhere herein.

[0254] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The heterocycle of R 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. 1The heterocycle of R 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 of R 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 of R 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 of R is a 5- to 6-membered monocyclic heterocycle or a 5- to 9-membered monocyclic heterocycle. 1 The heterocycle of R is an 8- to 9-membered monocyclic heterocycle. 1 The heterocycle of is saturated. Monocyclic heterocycles may be optionally substituted as described elsewhere herein.

[0255] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The heterocycle of R 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 of R 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. 1 The heterocycle of R 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 of R is a bridged 7- to 11-membered 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 of R is a 5- to 6-membered bridged heterocycle or a 5- to 9-membered bridged heterocycle. 1 The heterocycle of R is an 8- to 9-membered bridged heterocycle. 1 The heterocycle of is saturated. The bridged heterocycle may be optionally substituted as described elsewhere herein.

[0256] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is a 5- to 9-membered heterocycle, the 5- to 9-membered heterocycle containing at most one nitrogen atom. 1 is selected from optionally substituted 5- to 9-membered heterocycles, each of which is optionally substituted.

[0257] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The heterocycle of R contains at most one nitrogen atom. 1 The heterocycle of R contains at most one heteroatom. 1 The heterocycle of contains up to two heteroatoms. In some cases, the heteroatoms are selected from nitrogen, oxygen, and sulfur. In some cases, the heterocycle is a monocyclic heterocycle or a bridged heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle is a bridged heterocycle. In some cases, the heterocycle is [ka] In some instances, the heterocycle is selected from: [ka] In some instances, the bridged heterocycle is selected from: [ka] The heterocycle may be optionally substituted as described elsewhere herein.

[0258] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The spiro heterocycle of R contains at most one nitrogen atom. 1 The spiro heterocycle of R contains up to two heteroatoms. 1The spiro heterocycle of R contains up to three heteroatoms. 1 The spiro heterocycle of R contains at most one heteroatom. 1 The spiro heterocycle of R contains at least two heteroatoms. 1 The spiro heterocycle of R contains at least three heteroatoms. 1 The spiro heterocycle of R contains at least four heteroatoms. 1 The spiro heterocycle of R contains at least two nitrogen atoms. 1 The spiro heterocycle of R contains at most one heteroatom. 1 The spiroheterocycle of formula (I) contains up to one sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 The spiro heterocycle of [ka] In some embodiments, R 1 The spiro heterocycle of [ka] The spiroheterocycle may be optionally substituted as described elsewhere herein.

[0259] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted 7- to 8-membered spiro heterocycles. 1 is selected from optionally substituted 7-membered spiroheterocycles. 1 is selected from optionally substituted 8-membered spiroheterocycles.

[0260] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1The fused heterocycle of R 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 R 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 R 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 heterocycle of R is an 8- to 11-membered fused heterocycle. 1 is a 6-membered fused heterocycle. The fused heterocycle may be optionally substituted as described elsewhere herein.

[0261] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The fused heterocycle of R is selected from 6-, 9-, 10-, 11-, and 12-membered fused heterocycles. 1 The fused heterocycle of R is selected from 9- to 12-membered fused heterocycles. 1 The fused heterocyclic ring is selected from 10- to 12-membered fused heterocyclic rings. The fused heterocyclic ring is selected from halogen, -OR 20 , -N(R 20 )2, -NO2, =O, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 The fused heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OR alkyl, -OR 20 , -N(R 20 )2, -NO2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl.

[0262] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The fused heterocycle of R contains at most one nitrogen atom. 1 The fused heterocycle of the formula: contains at most one heteroatom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocycle is [ka] The fused heterocycle may be optionally substituted as described elsewhere herein.

[0263] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from a C6-C7 carbocycle, a 5- to 10-membered heterocycle, a 7- to 8-membered spiroheterocycle, and a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is optionally substituted.

[0264] In some embodiments, for compounds of Formula (I), R 1 is selected from a C6-C7 carbocycle, a 5- to 10-membered heterocycle, a 7- to 8-membered spiroheterocycle, and a 6-, 8- to 12-membered fused heterocycle, each of which may be selected from halogen, -OR 20 , -N(R 20 )2, -NO2, =O, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl.

[0265] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from a C6-C7 carbocycle, a 5- to 10-membered heterocycle, a 7- to 8-membered spiroheterocycle, and a 6-, 8- to 12-membered fused heterocycle, each of which may be selected from halogen, -OR 20 , -N(R20 )2, -NO2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl.

[0266] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 About -OR 20 and -N(R 20 )2R 20 is hydrogen and C 1~6 alkyl.

[0267] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from a C6-C7 carbocycle and a 5- to 10-membered heterocycle, each of which is optionally substituted. In some cases, the heterocycle contains up to one nitrogen atom. In some cases, R 1 is selected from C6 to C7 carbocycles, each of which is optionally substituted.

[0268] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 wherein one or more optional substituents are halogen, -OR 20 , -N(R 20 )2, -NO2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, -N(R 20 )C(O)N(R 20 )2, and C 1~6 alkyl.

[0269] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 wherein one or more optional substituents are halogen, -OR 20 , -N(R 20 )2, -NO2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 alkyl. In some instances, R 1 one or more optional substituents of -OR 20 , -N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 1~6 In some instances, one or more optional substituents of R are independently selected from -OR alkyl. 20 , -N(R 20 )2, C 1~6 Aminoalkyl, and C 1~6 In some instances, one or more optional substituents of R are independently selected from -OR 20 , -N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkyl, and C 1~6 hydroxyalkyl. In some instances, R 1 one or more optional substituents of -OR 20 , -N(R 20 )2, and C 1~6 alkyl. In some instances, R 1 wherein one or more optional substituents are —N(R 20 )C(O)N(R 20 )2 are independently selected.

[0270] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is C3~C 12selected from carbocycles and 5- to 12-membered heterocycles, the 5- to 12-membered heterocycles containing up to one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 is further selected from 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, and 12 Carbocycles, 5- to 12-membered heterocycles, 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles are not limited to halogen, -OR 20 , -SR 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -NO2, =O, =N(R 20 ), -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 each optionally substituted with one or more substituents independently selected from alkynyl;

[0271] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is C3~C 12 selected from carbocycles and 5- to 12-membered heterocycles, the 5- to 12-membered heterocycles containing up to one nitrogen atom and optionally one or more additional heteroatoms selected from oxygen, boron, and sulfur; or R 1 is further selected from 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, and 12Carbocycles, 5- to 12-membered heterocycles, 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles are not limited to halogen, -B(OR 20 )2, -OR 20 , -SR 20 , -N(R 20 )S(O)2(R 20 ), -C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -NO2, =O, =S, =N(R 20 ), -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 each optionally substituted with one or more substituents independently selected from alkynyl;

[0272] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from 5-10 membered heterocycles, 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, each of which is 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, -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 C1~6 and optionally substituted with one or more substituents independently selected from aminoalkyl.

[0273] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from 5-10 membered heterocycles, 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, each of which is 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 and optionally substituted with one or more substituents independently selected from aminoalkyl. 1 teeth, [ka] each 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 1~6and optionally substituted with one or more substituents independently selected from aminoalkyl. 1 teeth, [ka] [ka] is selected from.

[0274] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from a 5- to 10-membered heterocycle, and the 5- to 10-membered heterocycle is selected from -OR 20 , -N(R 20 )2, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , and -B(OR 20 )2. In some instances, R 1 teeth, [ka] each of which is selected from -OR 20 , -N(R 20 )2, C 1~6 Alkyl, C 1~6 Hydroxyalkyl, C 1~6 Aminoalkyl, -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)R 20 , and -B(OR 20 ) optionally substituted with one or more substituents independently selected from

[0275] In some embodiments, for compounds of Formula (I), Formula (II), or Formula (III), R 1teeth, [ka] is selected from.

[0276] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from 5- to 10-membered heterocycles, and the 5- to 10-membered heterocycle is selected from -N(R 20 )2, -OR 20 , and C 1~6 In some instances, the 5- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from -OR alkyl. 20 , and C 1~6 In some embodiments, for compounds of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each of which is selected from -OR 20 , and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] is selected from.

[0277] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] and wherein each of the groups is optionally substituted.

[0278] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each of which is selected from -OH, -CN, oxo, C 1~6 Optionally substituted with one or more substituents independently selected from cyanoalkyl.

[0279] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] is selected from.

[0280] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] and wherein each of the groups is optionally substituted.

[0281] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] and wherein each of the groups is optionally substituted.

[0282] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] and wherein each of the groups is optionally substituted.

[0283] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R1 teeth, [ka] where, substituted as necessary.

[0284] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] [ka] is selected from.

[0285] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is.

[0286] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 The 5- to 12-membered heterocycle of R is an unsaturated and bridged heterocycle. 1 is selected from optionally substituted 7-8 membered unsaturated and bridged heterocycles. In some cases, R 1 teeth, [ka] is selected from.

[0287] In some embodiments, for compounds of Formula (I) or Formula (II), R 1 is selected from 5-10 membered heterocycles, 7-, 8-, 10-, and 11-membered spiroheterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, each of which is 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 optionally substituted with one or more substituents independently selected from aminoalkyl; R 3 is naphthalene, which is a halogen atom, -OH, -NH2, -NO2, =O, C 1~6 Alkyl, C 2~6 Alkynyl, C 1~6 Aminoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 optionally substituted with one or more substituents independently selected from haloalkyl; R 4 is selected from hydrogen, halogen, or C1-C3 alkyl; Y is O; L is independently C1-C4 alkylene; R 2 is selected from -L-heterocycle, wherein the heterocycle moiety is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2. In some instances, Y, R 2 teeth, [ka] wherein the heterocyclic moiety is optionally substituted.

[0288] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), 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.

[0289] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from 6- to 7-membered heterocycles. 1 is selected from 7-membered heterocycles. 1 is selected from 6-membered heterocycles. In some cases, the 6- to 7-membered heterocycle contains only one nitrogen atom and, optionally, one or more additional heteroatoms selected from oxygen and sulfur. In some cases, the optional one or more additional heteroatoms are selected from sulfur. In some cases, the optional one or more additional heteroatoms are selected from oxygen. In some cases, the 6- to 7-membered heterocycle contains only one nitrogen atom and no further additional heteroatoms. In some cases, the 6- to 7-membered heterocycle is a non-aromatic 6- to 7-membered heterocycle. In some cases, R 1 The 6- to 7-membered heterocycle of formula (I) is attached to formula (I) through only one nitrogen atom. 1 The 6- to 7-membered heterocycle of formula (II) is attached to formula (II) through only one nitrogen atom. 1 The 6- to 7-membered heterocycle of formula (III) is attached to formula (III) through only one nitrogen atom. 1 teeth, [ka] and R 1 teeth, [ka] and R 1 The substituents of may be one or more halogens, -OR 20 , -SR 20 , -N(R 20 )2, -NHCN, -NO2, =O, -CN, C 1~6 Fluoroalkyl, and C 2~6 alkynyl; -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 In some instances, R is optionally further substituted with one or more substituents independently selected from alkenyl. 1 The substituents of may be one or more halogens, -OR 20 , -N(R 20 )2, -NHCN, =O, -CN, and C 2~6 alkynyl; -C(O)N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, and C 1~6 and optionally further substituted with one or more substituents independently selected from alkyl. 1 The substituents may be one or more of halogen, -OH, -NHCN, =O, -CN, and C 2~6 alkynyl; C 1~6 and optionally further substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] and R 1 teeth, [ka] and R 1 teeth, [ka] and R 1 wherein one or more optional substituents are fluorine, —OH, —C(O)NH, —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 alkynyl. In some instances, R 1 wherein one or more optional substituents are halogen, —OH, —CN, C 1~6 Cyanoalkyl, C 1~6 Alkyl, and C 2~6 alkynyl. In some instances, R 1 The one or more optional substituents in R are each independently selected from halogen, —OH, and —CN. 1 wherein one or more optional substituents are fluorine, —OH, —CN, C 1~6 Cyanoalkyl, C 1~6 Alkyl, oxo, and C 2~6alkynyl. In some instances, R 1 wherein one or more optional substituents are fluorine, —OH, —CN, C 1~6 Cyanoalkyl, C 1~6 Alkyl, and C 2~6 alkynyl. In some instances, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is selected from.

[0290] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted unsaturated 6- to 8-membered heterocycles. 1 is selected from optionally substituted unsaturated 6-membered heterocycles. 1is selected from optionally substituted unsaturated 7-membered heterocycles. In some cases, the heterocycle has one or two double bonds. In some cases, the heterocycle has only one double bond. In some cases, the heterocycle has only two double bonds. In some cases, R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] each substituted with one or more substituents independently selected from halogen.

[0291] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from unsaturated 6- to 7-membered heterocyclic rings, which are substituted with one or more substituents selected from halogens. In some cases, the unsaturated 6- to 7-membered heterocyclic rings are substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocyclic rings are substituted with only one halogen. In some cases, the unsaturated 7-membered heterocyclic rings are substituted with one fluorine. In some cases, R 1 is selected from unsaturated 6-membered heterocycles substituted with at least one halogen. 1 is selected from unsaturated 7-membered heterocycles substituted with at least one halogen. 1 teeth, [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is.

[0292] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted unsaturated 6- to 8-membered heterocycles. 1 is selected from optionally substituted unsaturated 7-membered heterocycles. 1 teeth, [ka] each of which is selected from halogen, -OH, -NH2, -NO2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C1~6 Hydroxyalkyl, C 1~6 Haloalkyl, and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] is selected from.

[0293] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted 6-membered heterocycles. In some cases, the 6-membered heterocycle contains only one nitrogen atom. In some cases, R 1 The six-membered heterocycle of formula (I) is attached to formula (I) through only one nitrogen atom. 1 The six-membered heterocycle of formula (II) is attached to formula (II) through only one nitrogen atom. 1 The six-membered heterocycle of formula (III) is attached to formula (III) through only one nitrogen atom. 1 teeth, [ka] In some cases, R 1 wherein one or more optional substituents are 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 alkynyl. In some instances, R 1 wherein one or more optional substituents are fluorine, —OH, —NH, —NH(CN), ═O, —CN, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Alkyl, and C 2~6alkynyl. In some instances, R 1 wherein one or more optional substituents are fluorine, —OH, —NH, —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 a partially unsaturated 6-membered heterocycle. 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, R 1 teeth, [ka] is selected from.

[0294] In some embodiments, for compounds of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted 6-membered unsaturated heterocycles and 6-membered saturated heterocycles.

[0295] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl.

[0296] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each selected from halogen, and C 1~6 and optionally substituted with one or more substituents independently selected from haloalkyl.

[0297] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] is selected from.

[0298] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each of which is 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 and optionally substituted with two substituents independently selected from alkyl.

[0299] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] each selected from halogen, and C 1~6 and optionally substituted with two substituents independently selected from haloalkyl. 1 teeth, [ka] is.

[0300] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted 6- to 10-membered heterocycles. In some instances, the 6- to 10-membered heterocycle contains at least one nitrogen atom. In some instances, R 1 teeth, [ka] [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl. In some instances, each R 20 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 1 teeth, [ka] is selected from.

[0301] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1is selected from optionally substituted 10-membered heterocycles. 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 one nitrogen atom. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, the 10-membered heterocycle contains at least one sulfur atom. In some cases, R 1 teeth, [ka] each of which is 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 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is 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 Haloalkyl, C 1~6 Alkyl, C 2~6 Alkenyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl.

[0302] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from optionally substituted unsaturated 9- to 11-membered heterocycles. 1 is selected from optionally substituted unsaturated 10-membered heterocycles. 1 is selected from optionally substituted unsaturated 10-membered fused heterocycles. 1 teeth, [ka] and optionally substituted. In some cases, one or more optional substituents may be 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 Haloalkyl, C 1~6 Alkyl, and C 2~6In some instances, R is selected from alkynyl. 1 is -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 Optionally substituted with one or more substituents selected from alkynyl [ka] In some cases, each R 20 are hydrogen; and each of them is a 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 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, and C 3~12 carbocycles.

[0303] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from 7- to 11-membered spiro heterocycles. 1 is selected from 10-membered spiroheterocycles. In some cases, the spiroheterocycle has at least three nitrogen atoms. In some cases, the spiroheterocycle has at least one sulfur atom. In some cases, R 1 teeth, [ka] each of which is optionally substituted. In some cases, one or more optional substituents are 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 In some instances, R is independently selected from alkynyl. 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, M is O, and NR 3 In some instances, M is selected from O. In some instances, M is selected from NR 3 In some cases, R 3 is C 1~6 In some cases, R 3 is C 1~2 In some cases, R 3 is selected from methyl.

[0304] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1is selected from optionally substituted 8- to 10-membered fused heterocycles. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered fused heterocycle is an unsaturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R 1 is selected from optionally substituted 9-membered fused heterocycles. 1 is selected from optionally substituted 10-membered fused heterocycles. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 9-membered heterocycle is a non-aromatic heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least one nitrogen atom. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, the 9-membered heterocycle contains at least one nitrogen atom. In some cases, the 9-membered heterocycle contains at least two nitrogen atoms. In some cases, the 9-membered heterocycle contains at least three nitrogen atoms. 1 teeth, [ka] and R 1 teeth, [ka] which is optionally substituted with one or more substituents. In some cases, R 1 teeth, [ka] which is optionally substituted with one or more substituents. In some cases, R 1 wherein one or more optional substituents are 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 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, and a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is selected from one or more R 1* In some cases, R 1 wherein one or more optional substituents are 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, C1~6 Haloalkyl, C 1~6 Alkyl, and C 2~6 In some cases, the optional one or more substituents are independently selected from halogen, ═O, —OH, —CN, —NHCN, —S(O)(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, the 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, the optional one or more substituents are independently selected from halogen, ═O, —S(O)(R 20 ), -S(O)N(R 20 )2, -S(O)R 20 (=NR 20 ), -C(O)R 20 , -C(O)N(R 20 )2, and -C(O)NR 20 OR 20 In some cases, one or more optional substituents are independently selected from -C(O)R 20 , -C(O)N(R 20 )2, and -C(O)NR20 OR 20 In some cases, one or more optional substituents are independently selected from -S(O)(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, the optional substituent(s) 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 teeth, [ka] [ka] each of which is further optionally substituted. In some cases, the further optional substituent(s) is 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 Haloalkyl, C 1~6 Alkyl, and C 2~6In some cases, the further optional substituents are selected from halogen, —CN, C2 alkenyl, and C 1~6 In some cases, the further optional substituents are selected from halogen, and C 1~6 In some cases, one or more further optional substituents are selected from halogen. In some cases, each R 20 is hydrogen; and C 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered heterocycle. 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered saturated heterocycle. 20 are independently selected from 5- to 6-membered saturated heterocycles. 20 The heterocycle of R has at least one nitrogen atom. 20 The heterocycle of R has at least one sulfur atom. 20 The heterocycle of R has at least one oxygen atom. 20 The heterocycle of R contains only one heteroatom. 20 The heterocycle of R has at least two heteroatoms. 20 The heterocycle of R contains only two heteroatoms. 1 The optional one or more substituents of are halogen, —CN, C2 alkenyl, [ka] In some cases, R 1 wherein the optional one or more substituents are halogen, [ka] In some cases, R 1 The optional one or more substituents of [ka] In some cases, R 1 wherein the optional one or more substituents are halogen, [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 The optional one or more substituents of 1~6 Alkyl-N(R 20 )2. In some cases, R 1 wherein the optional one or more substituents are halogen, [ka] In some cases, R 1 teeth, [ka] In some cases, each R 20 is hydrogen, C 1~6 Alkyl, and C 3~6 In some instances, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] is 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, C1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, a 5- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from halogen, -OR 20 , and C 1~6 and optionally substituted with one or more substituents selected from alkyl. 1 teeth, [ka] selected from halogen and C 1~6 and optionally substituted with one or more substituents independently selected from alkyl. 1 teeth, [ka] is selected from.

[0305] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] is selected from, where: [ka] is selected from a 5- to 12-membered heterocycle, the 5- to 12-membered heterocycle being selected from one or more R 1* independently and optionally substituted with R B is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 alkynyl, and -CN. In some instances, R B is selected from hydrogen and halogen. B is chlorine. In some cases, R B is hydrogen. In some cases, [ka] has at least 1, 2, 3, or 4 heteroatoms. [ka] has at least 1, 2, 3, or 4 nitrogen atoms. [ka] has at least one oxygen atom. In some cases, [ka] is a monocyclic heterocycle. [ka] is a bicyclic heterocycle. [ka] is selected from optionally substituted 5-membered heterocycles. [ka] is selected from optionally substituted 9-membered heterocycles. [ka] teeth, [ka] each of which is selected from one or more R 1* are substituted as necessary. In some cases, [ka] teeth, [ka] [ka] each of which is selected from one or more R 1* In some cases, each R 1* is 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 alkyl. In some instances, each R 1* is a 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 1~6alkyl. In some instances, each R 1* is a halogen, and C 1~6 In some cases, the alkyl is independently selected from [ka] teeth, [ka] is selected from.

[0306] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or for a compound or salt of formula (III), R 1 is -C(O)R 20 is replaced by R 20 is selected from 5- to 12-membered heterocycles, which are optionally substituted. In some instances, R 1 is -C(O)R 20 In some cases, R 20 is selected from unsubstituted 5- to 12-membered heterocycles. 20 is selected from 5- to 6-membered heterocycles, which are optionally substituted. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom. In some cases, the heterocycle has at least one oxygen atom. In some cases, the heterocycle has two heteroatoms. In some cases, R 20 The heterocycle of [ka] and R 20 teeth, [ka] In some cases, the optional substituents are selected from C 1~10 It is selected from alkyl, oxo, and =NH.

[0307] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or for a compound or salt of formula (III), each R 20 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 C optionally substituted with one or more substituents independently selected from alkyl, oxo, and =NH 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 20 is hydrogen; and unsubstituted C 1~6 alkyl, and 3- to 12-membered heterocycle, which is independently selected from halogen, —OH, —CN, —NO, —NH, —N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Optionally substituted with one or more substituents independently selected from alkyl, oxo, and =NH.

[0308] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R 1 is an optionally substituted 12-membered heterocycle. In some cases, R 1 is an optionally substituted 13-membered heterocycle. In some cases, R 1 is an optionally substituted 14-membered heterocycle. In some cases, R 1 is an optionally substituted 15-membered heterocycle. In some cases, R 1 The heterocycle of R is tricyclic. 1 The heterocycle of R contains fused heterocycles. 1 The heterocycle of R contains a spiro heterocycle.1 The heterocycle of R includes fused and spiro heterocycles. 1 The heterocycle of R is an unsaturated heterocycle. 1 The heterocycle of R is a non-aromatic heterocycle. 1 The heterocycle of R has at least one double bond. 1 The heterocycle of R has at least two double bonds. 1 The heterocycle of R has at least two heteroatoms. 1 The heterocycle of R has at least three heteroatoms. 1 The heterocycle of R has at least four heteroatoms. 1 The heterocycle of R has at least 5 heteroatoms. 1 The heterocycle of R has at least 6 heteroatoms. 1 The heterocycle of R has at least 7 heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, R 1 The heterocycle of R has at least 3, 4, or 5 nitrogen atoms and at least one sulfur atom. 1 The heterocycle of R has at least 3, 4, or 5 nitrogen atoms and at least one oxygen atom. 1 The heterocycle of R has at least 3, 4, or 5 nitrogen atoms. 1 The heterocycle of R has at least 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 teeth, [ka] [ka] and R 1 teeth, [ka] and R 1 The optional one or more substituents of are 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 Haloalkyl, C 1~6 Alkyl, and C 2~6 In some instances, R is independently selected from alkynyl. 1 The optional one or more substituents of are 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 1~6Alkyl, and C 2~6 In some instances, R is independently selected from alkynyl. 1 The optional one or more substituents of are halogen, —OH, C 1~6 Alkyl, and -C(O)N(R 20 )2. In some cases, R 1 teeth, [ka] [ka] is selected from.

[0309] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is an optionally substituted 12- to 15-membered heterocycle. In some cases, R 1 teeth, [ka] wherein ring W is an optionally substituted heterocycle, ring P is an optionally substituted carbocycle or an optionally substituted heterocycle, and 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 teeth, [ka] wherein ring P is an optionally substituted carbocycle or an optionally substituted heterocycle. In some cases, R 1 teeth, [ka] 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 on ring P may be 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 Haloalkyl, C 1~6 Alkyl, and C 2~6 In some cases, one or more optional substituents on ring P are independently selected from halogen, —OH, ═O, ═NH, —CN, and C 1~6 In some cases, one or more optional substituents on ring W are independently selected from halogen, —OH, —NHCN, —S(O)(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(R20 )2, -C(O)R 20 , -NO2, -CN, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, and C 2~6 In some instances, one or more optional substituents on ring W are independently selected from halogen, —S(O)(R 20 ), -S(O)2N(R 20 )2, -S(O)N(R 20 )2, -S(O)R 20 (=NR 20 ), -C(O)N(R 20 )2, -C(O)NR 20 OR 20 , -C(O)NHOR 20 , -N(R 20 )2, -C(O)R 20 , and C 1~6 In some instances, one or more optional substituents on ring W are independently selected from —C(O)R 20 In some cases, ring P is substituted. In some cases, ring W is substituted.

[0310] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] [ka] each of which is optionally substituted with one or more substituents. In some cases, one or more of the optional substituents is 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, C1~6 Alkyl, C 2~6 Alkenyl, C 1~6 Aminoalkyl, C 1~6 Hydroxyalkyl, and C 1~6 haloalkyl. In some instances, R 1 teeth, [ka] [ka] [ka] [ka] is selected from.

[0311] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 2 is selected from optionally substituted -L-heterocycles. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only one nitrogen atom. In some cases, the heterocycle has only one nitrogen atom and no other heteroatoms. In some cases, YR 2 teeth, [ka] and the heterocyclic moiety is optionally substituted. 2 teeth, [ka] and the heterocyclic moiety is optionally substituted. In some instances, YR 2 teeth, [ka] and the heterocyclic moiety is optionally substituted. In some instances, YR2 teeth, [ka] and the heterocyclic moiety is optionally substituted. In some cases, the heterocyclic ring is selected from halogen, hydroxy, C1-C3 alkyl, —N(R 5 )S(O)2(R 5 ), -OC(O)N(R 5 )2, oxo, =CH2, =NO-C1-C3 alkyl, -CH2OC(O) heterocycle, -CH2 heterocycle, -CH2OC(O)N(R 5 )2, and —O—C1-C3 alkyl, wherein the alkyl in —O—C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy. In some instances, YR 2 teeth, [ka] [ka] In some cases, YR 2 teeth, [ka] In some cases, YR 2 teeth, [ka] is selected from.

[0312] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 2 is -LN(R 21 )2. In some cases, each R 21 is hydrogen and C 1~6 In some cases, each R 21 is C 1~6In some instances, L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L are taken together to form a C3-C6 carbocycle, which is optionally substituted with one or more substituents selected from halogen. In some instances, L is independently selected from substituted C1-C4 alkylene, and two substituents on the same carbon atom of L are taken together to form a C3-C6 carbocycle, which is optionally substituted with one or more substituents selected from halogen. [ka] In some cases, R 2 teeth, [ka] In some cases, YR 2 teeth, [ka] is.

[0313] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R 21 are independently selected from hydrogen. 21 is hydrogen and C 1~6 alkyl. In some instances, each R 21 is C 1~6 alkyl. In some instances, each R 21 are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 C optionally substituted with one or more substituents independently selected from alkyl, oxo 3~12 are independently selected from carbocycles, and 3- to 12-membered heterocycles.

[0314] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1is selected from optionally substituted 8- to 10-membered fused heterocycles. In some cases, the 8- to 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 8- to 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 8- to 10-membered heterocycle is a non-aromatic heterocycle. In some cases, R 1 is selected from optionally substituted 9-membered fused heterocycles. 1 is selected from optionally substituted 10-membered fused heterocycles. In some cases, the 10-membered fused heterocycle is a bicyclic heterocycle. In some cases, the 10-membered fused heterocycle is a saturated heterocycle. In some cases, the 10-membered heterocycle is a non-aromatic heterocycle. In some cases, the fused heterocycle has one saturated ring and one aromatic ring. In some cases, the fused heterocycle has one saturated ring and one unsaturated ring. In some cases, the fused heterocycle has two saturated rings. In some cases, the 10-membered heterocycle contains at least one nitrogen atom. In some cases, the 9-membered heterocycle contains at least two nitrogen atoms. In some cases, the 9-membered heterocycle contains at least three nitrogen atoms. In some cases, the 10-membered heterocycle contains at least two nitrogen atoms. In some cases, the 10-membered heterocycle contains at least three nitrogen atoms. In some cases, R 1 teeth, [ka] and R 1 teeth, [ka] and R 1 teeth, [ka] which is optionally substituted with one or more substituents. In some cases, the optional one or more substituents are 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, the 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 is hydrogen; and C 1~6 Alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle. 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered heterocycle. 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered saturated heterocycle. 1The optional one or more substituents of [ka] In some cases, R 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is.

[0315] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from optionally substituted saturated 6- to 7-membered heterocycles. 1 is selected from optionally substituted saturated 6-membered heterocycles. 1 teeth, [ka] In some cases, the optional substituents are selected from halogen, —CN, —NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6 In some cases, the optional substituents are independently selected from -CN, -NHCN, C 1~6 Cyanoalkyl, and C 1~6In some cases, the optional substituents are independently selected from -NHCN, and C 1~6 alkyl. In some instances, R 1 teeth, [ka] -NHCN, and C 1~6 In some cases, R is substituted with one or more substituents selected from alkyl. 1 teeth, [ka] is selected from.

[0316] In some embodiments, for a compound or salt of Formula (I), R 1 is selected from substituted saturated 6-membered heterocycles, the saturated 6-membered heterocycles containing at least one -NHCN and, optionally, one or more C 1~6 alkyl; B is an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 fused carbocycles, each of which is selected from halogen, oxo, -NH, C-C alkyl, -OH, -C(O)NH, -NH, =O, -CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 optionally substituted with one or more substituents independently selected from alkynyl; ring A is selected from optionally substituted heterocycle; Y is O; R 2 is selected from -L-heterocycle, wherein the heterocycle moiety is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2; and L is selected from C1-C4 alkylene. In some instances, R 1 teeth, [ka] [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] In some cases, B is selected from [ka] is.

[0317] In some embodiments, for the compounds or salts of Formula (I), Formula (II), or Formula (III), B is an optionally substituted 8- to 10-membered fused carbocyclic ring. In some cases, B is a substituted 8- to 10-membered fused carbocyclic ring. In some cases, B is an unsubstituted 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 [ka] which is optionally substituted with one or more substituents. In some cases, B is [ka] which is substituted with one or more substituents. In some cases, for B, one or more substituents may be halogen, oxo, -NH, C-C alkyl, -B(OH), -OH, -C(O)NH, -NH, =O, -CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6In 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 [ka] [ka] In some cases, B is selected from [ka] which is the halogen and C 1~6 In some instances, B is substituted with one or more substituents selected from: haloalkyl. [ka] which is substituted with one or more substituents selected from halogen. In some cases, B is [ka] In some cases, B is selected from [ka] which is substituted with one or more substituents selected from fluorine. In some cases, B is [ka] In some cases, B is selected from [ka] which is substituted with one or more substituents selected from chlorine. In some cases, B is [ka] In some instances, B is a substituted 10-membered fused carbocycle. In some instances, for the 10-membered fused carbocycle of B, one or more substituents are selected from halogen, —NH, C-C alkyl, —B(OH), —OH, —C(O)NH, —NH, ═O, —CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 In some instances, B is independently selected from: [ka] In some cases, the 10-membered fused carbocyclic ring of B is substituted with at least one halogen. In some cases, B is selected from [ka] In some instances, B is an unsubstituted 9- to 10-membered fused carbocyclic ring. In some instances, B is selected from: [ka] each of which is unsubstituted. In some instances, B is selected from: [ka] In some cases, B is [ka] is.

[0318] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 wherein one or more optional substituents are 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(R20 )2, -C(O)NHOR 20 , -N(R 20 )2, -C(O)R 20 , -NO2, =O, -CN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Alkoxyalkyl, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is independently selected from halogen, and C 1~6 and optionally substituted with one or more substituents selected from alkyl.

[0319] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 teeth, [ka] and R 1 wherein one or more optional substituents are 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, C1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, and optionally substituted 5- to 12-membered heterocycle. 1 wherein one or more optional substituents are 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 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, and optionally substituted 5- to 12-membered heterocycle. 1 wherein one or more optional substituents are halogen, —CN, C 2~6 Alkynyl, -C(=NR 20 )N(R 20 )2, and an optionally substituted 5- to 12-membered heterocycle. In some instances, R 1 wherein one or more optional substituents are halogen, —C(═NR 20 )N(R 20 )2, and an optionally substituted 5- to 12-membered heterocycle. In some instances, R 1 wherein one or more optional substituents are —C(═NR 20 )N(R 20)2, and an optionally substituted 5- to 12-membered heterocycle. In some instances, R 1 wherein the one or more optional substituents are independently selected from an optionally substituted 5- to 12-membered heterocycle. 1 wherein the one or more optional substituents are independently selected from a 5-membered heterocycle and a 9-membered heterocycle, each of which is selected from one or more R 1* In some cases, R 1 is substituted with at least one halogen atom, -CN, C 2~6 Alkynyl, -C(=NR 20 )N(R 20 )2, and a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from one or more R 1* In some cases, the heterocyclic ring has at least one nitrogen atom. In some cases, the heterocyclic ring has at least one oxygen atom. In some cases, the heterocyclic ring has at least one nitrogen atom and at least one oxygen atom. In some cases, the heterocyclic ring has at least two heteroatoms. In some cases, the heterocyclic ring has at least three heteroatoms. In some cases, the heterocyclic ring has at least four heteroatoms. In some cases, R 1 The heterocycle of one or more optional substituents of [ka] [ka] each of which is selected from one or more R 1* In some cases, R 1 The heterocycle of one or more optional substituents of [ka] selected from one or more R 1*In some cases, each R 1* is 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 alkyl. In some instances, each R 1* is 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(R20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =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. In some instances, each R 1* is a 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 alkyl. In some instances, each R 1* is a halogen, C 1~6 Haloalkyl, and C 1~6 alkyl. In some instances, each R 1* is a halogen, and C 1~6 alkyl. In some instances, each R 1* are independently selected from halogen. In some cases, each R 1* is C 1~6 alkyl. In some instances, each R 1* -OR 20 In some cases, each R 1*is independently selected from —OH. In some instances, each R 1* is independently selected from -OMe. 1 The heterocycle of one or more optional substituents of [ka] is selected from.

[0320] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 wherein one or more optional substituents are —C(═NR 20 )N(R 20 )2, and an optionally substituted 5- to 12-membered heterocycle. In some instances, R 1 wherein the one or more optional substituents are independently selected from an optionally substituted 5- to 12-membered heterocycle. In some instances, the heterocycle is [ka] each of which is selected from one or more R 1* In some cases, R 1 wherein the one or more optional substituents are [ka] is selected from.

[0321] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), each R 1* is 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)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 Haloalkyl, and C 1~6 alkyl. In some instances, each R 1* is 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(R20 ), -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. In some instances, each R 1* is a 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 alkyl. In some instances, each R 1* is a halogen, C 1~6 Haloalkyl, and C 1~6 alkyl. In some instances, each R 1* is a halogen, and C 1~6 alkyl. In some instances, each R 1* are independently selected from halogen. In some cases, each R 1* is C 1~6 alkyl.

[0322] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 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 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 1~6Alkyl, C 1~6 Alkyl-N(R 20 )2, C 2~6 alkynyl, and a 5- to 12-membered heterocycle (preferably a 5- to 9-membered heterocycle), which is optionally substituted with one or more substituents independently selected from one or more R 1* each independently optionally substituted by 1* is a halogen, C 1~6 Haloalkyl, and C 1~6 In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 teeth, [ka] and R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] is.

[0323] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1is 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 selected from halogen, —C(O)N(R 20 )2, -C(O)NR 20 OR 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -NHCN, C 1~6 Cyanoalkyl, C 1~6 Alkyl, C 2~6 alkynyl, and a 5- to 12-membered heterocycle (preferably a 5- to 6-membered heterocycle), which is optionally substituted with one or more substituents independently selected from one or more R 1* each independently optionally substituted by 1* is a halogen, C 1~6 Haloalkyl, and C 1~6 In some cases, the 8- to 10-membered heterocycle is bicyclic. In some cases, the 10-membered heterocycle is substituted. In some cases, R 1 teeth, [ka] and R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, M is selected from O and NMe. In some cases, M is O. In some cases, M is NMe. In some cases, R2 is one or more R 6 -LN(R 21 )2 and -L-heterocycle. In some instances, YR 2 teeth, [ka] In some instances, B is selected from an optionally substituted carbocycle. In some instances, B is selected from [ka] In some instances, B is selected from: [ka] In some cases, B is selected from [ka] In some cases, B is [ka] In some cases, n is 0.

[0324] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is selected from the compounds in the Examples section. In some cases, Y is selected from the compounds in the Examples section. In some cases, L is selected from the compounds in the Examples section. In some cases, R 2 is selected from the compounds in the Examples section. In some cases, B is selected from the compounds in the Examples section. In some cases, M is selected from the compounds in the Examples section. In some cases, R 1 The optional substituents of the heterocycle for are selected from the compounds in the Examples section.

[0325] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 2 is -LN(R 21 )2. In some cases, R 2 -L-OR 21 In some cases, R 2 is a heterocycle. In some cases, R 2 is C1-C6 alkyl. In some cases, R 2 is an -L-heterocycle. In some cases, R 2 is -L-aryl. In some cases, R 2 is -L-heteroaryl. In some cases, R 2 is -L-cycloalkyl. In some cases, R 2 is -LN(R 21 )2. In some cases, R 2 is -L-NHC(=NH)NH2. In some cases, R 2 is -LC(O)N(R 21 )2. In some cases, R 2 is -L-C1-C6 haloalkyl. In some cases, R 2 -L-OR 21 In some cases, R 2 -L-NR 21 C(O)-aryl. In some cases, R 2 is -L-COOH. In some cases, R 2 -L-NR 21 S(O)2(R 21 ) In some cases, R 2 is -LS(O)2N(R 21 )2. In some cases, R 2 is -LN(R 21 )C(O)(OR 21 ) In some cases, R 2 is -L-OC(O)N(R 21 )2. In some cases, R 2 is -LC(=O)OC1-C6 alkyl. In some cases, a heterocycle, -L-NR 21The aryl portion of C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of -L-cycloalkyl can be one or more R 6 and the aryl portion of -L-aryl and the heteroaryl portion of -L-heteroaryl are each optionally substituted by one or more R 7 In some cases, when Y is a bond, O, or S, R 2 is further selected from hydrogen.

[0326] In some embodiments, Formula (I) or Formula (II) is Formula (II * ): [ka] or a pharmaceutically acceptable salt thereof [In the formula, M, O, and NR 3 Selected from; R 3 is hydrogen, C 1~6 Alkyl, and C 1~6 cyanoalkyl; R 1 is selected from 7- to 10-membered heterocycles, and the 7- to 10-membered heterocycles are 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(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)OR20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -OC(O)N(R 20 )2, -NO2, =O, =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 a 5- to 12-membered heterocycle, optionally substituted with one or more substituents independently selected from one or more R 1* independently and optionally substituted with; Each R 1* is 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 independently selected from: B is C6~C 15 Carbocyclic rings, C6-C 15 The carbocyclic ring is preferably a ring containing 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 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, and C 2~6 optionally substituted with one or more substituents independently selected from alkynyl; R 2 is selected from -L-heterocycle, wherein the heterocycle of -L-heterocycle is selected from one or more R 6 , substituted as needed; L is independently selected from C1-C4 alkylene, wherein C1-C4 alkylene is optionally substituted with one or more substituents selected from hydroxy, C1-C4 hydroxyalkyl, and C1-C4 alkyl; and optionally, two substituents on the same carbon atom of L, taken together, form a C3-C6 carbocyclic ring; Each R 20are hydrogen; and each of them is a halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -OC 1~10 Alkyl, oxo, =NH, C 3~12 C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle 1~6 Alkyl, C 3~6 carbocyclic ring, and 3- to 6-membered heterocyclic ring] is expressed by

[0327] In some embodiments, the compound of formula (II) * ) compounds or salts of R 1 is selected from optionally substituted 7- to 10-membered spiroheterocycles and optionally substituted 7- to 10-membered fused heterocycles. 1 The heterocycle of R has at least one nitrogen atom. 1 At least one nitrogen atom of the heterocycle of formula (II * ) in some cases, R 1 is selected from optionally substituted 10-membered spiroheterocycles and optionally substituted 10-membered fused heterocycles. 1 The optional one or more substituents of are 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, C1~6 Alkoxy, C 1~6 Alkoxyalkyl, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is independently selected from halogen, and C 1~6 and optionally substituted with one or more substituents selected from alkyl. 1 teeth, [ka] is 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 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, and C 1~6 and optionally substituted with one or more substituents selected from alkyl. 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some cases, M is selected from O. In some cases, M is NCH2CH3. In some cases, M is NMe. In some cases, R 2 The heterocycle of R is a saturated heterocycle. 2 R 6 is, at each occurrence, independently selected from halogen, ═CH, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 2 L is C1-C4 alkylene, and [ka] In some cases, R 2 teeth, [ka] In some instances, B is selected from optionally substituted C9-C 10 In some instances, B is selected from: [ka] In some instances, B is selected from halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —O—C-C haloalkyl, —C(O)NH, —NH, ═O, —CN, C 1~6Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 In some cases, B is optionally substituted with one or more substituents independently selected from: alkynyl; In some cases, B is optionally substituted with one or more substituents independently selected from: halogen; In some cases, B is optionally substituted with one or more substituents independently selected from: [ka] In some cases, B is [ka] In some cases, B is unsubstituted. In some cases, B is substituted.

[0328] In some embodiments, the compound of formula (II) * ) compounds or salts of R 1 is selected from optionally substituted 7- to 10-membered spiroheterocycles and optionally substituted 7- to 10-membered fused heterocycles. 1 is selected from optionally substituted 10-membered spiroheterocycles and optionally substituted 10-membered fused heterocycles. 1 is selected from optionally substituted 10-membered spiroheterocycles. 1 is selected from optionally substituted 10-membered fused heterocycles. 1 The heterocycle of R has at least three heteroatoms. 1 The optional one or more substituents of are halogen, —OH, —S(O)2(R 20 ), -S(O)N(R 20 )2, -S(O)2N(R 20 )2, -S(O)N(R 20 )2, -S(O)R 20 (=NR 20 ), -C(O)N(R 20 )2, -C(=NR 20 )N(R 20 )2, -C(O)OR 20 , -C(O)NHOR20 , -N(R 20 )2, -C(O)R 20 , -NO2, =O, -CN, C 1~6 Alkyl-N(R 20 )2, C 1~6 Aminoalkyl, C 1~6 Alkoxy, C 1~6 Alkoxyalkyl, C 1~6 Hydroxyalkyl, C 1~6 Cyanoalkyl, C 1~6 Haloalkyl, C 1~6 Alkyl, C 2~6 alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is independently selected from halogen, and C 1~6 and optionally substituted with one or more substituents selected from alkyl. 1 teeth, [ka] is 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 Haloalkyl, C 1~6 Alkyl, C 2~6alkynyl, 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is substituted with one or more substituents independently selected from halogen, and C 1~6 and optionally substituted with one or more substituents selected from alkyl. 1 teeth, [ka] [ka] In some cases, R 1 teeth, [ka] In some cases, R 1 teeth, [ka] In some instances, M is selected from O. In some instances, M is NMe. In some instances, R 2 The heterocycle of R is a saturated heterocycle. 2 R 6 is, at each occurrence, independently selected from halogen, ═CH, hydroxy, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, cyano, and C1-C3 aminoalkyl. 2 L is C1-C4 alkylene, and [ka] In some cases, R 2 teeth, [ka] In some instances, B is selected from optionally substituted C9-C 10 In some instances, B is selected from: [ka] In some instances, B is selected from halogen, oxo, —NH, C-C alkyl, —B(OH), —OH, —O—C-C haloalkyl, —C(O)NH, —NH, ═O, —CN, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, and C 2~6 In some cases, B is optionally substituted with one or more substituents independently selected from: alkynyl; In some cases, B is optionally substituted with one or more substituents independently selected from: halogen; In some cases, B is optionally substituted with one or more substituents independently selected from: [ka] In some cases, B is [ka] In some cases, B is unsubstituted. In some cases, B is substituted.

[0329] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or for a compound or salt of formula (III), R 1 The heterocyclic or carbocyclic ring is C 1~6 In some embodiments, for a compound or salt of Formula (I), R 1 The heterocyclic or carbocyclic ring is C 1~6 In some embodiments, for a compound or salt of Formula (II), R 1 The heterocyclic or carbocyclic ring is C 1~6 In some embodiments, for a compound or salt of Formula (III), R 1 The heterocyclic or carbocyclic ring is C 1~6 It is not substituted by cyanoalkyl.

[0330] In some embodiments, the compound of formula (I), formula (II), formula (II *) or for a compound or salt of formula (III), each R 20 is hydrogen; and C 1~6 alkyl.

[0331] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or a compound or salt of formula (III), C 1~6 It is not substituted by cyanoalkyl.

[0332] In some embodiments, for a compound or salt of Formula (I), Formula (II), or Formula (III), R 1 is not a piperazine. In some cases, R 1 is not a substituted piperazine.

[0333] In some embodiments, for compounds of Formula (I), the compound is not a Michael acceptor.

[0334] In some embodiments, for compounds of Formula (I), the compound or salt does not include an electrophilic substituent.

[0335] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or a compound or salt of formula (III), does not contain an electrophilic moiety.

[0336] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or a compound or salt of formula (III), does not contain a covalent modifier.

[0337] In some embodiments, the compound of formula (I), formula (II), formula (II * ) or for a compound or salt of formula (III), R 1 One or more optional substituents of is not an electrophile.

[0338] The present disclosure includes salts of the compounds described herein, particularly pharmaceutically acceptable salts.Compounds of the present invention that have sufficient acidic functional groups, sufficient basic functional groups, or both functional groups can react with many inorganic bases, and inorganic and organic acids to form salts.Alternatively, compounds that are inherently charged, such as compounds with quaternary nitrogen, can form salts with suitable counterions, such as halides, such as bromine, chlorine, or fluorine, especially bromine.

[0339] Chemical entities having carbon-carbon or carbon-nitrogen double bonds can exist in Z or E forms (or cis or trans forms). Furthermore, some chemical entities can exist in various tautomeric forms. Unless otherwise specified, the compounds described herein are intended to include all Z, E, and tautomeric forms as well.

[0340] "Tautomer" refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. The compounds presented herein exist as tautomers in certain embodiments. In situations where tautomerization is possible, a chemical equilibrium of tautomers exists. The exact ratio of tautomers depends on several factors, including physical conditions, temperature, solvent, and pH. Some examples of tautomeric equilibrium are: [ka] Includes.

[0341] The compounds disclosed herein may, in some embodiments, be present in different isotopically enriched forms, e.g., 2 H, 3 H, 11 C. 13 C and / or 14The compound is used in a form enriched in C content. In a particular embodiment, the compound is deuterated at at least one position. Such deuterated form can be prepared by the procedure described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997. As described in U.S. Patent No. 5,846,514 and U.S. Patent No. 6,334,997, deuteration can improve metabolic stability and / or efficacy, thus increasing the duration of action of the drug.

[0342] Unless otherwise stated, compounds described herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having this structure except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0343] 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 contain an isotope such as deuterium ( 2 H), tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 C) or the like. 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 with I 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.

[0344] In certain embodiments, the compounds disclosed herein are 1 Some or all of the H atoms 2 is replaced with an H atom. Methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods:

[0345] Deuterium-substituted compounds are synthesized using a variety of 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, 110 pp; 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.

[0346] Deuterated starting materials are readily available and can be subjected to the synthetic methods described herein to provide for the synthesis of deuterated compounds. Many deuterated reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0347] 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, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, and mixtures thereof.

[0348] The compounds described herein may in some cases exist in diastereomeric, enantiomeric, or other stereoisomeric forms.When absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and the appropriate mixtures thereof.Stereoisomer separation 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, which is incorporated herein by reference for the present disclosure).Stereoisomers can also be obtained by stereoselective synthesis.

[0349] The methods and compositions described herein include the use of amorphous and crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. Similarly, in some embodiments, active metabolites of these compounds with the same type of activity are included within the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated forms and solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. Solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0350] In certain embodiments, a compound or a salt of a compound may be a prodrug; for example, a hydroxyl in the compound is present as an ester or carbonate, or a carboxylic acid in the compound is present as an ester. The term "prodrug" is intended to encompass compounds that are converted to the pharmaceutical agents of the present disclosure under physiological conditions. One method for creating a prodrug is to include one or more selected moieties that are hydrolyzed under physiological conditions to yield 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 the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids, and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0351] Prodrug forms of the compounds described herein, where the prodrug is metabolized in vivo to yield a compound described herein, are included within the scope of the claims. In some cases, some of the compounds described herein may be prodrugs for another derivative or active compound.

[0352] Prodrugs are often useful because, under some circumstances, they may be easier to administer than the parent drug. They may be, for example, bioavailable by oral administration, whereas the parent drug is not. Prodrugs may help enhance the cell permeability of the compound compared to the parent drug. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent drug. Prodrugs may be designed as reversible drug derivatives for use as modifiers to enhance drug transport to site-specific tissues or increase drug resistance within cells.

[0353] In some embodiments, the prodrug design increases the lipid solubility of the pharmaceutical agent. In some embodiments, the prodrug design increases the effective water solubility. See, for example, Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium, the disclosures of which are incorporated herein in their entirety. Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987. 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 are conveniently synthesized from readily available starting materials.

[0354] Synthetic chemical transformations and methodologies 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 P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. 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). Pharmaceutical preparations

[0355] In certain embodiments, a therapeutically effective amount of a compound of Formula (I), (II), (II * ), and (III). Compositions comprising any compound or salt (also referred to herein as a "pharmaceutical agent") of any one of (III) are provided herein.

[0356] Pharmaceutical compositions can be formulated using one or more physiologically acceptable carriers, including excipients and auxiliary agents, which facilitate the processing of pharmaceutical agents into pharmaceutical preparations.Suitable formulations depend on the route of administration selected.Summary of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Edition (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Edition (Lippincott Williams & Wilkins, 1999).

[0357] The compositions and methods of the present disclosure can be used to treat individuals in need thereof. In certain embodiments, the individual is a mammal, for example, a human or non-human mammal. When administered to an animal, for example, a human, the composition or pharmaceutical agent is preferably administered as a pharmaceutical composition, for example, comprising a pharmaceutical agent and a pharmaceutically acceptable carrier or additive. Pharmaceutically acceptable carriers are well known in the art, and include, for example, aqueous solutions, for example, water or physiologically buffered saline, or other solvents or vehicles, for example, glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are intended for human administration, particularly for invasive routes of administration, such as injection or implantation, which avoid transport or diffusion through epithelial barriers, the aqueous solution is pyrogen-free or substantially pyrogen-free. Additives can be selected, for example, to cause delayed release of the drug or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in dosage unit form such as tablets, capsules, granules, lyophilized for reconstitution, powders, liquids, syrups, suppositories, injections, etc. The composition may also be present in a transdermal delivery system, e.g., a skin patch. The composition may also be present in a liquid suitable for topical administration, e.g., eye drops.

[0358] Pharmaceutically acceptable additives can contain physiologically acceptable agents that act to stabilize, increase solubility, or enhance absorption of compounds such as pharmaceutical agents. Examples of such physiologically acceptable agents include 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 a pharmaceutically acceptable additive, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying or self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymer matrix, into which, for example, the compound of the present invention can be incorporated. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively simple to prepare and administer.

[0359] Pharmaceutical compositions (preparations) can be administered to subjects by any of many routes of administration, including, for example, oral, for example, immersion in aqueous or non-aqueous solution or suspension, tablet, capsule including sprinkle capsule and gelatin capsule, bolus, powder, granule, paste for application to tongue; absorption through oral mucosa, for example, sublingual; anal, rectal or vaginal, for example, pessary, cream or foam; parenteral, for example, as sterile solution or suspension, including intramuscular, intravenous, subcutaneous or intrathecal; nasal; intraperitoneal; subcutaneous; transdermal, for example, patch applied to skin; and topical, for example, cream, ointment or spray applied to skin, or eye drops.Compound can also be formulated for inhalation.In certain embodiments, compound can be simply dissolved or suspended in sterile water.

[0360] Pharmaceutical compositions may be sterile aqueous or non-aqueous solutions, suspensions or emulsions, such as microemulsions.The additives described herein are examples and are in no way limiting.An effective amount or therapeutically effective amount refers to the amount of one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, that is effective to produce the desired therapeutic effect.

[0361] Generally, the subject can be monitored for therapeutic effectiveness by using assays and methods suitable for the condition to be treated, which assays are familiar to those skilled in the art and are described herein.The pharmacokinetics of the pharmaceutical agent or one or more of its metabolites administered to the subject can be monitored by determining the level of pharmaceutical agent or metabolite in biological fluids, such as blood, blood fractions, such as serum, and / or urine, and / or other biological samples or biological tissues from the subject.Any method that is practiced in the art for detecting pharmaceutical agents and described herein can be used to measure the level of pharmaceutical agent or metabolite during the course of treatment.

[0362] The dosage of the pharmaceutical agents described herein for treating a disease or disorder may depend on the subject's condition, i.e., the stage of the disease, the severity of symptoms caused by the disease, and overall health, as well as age, sex, and weight, and other factors apparent to those skilled in the medical field. Pharmaceutical compositions can be administered in a manner appropriate for the disease being treated, as determined by those skilled in the medical field. In addition to the factors described herein and above related to the use of pharmaceutical agents for treating a disease or disorder, the appropriate duration and frequency of administration of the pharmaceutical agent can also be determined or adjusted based on factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the pharmaceutical agent can generally be determined using experimental models and / or clinical trials. The optimal dosage may depend on the subject's body weight, weight, or blood volume. The use of the minimum dosage sufficient to provide effective treatment is usually preferred. The design and implementation of preclinical and clinical studies for the pharmaceutical agents described herein, including those administered for prophylactic benefit, is well within the skill of those skilled in the relevant fields. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as monotherapy. In certain embodiments, the two pharmaceutical agents in the combination may act synergistically or additively, allowing either agent to be used in a lower amount than when administered alone. The amount of pharmaceutical agent that can be administered per day can be, for example, about 0.01 mg / kg to 100 mg / kg of body weight, e.g., between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between 10 and 50 mg / kg, or between about 50 and 100 mg / kg. In other embodiments, the amount of pharmaceutical agent that can be administered per day can be about 0.01 mg / kg to 1000 mg / kg of body weight, between about 100 and 500 mg / kg, or between about 500 and 1000 mg / kg. The optimal dosage per day or course of treatment may vary for the disease or disorder being treated, and may also vary with the route of administration and treatment regimen.

[0363] Pharmaceutical compositions containing pharmaceutical agents can be formulated in a manner suitable for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, such as a tablet, capsule, semi-solid, such as a gel, liquid, or gas, such as an aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0364] Pharmaceutically acceptable excipients are well known in the pharmaceutical arts and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5 th Ed., 2006, and Remington: The Science and Practice of Pharmacy (Gennaro, 21 st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable additives include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. Generally, the type of additive is selected based on the chemical composition of the active ingredient as well as the mode of administration. Alternatively, the compositions described herein may be formulated as a lyophilizate. The compositions described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate additive solutions to dissolve and / or dilute the pharmaceutical agent of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated in a liposome using techniques known and practiced in the art. In certain embodiments, the pharmaceutical agent is not formulated in a liposome for application to a stent used to treat severely, but not completely, blocked arteries. The pharmaceutical composition may be formulated for any suitable mode of administration described herein and in the art.

[0365] Pharmaceutical compositions, for example, for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery, or other methods, may be in liquid form. Liquid pharmaceutical compositions may contain, for example, one or more of the following: a sterile diluent, such as water, saline, preferably saline, Ringer's solution, isotonic sodium chloride, fixed oils that can serve as solvents or suspending media, polyethylene glycol, glycerin, propylene glycol, or other solvents; antibacterial agents; antioxidants; chelating agents; buffers and agents for adjusting osmotic pressure, such as sodium chloride or dextrose. Parenteral compositions may be packaged in ampoules, disposable syringes, or multiple-dose vials made of glass or plastic. Physiological saline is preferred, and injectable pharmaceutical compositions are preferably sterile. In another embodiment, for the treatment of ophthalmic conditions or diseases, liquid pharmaceutical compositions may be applied to the eye in the form of eye drops. Liquid pharmaceutical compositions may be delivered orally.

[0366] For oral preparation, at least one of the pharmaceutical agents described herein can be used alone or in combination with suitable additives for making tablets, powders, granules or capsules, and optionally with diluents, buffers, humectants, preservatives, coloring agents and flavoring agents.The pharmaceutical agent can be formulated with a buffer that provides protection for the composition from the low pH of the stomach environment, and / or an enteric coating.The pharmaceutical agent contained in the pharmaceutical composition can be formulated for oral delivery, for example, with a flavoring agent in a liquid, solid or semi-solid formulation, and / or with an enteric coating.

[0367] Pharmaceutical compositions containing any one of the pharmaceutical agents described herein may be formulated for sustained or delayed release, also known as timed or controlled release. Such compositions can generally be prepared using well-known techniques and administered, for example, by oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate-controlling membrane. Additives for use within such formulations may be biocompatible and biodegradable, and preferably the formulation provides a relatively constant level of release of the active ingredient. The amount of pharmaceutical agent contained within a sustained-release formulation depends on the site of implantation, the rate and expected duration of release, and the nature of the condition, disease, or disorder being treated or prevented.

[0368] In certain embodiments, pharmaceutical compositions containing pharmaceutical agents are formulated for transdermal, intradermal, or topical administration. The compositions can be administered as powders / talc or other solids, liquids, sprays, aerosols, ointments, foams, creams, gels, or pastes using syringes, bandages, transdermal patches, inserts, or syringe-like applicators. They are preferably in the form of controlled-release or sustained-release formulations administered topically, or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active composition can also be delivered by 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.

[0369] Pharmaceutical compositions containing pharmaceutical agents can be formulated as emulsions for topical application. Emulsions contain one liquid dispersed in a majority of a second liquid. Emulsions can be oil-in-water or water-in-oil emulsions. Either or both the oil and aqueous phases can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other additives. The oil phase may also contain other oil-based pharmaceutically approved additives. Suitable surfactants include, but are not limited to, anionic surfactants, nonionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also contain at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0370] Ointments and creams can be formulated with aqueous or oily bases, for example, by adding suitable thickeners and / or gelling agents.Lotions can be formulated with aqueous or oily bases, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners, or colorants.Liquid sprays can be delivered from pressurized packs, for example, through specially shaped closures.Oil-in-water emulsions can also be used in compositions, patches, bandages, and articles.These systems are semisolid emulsions, microemulsions, or foam emulsion systems.

[0371] In some embodiments, the pharmaceutical agents described herein can be formulated as inhalants. Inhalation methods can deliver pharmaceuticals directly to the respiratory tract. Pharmaceutical agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. Pharmaceutical agents can be formulated using solvents, gases, nitrates, or any combination thereof. The compositions described herein are optionally formulated for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are optionally nebulized to a particle size that can be preferentially delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and ultimately to the parenchymal tissue.

[0372] The aerosolized formulations described herein are optionally delivered using an aerosol-forming device such as a jet, vibrating porous plate, or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles with a mass median average diameter of preferentially 1-5 μm. Furthermore, the formulations preferably have a balanced osmotic ionic strength and chloride concentration, as well as a minimum aerosolizable volume capable of delivering an effective dose of the pharmaceutical agent. Additionally, the aerosolized formulations preferably do not negatively affect airway function or cause undesirable side effects.

[0373] Aerosolization devices suitable for administering the aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers, and energized dry powder inhalers, which can nebulize the formulations preferentially into aerosol particle sizes in the 1-5 μm size range. Preferential, in this context, means that at least 70%, but preferably greater than 90%, of all aerosol particles produced are in the 1-5 μm range. Jet nebulizers operate by air pressure to break up liquid solutions into aerosol droplets. Vibrating porous plate nebulizers operate by using an acoustic vacuum created by a rapidly vibrating porous plate to force solvent droplets through a porous plate. Ultrasonic nebulizers operate by a piezoelectric crystal that shears 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), Sidestream® nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0374] In some embodiments, pharmaceutical agents can be formulated using an oleaginous base or ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical agent, these semi-solid compositions can contain a dissolving and / or suspending bactericide, a preservative, and / or a buffer system. Petrolatum components that can be included can be any paraffin ranging in viscosity from mineral oil to paraffin wax incorporating isobutylene, colloidal silica, or stearates. Absorbent bases can be used with oleaginous systems. Additives can include, alone or in combination, cholesterol, lanolin (lanolin derivatives), beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophilic-lipophilic balance) emulsifiers, and various ionic and non-ionic surfactants.

[0375] Controlled-release or sustained-release transdermal or topical formulations can be achieved by adding time-release additives, such as polymer structures or matrices, available in the art. For example, the composition can be administered by using a hot-melt extrusion, such as a bioadhesive hot-melt extrusion film. The formulation can include a cross-linked polycarboxylic acid polymer formulation. The cross-linking agent can be present in an amount that provides sufficient adhesiveness to allow the system to remain attached to the target epithelial or endothelial cell surface for a sufficient time to allow the desired release of the compound.

[0376] The insert, transdermal patch, bandage, or article can include a polymer blend or coating that provides a constant rate of release of the pharmaceutical agent over an extended period of time. In some embodiments, the article, transdermal patch, or insert includes a water-soluble pore-forming agent, such as polyethylene glycol (PEG), that can be blended with a water-insoluble polymer to increase the durability of the insert and extend the release of the active ingredient.

[0377] Transdermal devices (inserts, patches, bandages) may also contain water-insoluble polymers. Rate-controlling polymers may be useful for administration to sites where release can be achieved using pH changes. These rate-controlling polymers can be applied using a continuous coating film during the process of spraying with the active compound and drying. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient, which are compressed to form a solid biodegradable insert.

[0378] Polymer formulations can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art can be used. For example, sustained-release gels and compounds can be incorporated into polymer matrices, such as hydrophobic polymer matrices. Examples of polymer matrices include microparticles. Microparticles can be microspheres, and the core can be made of a different material than the polymer shell. Alternatively, the polymer can be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel, such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. Matrices can be formed by solvent evaporation, spray drying, solvent extraction, and other methods known to those skilled in the art.

[0379] Usually, the kit provided has one or more unit doses of oral or injectable doses of the medicament described herein.Such kit can comprise the container that contains unit doses, the package insert that describes the use of drug in treating disease and the accompanying benefits, and optionally the instrument or device that delivers the composition. Treatment method

[0380] In some embodiments, 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 involve administering an effective amount of a compound of Formula (I), Formula (II), Formula (II) to cells in which inhibition of KRas G12 mutant activity is desired. * ), a compound of Formula (III), or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to bringing the indicated moieties 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, as well as, for example, introducing a compound provided herein into a sample containing a cell preparation or purified preparation containing KRas G12D and / or other G12 mutants. In some cases, cells in which inhibition of KRas G12D and / or other G12 mutant activity is desired are contacted with an effective amount of a compound of Formula (I) or Formula (II) or Formula (II). *) or a compound of formula (III), or a pharmaceutically acceptable salt thereof, to negatively modulate the activity of KRas G12D and / or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and / or other G12 mutants, the methods described herein are designed to inhibit undesirable cell proliferation resulting from enhanced activity of KRas G12D and / or other G12 mutants in cells. The cells may be contacted in a single dose or multiple doses according to a particular treatment regimen that results in the desired negative modulation of KRas G12D and / or other G12 mutants. The ability of a compound to bind to KRas G12D and / or other G12 mutants may be monitored in vitro using well-known methods.

[0381] In some embodiments, the inhibitory activity of exemplary compounds in cells can be monitored by measuring inhibition of the activity of KRas G12D and / or other G12 mutants, for example, the amount of phosphorylated ERK.

[0382] In another aspect, there is provided a method of treating cancer in a patient in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (II * The compositions and methods provided herein comprise administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. *), a compound of Formula (III), any one of its pharmaceutically acceptable salts, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, may be used for the treatment of KRas G12D and / or other G12 mutant-associated cancers in a patient in need thereof, comprising administering to the patient a compound of Formula (III), any one of its pharmaceutically acceptable salts, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof. In some cases, the KRas G12D and / or other G12 mutant-associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide 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 may be treated by the compositions and methods of the present invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, pharyngeal, lung, mouth, ovarian, prostate, and thyroid carcinomas and sarcomas. More specifically, these compounds are effective against cardiac: sarcomas (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma), alveolar (bronchial) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroitin hamartoma, and 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), and small intestine (adenocarcinoma, lymphoma, carcinoid tumor). tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); 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, adenomatous tumor, lipoma); liver: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; bile duct: gallbladder carcinoma, ampullary carcinoma, cholangiocarcinoma;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma (osteochronfroma) (cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meninges (meningiomas, meningeal sarcomas, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pineal tumor), glioblastoma multiforme, oligodendroma) Dendroglioma, Schwannoma, Retinoblastoma, Congenital Tumors), Spinal Neurofibroma, Meningioma, Glioma, Sarcoma; Gynecology: Uterus (Endometrial Carcinoma), Cervix (Cervical Carcinoma, Preneoplastic Cervical Dysplasia), Ovarian (Ovarian Carcinoma (Serous Cystadenocarcinoma, Mucinous Cystadenocarcinoma, Unclassified Carcinoma), Granulosathecocytoma, Sertoli-Leydig Cell Carcinoma, Dysgerminoma, Malignant Teratoma), Vulva (Squamous Cell Carcinoma, Carcinoma in Situ, Adenocarcinoma, Fibrosarcoma, Melanoma), Vagina (Clear Cell Carcinoma, Squamous Cell Carcinoma, Botryoid Sarcoma (Embryonal Rhabdomyosarcoma), Fallopian Breast Cancer It can be used to treat: pius tube (carcinoma); hematology: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodysplastic syndromes), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevi, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and adrenal gland: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, pulmonary tuberculosis, pulmonary fibrosis ... In some cases, the cancer is 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 patients will vary depending on the cancer being treated. The compounds, their pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-neoplastic compounds, such as chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, as a pre- or post-surgical adjuvant.

[0383] A compound of formula (I), formula (II), formula (II) as defined herein for use in therapy. *), a compound of formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is also provided herein.

[0384] A compound of formula (I), formula (II), formula (II) as defined herein for use in the treatment of cancer. * ), a compound of formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is also provided herein.

[0385] A compound of formula (I), formula (II), formula (II) for use in inhibiting KRas G12D and / or other G12 mutants. * ), a compound of formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is also provided herein.

[0386] Also provided herein are compounds of Formula (I), Formula (II), Formula (III), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, as defined herein, for use in treating KRas G12D and / or other G12 mutant-associated diseases or disorders.

[0387] a compound of formula (I), formula (II), formula (II) as defined herein in the manufacture of a medicament for the treatment of cancer; * ), the use of a compound of formula (III), or a pharmaceutically acceptable salt thereof, is also provided herein.

[0388] a compound of formula (I), formula (II), formula (II) as defined herein in the manufacture of a medicament for inhibiting the activity of KRas G12D and / or other G12 mutants; * ), the use of a compound of formula (III), or a pharmaceutically acceptable salt thereof, is also provided herein.

[0389] Also provided herein is the use of a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt thereof, as defined herein, in the manufacture of a medicament for the treatment of a KRas G12D and / or other G12 mutant associated disease or disorder.

[0390] In another aspect, the disclosure provides a method for treating cancer in a patient in need thereof, comprising: (a) determining that the cancer is associated with a KRas G12D mutation and / or other G12 mutant (e.g., a 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 a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (II * ), a compound of formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is provided.

[0391] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of disease or condition.In addition, the method for treating any of the diseases or conditions described herein in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition containing a therapeutically effective amount of at least one compound described herein, or its pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate.

[0392] The composition comprising the compound described herein can be administered for preventive and / or therapeutic treatment.In therapeutic application, the composition is administered to the patient who has already suffered from disease or condition in an amount sufficient to cure or at least partially stop the symptoms of disease or condition.The amount that is effective for this use depends on the severity and course of disease or condition, previous therapy, patient's health condition, weight and response to drug, and the judgment of the treating physician.

[0393] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the exact amount also depends on the patient's health condition, weight, etc. When used in patients, the effective amount for this use depends on the severity and course of the disease, disorder or condition, previous therapy, the patient's health condition and response to the drug, and the judgment of the treating physician.

[0394] If the patient's condition does not improve, at the physician's discretion, administration of the compound may be administered chronically, i.e., for an extended period of time, including throughout the patient's lifetime, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0395] Once the patient's condition improves, maintenance dose is administered as needed.Then, dosage or frequency of administration, or both, can be reduced according to the function of symptoms, until the improved disease, disorder or condition is maintained at the level.However, patient may need to be treated intermittently on a long-term basis when any symptom recurs.

[0396] The amount of a given agent that corresponds to such an amount will vary depending on factors such as the particular compound, the disease or condition and its severity, the identity (e.g., body weight) of the subject or host requiring treatment, and the like, but can nevertheless be determined in an art-recognized manner according to the particular circumstances surrounding the case, including, for example, the particular agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses used for adult human treatment typically range from about 0.02 to about 5000 mg per day, and in some embodiments, from about 1 to about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, e.g., as two, three, four, or more sub-doses per day.

[0397] The pharmaceutical compositions described herein may be in unit dosage form suitable for single administration of precise dosage amounts.In unit dosage form, the formulation is divided into unit doses containing appropriate amounts of one or more compounds.The unit dosage may be in the form of a package containing a discrete amount of the formulation.Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules.Aqueous suspension compositions can be packaged in single-dose non-reclosable containers.Alternatively, multi-dose reclosable containers can be used, in which case it is typical to include a preservative in the composition.By way of example only, parenteral injection formulations can be presented in unit dosage form, including, but not limited to, ampoules, or multi-dose containers with added preservatives.

[0398] The toxicity and therapeutic efficacy of such treatment regimens include, but are not limited to, LD 50 (a dose lethal to 50% of the population) and ED 50 The LD (the dose therapeutically effective in 50% of a population) can be determined by standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is known as the LD 50 and ED 50 The therapeutic index can be expressed as a ratio between ED and ED. Compounds that exhibit a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a range of dosages for use in humans. The dosage of such compounds is preferably such that ED is achieved with minimal toxicity. 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0399] In certain embodiments, the present invention provides a method of treating or preventing a disease, condition, or state in a patient in need thereof, comprising administering to the patient an effective amount of a compound of any one of the embodiments of the present invention, or a pharmaceutically acceptable salt thereof. The disease, condition, or state may be selected from the group described elsewhere herein. Bifunctional compounds

[0400] In some embodiments, the compounds herein can be employed to selectively eliminate hyperactivated KRas signaling induced by KRas mutations by directly binding to mutant KRas proteins, either by stabilizing their GDP-bound (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 cell's protein degradation machinery with 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 both the mutant KRas protein and the E3 ligase, creating an interaction between these two proteins and inducing KRas degradation.

[0401] Disclosed herein are bifunctional compounds comprised of a target protein (i.e., KRAS G12D) binding moiety and an E3 ubiquitin ligase binding moiety, which can induce proteasome-mediated degradation of a selected protein. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D) binding moiety and an E3 ubiquitin ligase binding moiety known in the art. In some embodiments, disclosed herein is the use of the compounds disclosed herein in preparations for degrading target protein compounds by using chemical modifications of the compounds disclosed herein. In some cases, the target protein binding moiety is represented by Formula (I), Formula (II), Formula (II) * ), or derived from a compound of formula (III): Preparation of compounds

[0402] The compounds of the present disclosure can generally be prepared by many methods well known to those skilled in the art of organic synthesis.For example, the compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry or variations thereof that are recognized by those skilled in the art.The compounds of the present disclosure can be prepared as described in the schemes and examples described elsewhere herein.

[0403] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope. [Example]

[0404] The following synthetic schemes are provided for illustrative purposes, not for limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that those skilled in the art may be able to make these compounds by similar methods or by combining other methods known to those skilled in the art. It is also understood that those skilled in the art can prepare compounds in a similar manner to those described below by using appropriate starting materials and, if necessary, modifying the synthetic route. In general, starting materials and reagents can be obtained from commercial suppliers, or can be synthesized according to sources known to those skilled in the art, or can be prepared as described herein.

[0405] The present disclosure provides processes for preparing the compounds described herein (described below). (described in more detail below). General Scheme [ka]

[0406] Treatment of R1 with methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate in DCM in the presence of a base such as DIEA can provide IA-a, which can be deprotonated with LDA or LiHMDS in THF at −78 °C. IA-b can be formed by the addition of a solution of a ketone in THF at −78 °C, and the reaction is quenched at −78 °C. Ester IA-b can be reduced to diol IA-c with DIBAL or LiAlH4, which can be cyclized to IA-d via a Mitsunobu reaction or in the presence of BuLi and TsCl in THF at −78 °C. Compound I can be prepared via a Pd-mediated coupling reaction or in the presence of a base such as NaH or LiHMDS. [ka]

[0407] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS in THF at −78°C. IB-a can be formed by the addition of a solution of a ketone in THF at −78°C, and the reaction is quenched at −78°C. Ester IB-a can be reduced to diol IB-b with DIBAL or LiAlH4, which can be cyclized to IB-c via a Mitsunobu reaction or in the presence of BuLi and TsCl in THF at −78°C. Treatment of R1 with IB-c in the presence of a base such as DIEA in DCM can provide IB-d, which can be oxidized to sulfone IB-e. Compound I can be prepared via a Pd-mediated coupling reaction or in the presence of a base such as NaH or LiHMDS. [ka]

[0408] Treatment of t-butyl-sulfinimade and a ketone in the presence of Ti(OEt)4 can provide IIA-a. A solution of IIA-a in THF can be added to a solution of IA-a and deprotonated with LDA or LiHMDS in THF at -78 °C. The reaction can be quenched at -78 °C to provide IIA-b. Ester IIA-b can be reduced to IIA-c with DIBAL or LiAlH4, which can be cyclized to IIA-d via a series of sulfinimade elimination under HCl, OH chlorination, and cyclization in the presence of a base such as NaOH (Garcia, D.; Moreno, B.; Soler, T.; Foubelo, F.; Yus, M. Tetrahedron Lett. 2009, 50, 4710). R3 in IIA-e can be introduced via reductive amination or alkylation. Compound II can be prepared via a Pd-mediated coupling reaction or in the presence of a base such as NaH or LiHMDS. [ka]

[0409] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS in THF at −78°C. IIB-a can be formed by the addition of a solution of IIA-a in THF at −78°C, and the reaction is quenched at −78°C. The ester IIB-a can be reduced to the diol IIB-b with DIBAL or LiAlH4, which can be cyclized to IIB-c as described in Scheme IIA above. R3 in IIB-d can be introduced via reductive amination or alkylation. Treatment of R1 with IIB-d in the presence of a base such as DIEA in DCM can provide IIB-e. IIB-e can be oxidized to the sulfoxide IIB-f, which can be converted to II in the presence of a base such as NaH or LiHMDS. Example 1 Exemplary Synthesis of 4'-(azepan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (Compound 1) [ka]

[0410] Step 1: To a solution of methyl 2,4-dichloro-6-methylpyrimidine-5-carboxylate (1.0 g, 4.52 mmol, 1.0 equiv.) in ACN (7 mL) was added DIPEA (1.17 g, 9.05 mmol, 2.0 equiv.) and azepane (449 mg, 4.52 mmol, 1.0 equiv.) at 20 °C. The reaction was then stirred at 20 °C for 2 h. TLC showed the reaction was complete. The reaction was concentrated in vacuo. The residue was poured into water (20 mL). The aqueous phase was extracted with EtOAc (5 mL × 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE: EtOAc = 10:1) to give compound 1a (1.1 g, 3.88 mmol, 85.7% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 3.88 (s, 3H), 3.49-3.52 (m, 4H), 2.36 (s, 3H), 1.75-1.85 (m, 4H), 1.50-1.60 (m, 4H).

[0411] Step 2: To a solution of LDA (2 M, 2.11 mL, 1.2 equiv) in THF (30 mL) was added compound 1a (1.0 g, 3.52 mmol, 1.0 equiv) at −60° C. The mixture was stirred at −60° C. for 30 minutes. 4-Chloro-2,3-dihydro-1H-inden-1-one (587 mg, 3.52 mmol, 1.0 equiv) was added at −60° C. The mixture was stirred at −60° C. for 1 hour. The reaction mixture was quenched by the addition of HCl (5%, 50 mL) at 0° C. and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 5:1) to give compound 1b (0.5 g, 1.20 mmol, 33.9% yield) as a yellow solid. 22 H 25 Cl2N3O3(M+H) + LCMS calculated for m / z = 450.1; found 450.1. 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J =8.0 Hz, 1H), 7.13 (t, J =7.6 Hz, 1H), 7.03 (d, J =7.6 Hz, 1H), 6.06 (s, 1H), 3.69 (s, 3H), 3.47-3.54(m, 4H), 3.08-3.11 (m, 2H), 2.76-2.99 (m, 2H), 2.22-2.26 (m, 2H), 1.70-1.80 (m, 4H), 1.45-1.60 (m, 4H).

[0412] Step 3: To a solution of compound 1b (490 mg, 1.09 mmol, 1.0 equiv) in DCM (5 mL) was added DIBAL-H (1 M, 3.26 mL, 3.0 equiv) at 0 °C. The reaction was then stirred at 0 °C for 1 h. The reaction mixture was quenched with HO (20 ml) at 25 °C. The mixture was extracted with DCM (10 mL × 2). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc = 80 / 1 to 8 / 1) to give compound 1c (200 mg, 474 umol, 43.5% yield) as a white solid. 21 H 25 Cl2N3O2(M+H) + LCMS calculated for m / z = 422.1; found 422.1. 1 H NMR (400 MHz, CD3OD) δ 7.25 (d, J =8.0 Hz, 1H), 7.19 (t, J =7.6 Hz, 1H), 7.09 (d, J =7.6 Hz, 1H),4.40-4.44 (m, 1H), 4.29-4.32 (m, 1H), 3.78-3.81 (m, 4H), 3.25-3.26(m, 1H), 2.96-3.03 (m, 2H), 2.84-2.88 (m, 1H), 2.56-2.59 (m, 1H), 2.01-2.04 (m, 1H), 1.75-1.90 (m, 4H), 1.55-1.65 (m, 4H).

[0413] Step 4: To a solution of compound 1c (200 mg, 474 umol, 1 equiv.) in THF (10 mL) was added PPh3 (149 mg, 568 umol, 1.2 equiv.) and DIAD (115 mg, 568 umol, 1.2 equiv.) at 0°C under N2. The reaction was then stirred at 0°C under N2 for 2 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc = 20:1) to give compound 1d (100 mg, 247 umol, 52.2% yield) as a yellow solid. 21 H 23 Cl2N3O(M+H) + m / z=404.1; measured value 404.1. 1 H NMR (400 MHz, CDCl3) δ 7.31 (d, J =8.0 Hz, 1H), 7.17 (t, J =7.6 Hz, 1H), 7.12 (d, J =7.6 Hz, 1H),4.65-4.71 (m, 1H), 4.51-4.53 (m, 1H), 3.50-3.65 (m, 4H), 3.07-3.17(m, 3H), 2.96-3.00 (m, 1H), 2.36-2.38 (m, 1H), 2.15-2.20 (m, 1H), 1.70-1.75 (m, 4H), 1.50-1.65 (m, 4H).

[0414] Step 5: To a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (37.8 mg, 237 umol, 1.2 eq) in THF (2 mL) was added NaH (15.8 mg, 396 umol, 60% purity, 2.0 eq) at 0 °C. The reaction was stirred at 0 °C for 30 minutes. Then, a solution of compound 1d (80 mg, 198 umol, 1.0 eq) in THF (0.5 mL) was added to the above solution at 0 °C. The reaction was continued to stir at 60 °C for 8 hours. LC-MS showed that 11% of the starting material remained and 52.9% of the desired compound was detected. The reaction was quenched with HO (10 mL) at 0 °C. The aqueous phase was extracted with EtOAc (5 mL × 2). The combined organic phase was washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, DCM:MeOH = 6:1) to give 4'-(azepan-1-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (compound 1, 11.0 mg, 20.8 umol, 10.5% yield) as a yellow solid. 29 H 36 ClFN4O2(M+H) + m / z=526.25; measured value 527.2. 1 H NMR (400 MHz, CDCl3) δ 7.10 (d, J =8.0 Hz, 1H), 6.90-7.00 (m, 2H), 5.00-5.40 (m, 1H), 4.50-4.53 (m, 1H), 4.32-4.36 (m, 1H), 3.93-3.95 (m, 1H), 3.79-3.81 (m, 1H), 3.38-3.41 (m, 4H), 3.05-3.15(m, 2H), 2.90-3.00 (m, 2H), 2.85-2.87(m, 1H), 2.70-2.80 (m, 2H), 2.15-2.25 (m, 1H), 1.95-2.10 (m, 4H), 1.50-1.80 (m, 6H), 1.30-1.50 (m, 6H). Example 2 Exemplary Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (Compound 2) [ka]

[0415] Step 1. Synthesis of tert-butyl 3-(2-chloro-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2a). To a solution of methyl 2,4-dichloro-6-methyl-pyrimidine-5-carboxylate (200.0 mg, 0.9 mmol) in MeCN (4 mL) was added a mixture of DIEA (233.88 mg, 1.81 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (192.08 mg, 0.9 mmol) in DMF (1 mL) at 0 °C. The reaction mixture was stirred under Ar at 0 °C for 30 min. The solution was diluted with EtOAc (5 mL) and washed with HO (5 mL × 3) and brine (5 mL). The organic phase was dried over NaSO and concentrated. The residue was purified by silica gel chromatography (eluting with 1:7 EtOAc:PE) to give tert-butyl 3-(2-chloro-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2a, 280 mg, 0.71 mmol, 78% yield) as a white solid. LCMS (ESI): C 18 H 25 ClN4O4 + m / z calculated for H: 397.87, found: 397.2.

[0416] Step 2. Synthesis of tert-butyl 3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2b). To a degassed solution of tert-butyl 3-(2-chloro-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2a, 400.0 mg, 1.01 mmol) in toluene (15 mL) was added [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (332.67 mg, 2.09 mmol), Ruphos (97.5 mg, 0.21 mmol), Pd(dba) (95.71 mg, 0.1 mmol), and CsCO (851.06 mg, 2.61 mmol). The degassed mixture was stirred at 110 °C under Ar for 16 h. The reaction mixture was concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography (EtOAc:PE=1:1 to DCM:MeOH=10:1) to give tert-butyl 3-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-methoxycarbonyl-6-methyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2b, 460 mg, 0.88 mmol, 88% yield) as a sticky brown solid. LCMS (ESI): C 26 H 38 FN5O5 + m / z calculated for H: 520.2, found: 520.2.

[0417] Step 3. Synthesis of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-methoxycarbonyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c). To a solution of tert-butyl 3-[5-methoxycarbonyl-6-methyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2b, 150.0 mg, 0.29 mmol) in THF (15 mL) at −70° C., LDA (0.72 mL, 1.44 mmol, 2 mol / L in THF) was added dropwise. The reaction mixture was stirred under Ar between −70° C. and −20° C. for 1.5 h. Then, a solution of 4-chloroindan-1-one (240.47 mg, 1.44 mmol) in THF (3 mL) was added dropwise to the resulting solution at −70° C. The reaction mixture was stirred under Ar between -70 °C and 0 °C for 3 h. The reaction mixture was quenched with aqueous NH4Cl at -50 °C, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by preparative TLC (DCM:MeOH = 10:1) to give tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-methoxycarbonyl-pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c, 75 mg, 0.11 mmol, 38% yield) as a light yellow sticky solid. LCMS (ESI): C 35 H 45 ClFN5O6 + m / z calculated for H: 686.1, found: 686.2.

[0418] Step 4. Synthesis of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-(hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d). To a degassed solution of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-5-methoxycarbonyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2c, 120.0 mg, 0.17 mmol) in anhydrous THF (8 mL) at −70° C., DIBAL-H (2.91 mL, 4.37 mmol) was added dropwise at −70° C. The mixture was allowed to warm to 0° C. and stirred under Ar for 16 h. The reaction mixture was quenched with aqueous NH4Cl at 0 °C, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give the crude product, which was purified by pre-TLC (DCM:MeOH = 10:1) to give tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-(hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d, 60 mg, 0.091 mmol, 52.1% yield) as a colorless viscous solid. LCMS (ESI): C 34 H 45 ClFN5O5 + m / z calculated for H: 658.3, found: 658.3.

[0419] Step 5. Synthesis of tert-butyl 3-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indan]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2e). To a degassed mixture of tert-butyl 3-[6-[(4-chloro-1-hydroxy-indan-1-yl)methyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-5-(hydroxymethyl)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2d, 70.0 mg, 0.11 mmol) and DIPEA (0.04 mL, 0.23 mmol) in anhydrous THF (5 mL) at 0 °C, MsCl (60.92 mg, 0.53 mmol) was added dropwise. The degassed mixture was warmed to 10 °C and stirred under Ar for 16 h. The mixture was quenched with aqueous NaHCO, extracted with EtOAc, and washed with water and brine. The organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by pre-TLC (DCM:MeOH=15:1) to give the crude product (2e, 65 mg) as a sticky brown solid. LCMS (ESI): C 34 H 43 m / z calculated for ClFN5O4+H: 640.3, found: 640.2.

[0420] Step 6. Synthesis of 4'-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-chloro-2'-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-2,3,5',8'-tetrahydrospiro[indene-1,7'-pyrano[4,3-d]pyrimidine] (2). To a solution of tert-butyl 3-[4'-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydro-pyrrolidin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indan]-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (64.0 mg, 0.1 mmol) in DCM (1.5 mL) was added TFA (2.95 mL, 39.77 mmol). The mixture was stirred at room temperature for 20 minutes. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (eluted with 5.0% to 95% CHCN in HO (0.1% TFA)). The resulting solution was then treated with 1N hydrochloric acid to displace the TFA and give 4'-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]spiro[5,8-dihydropyrano[4,3-d]pyrimidine-7,1'-indane]; dihydrochloride salt (12.32 mg, 0.0141 mmol, 14% yield) as a white solid. LCMS (ESI): C 29 H 35 m / z calculated for ClFN5O2+H: 540.2, found: 540.2. 1 H NMR (400 MHz, CD3OD) δ 7.37 (m, 3H), 5.59 (dd, J = 52.0, 13.6 Hz, 1H), 5.07 (d, J = 13.9 Hz, 1H), 4.69 - 4.35 (m, 3H), 4.35 - 4.06 (m, 3H), 3.90 (m, 6H), 3.42 (s, 2H), 3.26 - 3.07 (m, 2H), 3.00 (s, 1H), 2.88 - 1.99 (m, 12H). Example 3 Exemplary Synthesis of (4'-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-2'-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]spiro[2H-indeno[1,2-c]pyrazole-4,7'-5,8-dihydropyrano[4,3-d]pyrimidine] (Compound 3) [ka]

[0421] Step 1. Synthesis of 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3a). To a solution of indan-1,3-dione (5.00 g, 34.2 mmol, 1.0 equiv.) in THF (50 mL) was added DMF-DMA (4.15 g, 34.9 mmol, 1.02 equiv.) dropwise. The resulting mixture was stirred at room temperature for 1 hour. TLC showed that SM was consumed. The mixture was concentrated in vacuo to give crude 2-(dimethylaminomethylene)indan-1,3-dione (3a, 6.87 g, 34.1 mmol, crude) as a black solid, which was used directly in the next step without further purification. 12 H 12 NO2(M+H) + LCMS calculated for m / z=202.1; found: 202.1.

[0422] Step 2. Synthesis of 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3b). To a solution of 2-(dimethylaminomethylene)indan-1,3-dione (3a, 6.87 g, 34.1 mmol, crude) in AcOH (10.0 mL) was added hydrazine hydrate (10.0 mL, 205 mmol, 5.0 equiv.) dropwise. The mixture was then stirred at 90 °C for 16 h, and the solvent was removed in vacuo. The residue was suspended in water (30 mL), and the solid was collected by filtration, washed with water (90 mL) and aqueous NaHCO (90 mL), and dried in vacuo to give 4-hydrazono-2,4-dihydroindeno[1,2-c]pyrazole (3b, 5.23 g, 30.7 mmol, 89.9% yield over two steps) as a yellow solid. 10 LCMS calculated for H9N4 (M+H) m / z = 185.0; found: 185.0.

[0423] Step 3. Synthesis of 2H-indeno[1,2-c]pyrazol-4-one (3c). A solution of NaIO4 (9.59 g, 44.8 mmol, 2.0 equiv.) in water (100 mL) and EtOAc (100 mL) was stirred at room temperature for 5 minutes. 2,4-Dihydroindeno[1,2-c]pyrazol-4-yldiazene (3b, 4.13 g, 22.4 mmol) was then added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were concentrated and purified by flash chromatography (silica gel, eluting with 0-30% EtOAc in PE) to give 2H-indeno[1,2-c]pyrazol-4-one (3c, 1.74 g, 10.2 mmol, 45.6% yield) as a white solid. 10 LCMS calculated for H7N2O (M+H) m / z = 171.0; found: 171.0.

[0424] Step 4. Synthesis of 2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one (3d). To a solution of 2H-indeno[1,2-c]pyrazol-4-one (800 mg, 4.70 mmol, 1.0 equiv.) in DMF (12 mL) was added NaH (3c, 169 mg, 7.05 mmol, 1.5 equiv.) at 0 °C. The mixture was stirred at the same temperature for 30 min, and then SEMCl (1.17 g, 7.05 mmol, 1.5 equiv.) was added. The resulting mixture was warmed to room temperature and stirred for 1 h. The reaction was quenched with NH4Cl (aq), extracted with EtOAc (50 mL x 3), and the combined organic phases were concentrated and purified by flash chromatography (silica gel, eluting with 0-25% EtOAc in PE) to give a mixture of 2-(2-trimethylsilylethoxymethyl)indeno[1,2-c]pyrazol-4-one and its regioisomer (not shown) (3d, 1.38 g, 4.60 ...

Claims

1. Compound of formula (II): 【Chemistry 463】 or a pharma- ceutically acceptable salt thereof [In the formula, M is O, S, SO, SO ２ , and N.R. ３ Selected from: R １ is C ３ ~C １２ carbocycle and 5- to 15-membered heterocycle, each of which is selected from halogen, —B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl-SO ２ R ２０ , C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３ ~C １２ and optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are each independently selected from one or more R １＊ each independently optionally substituted with ３ and Y is O and R １ is piperazine, said piperazine may be selected from one or more R ９ is replaced by; Each R １＊ is halogen, -B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３ ~C １２ independently selected from carbocycle; Y is a bond, O, S, or NR ５ Selected from: R ２ is -L-N(R ２１ ) ２ , -L-OR ２１ , heterocycle, C １ ~C ６ Alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH ２ , -LC(O)N(R ２１ ) ２ , -L-C １ ~C ６ Haloalkyl, -L-OR ２１ , -L-NR ２１ C(O)-aryl, -L-COOH, -L-NR ２１ S (O) ２ (R ２１ ), -L-S(O) ２ N (R ２１ ) ２ , -L-N(R ２１ ) C(O)(OR ２１ ), -L-OC(O)N(R ２１ ) ２ and -LC(=O)OC １ ~C ６ alkyl, and the heterocycle, -L-NR ２１ The aryl portion of C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of said -L-cycloalkyl may be one or more R ６ and the aryl portion of said -L-aryl and the heteroaryl portion of said -L-heteroaryl are each optionally substituted with one or more R ７ and when Y is a bond, O, or S, R ２ is further selected from hydrogen; Each L is hydroxy, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ Alkyl, C ３ ~C ６ C optionally substituted with one or more substituents selected from a carbocycle, or a 3- to 8-membered heterocycle １ ~C ４ alkylene; ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ haloalkyl; optionally two substituents on the same carbon atom of L taken together represent C ３ ~C ６ Form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ each optionally substituted with one or more substituents selected from haloalkyl; R ３ is hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkoxyalkyl, C ３～１２ carbocycle, and 3- to 12-membered heterocycle; ３～１２ Carbocycles and 3- to 12-membered heterocycles include halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ each optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle; n is selected from 0 to 2; Each R ４ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, oxo, hydroxyl, halogen, C ３～１２ carbocycle, and 3- to 12-membered heterocycle, １ ~C ６ Alkyl, C ３～１２ Carbocycles and 3- to 12-membered heterocycles include cyano, halogen, -OR ５ , and -N(R ５ ) ２ each optionally substituted with one or more substituents independently selected from: Each R ５ is hydrogen or C １ ~C ６ independently selected from alkyl; Each R ６ is halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, oxo, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, =CH ２ , = NO-C １ ~C ３ Alkyl, C １ ~C ３ Aminoalkyl, -N(R ５ ) S (O) ２ (R ５ ), -Q-phenyl, -Q-phenylSO ２ F, -NHC(O)phenyl, -NHC(O)phenylSO ２ F.C. １ ~C ３ Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxy CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ Alkoxy)C １ ~C ３ Alkyl-, (C １ ~C ３ alkyl)C(=O), oxo, (C １ ~C ３ haloalkyl)C(=O)-, -SO ２ F, (C １ ~C ３ Alkoxy)C １ ~C ３ Alkoxy, -CH ２ O.C. (O) N (R ５ ) ２ , -CH ２ NHC(O)OC １ ~C ６ Alkyl, -CH ２ NHC(O)N(R ５ ) ２ , -CH ２ NHC(O)C １ ~C ６ Alkyl, -CH ２ (pyrazolyl), -CH ２ N.H.S.O. ２ C １ ~C ６ Alkyl, -CH ２ OC(O)heterocycle, -OC(O)N(R ５ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl), -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl(C １ ~C ３ Alkyl)N(CH ３ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl, -OC(O)heterocycle, -OC １ ~C ３ Alkyl, and -CH ２ heterocycle, independently selected from -NHC(O)phenyl and -OC(O)NH(C １ ~C ３ Alkyl) (C １ ~C ３ The phenyl of the alkyl)phenyl is optionally substituted with one or more substituents selected from -C(O)H and OH, and -O-C １ ~C ３ The alkyl of the alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; ２ The heterocycle of the heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R ７ is halogen, hydroxy, HC(=O)-, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ Hydroxyalkyl, or -N(R ５ ) ２ are independently selected from; Each R ９ is halogen, -B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -NR ２０ S (O) ２ R ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -NO ２ , =O, =NO (R ２０ ), -CN, -NHCN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ haloalkyl; Each R ２０ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, =NH, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; Each R ２１ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; B is selected from heterocycles and carbocycles, said heterocycles and carbocycles being selected from halogen, cyano, hydroxy, ═O, —NO ２ , C １ ~C ４ Alkyl, C １～６ Aminoalkyl, -S-C １ ~C ３ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Hydroxyalkynyl, C １ ~C ３ Cyanoalkyl, triazolyl, C １ ~C ３ Haloalkyl, —O—C １ ~C ３ Haloalkyl, -S-C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Hydroxyalkyl, -CH ２ C(=O)N(R ５ ) ２ , -C ３ ~C ４ Alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , (C １ ~C ３ Alkoxy) HaloC １ ~C ３ Alkyl-, C １～６ Alkyl-N(R ２０ ) ２ , C ３ ~C １２ each optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are not limited to halogen, —OH, —NO ２ , -NH ２ ,=O,=S,-CN,C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ haloalkyl, each optionally substituted with one or more substituents selected from.

2. R ３ is hydrogen and C １～６ 2. The compound or salt of claim 1, wherein the aryl group is selected from alkyl.

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

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

5. M is NR ３ 2. The compound or salt of claim 1, selected from:

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

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

8. B is an optionally substituted 5- to 15-membered heterocycle and optionally substituted C ３ ~C １５ A compound or salt according to any one of claims 1 to 7, selected from carbocycles.

9. B is an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C ８ ~C １５ 9. The compound or salt of claim 8, wherein the ring is selected from fused carbocycles.

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

11. B is an optionally substituted unsaturated C ８ ~C １５ 11. The compound or salt of claim 10 which is a fused carbocyclic ring.

12. For B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C ８ ~C １５ 12. The compound or salt of any one of claims 9 to 11, wherein each fused carbocycle is independently bicyclic or tricyclic.

13. 13. The compound or salt of claim 12, wherein for B, the heterocycle and the carbocycle are each independently bicyclic.

14. 13. The compound or salt of claim 12, wherein for B, the heterocycle and the carbocycle are each independently tricyclic.

15. B, 【Chemistry 464】 15. The compound or salt of any one of claims 9 to 14, selected from: each of which is optionally substituted with one or more substituents.

16. B, 【Chemistry 465】 16. The compound or salt of claim 15, selected from:

17. B, 【Chemistry 466】 17. The compound or salt of claim 16, selected from: each of which is optionally substituted with one or more substituents.

18. For B, the one or more optional substituents are oxo, -NH ２ , halogen, C １ ~C ３ 18. The compound or salt of any one of claims 8 to 17, wherein each is independently selected from alkyl.

19. B, 【Chemistry 467】 The compound or salt according to any one of claims 1 to 18, selected from:

20. For B, the one or more optional substituents of the heterocycle and carbocycle are each selected from the group consisting of halogen, C １ ~C ３ Alkyl, -B(OR ２０ ) ２ , -OR ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) ２ , =O, -CN, -NHCN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, and C ２～６ 18. The compound or salt of any one of claims 8 to 17, independently selected from alkynyl.

21. For B, the one or more optional substituents of the heterocycle and carbocycle are each selected from the group consisting of halogen, oxo, -NH ２ , C １ ~C ３ Alkyl, -B(OH) ２ , —OH, —O—C １ ~C ３ Haloalkyl, —C(O)NH ２ , -NH ２ , =O, -CN, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C ２～６ 18. The compound or salt of any one of claims 8 to 17, independently selected from alkynyl.

22. B, 【Chemistry 468】 【Chemistry 469】 The compound or salt according to any one of claims 8 to 21, selected from:

23. Each R ４ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ 23. The compound or salt of any one of claims 1 to 22, independently selected from alkynyl, oxo, hydroxyl, halogen.

24. Each R ４ But, C １～６ 24. The compound or salt of claim 23, independently selected from alkyl, oxo, and halogen.

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

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

27. R １ 27. The compound or salt of any one of claims 1 to 26, wherein is selected from optionally substituted 5- to 12-membered heterocycles.

28. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , =O, -CN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 28. The compound or salt of claim 27, optionally substituted with one or more substituents independently selected from haloalkyl.

29. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 30. The compound or salt of claim 28, optionally substituted with one or more substituents independently selected from haloalkyl.

30. R ２０ is hydrogen and C １～３ 30. The compound or salt of claim 28 or 29, wherein the alkyl is selected from the group consisting of alkyl, aryl ... and alkyl.

31. R １ 30. The compound or salt of any one of claims 27 to 29, wherein the 5-12 membered heterocyclic ring of is unsaturated.

32. R １ 30. The compound or salt of any one of claims 27 to 29, wherein the 5-12 membered heterocycle of is saturated.

33. R １ 30. The compound or salt according to any one of claims 27 to 29, wherein the 5-12 membered heterocycle of the formula: is a bridged heterocycle.

34. R １ but, 【Chemistry 470】 34. The compound or salt of any one of claims 27 to 33, selected from:

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

36. R １ but, 【Chemistry 471】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, =O, -CN, C １～６ Hydroxyalkyl, and C １～６ 35. The compound or salt of claim 34, optionally substituted with one or more substituents independently selected from haloalkyl.

37. R １ but, 【Chemistry 472】 37. The compound or salt of claim 36, selected from:

38. R １ 34. The compound or salt of any one of claims 27 to 33, wherein is selected from a 6-8 membered heterocycle, which is optionally substituted.

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

40. R １ but, 【Chemistry 473】 40. The compound or salt of claim 39, selected from:

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

42. R １ but, 【Chemical 474】 42. The compound or salt of claim 40 or 41, selected from:

43. R １ 27. The compound or salt of any one of claims 1 to 26, wherein is selected from optionally substituted 6- to 7-membered heterocycles.

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

45. R １ 45. The compound or salt of claim 44, wherein said 6-7 membered heterocycle of the formula: is attached to formula (II) through only one nitrogen atom.

46. R １ 46. ​​The compound or salt of any one of claims 43 to 45, wherein is selected from optionally substituted unsaturated 6-membered heterocycles.

47. R １ 46. ​​The compound or salt of any one of claims 43 to 45, wherein is selected from optionally substituted unsaturated 7-membered heterocycles.

48. R １ but, 【Chemistry 475】 48. The compound or salt of any one of claims 43 to 47, selected from:

49. R １ but, 【Chemistry 476】 49. The compound or salt of any one of claims 43 to 48, selected from:

50. R １ one or more of the optional substituents of ２０ , -N(R ２０ ) ２ , =O, -CN, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Alkyl, -NHCN, and C ２～６ 50. The compound or salt of any one of claims 43 to 49, each independently selected from the group consisting of alkynyl.

51. Each of them is a halogen, -OH, or -NH. ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, and C １～６ 51. The compound or salt of any one of claims 43 to 50, optionally substituted with one or more substituents independently selected from alkyl.

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

53. R １ but, 【Chemistry 477】 53. The compound or salt according to any one of claims 43 to 52, selected from:

54. R １ but, 【Chemistry 478】 each of which is selected from halogen, —OH, —NH ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, and C １～６ 52. The compound or salt of any one of claims 43 to 51, optionally substituted with one or more substituents independently selected from alkyl.

55. R １ but, 【Chemical 479】 each of which is selected from halogen, —OH, —NH ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, and C １～６ 55. The compound or salt of claim 54, optionally substituted with one or more substituents independently selected from alkyl.

56. R １ but, 【Chemistry 480】 each of which is selected from halogen, and C １～６ 56. The compound or salt of claim 55, optionally substituted with one or more substituents independently selected from haloalkyl.

57. R １ but, 【Chemistry 481】 57. The compound or salt of claim 56, selected from:

58. R １ but, 【Chemistry 482】 is selected from halogen, —OH, —NH ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Haloalkyl, and C １～６ 52. The compound or salt of any one of claims 43 to 51, optionally substituted with one or more substituents independently selected from alkyl.

59. R １ but, 【Chemistry 483】 59. The compound or salt of claim 58, wherein the compound or salt is selected from the group consisting of:

60. R １ but, 【Chemistry 484】 60. The compound or salt of claim 59, selected from:

61. R １ 44. The compound or salt of claim 43, wherein is selected from 6- to 7-membered heterocycles.

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

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

64. 64. The compound or salt of any one of claims 61 to 63, wherein the 6- to 7-membered heterocycle contains only one nitrogen atom and no further additional heteroatoms.

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

66. R １ 66. The compound or salt of any one of claims 62 to 65, wherein said 6-7 membered heterocycle is attached to formula (II) via only said one nitrogen atom.

67. R １ but, 【Chemistry 485】 67. The compound or salt of any one of claims 61 to 66, selected from:

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

69. R １ 44. The compound or salt of claim 43, wherein is selected from optionally substituted 6- to 10-membered heterocycles.

70. R １ but, 【Chemistry 486】 70. The compound or salt of claim 69, selected from:

71. The one or more optional substituents are 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 71. The compound or salt of claim 70, wherein each is independently selected from alkyl.

72. R １ but, 【Chemistry 487】 72. The compound or salt of claim 71, selected from:

73. R １ 28. The compound or salt of claim 27, wherein is selected from 7-11 membered spiro heterocycles.

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

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

76. R １ but, 【Chemistry 488】 76. The compound or salt of claim 75, selected from:

77. R １ but, 【Chemistry 489】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , =O, -CN, -NHCN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, and C ２～６ 77. The compound or salt of claim 76, optionally substituted with one or more substituents independently selected from alkynyl.

78. R １ but, 【Chemistry 490】 Preferably, 【Chemistry 491】 78. The compound or salt of claim 77, selected from:

79. R １ 28. The compound or salt of claim 27, wherein is selected from optionally substituted unsaturated 9-11 membered heterocycles.

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

81. R １ but, 【Chemistry 492】 81. The compound or salt of claim 80, wherein:

82. R １ but, 【Chemistry 493】 which is a halogen, —OH, —C(O)N(R ２０ ) ２ , -C(O)OR ２０ , -C(O)NHOR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -NO ２ , =O, -CN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, and C ２～６ 82. The compound or salt of claim 81, optionally substituted with one or more substituents selected from alkynyl.

83. R １ but, 【Chemistry 494】 each of which is 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 83. The compound or salt of claim 82, optionally substituted with one or more substituents selected from alkynyl.

84. R １ 28. The compound or salt of claim 27, wherein is selected from optionally substituted unsaturated 9-11 membered heterocycles.

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

86. R １ but, 【Chemistry 495】 86. The compound or salt of claim 85, which is optionally substituted.

87. R １ one or more optional substituents are halogen, —OH, —S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)OR ２０ , -C(O)NHOR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -NO ２ , =O, -CN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Alkoxyalkyl, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ alkynyl, and a 5- to 12-membered heterocycle, said 5- to 12-membered heterocycle being independently selected from halogen, —OR ２０ , and C １～６ 87. The compound or salt of claim 86, optionally substituted with one or more substituents selected from alkyl.

88. R １ but, 【Chemistry 496】 88. The compound or salt of any one of claims 84 to 87, selected from:

89. R １ but, 【Chemistry 497】 【Chemistry 498】 89. The compound or salt according to any one of claims 84 to 88, selected from:

90. R １ one or more optional substituents of are 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 88. The compound or salt of any one of claims 84 to 87, independently selected from alkynyl.

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

92. R １ but, 【Chemistry 499】 92. The compound or salt of claim 91, selected from:

93. R １ one or more of the optional substituents of ２０ ) ２ , -C.N., 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 heterocycle, said 5- to 10-membered heterocycle being independently selected from one or more R １＊ and each R １＊ is halogen, -OR ２０ , and C １～６ 88. The compound or salt of any one of claims 84 to 87, independently selected from alkyl.

94. R １ wherein said one or more optional substituents are chlorine, —NH ２ , -C.N., C. １ Alkyl, C ２ Alkenyl, 【Chemistry 500】 94. The compound or salt of claim 93, selected from:

95. R １ but, 【Chemistry 501】 【Chemistry 502】 【Chemistry 503】 95. The compound or salt of claim 94, selected from:

96. R １ 27. The compound or salt of any one of claims 1 to 26, wherein is an optionally substituted 12-15 membered heterocycle.

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

98. R １ 97. The compound or salt of claim 96, wherein is an optionally substituted 13-membered heterocycle.

99. R １ 97. The compound or salt of claim 96, wherein is an optionally substituted 14-membered heterocycle.

100. R １ 97. The compound or salt of claim 96, wherein is an optionally substituted 15-membered heterocycle.

101. R １ 101. The compound or salt of any one of claims 96 to 100, wherein the heterocycle is tricyclic.

102. R １ 102. The compound or salt of any one of claims 96 to 101, wherein the heterocycle of formula (I) contains a fused heterocycle.

103. R １ 103. The compound or salt of any one of claims 96 to 102, wherein the heterocycle of formula (I) contains a spiro heterocycle.

104. R １ 104. The compound or salt of any one of claims 96 to 103, wherein the heterocycle of the formula:

105. R １ 105. The compound or salt according to any one of claims 96 to 104, wherein the heterocycle is an unsaturated heterocycle.

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

107. R １ 107. The compound or salt of any one of claims 96 to 106, wherein the heterocycle has at least one double bond.

108. R １ 108. The compound or salt of any one of claims 96 to 107, wherein the heterocycle has at least two double bonds.

109. R １ 109. The compound or salt of any one of claims 96 to 108, wherein the heterocycle has two double bonds.

110. R １ but, 【Chemistry 504】 110. The compound or salt of any one of claims 96-109, selected from:

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

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

113. R １ but, 【Chemistry 505】 【Chemistry 506】 113. The compound or salt according to any one of claims 96 to 112, selected from:

114. R １ is selected from a substituted 6- to 7-membered heterocycle, said 6- to 7-membered heterocycle being substituted with at least one -NHCN and one or more C １～６ 44. The compound or salt of claim 43, further optionally substituted with alkyl.

115. R １ but, 【Chemistry 507】 115. The compound or salt of claim 114, selected from:

116. R １ is selected from 8-10 membered heterocycles, each of which is selected from halogen, —C(O)N(R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -NHCN, C １～６ Cyanoalkyl, C １～６ Alkyl, C ２～６ alkynyl, and a 5- to 12-membered heterocycle (preferably a 5- to 6-membered heterocycle), which is optionally substituted with one or more substituents independently selected from R １＊ each independently optionally substituted with １＊ But halogen, C １～６ Haloalkyl, and C １～６ 26. The compound or salt of any one of claims 1 to 25, independently selected from alkyl.

117. R １ but, 【Chemistry 508】 117. The compound or salt of claim 116, selected from:

118. R １ but, 【Chemistry 509】 118. The compound or salt of claim 117, selected from, which is optionally substituted.

119. R １ but, 【Chemistry 510】 119. The compound or salt of claim 118, selected from:

120. R １ but, 【Chemistry 511】 118. The compound or salt of claim 117, selected from:

121. 121. The compound or salt of any one of claims 1 to 120, wherein Y is O.

122. R ２ is one or more R ６ 122. The compound or salt of any one of claims 1 to 121, which is -L-heterocycle optionally substituted with:

123. L is C １ ~C ４ 123. The compound or salt of claim 122, selected from alkylene.

124. L is unsubstituted C １ ~C ４ 124. The compound or salt of claim 123, selected from alkylene.

125. Each L is optionally substituted C １ ~C ４ alkylene; optionally, two substituents on the same carbon atom of L are taken together to form C ３ ~C ６ Form a carbocyclic ring, ３ ~C ６ The carbocyclic ring is halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ 124. The compound or salt of claim 123, optionally substituted with one or more substituents selected from haloalkyl.

126. The optional substituents of L are １ ~C ４ Hydroxyalkyl, C １ ~C ４ Alkyl, C ３ ~C ６ carbocycle; optionally two substituents on the same carbon atom of L are taken together to form C ３ ~C ６ Form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, ３ ~C ６ Carbocyclic and 3- to 8-membered heterocyclic rings are １～６ 126. The compound or salt of claim 125, optionally substituted with one or more substituents selected from haloalkyl.

127. Y-R ２ but, 【Chemistry 512】 and the heterocyclic moiety is selected from one or more R ６ 127. The compound or salt of claim 1, optionally substituted with

128. R ２ R ６ Each occurrence of halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, and C １ ~C ３ 128. The compound or salt of claim 127, independently selected from aminoalkyl.

129. R ２ R ６ However, in each occurrence, C １ ~C ３ 129. The compound or salt of claim 128, wherein is independently selected from alkyl and halogen.

130. Y-R ２ but, 【Chemistry 513】 130. The compound or salt according to claims 127 to 129, selected from:

131. Y-R ２ but, 【Chemistry 514】 and the heterocyclic moiety is selected from one or more R ６ 126. The compound or salt of any one of claims 121 to 125, optionally substituted with

132. R ６ is halogen, -OH, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, oxo, C １ ~C ３ Alkoxy, -CN, and C １ ~C ３ 132. The compound or salt of claim 131, wherein said compound or salt is selected from aminoalkyl.

133. R ６ is halogen and C １ ~C ３ 133. The compound or salt of claim 132, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

134. Y-R ２ but, 【Chemistry 515】 134. The compound or salt of claim 133, selected from:

135. Y-R ２ but, 【Chemistry 516】 132. The compound or salt of claim 131, selected from:

136. R ２ is selected from -L-heterocycle, the heterocycle portion of which is selected from one or more R ６ 122. The compound or salt of claim 1, optionally substituted with:

137. Each L is a substituted C １ ~C ４ alkylene, and two substituents on the same carbon atom of L taken together represent C ３ ~C ６ Form a carbocyclic ring, ３ ~C ６ The carbocyclic ring is halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ 137. The compound or salt of claim 136, optionally substituted with one or more substituents selected from haloalkyl.

138. Each L is a substituted C １ ~C ４ alkylene, and two substituents on the same carbon atom of L taken together represent C ３ ~C ６ 138. The compound or salt of claim 137, which forms a carbocyclic ring.

139. Each L is a substituted C ３ alkylene, and two substituents on the same carbon atom of L taken together represent C ３ 139. The compound or salt of claim 138, which forms a carbocyclic ring.

140. Each L is, 【Chemistry 517】 140. The compound or salt of claim 139, independently selected from:

141. Y-R ２ but, 【Chemistry 518】 141. The compound or salt of claim 140,

142. Y-R ２ but, 【Chemistry 519】 and wherein the heterocycle is optionally substituted.

143. The heterocycle is selected from the group consisting of halogen, hydroxy, C １ ~C ３ Alkyl, -N(R ５ ) S (O) ２ (R ５ ), -OC(O)N(R ５ ) ２ , =CH ２ , oxo, =NO-C １ ~C ３ Alkyl, -CH ２ OC(O)heterocycle, -CH ２ Heterocycle, -CH ２ O.C. (O) N (R ５ ) ２ and -O-C １ ~C ３ optionally substituted with one or more substituents selected from alkyl, —O—C １ ~C ３ 143. The compound or salt of claim 142, wherein the alkyl of the alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy.

144. Y-R ２ but, 【Chemistry 520】 144. The compound or salt of claim 143, selected from:

145. R ２ But -L-N(R ２１ ) ２ 141. The compound or salt according to any one of claims 1 to 126 or 136 to 140, selected from:

146. L is a substituted C １ ~C ４ alkylene, and two substituents on the same carbon atom of L taken together represent C ３ ~C ６ Form a carbocyclic ring, ３ ~C ６ 146. The compound or salt of claim 145, wherein the carbocycle is optionally substituted with one or more substituents selected from halogen.

147. L, 【Chemistry 521】 147. The compound or salt of claim 1, 145 or 146,

148. R ２ but, 【Chemistry 522】 148. The compound or salt of claim 1, wherein

149. Y-R ２ but, 【Chemistry 523】 148. The compound or salt of claim 1, wherein

150. The compound is 【Chemistry 524】 【Chemistry 525】 【Chemistry 526】 【Chemistry 527】 or any one of pharma- ceutically acceptable salts thereof.

151. Compound of formula (III): 【Chemistry 528】 or a pharma- ceutically acceptable salt thereof [In the formula, R １ is C ３ ~C １２ carbocycle and 5- to 15-membered heterocycle, each of which is selected from halogen, —B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３ ~C １２ and optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are each independently selected from one or more R １＊ each independently optionally substituted with; Each R １＊ is halogen, -B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３ ~C １２ independently selected from carbocycle; R ２ is -L-NR ２１ S (O) ２ (R ２１ ), -L-S(O) ２ N (R ２１ ) ２ , -L-N(R ２１ ) C(O)(OR ２１ ), -L-OC(O)N(R ２１ ) ２ and L-bicyclic heterocycle, said bicyclic heterocycle being selected from one or more R ６ where appropriate replaced by; Each L is hydroxy, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ Alkyl, C ３ ~C ６ C optionally substituted with one or more substituents selected from a carbocycle, or a 3- to 8-membered heterocycle １ ~C ４ alkylene; ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ haloalkyl; optionally two substituents on the same carbon atom of L taken together represent C ３ ~C ６ Form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ each optionally substituted with one or more substituents selected from haloalkyl; n is selected from 0 to 3; Each R ４ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, oxo, hydroxyl, halogen, C ３～１２ carbocycle, and 3- to 12-membered heterocycle, １ ~C ６ Alkyl, C ３～１２ Carbocycles and 3- to 12-membered heterocycles include cyano, halogen, -OR ５ , and -N(R ５ ) ２ each optionally substituted with one or more substituents independently selected from: B is selected from heterocycles and carbocycles, said heterocycles or carbocycles being halogen, cyano, hydroxy, =O, -NO ２ , C １ ~C ４ Alkyl, C １～６ Aminoalkyl, -S-C １ ~C ３ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Hydroxyalkynyl, C １ ~C ３ Cyanoalkyl, triazolyl, C １ ~C ３ Haloalkyl, —O—C １ ~C ３ Haloalkyl, -S-C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Hydroxyalkyl, -CH ２ C(=O)N(R ５ ) ２ , -C ３ ~C ４ Alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , (C １ ~C ３ Alkoxy) HaloC １ ~C ３ Alkyl-, C １～６ Alkyl-N(R ２０ ) ２ , C ３ ~C １２ Optionally substituted with one or more substituents independently selected from carbocycle and 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are not limited to halogen, —OH, —NO ２ , -NH ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ each optionally substituted with one or more substituents selected from haloalkyl; Y is a bond, O, S, or NR ５ Selected from: Each R ６ is halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, oxo, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, =CH ２ , = NO-C １ ~C ３ Alkyl, C １ ~C ３ Aminoalkyl, -N(R ５ ) S (O) ２ (R ５ ), -Q-phenyl, -Q-phenylSO ２ F, -NHC(O)phenyl, -NHC(O)phenylSO ２ F.C. １ ~C ３ Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxy CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ Alkoxy)C １ ~C ３ Alkyl-, (C １ ~C ３ alkyl)C(=O), oxo, (C １ ~C ３ haloalkyl)C(=O)-, -SO ２ F, (C １ ~C ３ Alkoxy)C １ ~C ３ Alkoxy, -CH ２ O.C. (O) N (R ５ ) ２ , -CH ２ NHC(O)OC １ ~C ６ Alkyl, -CH ２ NHC(O)N(R ５ ) ２ , -CH ２ NHC(O)C １ ~C ６ Alkyl, -CH ２ (pyrazolyl), -CH ２ N.H.S.O. ２ C １ ~C ６ Alkyl, -CH ２ OC(O)heterocycle, -OC(O)N(R ５ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl), -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl(C １ ~C ３ Alkyl)N(CH ３ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl, -OC(O)heterocycle, -OC １ ~C ３ Alkyl, and -CH ２ heterocycle, independently selected from -NHC(O)phenyl and -OC(O)NH(C １ ~C ３ Alkyl) (C １ ~C ３ The phenyl of the alkyl)phenyl is optionally substituted with one or more substituents selected from -C(O)H and OH, and -O-C １ ~C ３ The alkyl of the alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; ２ The heterocycle of the heterocyclyl is optionally substituted with oxo; each Q is independently selected from a bond, S, and O; Each R ２０ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; Each R ２１ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; Each R ５ is hydrogen or C １ ~C ６ alkyl.

152. R ２ is selected from L-pyrrolidine, said pyrrolidine being selected from one or more R ６ 152. The compound or salt of claim 151, optionally substituted with:

153. B is an optionally substituted 5- to 15-membered heterocycle and optionally substituted C ３ ~C １５ 153. The compound or salt of any one of claims 151 to 152, selected from carbocycles.

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

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

156. B is an optionally substituted unsaturated C ８ ~C １５ 155. The compound or salt of claim 154, wherein said ring is selected from fused carbocycles.

157. For B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C ８ ~C １５ 157. The compound or salt of any one of claims 153 to 156, wherein the fused carbocycles are bicyclic and tricyclic, respectively.

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

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

160. B, 【Chemistry 529】 160. The compound or salt of any one of claims 151-159, selected from:

161. B, 【Chemistry 530】 161. The compound or salt of claim 160, selected from:

162. B, 【Chemistry 531】 162. The compound or salt of claim 161, selected from:

163. For B, the one or more optional substituents of the heterocycle and carbocycle are oxo, -NH ２ , halogen, C １ ~C ３ 163. The compound or salt of any one of claims 151 to 162, independently selected from alkyl.

164. B, 【Chemistry 532】 164. The compound or salt of any one of claims 151 to 163, selected from:

165. For B, the one or more optional substituents of the heterocycle and carbocycle are each selected from the group consisting of halogen, C １ ~C ３ Alkyl, -B(OR ２０ ) ２ , -OR ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) ２ , =O, -CN, -NHCN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, and C ２～６ 163. The compound or salt of any one of claims 151 to 162, independently selected from alkynyl.

166. For B, the one or more optional substituents of the heterocycle and carbocycle are each selected from the group consisting of halogen, oxo, -NH ２ , C １ ~C ３ Alkyl, -B(OH) ２ , -OH, -C(O)NH ２ , -NH ２ , =O, -CN, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C ２～６ 156. The compound or salt of claim 155, independently selected from alkynyl.

167. B, 【Chemistry 533】 167. The compound or salt according to any one of claims 165 to 166, selected from:

168. Each R ４ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ 168. The compound or salt of any one of claims 151 to 167, independently selected from alkynyl, oxo, hydroxyl, halogen.

169. Each R ４ But, C １～６ 169. The compound or salt of claim 168, independently selected from alkyl, oxo, and halogen.

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

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

172. 172. The compound or salt of any one of claims 151 to 171, wherein Y is O.

173. R １ is selected from optionally substituted 5-12 membered heterocycles.

174. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , =O, -CN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 174. The compound or salt of claim 173, optionally substituted with one or more substituents independently selected from haloalkyl.

175. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 175. The compound or salt of claim 174, optionally substituted with one or more substituents independently selected from haloalkyl.

176. R ２０ is hydrogen and C １～３ 176. The compound or salt of claim 174 or 175, wherein said alkyl is selected from the group consisting of aryl, ... and alkyl.

177. R １ 177. The compound or salt of claim 151-176, wherein said 5- to 12-membered heterocyclic ring is unsaturated.

178. R １ 177. The compound or salt of claim 151-176, wherein said 5-12 membered heterocycle is saturated.

179. R １ 177. The compound or salt of claim 151-176, wherein said 5- to 12-membered heterocycle of the formula: is bridged.

180. R １ 177. The compound or salt of claim 151-176, wherein said 5- to 12-membered heterocycle is a spiro heterocycle.

181. R １ but, 【Chemical 534】 【Chemistry 535】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, =O, -CN, C １～６ Hydroxyalkyl, and C １～６ 181. The compound or salt of claims 151-180, optionally substituted with one or more substituents independently selected from haloalkyl.

182. R １ but, 【Chemistry 536】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, =O, -CN, C １～６ Hydroxyalkyl, and C １～６ 182. The compound or salt of claim 181, optionally substituted with one or more substituents independently selected from haloalkyl.

183. R １ but, 【Chemistry 537】 183. The compound or salt of claim 182, selected from:

184. R ２ is one or more R ６ 184. The compound or salt of claim 151-183, which is -L-heterocycle optionally substituted with:

185. L is C １ ~C ４ 185. The compound or salt of claim 184, selected from alkylene.

186. L is unsubstituted C １ ~C ４ 186. The compound or salt of claim 185, selected from alkylene.

187. Y-R ２ but, 【Chemistry 538】 and the heterocyclic moiety is selected from one or more R ６ 187. The compound or salt of any one of claims 184 to 186, optionally substituted with:

188. R ２ R ６ Each occurrence of halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, and C １ ~C ３ 188. The compound or salt of claim 187, independently selected from aminoalkyl.

189. R ２ R ６ However, in each occurrence, C １ ~C ３ 189. The compound or salt of claim 188, wherein is independently selected from alkyl and halogen.

190. Y-R ２ but, 【Chemistry 539】 190. The compound or salt of claim 189, selected from:

191. Compounds of formula (I): 【Chemistry 540】 or a pharma- ceutically acceptable salt thereof [In the formula, R １ is C ３ ~C １２ carbocycle and 5- to 15-membered heterocycle, each of which is selected from halogen, —B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３ ~C １２ and optionally substituted with one or more substituents independently selected from a carbocycle and a 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are each independently selected from one or more R １＊ each independently optionally substituted with; Each R １＊ is halogen, -B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３ ~C １２ independently selected from carbocycle; Y is a bond, O, S, or NR ５ Selected from: R ２ is hydrogen, -N(R ２１ ) ２ , -L-N(R ２１ ) ２ , -L-OR ２１ , heterocycle, C １ ~C ６ Alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-N(R ２１ ) ２、 -L-NHC(=NH)NH ２ , -LC(O)N(R ２１ ) ２ , -L-C １ ~C ６ Haloalkyl, -L-OR ２１ , -L-NR ２１ C(O)-aryl, -L-COOH, -L-NR ２１ S (O) ２ (R ２１ ), -L-S(O) ２ N (R ２１ ) ２ , -L-N(R ２１ ) C(O)(OR ２１ ), -L-OC(O)N(R ２１ ) ２ and -LC(=O)OC １ ~C ６ alkyl, said heterocycle, and -L-NR ５ The aryl portion of C(O)-aryl, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of said -L-cycloalkyl may be one or more R ６ wherein the aryl or heteroaryl of said -L-aryl and said -L-heteroaryl are optionally substituted with one or more R ７ and optionally substituted with; Each L is hydroxy, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ Alkyl, C ３ ~C ６ C optionally substituted with one or more substituents selected from a carbocycle, or a 3- to 8-membered heterocycle １ ~C ４ alkylene; ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ haloalkyl; optionally two substituents on the same carbon atom of L taken together represent C ３ ~C ６ Form a carbocyclic ring or a 3- to 8-membered heterocyclic ring, ３ ~C ６ Carbocyclic rings and 3- to 8-membered heterocyclic rings are preferably substituted with halogen, —OH, —NO ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ optionally substituted with one or more substituents selected from haloalkyl; Each R ４ is C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; ３～１２ Carbocycles and 3- to 12-membered heterocycles include halogen, —OH, —CN, —NO ２ , -NH ２ , -NH(C １～６ Alkyl), -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ each optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle; Each R ５ is hydrogen or C １ ~C ６ independently selected from alkyl; Each R ６ is halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, oxo, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, =CH ２ , = NO-C １ ~C ３ Alkyl, C １ ~C ３ Aminoalkyl, -N(R ５ ) S (O) ２ (R ５ ), -Q-phenyl, -Q-phenylSO ２ F, -NHC(O)phenyl, -NHC(O)phenylSO ２ F.C. １ ~C ３ Alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxy CH ２ -, -N(R ５ ) ２ , (C １ ~C ３ Alkoxy)C １ ~C ３ Alkyl-, (C １ ~C ３ alkyl)C(=O), oxo, (C １ ~C ３ haloalkyl)C(=O)-, -SO ２ F, (C １ ~C ３ Alkoxy)C １ ~C ３ Alkoxy, -CH ２ O.C. (O) N (R ５ ) ２ , -CH ２ NHC(O)OC １ ~C ６ Alkyl, -CH ２ NHC(O)N(R ５ ) ２ , -CH ２ NHC(O)C １ ~C ６ Alkyl, -CH ２ (pyrazolyl), -CH ２ N.H.S.O. ２ C １ ~C ６ Alkyl, -CH ２ OC(O)heterocycle, -OC(O)N(R ５ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl), -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl(C １ ~C ３ Alkyl)N(CH ３ ) ２ , -OC(O)NH(C １ ~C ３ Alkyl)O(C １ ~C ３ alkyl)phenyl, -OC(O)heterocycle, -OC １ ~C ３ Alkyl, and -CH ２ heterocycle, independently selected from -NHC(O)phenyl and -OC(O)NH(C １ ~C ３ Alkyl) (C １ ~C ３ The phenyl of the alkyl)phenyl is optionally substituted with one or more substituents selected from -C(O)H and OH, and -O-C １ ~C ３ The alkyl of the alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; ２ The heterocycle of the heterocyclyl is optionally substituted with oxo; Each R ７ is halogen, hydroxy, HC(=O)-, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C １ ~C ４ Haloalkyl, C １ ~C ４ Hydroxyalkyl, or -N(R ５ ) ２ are independently selected from; Each R ２０ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, =NH, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; Each R ２１ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～１２ independently selected from carbocycle, and 3- to 12-membered heterocycle; each Q is independently selected from a bond, S, and O; B is selected from heterocycles and carbocycles, said heterocycles and carbocycles being selected from halogen, cyano, hydroxy, ═O, —NO ２ , C １ ~C ４ Alkyl, C １～６ Aminoalkyl, -S-C １ ~C ３ Alkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Hydroxyalkynyl, C １ ~C ３ Cyanoalkyl, triazolyl, C １ ~C ３ Haloalkyl, —O—C １ ~C ３ Haloalkyl, -S-C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Hydroxyalkyl, -CH ２ C(=O)N(R ５ ) ２ , -C ３ ~C ４ Alkynyl (NR ５ ) ２ , -N(R ５ ) ２ , (C １ ~C ３ Alkoxy) HaloC １ ~C ３ Alkyl-, C １～６ Alkyl-N(R ２０ ) ２ , C ３ ~C １２ Optionally substituted with one or more substituents independently selected from carbocycle and 5- to 12-membered heterocycle; ３ ~C １２ Carbocycles and 5- to 12-membered heterocycles are not limited to halogen, —OH, —NO ２ , -NH ２ ,=O,=S,-CN,C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ haloalkyl, each optionally substituted with one or more substituents selected from, B forms a spiro ring with ring A; Ring A is selected from heterocycles and carbocycles, and said heterocycles or carbocycles are selected from R ４ and optionally substituted with one or more substituents selected from:

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

193. B is an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C ８ ~C １５ 193. The compound or salt of claim 192, wherein said ring is selected from fused carbocycles.

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

195. B is an optionally substituted unsaturated C ８ ~C １５ 194. The compound or salt of claim 193 which is a fused carbocyclic ring.

196. For B, the optionally substituted 8- to 15-membered fused heterocycle and the optionally substituted C ８ ~C １５ 196. The compound or salt of any one of claims 191 to 195, wherein the fused carbocycles are each independently bicyclic or tricyclic.

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

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

199. B, 【Chemistry 541】 200. The compound or salt of any one of claims 191-198, selected from:

200. B, 【Chemical Formula 542】 200. The compound or salt of claim 199, wherein each of said compounds is optionally substituted with one or more substituents.

201. B, 【Chemistry 543】 201. The compound or salt of claim 200, selected from:

202. For B, the one or more optional substituents of the heterocyclic or carbocyclic ring are oxo, -NH ２ , halogen, C １ ~C ３ 202. The compound or salt of any one of claims 191 to 201, wherein:

203. B, 【Chemical 544】 203. The compound or salt according to any one of claims 191 to 202, selected from:

204. Each R ４ But, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ 204. The compound or salt of any one of claims 191 to 203, independently selected from alkynyl, oxo, hydroxyl, halogen.

205. Each R ４ But, C １～６ 205. The compound or salt of claim 204, independently selected from alkyl, oxo, and halogen.

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

207. R １ is selected from optionally substituted 5- to 5-membered heterocycles.

208. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , =O, -CN, C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 208. The compound or salt of claim 207, optionally substituted with one or more substituents independently selected from haloalkyl.

209. R １ is selected from a 5- to 12-membered heterocycle, and the 5- to 12-membered heterocycle is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C １～６ 209. The compound or salt of claim 208, optionally substituted with one or more substituents independently selected from haloalkyl.

210. R ２０ is hydrogen and C １～３ 210. The compound or salt of claims 208-209, wherein the aryl group is selected from alkyl.

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

212. R １ 211. The compound or salt of any one of claims 191 to 210, wherein the 5- to 12-membered heterocycle is saturated.

213. R １ 211. The compound or salt of any one of claims 191 to 210, wherein said 5-12 membered heterocycle of is bridged.

214. R １ but, 【Chemistry 545】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, =O, -CN, C １～６ Hydroxyalkyl, and C １～６ 211. The compound or salt of any one of claims 195-210, optionally substituted with one or more substituents independently selected from haloalkyl.

215. R １ but, 【Chemical 546】 each of which is selected from halogen, —OH, —N(R ２０ ) ２ , -NO ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, =O, -CN, C １～６ Hydroxyalkyl, and C １～６ 215. The compound or salt of claim 214, optionally substituted with one or more substituents independently selected from haloalkyl.

216. R １ but, 【Chemical Formula 547】 216. The compound or salt of claim 215, selected from:

217. R ２ is one or more R ６ 217. The compound or salt of any one of claims 191 to 216, which is -L-heterocycle optionally substituted with:

218. L is C １ ~C ４ 218. The compound or salt of any one of claims 191 to 217, selected from alkylene.

219. L is unsubstituted C １ ~C ４ 219. The compound or salt of claim 217 or 218, selected from alkylene.

220. Y-R ２ but, 【Chemistry 548】 and the heterocyclic moiety is selected from one or more R ６ 210. The compound or salt of any one of claims 181 to 209, optionally substituted with:

221. R ２ R ６ Each occurrence of halogen, hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, and C １ ~C ３ 221. The compound or salt of claim 220, independently selected from aminoalkyl.

222. R ２ R ６ However, in each occurrence, C １ ~C ３ 222. The compound or salt of claim 221, wherein is independently selected from alkyl and halogen.

223. Y-R ２ but, 【Chemical 549】 223. The compound or salt of claim 222, selected from:

224. Formula (II ＊ ) compound: 【Chemistry 550】 or a pharma- ceutically acceptable salt thereof [In the formula, M is O and NR ３ Selected from: R ３ is hydrogen, C １～６ Alkyl, and C １～６ cyanoalkyl; R １ is selected from a 7- to 10-membered heterocycle, the 7- to 10-membered heterocycle being selected from halogen, —B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ alkynyl, and a 5- to 12-membered heterocycle, wherein the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from one or more R １＊ independently and optionally substituted with; Each R １＊ is halogen, -B(OR ２０ ) ２ , -OR ２０ , -SR ２０ , -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -NR ２０ S (O) ２ R ２０ , -C(O)N(R ２０ ) ２ , -C(O)NR ２０ OR ２０ , -N(R ２０ ) C(O)R ２０ , -N(R ２０ ) C(O)N(R ２０ ) ２ , -N(R ２０ ) C(O)OR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ) ２ , -NO ２ , =O, =N(R ２０ ), = NO (R ２０ ), -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, and C ３ ~C １２ independently selected from carbocycle; B is C ６ ~C １５ carbocyclic ring, ６ ~C １５ The carbocycle is halogen, C １ ~C ３ Alkyl, -B(OR ２０ ) ２ , -OR ２０ , -C(O)N(R ２０ ) ２ , -N(R ２０ ) ２ , =O, -CN, -NHCN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, and C ２～６ Optionally substituted with one or more substituents independently selected from alkynyl; R ２ is selected from -L-heterocycle, the heterocycle of which is selected from one or more R ６ where appropriate replaced by; L is C １ ~C ４ alkylene; １ ~C ４ Alkylene is hydroxy, C １ ~C ４ Hydroxyalkyl, C １ ~C ４ alkyl; optionally, two substituents on the same carbon atom of L together represent C ３ ~C ６ forming a carbocyclic ring; Each R ２０ is hydrogen; and each of them is a halogen, —OH, —CN, —NO ２ , -NH ２ , -N(C １～６ Alkyl) ２ , C １～１０ Alkyl, -C １～１０ Haloalkyl, —O—C １～１０ Alkyl, oxo, =NH, C ３～１２ C optionally substituted with one or more substituents independently selected from carbocycle, and 3- to 12-membered heterocycle. １～６ Alkyl, C ３～６ carbocycle, and 3- to 6-membered heterocycle.

225. R １ is selected from optionally substituted 7- to 10-membered spiro heterocycles and optionally substituted 7- to 10-membered fused heterocycles.

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

227. R １ wherein said at least one nitrogen atom of said heterocycle is represented by formula (II ＊ 227. The compound or salt of claim 226, wherein the compound or salt binds to

228. R １ is selected from optionally substituted 10-membered spiro heterocycles and optionally substituted 10-membered fused heterocycles.

229. R １ wherein the optional one or more substituents are halogen, —OH, —S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)OR ２０ , -C(O)NHOR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -NO ２ , =O, -CN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Alkoxyalkyl, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ alkynyl, 5- to 12-membered heterocycle, said 5- to 12-membered heterocycle being independently selected from halogen, and C １～６ 229. The compound or salt of any one of claims 225 to 228, optionally substituted with one or more substituents selected from alkyl.

230. R １ wherein the optional one or more substituents are halogen, —OH, —S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)OR ２０ , -C(O)NHOR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -NO ２ , =O, -CN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Alkoxyalkyl, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ alkyl, 5- to 12-membered heterocycle, said 5- to 12-membered heterocycle being independently selected from halogen, and C １～６ 230. The compound or salt of any one of claims 225 to 229, optionally substituted with one or more substituents selected from alkyl.

231. R １ but, 【Chemistry 551】 231. The compound or salt of any one of claims 225 to 230, which is substituted and selected from:

232. R １ is halogen, -OH, -S(O) ２ (R ２０ ), -S(O) ２ N (R ２０ ) ２ , -S(O)N(R ２０ ) ２ , -S(O)R ２０ (=NR ２０ ), -C(O)N(R ２０ ) ２ , -C(=NR ２０ ) N (R ２０ ) ２ , -C(O)OR ２０ , -C(O)NHOR ２０ , -N(R ２０ ) ２ , -C(O)R ２０ , -NO ２ , =O, -CN, C １～６ Alkyl-N(R ２０ ) ２ , C １～６ Aminoalkyl, C １～６ Alkoxy, C １～６ Alkoxyalkyl, C １～６ Hydroxyalkyl, C １～６ Cyanoalkyl, C １～６ Haloalkyl, C １～６ Alkyl, C ２～６ alkynyl, 5- to 12-membered heterocycle; 【Chemistry 552】 wherein the 5- to 12-membered heterocycle is selected from halogen, and C １～６ 232. The compound or salt of any one of claims 225-231, optionally substituted with one or more substituents selected from alkyl.

233. R １ but, 【Chemistry 553】 232. The compound or salt of any one of claims 225 to 231, selected from:

234. R １ but, 【Chemical 554】 【Chemistry 555】 233. The compound or salt of any one of claims 225 to 232, selected from:

235. R １ but, 【Chemistry 556】 229. The compound or salt of claim 228,

236. 225. The compound or salt of claim 224, wherein M is selected from O.

237. M is NCH ３ and N.C.H. ２ CH ３ 225. The compound or salt of claim 224, selected from:

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

239. R ２ 239. The compound or salt of any one of claims 224 to 238, wherein the heterocycle is a saturated heterocycle.

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

241. R ２ R ６ In each occurrence, halogen, =CH ２ , Hydroxy, C １ ~C ３ Hydroxyalkyl, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, cyano, and C １ ~C ３ 241. The compound or salt of claim 240, independently selected from aminoalkyl.

242. R ２ The L in the letter C １ ~C ４ Alkylene and 【Chemistry 557】 242. The compound or salt of claim 241, selected from:

243. R ２ but, 【Chemistry 558】 243. The compound or salt of any one of claims 224 to 242, selected from:

244. B is optionally substituted C ９ ~C １０ 244. The compound or salt of any one of claims 224 to 243, wherein said compound or salt is selected from fused carbocycles.

245. B, 【Chemical Formula 559】 245. The compound or salt of any one of claims 224-244, selected from:

246. B is halogen, oxo, -NH ２ , C １ ~C ３ Alkyl, -B(OH) ２ , —OH, —O—C １ ~C ３ Haloalkyl, —C(O)NH ２ , -NH ２ , =O, -CN, C １～６ Alkoxy, C １～６ Hydroxyalkyl, and C ２～６ 246. The compound or salt of any one of claims 224-245, optionally substituted with one or more substituents independently selected from alkynyl.

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

248. B, 【Chemistry 560】 247. The compound or salt of claim 246, selected from:

249. B, 【Chemistry 561】 249. The compound or salt of claim 248,

250. B, 【Chemistry 562】 249. The compound or salt of claim 248,

251. 225. The compound or salt of claim 224, wherein B is unsubstituted.

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

253. 253. A pharmaceutical composition comprising a compound or salt according to any one of claims 1 to 252, and a pharma- ceutically acceptable excipient.

254. A method for treating a disease or disorder, using a compound or salt according to any one of claims 1 to 252, or a pharmaceutical composition according to claim 253.

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

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

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

258. Use of a compound according to any one of claims 1 to 252 in the preparation of a compound for degrading a target protein by using chemical modification of the compound according to any one of claims 1 to 253.

259. A bifunctional compound composed of a target protein binding portion and an E3 ubiquitin ligase binding portion, wherein said target protein binding portion is derived from a compound according to any one of claims 1 to 252.

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