KRAS Modulators and Their Use

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 No. 63 / 308,424, filed Feb. 9, 2022; No. 63 / 368,584, filed Jul. 15, 2022; No. 63 / 373,302, filed Aug. 23, 2022; No. 63 / 378,843, filed Oct. 7, 2022; and No. 63 / 384,374, filed Nov. 18, 2022, the entire contents of each of which are incorporated herein by reference.

Background Art

[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): p. 1292-1292 e1). KRAS mutations drive approximately 25% of human cancers through the dysregulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (see, e.g., Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014. 25(3): p. 272-81). Ras has been recognized as a target in cancer for approximately 40 years, but Ras-driven cancers remain among the most difficult to treat due to their insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS, and HRAS, has the highest frequency of mutation among all oncogenes. All oncogenic Ras mutations drive a switch that accumulates in the 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): p. 818-831. Dataset Version 4). Activating mutations at codon 12 impair the ability of these small GTPases to perform their role of hydrolyzing GTP. This regulatory dysfunction is the basis for initiating and maintaining tumor progression.

[0003] Despite great efforts, small molecules that block effector binding or restore GTPase-activating protein (GAP) sensitivity have not been identified, 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 most common KRAS G12C mutation 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 less likely to achieve similar results for G12D, despite the presence of a similar binding pocket in the GDP state. In addition, the cysteine present at the site of the activating mutation is exploited for covalent chemistry, whereas aspartic acid does not provide a typical medicinal chemistry approach for selective covalent modification.

[0004] To achieve selective inhibition of cancer cells by potentially exploiting the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability while preserving normal Ras function, selectively binding to the GTP state and stabilizing a conformation that is incompetent for oncogenic signaling interactions with effector proteins is attractive for small molecule inhibitors. Furthermore, it has been shown that only the constitutive activation of Raf, MEK, and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras protein in proliferative signaling (see, for example, Drosten, M., et al., Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival. EMBO J, 2010. 29(6): p. 1091-104). Since 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 lead-out for potential clinical benefits of new 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 more active GTP-bound state over the inactive GDP-bound state.

Prior Art Documents

Non-Patent Documents

[0005]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Means for Solving the Problems

[0006] The present disclosure relates to a compound of formula (I) or formula (II) or formula (III), including its stereoisomers, tautomers, solvates, and pharmaceutically acceptable salts, and its use, for example, in the inhibition of KRas G12D and / or other G12 mutants.

[0007] In one aspect, the present disclosure provides a compound represented by the structure of formula (I):

Chemical Formula

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

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

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

[0011] In one aspect, the present disclosure provides a compound represented by the structure of formula (II):

Chemical formula

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

[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 additive.

[0014] In certain embodiments, the present disclosure provides a method of 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 of inhibiting KRas G12D and / or other G12 mutants using a compound or salt of formula (II) and a pharmaceutically acceptable additive.

[0015] In one aspect, the present disclosure provides a compound represented by the structure of formula (III):

Chemical formula

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

[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 additive.

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

[0019] All publications, patents, and patent applications cited herein are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

[0020] DETAILED DESCRIPTION OF THE INVENTION The following description sets forth numerous exemplary 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 rather is provided as an alternative to a description of exemplary embodiments.

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

[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 hereby incorporated by reference into this specification.

[0023] "Alkyl" refers to a straight-chain or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms and containing no unsaturation, preferably having from 1 to 15 carbon atoms (i.e., C1-C 15(alkyl). In certain embodiments, alkyl contains from 1 to 13 carbon atoms (i.e., C1-C 13 (alkyl). In certain embodiments, alkyl contains from 1 to 8 carbon atoms (i.e., C1-C8 alkyl). In other embodiments, alkyl contains from 1 to 5 carbon atoms (i.e., C1-C5 alkyl). In other embodiments, alkyl contains from 1 to 4 carbon atoms (i.e., C1-C4 alkyl). In other embodiments, alkyl contains from 1 to 3 carbon atoms (i.e., C1-C3 alkyl). In other embodiments, alkyl contains from 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 from 5 to 15 carbon atoms (i.e., C5-C 15 (alkyl). In other embodiments, alkyl contains from 5 to 8 carbon atoms (i.e., C5-C8 alkyl). In other embodiments, alkyl contains from 2 to 5 carbon atoms (i.e., C2-C5 alkyl). In other embodiments, alkyl contains from 3 to 5 carbon atoms (i.e., C3-C5 alkyl). In certain embodiments, the 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), 1-pentyl (n-pentyl). Alkyl is attached to the remainder of the molecule by a single bond.

[0024] "C x~y " When used in conjunction with a chemical moiety such as alkyl, alkenyl, or alkynyl, the term means a group containing x to y carbons in the chain. For example, "C 1~6 alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group containing from 1 to 6 carbons, including linear or branched alkyl groups. -C x~y alkylene- refers to a substituted or unsubstituted alkylene chain having x to y carbons in the alkylene chain. For example, -C 1~6Alkylene- can be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, and any one of them may be optionally substituted.

[0025] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl (wherein alkyl is an alkyl chain as defined above).

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

[0027] "Alkynyl" refers to a linear or branched hydrocarbon chain radical group consisting only of carbon atoms and hydrogen atoms and containing at least one carbon-carbon triple bond, preferably having 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 and is, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc.

[0028] "C x~y"Alkenyl" and "C" x~y The terms "alkenyl" and "alkynyl" each refer to a substituted or unsubstituted unsaturated aliphatic group analog having at least one double bond or triple bond, respectively, but of the length and possible substitutions relative to the alkyl described above.-C x~y The term "-alkenylene-" refers to a substituted or unsubstituted alkenylene chain having x to y carbons in the alkenylene chain. For example, -C 2~6 -alkenylene- can be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. The alkenylene chain can 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 carbons 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 two or more triple bonds in the alkynylene chain.

[0029] "Alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing no unsaturation, and connecting the remainder of the molecule to a radical group. Preferably, it has 1 to 12 carbon atoms, for example, methylene, ethylene, propylene, n-butylene, etc. The alkylene chain attaches to the remainder of the molecule through a single bond and to the radical group through a single bond. The attachment points to the remainder of the molecule and the radical group of the alkylene chain 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-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon double bond, and connecting the remainder of the molecule to a radical group. Preferably, it has 2 to 12 carbon atoms. The alkenylene chain attaches to the remainder of the molecule through a single bond and to the radical group through a single bond. The attachment points to the remainder of the molecule and the radical group of the alkenylene chain can be through any two carbons within the chain. In certain embodiments, alkenylene contains 2 to 10 carbon atoms (i.e., C2-C 10(alkenylene). 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-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, containing at least one carbon-carbon triple bond, and connecting the remainder of the molecule to a radical group, preferably having 2 to 12 carbon atoms. The alkynylene chain attaches to the remainder of the molecule and to the radical group through single bonds. The attachment points to the remainder of the molecule and to the radical group of the alkynylene chain can be through any two carbons within the chain. In certain embodiments, alkynylene contains 2 to 10 carbon atoms (i.e., C2-C 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 polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon, contains 5 to 18 carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic delocalized (4n + 2)π electron system in accordance with Hückel's rule. Examples of ring systems from which an aryl group is derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene.

[0033] "Aralkyl" has the formula -R c -aryl (wherein R c is an alkylene chain as defined above, for example, methylene, ethylene, etc.).

[0034] "Aralkenyl" has the formula -R d -aryl (wherein R d is an alkenylene chain as defined above). "Aralkynyl" has the formula -R e -aryl (wherein R e is an alkynylene chain as defined above).

[0035] "Carbon ring" refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon. The carbon ring may include a 3- to 10-membered monocyclic ring, a 6- to 12-membered bicyclic ring, and a 6- to 12-membered bridged ring. Each ring of the bicyclic carbon ring may be selected from saturated, unsaturated, and aromatic rings. An aromatic ring, for example, phenyl, may be fused to a saturated or unsaturated ring, for example, cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings is included in the definition of a carbon ring when the valency permits. Exemplary carbon rings include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. The bicyclic carbon ring may be a fused, bridged or spiro ring system. In some cases, the spiro carbon ring has at least two molecular rings having only one common atom.

[0036] The term "unsaturated carbon ring" refers to a carbon ring having at least one degree of unsaturation, excluding aromatic carbon rings. Examples of unsaturated carbon rings include cyclohexadiene, cyclohexene, and cyclopentene.

[0037] "Cycloalkyl" refers to a completely saturated monocyclic or polycyclic hydrocarbon radical consisting of only carbon and hydrogen atoms, which includes fused or bridged ring systems and preferably has 3 to 12 carbon atoms. In certain embodiments, cycloalkyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkyl contains 5 to 7 carbon atoms. Cycloalkyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkyl include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of 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 only of carbon and hydrogen atoms, which preferably has 3 to 12 carbon atoms and contains at least one double bond and includes a fused or bridged ring system. In certain embodiments, cycloalkenyl contains 3 to 10 carbon atoms. In other embodiments, cycloalkenyl contains 5 to 7 carbon atoms. Cycloalkenyl may be attached to the remainder of the molecule by a single bond. Examples of monocyclic cycloalkenyl include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0039] "Cycloalkylalkyl" has the formula -R c -cycloalkyl (wherein R c is the alkylene chain described above).

[0040] "Cycloalkylalkoxy" has the formula -O-R c -cycloalkyl (wherein R c is the alkylene chain described above) and refers to a radical bonded through an oxygen atom.

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

[0042] As used herein, the terms "haloalkyl" or "haloalkane" refer to an alkyl radical as defined above substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl portion of the fluoroalkyl radical is further substituted as necessary. 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, for example, 1-chloro,2-fluoroethane.

[0043] "Fluoroalkyl" refers to an alkyl radical as defined above 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 substituted by one or more amine radicals, for example, propane-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine, and the like.

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

[0046] "Alkoxyalkyl" refers to an alkyl radical as defined above which is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, etc.

[0047] "Cyanoalkyl", as used herein, refers to an alkyl radical as defined above which is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3-methylsuccinonitrile, butyronitrile, etc.

[0048] "Heterocyclic ring", as used herein, refers to a saturated, unsaturated or aromatic ring containing one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocyclic ring may be attached to the remainder of the molecule through any atom of the heterocyclic ring, such as a carbon atom or a nitrogen atom of the heterocyclic ring, provided that the valence is acceptable. The heterocyclic ring includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. The bicyclic heterocyclic ring includes any combination of saturated, unsaturated and aromatic bicyclic rings when the valence is acceptable. In an exemplary embodiment, an aromatic ring, such as pyridyl, may be condensed with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. Exemplary bicyclic heterocyclic rings 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. The bicyclic heterocyclic ring may be a fused, bridged or spiro ring system. The spiro ring system may be referred to as "spiroheterocycle", "spiro heterocycle", or "spiro-heterocycle". In some cases, spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings having only one common atom. The spiro-heterocycle, spiro heterocycle, or spiroheterocycle contains one or more heteroatoms.

[0049] "Heterocylene" refers to a divalent heterocyclic ring that links the remainder of the molecule to a radical group.

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

[0051] "X-membered heteroaryl" refers to the number of intra-ring atoms in the ring, i.e., X. For example, a 5-membered heteroaryl ring or a 5-membered aromatic heterocycle has 5 intra-ring atoms, such as triazole, oxazole, thiophene, etc.

[0052] The term "unsaturated heterocycle" refers to a heterocycle having at least 1 degree of unsaturation, excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. The heterocycle may be optionally substituted by one or more substituents, e.g., the substituents described herein.

[0053] The term "substituted" refers to a moiety having a substituent that replaces one or more carbons or replaceable heteroatoms of a structure, such as hydrogen on NH. It is understood that the terms "substituted" or "substituted with" include the implied proviso that such substitution follows the allowed valences of the atoms and substituents being substituted and that the substitution results in a stable compound, i.e., a compound that does not spontaneously undergo transformations such as rearrangements, cyclizations, eliminations, etc. In certain embodiments, substituted refers to a moiety having a substituent that replaces two hydrogen atoms on the same carbon atom, e.g., replacing two hydrogen atoms on a single carbon with an oxo group, an imino group, or a thioxo group. As used herein, the term "substituted" is intended to include all allowed substituents of an organic compound. In a broad aspect, allowed substituents include substituents of acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. Allowed substituents can be one or more and can be the same or different for a suitable organic compound. For the purposes of this disclosure, a heteroatom such as nitrogen may have a hydrogen substituent and / or any allowed substituent of the organic compounds described herein that satisfies the valence of the heteroatom.

[0054] In some embodiments, the substituent is any substituent described herein, such as: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=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 -O-R c -C(O)N(R a )2, -R b -N(R a )C(O)OR a , -R b -N(R a )C(O)R a , -R b -N(R a )S(O) t R a (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), and -R b -S(O) t N(R a )2 (where t is 1 or 2); and may include alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, and heterocyclic ring, any of which may be alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), 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 -O-R 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 (where t is 1 or 2), -R b -S(O) t R a (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2) may be optionally substituted; each R a is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each R a is, when valence permits, alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(=O), thioxo(=S), cyano(-CN), nitro(-NO2), imino(=N-H), 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 -O-Rc -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) may be optionally substituted; each R b is independently selected from a direct bond, or a linear or branched alkylene, alkenylene or alkynylene chain, and each R c is a linear or branched alkylene, alkenylene or alkynylene chain.

[0055] As used herein, the term "electrophile" or "electrophilic moiety" refers to any moiety that can react with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, such as a -SH group). An electrophile is typically electron-deficient or contains an electron-deficient atom. In certain embodiments, the electrophile contains a positive charge or a partial positive charge, has a resonance structure containing a positive charge or a partial positive charge, or is a moiety where delocalization or polarization of electrons results in one or more atoms containing a positive charge or a partial positive charge. In some embodiments, the electrophile includes a conjugated double bond, e.g., an α,β-unsaturated carbonyl compound or an α,β-unsaturated thiocarbonyl compound.

[0056] As used herein, the terms "optionally" or "optionally" mean that the events of the situations described thereafter may or may not occur, and that the description includes examples where the event or situation occurs and examples where 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 the 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 well-known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of 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, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic bases and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Examples of 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 can be mentioned. In some embodiments, the pharmaceutically acceptable base addition salts are selected from salts of ammonium, potassium, sodium, calcium, and magnesium.

[0059] As used herein, the phrases "parenteral administration" and "administered parenterally" mean a mode of administration other than enteral and topical administration, usually by injection, including, but not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subdural, intraspinal, and intrasternal injection and infusion.

[0060] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that have a reasonable benefit / risk ratio.

[0061] As used herein, the terms "pharmaceutically acceptable additive" or "pharmaceutically acceptable carrier" mean a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) tragacanth powder; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and 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) buffering agents, 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 solutions; 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, can refer to a compound that reduces the occurrence of a disorder or condition in a treated sample compared to an untreated control sample, or delays the onset of one or more symptoms of a disorder or condition compared to an untreated control sample, or reduces its severity, in a statistical sample.

[0063] The terms "treat," "treating," or "treatment," as used herein, can include reducing, alleviating, or ameliorating 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., stopping the occurrence of the disease or condition, alleviating the disease or condition, causing regression of the disease or condition, alleviating the condition caused by the disease or condition, or prophylactically and / or therapeutically stopping the symptoms of the disease or condition.

[0064] The term "G12 mutant," as used herein, refers to other oncogenic alleles of KRAS at amino acid position 12 (i.e., G12X). The compounds of the present disclosure

[0065] The following is a discussion of compounds and salts thereof that can 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):

Chemical formula

[0067] In some embodiments, formula (I) is represented by formula (II), formula (II * ), or formula (III).

[0068] In some embodiments, for the compound or salt of formula (I), ring A is selected from heterocycles, and the heterocycle is optionally substituted with one or more substituents selected from R 4 and is optionally substituted with one or more substituents selected from R. In some cases, ring A contains at least one heteroatom selected from nitrogen, sulfur, and oxygen. In some cases, the heteroatom of ring A is nitrogen, and the nitrogen is optionally substituted with R 3 and 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 carbocycle, and 3- to 12-membered heterocycle, and the C 3~12 carbocycle and 3- to 12-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo, C 3~12 carbocycle, and 3- to 12-membered heterocycle. In some cases, the heteroatom of ring A is sulfur, and the sulfur is optionally substituted with one or two oxygen atoms. In some cases, the heteroatom of ring A is oxygen.

[0069] In some embodiments, for the compound or salt of formula (I), ring A is selected from carbocycles, and the carbocycle is optionally substituted with one or more substituents selected from R 4 and is optionally substituted with one or more substituents selected from R.

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

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

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

[0073] In some embodiments, for a compound or salt of formula (I), R 2 is selected from L-bicyclic heterocycles, and the bicyclic heterocycles are optionally substituted with one or more R 6 .

[0074] In some embodiments, for a compound or salt of formula (I), R 2 is selected from L-pyrrolidine, and the pyrrolidine is optionally substituted with one or more R 6 .

[0075] In some embodiments, for the compound or salt of formula (I), each L is independently selected from optionally substituted C1-C4 alkylene; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring, and the C3-C6 carbocyclic ring is 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. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocyclic ring; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocyclic ring or a 3-8 membered heterocyclic ring, and the C3-C6 carbocyclic ring and the 3-8 membered heterocyclic ring are halogen and C 1~6 optionally substituted with one or more substituents selected from haloalkyl.

[0076] In some embodiments, for the 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 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.

[0077] In some embodiments, for the 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, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L together form a C3 carbocyclic ring. In some cases, each L is

Chemical formula

[0078] In some embodiments, for the compound or salt of formula (I), R 2 is selected from -L-heterocyclic ring, and the heterocyclic ring moiety of -L-heterocyclic ring is optionally substituted with one or more R 6 . In some cases, the heterocyclic ring is a saturated heterocyclic ring. In some cases, the heterocyclic ring has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocyclic ring has at least one nitrogen atom. In some cases, the heterocyclic ring has at least one sulfur atom.

[0079] In some embodiments, for the compound or salt of formula (I), R 2 is

Chemical formula

[0080] In some embodiments, for the compound or salt of formula (I), Y-R 2 is

Chemical formula

[0081] In some embodiments, for the compound or salt of formula (I), Y-R 2 is

Chemical formula

[0082] In some embodiments, for the compound or salt of formula (I), Y-R 2 is

Chemical formula

[0083] In some embodiments, for the compound or salt of formula (I), R 2 is selected from -L-saturated heterocycles, and the saturated heterocyclic moiety of the -L-saturated heterocycle is optionally substituted with one or more R 6 and contains one nitrogen atom and one sulfur atom. In some cases, Y-R 2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0084] In some embodiments, for the 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, independently selected, and the phenyl of -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 of -CH2heterocyclyl is optionally substituted with oxo.

[0085] In some embodiments, for the compound or salt of formula (I), each R 6 is 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 the compound or salt of formula (I), each R 6 is independently selected from 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 cases, each R 6 is independently selected from -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 independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2.

[0087] In some embodiments, for the 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. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is 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 the compound or salt of formula (I), R 2 is

Chemical formula

[0089] In some embodiments, for the compound or salt of formula (I), Y-R2 is selected from [Chem.] .

[0090] In some embodiments, for the compound or salt of formula (I), Y-R 2 is selected from [Chem.] .

[0091] In some embodiments, for the compound or salt of formula (I), Y-R 2 is [Chem.] .

[0092] In some embodiments, for the compound or salt of formula (I), Y-R 2 is selected from [Chem.] .

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

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

[0095] In some embodiments, for the compound or salt of formula (I), with respect to B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocyclic rings are each bicyclic or tricyclic. In some cases, with respect to B, the optionally substituted 8- to 15-membered fused heterocycles are each bicyclic or tricyclic. In some cases, with respect to B, the optionally substituted 8- to 15-membered fused heterocycle or the optionally substituted C8-C 15 The fused carbocyclic rings are each bicyclic or tricyclic.

[0096] In some embodiments, for the compound or salt of formula (I), the heterocyclic or carbocyclic ring of B is each independently bicyclic. In some cases, the heterocyclic ring is bicyclic. In some cases, the carbocyclic ring is bicyclic.

[0097] In some embodiments, for the compound or salt of formula (I), the heterocyclic or carbocyclic ring of B is each independently tricyclic. In some cases, the heterocyclic ring is tricyclic. In some cases, the carbocyclic ring is tricyclic.

[0098] In some embodiments, for the compound or salt of formula (I), the optionally substituted 8- to 15-membered fused heterocycle or the optionally substituted C8-C 15 fused carbocyclic ring of B is

Chemical formula

[0099] In some embodiments, for the compound or salt of formula (I), with respect to B, the optionally substituted 8- to 15-membered fused heterocycle or the optionally substituted C8-C 15 fused carbocyclic ring of B is

Chemical formula

[0100] In some embodiments, for the compound or salt of formula (I), for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 The fused carbocycle is

Chemical formula

[0101] In some embodiments, for the compound or salt of formula (I), for B, one or more optional substituents of the heterocycle and the carbocycle are, in 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 alkynyl, independently selected. In some cases, one or more optional substituents of the heterocycle and the carbocycle are, in each occurrence, halogen, oxo, -NH2, C1-C3 alkyl, -B(OR 20 )2, -OH, -C(O)N(R 20 )2, =O, -CN, C 1~6 alkoxy, and C 2~6 alkynyl, independently selected. In some cases, one or more optional substituents of the heterocycle and the carbocycle are, in each occurrence, halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, and C 2~6It is independently selected from alkynyl. In some cases, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are each independently selected from oxo, -NH2, -CN, halogen, C1-C3 alkyl. In some cases, one or more optional substituents of the heterocyclic ring or the carbocyclic ring are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

[0102] In some embodiments, for the compound or salt of formula (I), B is

Chemical formula

[0103] In some embodiments, for the compound or salt of formula (I), for B, one or more optional substituents of the heterocyclic ring or the carbocyclic ring are independently selected from oxo, -NH2, CN, halogen, C1-C3 alkyl.

[0104] In some embodiments, for the compound or salt of formula (I), B is

Chemical formula

[0105] In some embodiments, for the compound or salt of formula (I), each R 4 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, oxo, hydroxyl, halogen, independently selected. In some cases, each R 4 is C 1~6 alkyl, oxo, and halogen, independently selected.

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

[0107] In some embodiments, for the compound or salt of formula (I), Y is O.

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

[0109] In some embodiments, for the compound or salt of formula (I), R 1 is selected from C3-C 12 carbocycles and 5- to 12-membered heterocycles, each of which is independently selected from one or more substituents selected from 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 , 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 alkynyl, and is optionally substituted with one or more substituents independently selected therefrom.

[0110] In some embodiments, for the compound or salt of formula (I), R 1 is C3-C 12Selected from a carbon ring and a 5- to 12-membered heterocyclic ring, each of which is 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 alkynyl, and is optionally substituted with one or more substituents independently selected therefrom.

[0111] In some embodiments, for the compound or salt of formula (I), R 1 is selected from a C3-C 12 carbon ring and a 5- to 12-membered heterocyclic ring, each of which is -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 )2, and is optionally substituted with one or more substituents independently selected therefrom.

[0112] In some embodiments, for the compound or salt of formula (I), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 )2, -NO2, =O, -CN, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl.

[0113] In some embodiments, for the compound or salt of formula (I), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl.

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

[0115] In some embodiments, for the compound or salt of formula (I), the 5- to 12-membered heterocycle of R 1 is an unsaturated heterocycle.

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

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

[0118] In some embodiments, for the compound or salt of formula (I), R 1 is

Chemical formula

[0119] In some embodiments, for the compound or salt of formula (I), R 1 is

Chemical formula

[0120] In some embodiments, for the compound or salt of formula (I), R 1 is

Chemical formula

[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 the compound or salt of formula (I), R 2 is an -L-heterocycle optionally substituted with 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 the compound or salt of formula (I), Y-R 2 is

Chemical formula

[0125] In some embodiments, for the compound or salt of formula (I), each occurrence of R 2 of R 6 is independently selected 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 the compound or salt of formula (I), each occurrence of R 2 of R 6 is independently selected from C1-C3 alkyl and halogen.

[0127] In some embodiments, for the compound or salt of formula (I), Y-R 2 is

Chemical formula

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

[0129] The compound of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof [wherein, M is selected from O, S, SO, SO2, and NR 3 ; R 1 is selected from C3-C 12 carbocyclic rings and 5- to 15-membered heterocyclic rings, each of which 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(=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 - 12 - membered heterocycles, C3 - C 12 the carbocycles and 5 - 12 - membered heterocycles are each independently optionally substituted with one or more R 1* ; M is NR 3 ; Y is O; when R 1 is piperazine, piperazine is substituted with one or more R 9 ; 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 carbocycles; Y is a bond, O, S, and NR 5 Selected from; R 2 Is -L-N(R 21 )2, -L-OR 21 , Heterocycle, C1 - C6 alkyl, -L-heterocycle, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(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 ), -L-S(O)2N(R 21 )2, -L-N(R 21 )C(O)(OR 21 ), -L-OC(O)N(R 21 )2, and -LC(=O)OC1 - C6 alkyl, and the aryl moiety of -L-NR 21 C(O)-aryl, the heterocyclic moiety of -L-heterocycle, and the cycloalkyl moiety of -L-cycloalkyl are each optionally substituted with one or more R 6 , and the aryl moiety of -L-aryl and the heteroaryl moiety of -L-heteroaryl are each optionally substituted with one or more R 7 , When Y is a bond, O, or S, R 2 Is further selected from hydrogen; Each L is independently selected from hydroxy, C1 - C4 hydroxyalkyl, C1 - C4 alkyl, C3 - C6 carbocycle, or C1 - C4 alkylene optionally substituted with one or more substituents selected from 3 - 8 membered heterocycles, and the C3 - C6 carbocycle and 3 - 8 membered heterocycle are 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 are taken together to form a C3-C6 carbocyclic ring or a 3- to 8-membered heterocyclic ring, and the C3-C6 carbocyclic ring and the 3- to 8-membered heterocyclic ring are 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, respectively; 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, C 3~12 The carbocyclic ring and the 3- to 12-membered heterocyclic ring are halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 Alkyl)2, C 1~10 Alkyl, -C 1~10 Haloalkyl, -O-C 1~10 Alkyl, oxo, C 3~12 Optionally substituted with one or more substituents independently selected from carbocyclic rings and 3- to 12-membered heterocyclic rings, respectively; 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 Selected independently from carbocyclic rings and 3- to 12-membered heterocyclic rings, C1-C6 alkyl, C 3~12The carbon ring and 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from cyano, halogen, -OR 5 , and -N(R 5 )2; Each R 5 is 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 -CH2 heterocycle, independently selected, wherein the phenyl of -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; the alkyl of -O-C1-C3 alkyl is optionally substituted with a substituent selected from heterocycle, oxo, and hydroxy; the heterocycle of -CH2 heterocyclyl is optionally substituted with oxo; Each Q is independently selected from a bond, S, and O; Each R 7 is independently selected from halogen, hydroxy, HC(=O)-, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2; Each R 9 is independently selected from 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 haloalkyl; Each R 20 is hydrogen; and each of them is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo, =NH, C 3~12 alkyl optionally substituted with one or more substituents independently selected from carbocyclic ring and 3- to 12-membered heterocyclic ring, C 1~6 alkyl, C 3~12 carbocyclic ring, and 3- to 12-membered heterocyclic ring; Each R 21 is hydrogen; and each of them is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo, C 3~12 alkyl optionally substituted with one or more substituents independently selected from carbocyclic ring and 3- to 12-membered heterocyclic ring, C 1~6 alkyl, C 3~12 carbocyclic ring, and 3- to 12-membered heterocyclic ring; B is selected from heterocyclic ring and carbocyclic ring, and the heterocyclic ring and carbocyclic ring are 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 a carbon ring and a 5- to 12-membered heterocyclic ring, C3-C 12 The carbon ring and the 5- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents selected from 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].

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

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

[0132] In some embodiments, for the compound or salt of formula (II), each R 21 is hydrogen; each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, and oxo, and is optionally substituted with C 1~6 alkyl, C 3~12 a carbon ring, and a 3- to 12-membered heterocyclic ring. In some cases, each R 21 is hydrogen; C 1~6 alkyl, C 3~12It is independently selected from a carbon ring and a 3- to 12-membered heterocyclic ring. In some cases, each R 21 is independently selected from hydrogen and C 1~6 alkyl.

[0133] In some embodiments, for the compound or salt of formula (II), R 3 is selected from 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- to 15-membered heterocyclic ring or an optionally substituted C3-C 15 carbon ring. In some cases, B is an optionally substituted 5- to 15-membered heterocyclic ring. In some cases, B is an optionally substituted C3-C 15 carbon ring. In some cases, B is an optionally substituted 8- to 15-membered heterocyclic ring. In some cases, B is an optionally substituted C8-C 15 carbon ring.

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

[0137] In some embodiments, for the compound or salt of formula (II), for B, an optionally substituted 8- to 15-membered fused heterocyclic ring or an optionally substituted C8-C 15The condensed carbon rings are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered condensed heterocyclic ring is each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered condensed heterocyclic ring or the optionally substituted C8-C 15 The condensed carbon rings are each 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), the heterocyclic ring or carbon ring of B is each independently bicyclic. In some cases, the heterocyclic ring is bicyclic. In some cases, the carbon ring is bicyclic.

[0140] In some embodiments, for the compound or salt of formula (II), the heterocyclic ring or carbon ring of B is each independently tricyclic. In some cases, the heterocyclic ring is tricyclic. In some cases, the carbon ring is tricyclic.

[0141] In some embodiments, for the compound or salt of formula (II), the optionally substituted 8- to 15-membered condensed heterocyclic ring or the optionally substituted C8-C of B 15 The condensed carbon ring is

Chemical formula

[0142] In some embodiments, for the compound or salt of formula (II), for B, an optionally substituted 8- to 15-membered fused heterocyclic ring or an optionally substituted C8-C 15 The fused carbocyclic ring is

Chemical formula

[0143] In some embodiments, for the compound or salt of formula (II), for B, an optionally substituted 8- to 15-membered fused heterocyclic ring or an optionally substituted C8-C 15 The fused carbocyclic ring is

Chemical formula

[0144] In some embodiments, for the compound or salt of formula (II), for B, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are, in 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 alkynyl, independently selected. In some cases, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are, in each occurrence, halogen, oxo, -NH2, C1-C3 alkyl, -B(OR 20 )2, -OH, -C(O)N(R 20 )2, =O, -CN, C 1~6 alkoxy, and C 2~6It is independently selected from alkynyl. In some cases, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are, in each occurrence, halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, and C 2~6 It is independently selected from alkynyl. In some cases, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are independently selected from oxo, -NH2, -CN, halogen, C1-C3 alkyl in each occurrence. In some cases, one or more optional substituents of the heterocyclic ring or the carbocyclic ring are independently selected from oxo, -NH2, halogen, C1-C3 alkyl.

[0145] In some embodiments, for the compound or salt of formula (II), B is

Chemical formula

[0146] In some embodiments, for the compound or salt of formula (II), B is

Chemical formula

[0147] In some embodiments, for the compound or salt of formula (II), each R 4 is C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, oxo, hydroxyl, halogen independently selected from. In some cases, each R 4 is C 1~6 alkyl, oxo, and halogen independently selected from.

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

[0149] In some embodiments, for the compound or salt of formula (II), Y is O.

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

[0151] In some embodiments, for the compound or salt of formula (II), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 )2, -NO2, =O, -CN, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl.

[0152] In some embodiments, for the compound or salt of formula (II), R 1 is selected from C3-C 12 carbocycles and 5- to 12-membered heterocycles, each of which 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 , -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 Alkynyl, and is optionally substituted with one or more substituents independently selected from

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

[0154] In some embodiments, for the compound or salt of formula (II), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycle is independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl, and is optionally substituted with one or more substituents

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

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

[0157] In some embodiments, for the compound or salt of formula (II), R 1 's 5- to 12-membered heterocyclic ring is a saturated heterocyclic ring.

[0158] In some embodiments, for the compound or salt of formula (II), R 1 's 5- to 12-membered heterocyclic ring is a bridged heterocyclic ring.

[0159] In some embodiments, for the compound or salt of formula (II), R 1 is

Chemical formula

Chemical formula

[0160] In some embodiments, for the compound or salt of formula (II), R 1 is

Chemical formula

[0161] In some embodiments, for the compound or salt of formula (II), R 1 is selected from a saturated 6- to 7-membered heterocyclic ring optionally substituted. In some cases, R 1 is selected from a saturated 6-membered heterocyclic ring optionally substituted. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0162] In some embodiments, for the compound or salt of formula (II), R 1is selected from substituted saturated 6-membered heterocycles, the saturated 6-membered heterocycle having at least one -NHCN and, optionally, one or more C 1~6 alkyl substituents; 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 carbocycle, each of which is independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 2~6 alkynyl; Y is O; R 2 is selected from -L-heterocycles, the heterocyclic moiety being optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2; L is selected from C1-C4 alkylene. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0163] In some embodiments, for the 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, independently selected. In some cases, 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, independently selected. In some cases, 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 ) independently selected. In some cases, each R 9 is halogen, and -N(R 20 )2, independently selected.

[0164] In some embodiments, for the compound or salt of formula (II), each L is independently selected from optionally substituted C1-C4 alkylene; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle, and the C3-C6 carbocycle is 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. In some cases, the optional substituents of L are selected from C1-C4 hydroxyalkyl, C1-C4 alkyl, C3-C6 carbocycle; optionally, two substituents on the same carbon atom of L together form a C3-C6 carbocycle or a 3- to 8-membered heterocycle, and the C3-C6 carbocycle and the 3- to 8-membered heterocycle are halogen and C 1~6 optionally substituted with one or more substituents selected from haloalkyl.

[0165] In some embodiments, for the 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 carbocycle. In some cases, the C3-C6 carbocycle is 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.

[0166] In some embodiments, for the 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 carbocycle. In some cases, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L together form a C3 carbocycle. In some cases, each L is [Chemical formula] is independently selected from

[0167] In some embodiments, for the compound or salt of formula (II), R 2 is selected from -L-heterocycles, and the heterocyclic moiety of the -L-heterocycle is optionally substituted with 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 the compound or salt of formula (II), R 2 is [Chemical formula] selected from, and the heterocyclic moiety is optionally substituted with one or more R 6 .

[0169] In some embodiments, for the compound or salt of formula (II), Y-R 2 is [Chemical formula] selected from, and the heterocyclic moiety is optionally substituted with one or more R 6 .

[0170] In some embodiments, for the compound or salt of formula (II), Y-R 2 is [Chemical formula] selected from, and the heterocyclic moiety is optionally substituted with one or more R 6 .

[0171] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chem.

[0172] In some embodiments, for the compound or salt of formula (II), R 2 is selected from -L-saturated heterocycles, and the saturated heterocyclic moiety of the -L-saturated heterocycle is optionally substituted with one or more R 6 as required and contains one nitrogen atom and one sulfur atom. In some cases, Y-R 2 is

Chem.

Chem.

Chem.

Chem.

[0173] In some embodiments, for the compound or salt of formula (II), each R 6is selected independently from 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 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 -CH2 heterocycle, and the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl is optionally substituted with -C(O)H and OH, and the heterocycle of -CH2 heterocyclyl is optionally substituted with oxo.

[0174] 6 In some embodiments, for the compound or salt of formula (II), each R

[0175] In some embodiments, for the compound or salt of formula (II), each R 6is independently selected from 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 cases, each R 6 is independently selected from -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 independently selected from C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2.

[0176] In some embodiments, for the 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. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is 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 the compound or salt of formula (II), R 2 is

Chemical formula

[0178] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chemical formula

[0179] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chemical formula

[0180] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chemical formula

[0181] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chemical formula

[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 the compound or salt of formula (II), R 2 is a -L-heterocyclic ring optionally substituted with 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 the compound or salt of formula (II), R 2 is selected from L-bicyclic heterocycles, and the bicyclic heterocycle is optionally substituted with one or more R6 is optionally substituted as needed.

[0186] In some embodiments, for the compound or salt of formula (II), R 2 is selected from L-pyrrolidine, and the pyrrolidine is optionally substituted with one or more R 6 as needed.

[0187] In some embodiments, for the compound or salt of formula (II), Y-R 2 is

Chemical formula

[0188] In some embodiments, for the compound or salt of formula (II), R 2 of 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. In some cases, R 2 of R 6 is independently selected, at each occurrence, from C1-C3 alkyl and halogen. In some cases, Y-R 2 is

Chemical formula

[0189] In some embodiments, for the compound or salt of formula (II), M is selected from NR 3 In some cases, M is selected from NH and NMe. In some cases, M is selected from NMe and NCH2CH3. In some cases, M is NMe. In some cases, M is C 1~6is selected from cyanoalkyl. In some cases, M is selected from C2 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 haloalkyl. In some cases, R 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 haloalkyl. In some cases, R 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 haloalkyl. In some cases, R 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 1~6is selected from haloalkyl. In some cases, R 3 is 1~6 alkyl-N(R 20 )2, 1~6 aminoalkyl, 1~6 alkoxy, 1~6 hydroxyalkyl, 1~6 cyanoalkyl, 1~6 alkoxyalkyl, and 1~6 haloalkyl. In some cases, R 3 is 1~6 cyanoalkyl, 1~6 alkoxyalkyl, and 1~6 haloalkyl. In some cases, R 3 is hydrogen, 1~6 alkyl, 1~6 alkyl-N(R 20 )2, 1~6 aminoalkyl, 1~6 alkoxy, 1~6 hydroxyalkyl, 1~6 cyanoalkyl, and 1~6 haloalkyl. In some cases, R 3 is 1~6 alkoxyalkyl, 1~6 cyanoalkyl, and 1~6 alkyl. In some cases, R 3 is

Chemical formula

[0190] In some embodiments, for the compound or salt of formula (II), M is NR 3 and B is

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0191] or a pharmaceutically acceptable salt thereof

Chemical formula

[0192] In some embodiments, for the compound or salt of formula (III), R 1 is C3-C 12 is selected from a carbocyclic ring and a 5- to 12-membered heterocyclic ring, each of which is 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 alkynyl, and is optionally substituted with one or more substituents independently selected therefrom.

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

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

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

[0196] In some embodiments, for the compound or salt of formula (III), R 2 is selected from L-bicyclic heterocycles, and the bicyclic heterocycle is optionally substituted with one or more R 6 .

[0197] In some embodiments, for the compound or salt of formula (III), R 2 is selected from L-pyrrolidine, and the pyrrolidine is optionally substituted with one or more R 6 .

[0198] In some embodiments, for the compound or salt of formula (III), B is an optionally substituted 5- to 15-membered heterocyclic ring or an optionally substituted C3-C 15 carbocyclic ring. In some cases, B is an optionally substituted 5- to 15-membered heterocyclic ring. In some cases, B is an optionally substituted 8- to 15-membered heterocyclic ring. In some cases, B is an optionally substituted C3-C 15 carbocyclic ring. In some cases, B is an optionally substituted C8-C 15 carbocyclic ring.

[0199] In some embodiments, for the compound or salt of formula (III), B is an optionally substituted 8- to 15-membered fused heterocyclic ring or an optionally substituted C8-C 15 fused carbocyclic ring. In some cases, B is an optionally substituted 8- to 15-membered fused heterocyclic ring. In some cases, B is an optionally substituted C8-C 15 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), for B, the optionally substituted 8- to 15-membered fused heterocyclic ring or the optionally substituted C8-C 15The fused carbon rings are each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic ring is each bicyclic or tricyclic. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocyclic ring or the optionally substituted C8-C 15 The fused carbon rings are each bicyclic or tricyclic.

[0202] In some embodiments, for the compound or salt of formula (III), the heterocyclic ring or carbon ring of B is each independently bicyclic. In some cases, the heterocyclic ring is bicyclic. In some cases, the carbon ring is bicyclic.

[0203] In some embodiments, for the compound or salt of formula (III), the heterocyclic ring or carbon ring of B is each independently tricyclic. In some cases, the heterocyclic ring is tricyclic. In some cases, the carbon ring is tricyclic.

[0204] In some embodiments, for the compound or salt of formula (III), the optionally substituted 8- to 15-membered fused heterocyclic ring or the optionally substituted C8-C of B 15 The fused carbon ring is

Chemical formula

[0205] In some embodiments, for the compound or salt of formula (III), for B, the optionally substituted 8- to 15-membered fused heterocyclic ring or the optionally substituted C8-C 15 The fused carbon ring is

Chemical formula

[0206] In some embodiments, for the compound or salt of formula (III), for B, an optionally substituted 8- to 15-membered fused heterocycle or an optionally substituted C8-C 15 fused carbocycle is [Chemical formula] selected from, each of which is optionally substituted with one or more substituents.

[0207] In some embodiments, for the compound or salt of formula (III), for B, one or more optional substituents of the heterocycle and the carbocycle are, in 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 alkynyl, independently selected. In some cases, one or more optional substituents of the heterocycle and the carbocycle are, in each occurrence, halogen, oxo, -NH2, C1-C3 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 alkynyl, independently selected. In some cases, one or more optional substituents of the heterocycle and the carbocycle are, in each occurrence, halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 2~6It is independently selected from alkynyl. In some cases, one or more optional substituents of the heterocyclic ring and the carbocyclic ring are independently selected from oxo, -NH2, -CN, halogen, and C1-C3 alkyl at each occurrence. In some cases, one or more optional substituents of the heterocyclic ring or the carbocyclic ring are independently selected from oxo, -NH2, halogen, and C1-C3 alkyl.

[0208] In some embodiments, for the compound or salt of formula (III), B is

Chemical formula

[0209] In some embodiments, for the compound or salt of formula (III), for B, one or more optional substituents of the heterocyclic ring or the carbocyclic ring are independently selected from oxo, -NH2, halogen, and C1-C3 alkyl.

[0210] In some embodiments, for the compound or salt of formula (III), B is

Chemical formula

[0211] In some embodiments, for the compound or salt of formula (III), each R 4 is independently selected from C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, oxo, hydroxyl, and halogen. In some cases, each R 4 is independently selected from C 1~6 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 cases, n is 0.

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

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

[0215] In some embodiments, for the compound or salt of formula (III), R 1 is selected from C3-C 12 carbocycles and 5- to 12-membered heterocycles, each of which is independently selected from one or more substituents selected from 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 , 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 alkynyl.

[0216] In some embodiments, for the compound or salt of formula (III), R 1 is C3-C12 Selected from a carbon ring and a 5- to 12-membered heterocyclic ring, each of which 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 , 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 alkynyl, and is optionally substituted with one or more substituents independently selected therefrom.

[0217] In some embodiments, for the compound or salt of formula (III), R 1 is selected from a C3-C 12 carbon ring and a 5- to 12-membered heterocyclic ring, each of which is -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 )2, and is optionally substituted with one or more substituents independently selected therefrom.

[0218] In some embodiments, for the compound or salt of formula (III), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 )2, -NO2, =O, -CN, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl.

[0219] In some embodiments, for the compound or salt of formula (III), R 1 is selected from 5- to 12-membered heterocycles, and the 5- to 12-membered heterocycles are optionally substituted with one or more substituents independently selected from halogen, -OH, -N(R 20 )2, -NO2, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 haloalkyl.

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

[0221] In some embodiments, for the compound or salt of formula (III), R 1 of the 5- to 12-membered heterocycle is an unsaturated heterocycle.

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

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

[0224] In some embodiments, for the compound or salt of formula (III), R 1 is

Chemical formula

[0225] In some embodiments, for the compound or salt of formula (III), R 1 is

Chemical formula

[0226] In some embodiments, for the compound or salt of formula (III), R 1 is

Chemical formula

[0227] In some embodiments, for the compound or salt of formula (III), R 1 is selected from a saturated 6- to 7-membered heterocyclic ring optionally substituted. In some cases, R 1 is selected from a saturated 6-membered heterocyclic ring optionally substituted. In some cases, R 1 is [Chemistry] selected from, which is optionally substituted. In some cases, one or more optional substituents are halogen, -CN, -NHCN, C 1~6 cyanoalkyl, and C 1~6 alkyl, independently selected. In some cases, one or more optional substituents are -CN, -NHCN, C 1~6 cyanoalkyl, and C 1~6 alkyl, independently selected. In some cases, one or more optional substituents are -CN, -NHCN, C 1~6 cyanoalkyl, and C 1~6 alkyl, independently selected. In some cases, one or more optional substituents are -NHCN, and C 1~6 alkyl, independently selected. In some cases, R 1 is [Chemistry] selected from, which is substituted with one or more substituents selected from -NHCN, and C 1~6 alkyl. In some cases, R 1 is [Chemistry] selected from.

[0228] In some embodiments, for the compound or salt of formula (III), R 1 is selected from a substituted saturated 6-membered heterocycle, the saturated 6-membered heterocycle being substituted with at least one -NHCN, and optionally, one or more C 1~6 alkyl; M is O; n is 0; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 fused carbocycle, each of which is halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, C1~6 Hydroxyalkyl, and C 2~6 Optionally substituted with one or more substituents independently selected from alkynyl; Y is O; R 2 Is selected from -L-bicyclic heterocycles, and the bicyclic heterocyclic moiety is halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 Optionally substituted with one or more substituents independently selected from; L is selected from C1-C4 alkylene. In some cases, R 1 Is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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

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

[0231] In some embodiments, for the 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 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.

[0232] In some embodiments, for the 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, each L is independently selected from substituted C3 alkylene, and two substituents on the same carbon atom of L together form a C3 carbocyclic ring. In some cases, each L is

Chemical formula

[0233] In some embodiments, for the compound or salt of formula (III), R 2 is selected from -L-heterocyclic ring, and the heterocyclic ring moiety of the -L-heterocyclic ring is one or more R 6is replaced as necessary. In some cases, the heterocyclic ring is a saturated heterocyclic ring. In some cases, the heterocyclic ring has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocyclic ring has at least one nitrogen atom. In some cases, the heterocyclic ring has at least one sulfur atom.

[0234] In some embodiments, for the compound or salt of formula (III), R 2 is

Chemical formula

[0235] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0236] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0237] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

Chemical formula

[0238] In some embodiments, for the compound or salt of formula (III), R 2 is selected from -L-saturated heterocycles, and the saturated heterocyclic moiety of the -L-saturated heterocycle is optionally substituted with one or more R 6 and contains one nitrogen atom and one sulfur atom. In some cases, Y-R 2 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0239] In some embodiments, for the 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, independently selected from -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(C1-C3 alkyl)phenyl, the phenyl of which is optionally substituted with -C(O)H and OH respectively, and the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0240] In some embodiments, for the compound or salt of formula (III), each R 6 is 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 the compound or salt of formula (III), each R 6 is independently selected from 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 cases, each R 6 is -OH, C1-C3 hydroxyalkyl, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 alkoxy, and -N(R5 ) is independently selected from 2. In some cases, each R 6 is C1-C3 alkyl, C1-C3 alkoxy, and -N(R 5 )2 is independently selected from.

[0242] In some embodiments, for the 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. In some cases, R 6 is selected from halogen and C1-C3 alkyl. In some cases, R 6 is 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 the compound or salt of formula (III), R 2 is

Chemical formula

[0244] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0245] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0246] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[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 the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0249] In some embodiments, for the compound or salt of formula (III), each occurrence of R 2 of R 6 is independently selected 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 the compound or salt of formula (III), each occurrence of R 2 of R 6 is independently selected from C1-C3 alkyl and halogen.

[0251] In some embodiments, for the compound or salt of formula (III), Y-R 2 is

Chemical formula

[0252] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 's carbocyclic ring is C3 - C 12 carbocyclic ring, C3 - C 10 carbocyclic ring, C3 - C9 carbocyclic ring, C3 - C8 carbocyclic ring, or C3 - C6 carbocyclic ring. In some cases, R 1 's carbocyclic ring is C3 - C 12 carbocyclic ring, C4 - C 12 carbocyclic ring, C5 - C 12 carbocyclic ring, C6 - C 12 carbocyclic ring, C7 - C 12 carbocyclic ring, C8 - C 12 carbocyclic ring, or C9 - C 12 carbocyclic ring.

[0253] In some embodiments, for the compound of formula (I), the heterocyclic ring of R 1 is a 5 - to 12 - membered heterocyclic ring, 6 - to 12 - membered heterocyclic ring, 7 - to 12 - membered heterocyclic ring, or 8 - to 12 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is a 5 - to 11 - membered heterocyclic ring, 5 - to 10 - membered heterocyclic ring, 5 - to 9 - membered heterocyclic ring, or 5 - to 8 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is a 6 - to 11 - membered heterocyclic ring, 6 - to 10 - membered heterocyclic ring, 6 - to 9 - membered heterocyclic ring, or 6 - to 8 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is a 7 - to 11 - membered heterocyclic ring, 7 - to 10 - membered heterocyclic ring, 7 - to 9 - membered heterocyclic ring, or 7 - to 8 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is a 5 - to 6 - membered heterocyclic ring or 5 - to 9 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is an 8 - to 9 - membered heterocyclic ring. In some cases, the heterocyclic ring of R 1 is saturated. The heterocyclic ring may be optionally substituted as described elsewhere in this specification.

[0254] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), the heterocyclic ring of R 1 is a 5 - to 12 - membered monocyclic heterocyclic ring, 6 - to 12 - membered monocyclic heterocyclic ring, 7 - to 12 - membered monocyclic heterocyclic ring, or 8 - to 12 - membered monocyclic heterocyclic ring. In some cases, the heterocyclic ring of R 1The heterocyclic ring is a 5- to 11-membered monocyclic heterocyclic ring, a 5- to 10-membered monocyclic heterocyclic ring, a 5- to 9-membered monocyclic heterocyclic ring, or a 5- to 8-membered monocyclic heterocyclic ring. In some cases, R 1 The heterocyclic ring is a 6- to 11-membered monocyclic heterocyclic ring, a 6- to 10-membered monocyclic heterocyclic ring, a 6- to 9-membered monocyclic heterocyclic ring, or a 6- to 8-membered monocyclic heterocyclic ring. In some cases, R 1 The heterocyclic ring is a monocyclic 7- to 11-membered heterocyclic ring, a 7- to 10-membered monocyclic heterocyclic ring, a 7- to 9-membered monocyclic heterocyclic ring, or a 7- to 8-membered monocyclic heterocyclic ring. In some cases, R 1 The heterocyclic ring is a 5- to 6-membered monocyclic heterocyclic ring or a 5- to 9-membered monocyclic heterocyclic ring. In some cases, R 1 The heterocyclic ring is an 8- to 9-membered monocyclic heterocyclic ring. In some cases, R 1 The heterocyclic ring is saturated. The monocyclic heterocyclic ring may be optionally substituted as described elsewhere in this specification.

[0255] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 The heterocyclic ring is a 5- to 12-membered bridged heterocyclic ring, a 6- to 12-membered bridged heterocyclic ring, a 7- to 12-membered bridged heterocyclic ring, or an 8- to 12-membered bridged heterocyclic ring. In some cases, R 1 The heterocyclic ring is a 5- to 11-membered bridged heterocyclic ring, a 5- to 10-membered bridged heterocyclic ring, a 5- to 9-membered bridged heterocyclic ring, or a 5- to 8-membered bridged heterocyclic ring. In some cases, R 1 The heterocyclic ring is a 6- to 11-membered bridged heterocyclic ring, a 6- to 10-membered bridged heterocyclic ring, a 6- to 9-membered bridged heterocyclic ring, or a 6- to 8-membered bridged heterocyclic ring. In some cases, R 1 The heterocyclic ring is a bridged 7- to 11-membered heterocyclic ring, a 7- to 10-membered bridged heterocyclic ring, a 7- to 9-membered bridged heterocyclic ring, or a 7- to 8-membered bridged heterocyclic ring. In some cases, R 1 The heterocyclic ring is a 5- to 6-membered bridged heterocyclic ring or a 5- to 9-membered bridged heterocyclic ring. In some cases, R 1 The heterocyclic ring is an 8- to 9-membered bridged heterocyclic ring. In some embodiments, R 1 The heterocyclic ring is saturated. The bridged heterocyclic ring may be optionally substituted as described elsewhere in this specification.

[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 heterocyclic ring, and the 5- to 9-membered heterocyclic ring contains at most one nitrogen atom. In some embodiments, R 1 is selected from 5- to 9-membered heterocyclic rings optionally substituted, 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 's heterocyclic ring contains at most one nitrogen atom. In some embodiments, R 1 's heterocyclic ring contains at most one heteroatom. In some embodiments, R 1 's heterocyclic ring contains at most two heteroatoms. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the heterocyclic ring is a monocyclic heterocyclic ring or a bridged heterocyclic ring. In some cases, the heterocyclic ring is a monocyclic heterocyclic ring. In some cases, the heterocyclic ring is a bridged heterocyclic ring. In some cases, the heterocyclic ring is

Chemical formula

Chemical formula

Chemical formula

[0258] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 's spiro heterocyclic ring contains at most one nitrogen atom. In some embodiments, R 1 's spiro heterocyclic ring contains at most two heteroatoms. In some embodiments, R 1The spiro heterocyclic ring contains up to 3 heteroatoms. In some embodiments, R 1 's spiro heterocyclic ring contains up to 1 heteroatom. In some cases, R 1 's spiro heterocyclic ring contains at least 2 heteroatoms. In some cases, R 1 's spiro heterocyclic ring contains at least 3 heteroatoms. In some cases, R 1 's spiro heterocyclic ring contains at least 4 heteroatoms. In some cases, R 1 's spiro heterocyclic ring contains at least 2 nitrogen atoms. In some embodiments, R 1 's spiro heterocyclic ring contains up to 1 heteroatom. In some cases, R 1 's spiro heterocyclic ring contains up to 1 sulfur atom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some embodiments, R 1 's spiro heterocyclic ring is

Chemical formula

Chemical formula

[0259] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from optionally substituted 7- to 8-membered spiro heterocyclic rings. In some cases, R 1 is selected from optionally substituted 7-membered spiro heterocyclic rings. In some cases, R 1 is selected from optionally substituted 8-membered spiro heterocyclic rings.

[0260] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1The fused heterocyclic ring is a 6- to 12-membered fused heterocyclic ring, a 6- to 12-membered fused heterocyclic ring, a 7- to 12-membered fused heterocyclic ring, or an 8- to 12-membered fused heterocyclic ring. In some cases, R 1 The fused heterocyclic ring is a 6- to 11-membered fused heterocyclic ring, a 6- to 10-membered fused heterocyclic ring, a 6- to 9-membered fused heterocyclic ring, or a 6- to 8-membered fused heterocyclic ring. In some cases, R 1 The fused heterocyclic ring is a 7- to 11-membered fused heterocyclic ring, a 7- to 10-membered fused heterocyclic ring, a 7- to 9-membered fused heterocyclic ring, or a 7- to 8-membered fused heterocyclic ring. In some cases, R 1 The fused heterocyclic ring is an 8- to 11-membered fused heterocyclic ring. In some cases, R 1 The fused heterocyclic ring is a 6-membered fused heterocyclic ring. The fused heterocyclic ring may be optionally substituted as described elsewhere in this specification.

[0261] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 The fused heterocyclic ring is selected from 6-, 9-, 10-, 11-, and 12-membered fused heterocyclic rings. In some cases, R 1 The fused heterocyclic ring is selected from 9- to 12-membered fused heterocyclic rings. In some cases, R 1 The fused heterocyclic ring is selected from 10- to 12-membered fused heterocyclic rings. The fused heterocyclic ring is optionally substituted with one or more substituents independently 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 alkyl. The fused heterocyclic ring is optionally substituted with one or more substituents independently selected from 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.

[0262] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 's fused heterocyclic ring contains at most one nitrogen atom. In some embodiments, R 1 's fused heterocyclic ring contains at most one heteroatom. In some cases, the heteroatom is selected from nitrogen, oxygen, and sulfur. In some cases, the fused heterocyclic ring is

Chemical formula

[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 carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 7- to 8-membered spiro heterocyclic ring, and 6-, 9-, 10-, 11-, and 12-membered fused heterocyclic rings, each of which is optionally substituted.

[0264] In some embodiments, for a compound of formula (I), R 1 is selected from a C6-C7 carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 7- to 8-membered spiro heterocyclic ring, and 6-, 8- to 12-membered fused heterocyclic rings, each of which is optionally substituted with one or more substituents independently 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 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 carbocyclic ring, a 5- to 10-membered heterocyclic ring, a 7- to 8-membered spiro heterocyclic ring, and 6-, 8- to 12-membered fused heterocyclic rings, each of which is optionally substituted with one or more substituents independently 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 is 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 for -OR 20 and -N(R 20 )2, R 20 is selected from 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 carbocyclic ring and a 5- to 10-membered heterocyclic ring, each of which is optionally substituted. In some cases, the heterocyclic ring contains at most one nitrogen atom. In some cases, R 1 is selected from a C6-C7 carbocyclic ring, each of which is optionally substituted.

[0268] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), one or more optional substituents of R 1 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, independently selected.

[0269] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R1 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, independently selected. In some cases, one or more optional substituents of R 1 are -OR 20 , -N(R 20 )2, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 1~6 alkyl, independently selected. In some cases, one or more optional substituents of R1 are -OR 20 , -N(R 20 )2, C 1~6 aminoalkyl, and C 1~6 hydroxyalkyl, independently selected. In some cases, one or more optional substituents of R1 are -OR 20 , -N(R 20 )2, C 1~6 aminoalkyl, C 1~6 alkyl, and C 1~6 hydroxyalkyl, independently selected. In some cases, one or more optional substituents of R 1 are -OR 20 , -N(R 20 )2, and C 1~6 alkyl, independently selected. In some cases, one or more optional substituents of R 1 are independently selected from -N(R 20 )C(O)N(R 20 )2.

[0270] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 is C3-C 12Selected from a carbon ring and a 5- to 12-membered heterocyclic ring, the 5- to 12-membered heterocyclic ring contains at most 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-, 11-membered spiro heterocyclic rings and 6-, 9-, 10-, 11- and 12-membered fused heterocyclic rings, C3-C 12 The carbon ring, 5- to 12-membered heterocyclic ring, 7-, 8-, 10-, 11-membered spiro heterocyclic ring, and 6-, 9-, 10-, 11-, and 12-membered fused heterocyclic ring are each optionally substituted with one or more substituents independently selected from 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 alkynyl.

[0271] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from a C3-C 12 carbon ring and a 5- to 12-membered heterocyclic ring, the 5- to 12-membered heterocyclic ring contains at most 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-, 11-membered spiro heterocyclic rings and 6-, 9-, 10-, 11-, and 12-membered fused heterocyclic rings, C3-C 12Carbon rings, 5- to 12-membered heterocycles, 7-, 8-, 10-, and 11-membered spiro heterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles are each optionally substituted with one or more substituents independently selected from 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 alkynyl, respectively.

[0272] 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, 7-, 8-, 10-, and 11-membered spiro heterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, each of which is 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 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 a 5- to 10-membered heterocycle, a 7-, 8-, 10-, 11-membered spiro heterocycle, and a 6-, 9-, 10-, 11-, and 12-membered fused heterocycle, each of which is 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. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0274] 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 heterocycles are -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, optionally substituted with one or more substituents independently selected therefrom. In some cases, R 1 is

Chemical formula

[0275] In some embodiments, for a compound of formula (I), formula (II), or formula (III), R 1is selected from [Chem.] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R

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

[0277] is selected from 1 [Chem.] , each of which is optionally substituted.

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

[0279] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] selected from.

[0280] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] selected from, each of which is optionally substituted.

[0281] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] selected from, each of which is optionally substituted.

[0282] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] selected from, each of which is optionally substituted.

[0283] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R1 is, [Chem.] and is optionally substituted.

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

[0285] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 is, [Chem.] [Chem.] selected from. In some cases, R 1 is, [Chem.] is. In some cases, R 1 is, [Chem.] is.

[0286] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), the 5- to 12-membered heterocyclic ring of R 1 is an unsaturated and bridged heterocyclic ring. In some cases, R 1 is selected from optionally substituted 7- to 8-membered unsaturated and bridged heterocyclic rings. In some cases, R 1 is, [Chem.] selected from

[0287] In some embodiments, for a compound of formula (I) or formula (II), R 1 is selected from 5- to 10-membered heterocycles, 7-, 8-, 10-, 11-membered spiro heterocycles, and 6-, 9-, 10-, 11-, and 12-membered fused heterocycles, each of which is independently selected from halogen, -N(R 20 )2, C 1~6 alkyl, -OR 20 , -N(R 20 )C(O)N(R 20 )2, -B(OR 20 )2, C 1~6 cyanoalkyl, -N(R 20 )C(O)N(R 20 )2, =O, C 1~6 hydroxyalkyl, halogen, -N(R 20 )C(O)R 20 , -N(R 20 )S(O)2(R 20 ), and C 1~6 aminoalkyl, and is optionally substituted with one or more substituents independently selected therefrom; R 3 is naphthalene, and naphthalene is optionally substituted with one or more substituents independently selected from halogen, -OH, -NH2, -NO2, =O, C 1~6 alkyl, C 2~6 alkynyl, C 1~6 aminoalkyl, C 1~6 hydroxyalkyl, and C 1~6 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, and the heterocyclic moiety is optionally substituted with one or more substituents independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2. In some cases, Y-R 2 is [Chemistry] selected from, and the heterocyclic moiety is optionally substituted.

[0288] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from optionally substituted 5- to 12-membered unsaturated heterocycles, and the heterocycle has at most one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at least one nitrogen atom. In some cases, the 5- to 12-membered unsaturated heterocycle has at most one nitrogen atom.

[0289] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from 6- to 7-membered heterocycles. In some cases, R 1 is selected from 7-membered heterocycles. In some cases, R 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 one or more additional heteroatoms, if any, are selected from sulfur. In some cases, the one or more additional heteroatoms, if any, 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 's 6- to 7-membered heterocycle is attached to formula (I) through only one nitrogen atom. In some cases, R 1 's 6- to 7-membered heterocycle is attached to formula (II) through only one nitrogen atom. In some cases, R 1 's 6- to 7-membered heterocycle is attached to formula (III) through only one nitrogen atom. In some cases, R 1 is [Chemistry] selected from, each of which is substituted. In some cases, R 1 is

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0290] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocyclic ring. In some cases, R 1 is selected from an optionally substituted unsaturated 6-membered heterocyclic ring. In some cases, R 1is selected from an optionally substituted unsaturated 7-membered heterocyclic ring. In some cases, the heterocyclic ring has one or two double bonds. In some cases, the heterocyclic ring has only one double bond. In some cases, the heterocyclic ring has only two double bonds. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0291] In some embodiments, for the compounds or salts of formula (I), formula (II) or formula (III), R 1 is selected from unsaturated 6- to 7-membered heterocycles, and the unsaturated 6- to 7-membered heterocycles are substituted with one or more substituents selected from halogens. In some cases, the unsaturated 6- to 7-membered heterocycles are substituted with at least one halogen. In some cases, the unsaturated 6- to 7-membered heterocycles are substituted with only one halogen. In some cases, the unsaturated 7-membered heterocycles are substituted with one fluorine. In some cases, R 1 is selected from unsaturated 6-membered heterocycles substituted with at least one halogen. In some cases, R 1 is selected from unsaturated 7-membered heterocycles substituted with at least one halogen. In some cases, R 1 is

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0292] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from an optionally substituted unsaturated 6- to 8-membered heterocyclic ring. In some cases, R 1 is selected from an optionally substituted unsaturated 7-membered heterocyclic ring. In some cases, R 1 is

Chem.

Chemical formula

[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, the 6-membered heterocycle of R 1 is attached to formula (I) via only one nitrogen atom. In some cases, the 6-membered heterocycle of R 1 is attached to formula (II) via only one nitrogen atom. In some cases, the 6-membered heterocycle of R 1 is attached to formula (III) via only one nitrogen atom. In some cases, R 1 is

Chemical formula

Chemical formula

[0294] In some embodiments, for a compound of formula (I), formula (II), or formula (III), R 1 is selected from an optionally substituted 6-membered unsaturated heterocycle and a 6-membered saturated heterocycle.

[0295] In some embodiments, for a compound or salt of formula (I), formula (II), or formula (III), R 1 is

Chemical formula

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

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

[0298] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] selected from, each being optionally substituted with two substituents independently selected from halogen, -OH, -NH2, -NO2, C 1~6 aminoalkyl, C 1~6 alkoxy, C 1~6 hydroxyalkyl, C 1~6 haloalkyl, and C 1~6 alkyl.

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

[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 cases, the 6- to 10-membered heterocycle contains at least one nitrogen atom. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0301] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1is selected from a 10-membered heterocyclic ring optionally substituted. In some cases, the 10-membered heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a spiro heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a fused heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a saturated heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the 10-membered heterocyclic ring contains at least 1 nitrogen atom. In some cases, the 10-membered heterocyclic ring contains at least 2 nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least 3 nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least 1 sulfur atom. In some cases, R 1 is

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

[0302] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1 is selected from an optionally substituted unsaturated 9- to 11-membered heterocyclic ring. In some cases, R 1 is selected from an optionally substituted unsaturated 10-membered heterocyclic ring. In some cases, R 1 is selected from an optionally substituted unsaturated 10-membered fused heterocyclic ring. In some cases, R 1 is

Chem.

Chemical formula

[0303] In some embodiments, for the compounds or salts of formula (I), formula (II) or formula (III), R 1 is selected from 7- to 11-membered spiro heterocycles. In some cases, R 1 is selected from 10-membered spiro heterocycles. In some cases, the spiro heterocycle has at least 3 nitrogen atoms. In some cases, the spiro heterocycle has at least 1 sulfur atom. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0304] In some embodiments, for a compound or salt of formula (I), formula (II) or formula (III), R 1is selected from 8- to 10-membered fused heterocyclic rings which are optionally substituted. In some cases, the 8- to 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is an unsaturated heterocyclic ring. In some cases, the 8- to 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, R 1 is selected from 9-membered fused heterocyclic rings which are optionally substituted. In some cases, R 1 is selected from 10-membered fused heterocyclic rings which are optionally substituted. In some cases, the 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 9-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the fused heterocyclic ring has one saturated ring and one aromatic ring. In some cases, the fused heterocyclic ring has one saturated ring and one unsaturated ring. In some cases, the fused heterocyclic ring has two saturated rings. In some cases, the 10-membered heterocyclic ring contains at least one nitrogen atom. In some cases, the 10-membered heterocyclic ring contains at least two nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least three nitrogen atoms. In some cases, the 9-membered heterocyclic ring contains at least one nitrogen atom. In some cases, the 9-membered heterocyclic ring contains at least two nitrogen atoms. In some cases, the 9-membered heterocyclic ring contains at least three nitrogen atoms. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

[0305] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0306] In some embodiments, for the compound or salt of formula (I), formula (II), formula (II * ), or formula (III), R 1 is substituted with -C(O)R 20 , and R 20 is selected from 5- to 12-membered heterocycles, which are optionally substituted. In some cases, R 1 is substituted with -C(O)R 20 . In some cases, R 20 is selected from unsubstituted 5- to 12-membered heterocycles. In some cases, R 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, the heterocycle of R 20 is

Chemical formula

Chemical formula

[0307] In some embodiments, for the compounds or salts of formula (I), formula (II), formula (II * ) or formula (III), each R 20 is hydrogen; and each of them is independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo, and =NH, and is optionally substituted with one or more substituents independently selected therefrom, and is optionally substituted with a C 1~6 alkyl, C 3~12 carbocycle, and a 3- to 12-membered heterocycle. In some cases, each R 20 is hydrogen; and is independently selected from unsubstituted C 1~6 alkyl, and a 3- to 12-membered heterocycle, which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo, and =NH.

[0308] In some embodiments, for the compounds or salts 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, the heterocycle of R 1 is tricyclic. In some cases, the heterocycle of R 1 contains a fused heterocycle. In some cases, the heterocycle of R 1 contains a spiro heterocycle. In some cases, R1 The complex ring of [compound] contains fused and spiro complex rings. In some cases, R 1 's complex ring is an unsaturated complex ring. In some cases, R 1 's complex ring is a non-aromatic complex ring. In some cases, R 1 's complex ring has at least one double bond. In some cases, R 1 's complex ring has at least two double bonds. In some cases, R 1 's complex ring has at least two heteroatoms. In some cases, R 1 's complex ring has at least three heteroatoms. In some cases, R 1 's complex ring has at least four heteroatoms. In some cases, R 1 's complex ring has at least five heteroatoms. In some cases, R 1 's complex ring has at least six heteroatoms. In some cases, R 1 's complex ring has at least seven heteroatoms. In some cases, the heteroatoms are selected from oxygen, nitrogen, and sulfur. In some cases, R 1 's complex ring has at least three, four, or five nitrogen atoms and at least one sulfur atom. In some cases, R 1 's complex ring has at least three, four, or five nitrogen atoms and at least one oxygen atom. In some cases, R 1 's complex ring has at least three, four, or five nitrogen atoms. In some cases, R 1 's complex ring has at least three, four, or five 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 is

Chemical Structure

Chemical Structure

Chemical formula

Chemical formula

Chemical formula

[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 heterocyclic ring. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0310] In some embodiments, for the compounds or salts of formula (I), formula (II) or formula (III), R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0311] In some embodiments, for the compounds or salts 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, Y-R 2 is

Chemical formula

Chemical formula

Chemical formula

[0312] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 2 is selected from -L-N(R 21 )2. In some cases, each R 21 is selected from hydrogen and C 1~6 alkyl. In some cases, each R 21 is C 1~6It is selected from alkyl. 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, and the C3-C6 carbocyclic ring is optionally substituted with one or more substituents selected from halogen. In some cases, L is

Chemical formula

Chemical formula

Chemical formula

[0313] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), each R 21 is independently selected from hydrogen. In some cases, each R 21 is independently selected from hydrogen and C 1~6 alkyl. In some cases, each R 21 is independently selected from C 1~6 alkyl. In some cases, each R 21 is hydrogen; and each of them is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C 1~6 alkyl)2, C 1~10 alkyl, -C 1~10 haloalkyl, -O-C 1~10 alkyl, oxo-substituted C 3~12 carbocyclic ring, and 3- to 12-membered heterocyclic ring.

[0314] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1is selected from an 8- to 10-membered fused heterocyclic ring optionally substituted. In some cases, the 8- to 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 8- to 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 8- to 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, R 1 is selected from a 9-membered fused heterocyclic ring optionally substituted. In some cases, R 1 is selected from a 10-membered fused heterocyclic ring optionally substituted. In some cases, the 10-membered fused heterocyclic ring is a bicyclic heterocyclic ring. In some cases, the 10-membered fused heterocyclic ring is a saturated heterocyclic ring. In some cases, the 10-membered heterocyclic ring is a non-aromatic heterocyclic ring. In some cases, the fused heterocyclic ring has one saturated ring and one aromatic ring. In some cases, the fused heterocyclic ring has one saturated ring and one unsaturated ring. In some cases, the fused heterocyclic ring has two saturated rings. In some cases, the 10-membered heterocyclic ring contains at least one nitrogen atom. In some cases, the 9-membered heterocyclic ring contains at least two nitrogen atoms. In some cases, the 9-membered heterocyclic ring contains at least three nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least two nitrogen atoms. In some cases, the 10-membered heterocyclic ring contains at least three nitrogen atoms. In some cases, R 1 is [Chemical formula] selected from, each of which is optionally substituted with one or more substituents. In some cases, R 1 is [Chemical formula] selected from, each of which is optionally substituted with one or more substituents. In some cases, R 1 is [Chemical formula] and which is optionally substituted with one or more substituents. In some cases, the one or more optional 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 alkyl, independently selected. In some cases, the one or more optional substituents are halogen, =O, -C(O)R 20 , -C(O)N(R 20 )2, and -C(O)NR 20 OR 20 , independently selected. In some cases, the one or more optional substituents are -C(O)R 20 , -C(O)N(R 20 )2, and -C(O)NR 20 OR 20 , independently selected. In some cases, the one or more optional substituents are -C(O)R 20 , independently selected. In some cases, the one or more optional substituents are -C(O)N(R 20 )2, independently selected. In some cases, the one or more optional substituents are -C(O)NR 20 OR 20 , independently selected. In some cases, each R 20 is hydrogen; and C 1~6 alkyl, C 3~12 carbocycle, and 3- to 12-membered heterocycle, independently selected. In some cases, each R 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered heterocycle, independently selected. In some cases, each R 20 is hydrogen; and C 1~6 alkyl, and 3- to 12-membered saturated heterocycle, independently selected. In some cases, R 1One or more substituents as needed are

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0315] In some embodiments, for the compound or salt of formula (I), R 1 is selected from a saturated 6- to 7-membered heterocyclic ring optionally substituted. In some cases, R 1 is selected from a saturated 6-membered heterocyclic ring optionally substituted. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

[0316] In some embodiments, for the compound or salt of formula (I), R 1 is selected from a substituted saturated 6-membered heterocycle, the saturated 6-membered heterocycle is substituted with at least one -NHCN, and optionally, one or more C 1~6 alkyl; B is selected from an optionally substituted 8- to 15-membered fused heterocycle and an optionally substituted C8-C 15 fused carbocycle, each of which is independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -OH, -C(O)NH2, -NH2, =O, -CN, C 1~6 alkoxy, C 1~6 hydroxyalkyl, and C 2~6 alkynyl and optionally substituted with one or more substituents; ring A is selected from an optionally substituted heterocycle; Y is O; R 2 is selected from -L-heterocycle, the heterocyclic moiety is independently selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, or -N(R 5 )2 and optionally substituted with one or more substituents; L is selected from C1-C4 alkylene. In some cases, R 1 is

Chemical formula

Chem.

Chem.

Chem.

Chem.

[0317] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), B is an optionally substituted 8- to 10-membered fused carbon ring. In some cases, B is a substituted 8- to 10-membered fused carbon ring. In some cases, B is an unsubstituted 8- to 10-membered fused carbon ring. In some cases, B is an optionally substituted 9-membered fused carbon ring. In some cases, B is a substituted 9-membered fused carbon ring. In some cases, B is

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

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Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0318] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 one or more optional 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(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, independently selected from 5 - to 12 - membered heterocycles, the 5 - to 12 - membered heterocycles are optionally substituted with one or more substituents selected from halogen, and C 1~6 alkyl.

[0319] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1 is [Chemical formula] and one or more optional substituents of R 1 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 independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, one or more optional substituents of R 1 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 independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, one or more optional substituents of R 1 are halogen, -CN, C 2~6 Alkynyl, -C(=NR 20 )N(R 20 )2, and independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, one or more optional substituents of R 1 are halogen, -C(=NR 20 )N(R 20 )2, and independently selected from optionally substituted 5- to 12-membered heterocycles. In some cases, one or more optional substituents of R 1 are -C(=NR 20 )N(R 20)2, and are independently selected from optionally substituted 5- to 12-membered heterocyclic rings. In some cases, R 1 One or more optional substituents of are independently selected from optionally substituted 5- to 12-membered heterocyclic rings. In some cases, R 1 One or more optional substituents of are independently selected from 5-membered heterocyclic rings and 9-membered heterocyclic rings, each of which is independently optionally substituted with 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 is optionally substituted with one or more substituents independently selected from 5- to 12-membered heterocyclic rings, and the 5- to 12-membered heterocyclic ring is independently optionally substituted with 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, the heterocyclic ring of one or more optional substituents of R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0320] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), one or more optional substituents of R 1 is independently selected from -C(=NR 20 )N(R 20 )2, and an optionally substituted 5- to 12-membered heterocycle. In some cases, one or more optional substituents of R 1 is independently selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, the heterocycle is

Chemical formula

Chemical formula

[0321] In some embodiments, for the 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, independently selected. 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(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 is independently selected from alkyl. In some cases, each R 1* is 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 is independently selected from alkyl. In some cases, each R 1* is halogen, C 1~6 haloalkyl, and C 1~6 is independently selected from alkyl. In some cases, each R 1* is halogen, and C 1~6 is independently selected from alkyl. In some cases, each R 1* is independently selected from halogen. In some cases, each R 1* is C 1~6 is independently selected from alkyl.

[0322] In some embodiments, for the compounds or salts of formula (I), formula (II) or formula (III), R 1 is selected from 5 - to 15 - membered heterocycles (preferably 8 - to 10 - membered heterocycles or preferably 10 - membered heterocycles), each of which is 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 one or more substituents independently selected from 5- to 12-membered heterocycles (preferably 5- to 9-membered heterocycles), optionally substituted, the 5- to 12-membered heterocycle is independently optionally substituted with one or more R 1* ; each R 1* is independently selected from halogen, C 1~6 haloalkyl, and C 1~6 alkyl. 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 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0323] In some embodiments, for the compound or salt of formula (I), formula (II) or formula (III), R 1is selected from 5- to 15-membered heterocycles (preferably 8- to 10-membered heterocycles or preferably 10-membered heterocycles), each of which is 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 optionally substituted with one or more substituents independently selected from 5- to 12-membered heterocycles (preferably 5- to 6-membered heterocycles), the 5- to 12-membered heterocycle is independently optionally substituted with one or more R 1* ; each R 1* is independently selected from halogen, C 1~6 haloalkyl, and C 1~6 alkyl. 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 is

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0324] In some embodiments, for the 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 heterocyclic ring 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 -L-N(R 21 )2. In some cases, R 2 is -L-OR 21 . In some cases, R 2 is a heterocyclic ring. In some cases, R 2 is C1-C6 alkyl. In some cases, R 2 is -L-heterocyclic ring. 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 -L-N(R 21 )2. In some cases, R 2 is -L-NHC(=NH)NH2. In some cases, R 2 is -L-C(O)N(R 21 )2. In some cases, R 2 is -L-C1-C6 haloalkyl. In some cases, R 2 is -L-OR 21 . In some cases, R 2 is -L-NR 21 C(O)-aryl. In some cases, R 2 is -L-COOH. In some cases, R 2 is -L-NR 21 S(O)2(R 21 ). In some cases, R 2 is -L-S(O)2N(R 21 )2. In some cases, R 2 is -L-N(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, heterocyclic ring, -L-NR 21The aryl moiety of C(O)-aryl, the heterocyclic moiety of -L-heterocycle, and the cycloalkyl moiety of -L-cycloalkyl are each optionally substituted with one or more R 6 and the aryl moiety of -L-aryl and the heteroaryl moiety of -L-heteroaryl are each optionally substituted with 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 * ):

Chemical formula

[0327] In some embodiments, for the compound or salt of formula (II * ), R 1 is selected from optionally substituted 7- to 10-membered spiro heterocyclic ring and optionally substituted 7- to 10-membered fused heterocyclic ring. In some cases, the heterocyclic ring of R 1 has at least one nitrogen atom. In some cases, at least one nitrogen atom of the heterocyclic ring of R 1 is bonded to formula (II * ). In some cases, R 1 is selected from optionally substituted 10-membered spiro heterocyclic ring and optionally substituted 10-membered fused heterocyclic ring. In some cases, one or more optional substituents of R 1 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, independently selected from 5- to 12-membered heterocycles, the 5- to 12-membered heterocycles being optionally substituted with one or more substituents selected from halogen, and C 1~6 alkyl. In some cases, R 1 is [Chemical formula] selected from, which is 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, substituted with one or more substituents independently selected from 5- to 12-membered heterocycles, the 5- to 12-membered heterocycles being optionally substituted with one or more substituents selected from halogen, and C 1~6 alkyl. In some cases, R 1 is [Chemical formula]

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chemical formula

Chemical formula

[0328] In some embodiments, for the compound or salt of formula (II * ), R 1 is selected from optionally substituted 7- to 10-membered spiro heterocycles and optionally substituted 7- to 10-membered fused heterocycles. In some cases, R 1 is selected from optionally substituted 10-membered spiro heterocycles and optionally substituted 10-membered fused heterocycles. In some cases, R 1 is selected from optionally substituted 10-membered spiro heterocycles. In some cases, R 1 is selected from optionally substituted 10-membered fused heterocycles. In some cases, the heterocycle of R 1 has at least 3 heteroatoms. In some cases, one or more optional substituents of R 1 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, independently selected from 5 - to 12 - membered heterocycles, and the 5 - to 12 - membered heterocycles are optionally substituted with one or more substituents selected from halogen and C 1~6 alkyl. In some cases, R 1 is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0329] In some embodiments, for the compounds or salts of formula (I), formula (II), formula (II * ) or formula (III), the heterocyclic or carbocyclic ring of R 1 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (I), the heterocyclic or carbocyclic ring of R 1~6 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (II), the heterocyclic or carbocyclic ring of R 1 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (III), the heterocyclic or carbocyclic ring of R 1~6 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (III), the heterocyclic or carbocyclic ring of R 1 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (III), the heterocyclic or carbocyclic ring of R 1~6 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (III), the heterocyclic or carbocyclic ring of R 1 is not substituted by cyanoalkyl. In some embodiments, for the compounds or salts of formula (III), the heterocyclic or carbocyclic ring of R 1~6 is not substituted by cyanoalkyl.

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

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

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

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

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

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

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

[0337] In some embodiments, for the compound or salt of formula (I), formula (II), formula (II * ) or formula (III), one or more optional substituents of R 1 are not electrophiles.

[0338] Salts of the compounds described herein, particularly pharmaceutically acceptable salts, are included in the present disclosure. Compounds of the present invention having sufficient acidic functional groups, sufficient basic functional groups, or both functional groups can react with many inorganic bases, as well as either inorganic acids or organic acids, to form salts. Alternatively, inherently charged compounds, such as compounds having a quaternary nitrogen, can form salts with suitable counterions, such as bromide, chloride, or fluoride, particularly halides such as bromide.

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

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

Chemical Structure

[0341] The compounds disclosed herein, in some embodiments, are in different enriched isotopic forms, such as 2 H, 3 H, 11 C, 13 C and / or 14The content of C is used in an enriched form. In certain embodiments, the compound is deuterated at at least one position. Such deuterated forms can be prepared by the procedures described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve metabolic stability and / or efficacy and thus increase the duration of action of the drug.

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

[0343] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes in one or more atoms that make up such compounds. For example, the compound may be labeled with an isotope such as deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). 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 Isotopic substitution with I is contemplated for all. All isotopic variants of the compounds of the present invention are included within the scope of the present invention, whether radioactive or not.

[0344] In certain embodiments, the compounds disclosed herein are 1 Part or all of the H atoms are 2 Replaced by H atoms. 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 are subjected to the synthetic methods described herein to provide the synthesis of deuterium-containing compounds. A number of deuterium-containing reagents and building blocks are commercially available from chemical suppliers such as Aldrich Chemical Co.

[0347] The compounds of the present invention include, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of these compounds, pharmaceutically acceptable salts, and crystalline and amorphous forms of active metabolites of these compounds having the same type of activity, as well as mixtures thereof.

[0348] The compounds described herein may, in some cases, exist in diastereomeric, enantiomeric, or other stereoisomeric forms. Where the absolute stereochemistry is not established, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms, and appropriate mixtures thereof. Separation of stereoisomers can be effected by chromatography, or by forming diastereomers and separating them by recrystallization or chromatography, or by 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 purposes of this 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 having the same type of activity are included within the scope of this disclosure. In addition, the compounds described herein can exist in non-solvated forms, and in 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, the compound or a salt of the compound may be a prodrug. For example, a hydroxyl in the present compound may exist as an ester or a carbonate, or a carboxylic acid present in the present compound may exist 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 way to make 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 in which the prodrug is metabolized in vivo to yield the compounds shown herein are included within the scope of the claims. In some cases, a portion of the compounds described herein may be prodrugs for another derivative or active compound.

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

[0353] In some embodiments, the prodrug design increases the lipophilicity of the pharmaceutical agent. In some embodiments, the prodrug design increases effective water solubility. For example, for such disclosures, see 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 A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all of which are incorporated herein by reference. 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 the synthesis of 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 formulation

[0355] In certain embodiments, compositions are provided herein that comprise a therapeutically effective amount of any one of the compounds or salts of any of formulas (I), (II), (II * ), and (III) (also referred to herein as "pharmaceutical agents").

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

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

[0358] Pharmaceutically acceptable additives can contain physiologically acceptable agents that act, for example, to stabilize, increase the solubility of, or increase the absorption of compounds such as pharmaceutical agents. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextran, antioxidants such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, or other stabilizers or excipients. The selection of pharmaceutically acceptable additives containing physiologically acceptable agents depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) can also be a liposome or other polymeric matrix, which can, for example, incorporate the compounds of the present invention therein. For example, liposomes containing phospholipids or other lipids are non-toxic, physiologically acceptable, and metabolizable carriers that are relatively easy to prepare and administer.

[0359] The pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration, for example, orally, such as by immersion in an aqueous or non-aqueous solution or suspension, tablets, sprinkle capsules and gelatin capsules including capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, such as sublingually; anal, rectal, or vaginal, such as pessaries, creams or foams; parenterally, such as intramuscularly, intravenously, subcutaneously or intrathecally as a sterile solution or suspension; intranasally; intraperitoneally; subcutaneously; transdermally, such as patches applied to the skin; and topically, such as creams, ointments or sprays applied to the skin, or eye drops. The compound can also be formulated for inhalation. In certain embodiments, the compound can simply be dissolved or suspended in sterile water.

[0360] The pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, for example, a microemulsion. 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 portions of a series of doses, which is effective to produce the desired therapeutic effect.

[0361] The subject can generally be monitored for therapeutic efficacy using assays and methods suitable for the condition being 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 levels of the pharmaceutical agent or metabolite in a biological fluid from the subject, such as blood, blood fractions, such as serum, and / or urine, and / or other biological samples or tissues. The levels of the pharmaceutical agent or metabolite can be measured during the course of treatment using any method practiced in the art for detecting the agent and described herein.

[0362] The dosage of the pharmaceutical agent described herein for treating a disease or disorder may depend on the condition of the subject, i.e., not only the stage of the disease, the severity of the symptoms caused by the disease, the overall health condition, but also age, gender and weight, as well as other factors apparent to those skilled in the medical art. The pharmaceutical composition may be administered in a manner appropriate for the disease being treated, as determined by those skilled in the medical art. In addition to the factors described herein and above in connection with the use of a pharmaceutical agent for treating a disease or disorder, the preferred period and frequency of administration of the pharmaceutical agent may also be determined or adjusted by factors such as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. The optimal dosage of the agent can generally be determined using experimental models and / or clinical trials. The optimal dosage may depend on the weight, mass, or blood volume of the subject. The use of the minimum dosage sufficient to provide an effective treatment is usually preferred. The design and conduct of preclinical and clinical studies for the pharmaceutical agents described herein, including when administered for prophylactic benefit, are well within the skill of those of ordinary skill in the relevant art. If two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dosage of each agent may be different, such that it is less than if any of the agents were administered alone as monotherapy. In certain particular embodiments, the two pharmaceutical agents in the combination may act synergistically or additively, and either agent may be used in a lesser amount than when administered alone. The amount of the pharmaceutical agent that may be administered per day may be, for example, between about 0.01 mg / kg and 100 mg / kg of body weight, such as between about 0.1 and 1 mg / kg, between about 1 and 10 mg / kg, between 10 and 50 mg / kg, between about 50 and 100 mg / kg. In other embodiments, the amount of the pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 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 per course of treatment may vary for the disease or disorder being treated and may also vary with the route of administration and the treatment regimen.

[0363] A pharmaceutical composition containing a medicament can be formulated in a manner suitable for the delivery method by using techniques routinely practiced in the art. The composition can be in solid form, such as tablets, capsules, semi-solid, such as gels, liquids, or gases, such as aerosols. In other embodiments, the pharmaceutical composition is administered as a bolus injection.

[0364] Pharmaceutically acceptable additives are well known in the pharmaceutical field 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 not only the mode of administration but also the chemical composition of the active ingredient. Alternatively, the compositions described herein may be formulated as lyophilized products. The compositions described herein may be lyophilized or, alternatively, formulated as lyophilized products using one or more suitable additive solutions for dissolving and / or diluting the medicament of the composition upon administration. In other embodiments, the medicament may be encapsulated within liposomes using techniques known and practiced in the art. In certain specific embodiments, the medicament is not formulated within liposomes for application to stents used to treat, although not completely, highly occluded arteries. The pharmaceutical composition can 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 include, for example, one or more of the following: sterile diluents, such as water, saline, preferably physiological 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 enclosed in glass or plastic ampoules, disposable syringes, or multi-dose vials. The use of physiological saline is preferred, and pharmaceutical compositions for injection are preferably sterile. In another embodiment, for the treatment of ophthalmic conditions or diseases, the liquid pharmaceutical composition may be applied to the eye in the form of eye drops. The liquid pharmaceutical composition may be delivered orally.

[0366] For oral formulations, 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, diluents, buffers, humectants, preservatives, coloring agents, and flavoring agents. The pharmaceutical agent may be formulated using a buffer that provides protection of the composition from the low pH of the gastric environment and / or an enteric coating. The pharmaceutical agent contained in the pharmaceutical composition may be formulated for oral delivery, for example, using a flavoring agent in a liquid, solid, or semi-solid formulation and / or using an enteric coating.

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

[0368] In certain embodiments, a pharmaceutical composition comprising a pharmaceutical agent is formulated for transdermal, intradermal, or topical administration. The composition can be administered as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste, using a syringe, bandage, transdermal patch, insert, or syringe-like applicator. This is preferably in the form of a controlled release or sustained release formulation for topical administration or is injected directly into the skin adjacent to or within the area to be treated, for example, 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, butyl paraben, ethyl paraben, methyl paraben, propyl paraben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0369] A pharmaceutical composition containing a medicament can be formulated as an emulsion for topical application. An emulsion contains one liquid dispersed in a majority of a second liquid. The emulsion can be a water-in-oil emulsion or an oil-in-water emulsion. Either or both of the oil phase and the water phase can contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other additives. The oil phase may contain other oily 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 include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0370] Ointments and creams may be formulated using an aqueous or oily base, for example, by the addition of suitable thickening and / or gelling agents. Lotions may be formulated using an aqueous or oily base and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickening agents, or colorants. Liquid sprays may be delivered from a pressurized pack, for example, via a specially shaped closure. Water-in-oil emulsions can also be used in compositions, patches, bandages, and articles. These systems are semi-solid emulsions, microemulsions, or foam emulsion systems.

[0371] In some embodiments, the pharmaceutical agents described herein can be formulated as inhalants. The inhalation method can directly deliver the pharmaceuticals to the airway. The pharmaceutical agents can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agents can be formulated using solvents, gases, nitrates, or any combination thereof. The compositions described herein are formulated, as necessary, for delivery as liquid aerosols or inhalable dry powders. Liquid aerosol formulations are nebulized, as necessary, preferably to a particle size that can be preferentially delivered to the terminal bronchioles and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered from the entire bronchial tree to the terminal bronchioles and ultimately to the parenchyma.

[0372] The aerosolized formulations described herein are delivered, as necessary, using an aerosol-forming device such as a jet, vibrating porous plate, or ultrasonic nebulizer, and are preferably selected to enable the formation of aerosol particles having a mass medium average diameter of preferably 1 to 5 μm. Additionally, the formulation preferably has an equilibrium osmotic pressure ionic strength and chloride concentration, and a minimum aerosolizable volume capable of delivering an effective dose of the pharmaceutical agent. Further, the aerosolized formulation preferably does not negatively affect the function of the airway and does not cause undesirable side effects.

[0373] As an aerosolization device suitable for administration of the aerosol formulations described in this specification, for example, jets, vibrating porous plates, ultrasonic nebulizers, and voltage-applied dry powder inhalers that can preferentially nebulize the formulation into aerosol particle sizes in the range of 1 to 5 μm can be mentioned. By "preferential" in this application is meant that at least 70%, but preferably more than 90%, of all the aerosol particles created are within the range of 1 to 5 μm. Jet nebulizers are actuated by air pressure to break down a liquid solution into aerosol droplets. Vibrating porous plate nebulizers operate by using the acoustic vacuum created by a rapidly vibrating porous plate to extrude solvent droplets through the porous plate. Ultrasonic nebulizers operate by piezoelectric crystals that shear the liquid into small aerosol droplets. For example, various suitable devices are available, including the AeroNeb™ and AeroDose™ vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), the Sidestream® nebulizer (Medic-Aid Ltd., West Sussex, England), the Pari LC® and Pari LC Star® jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and the Aerosonic™ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire® (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0374] In some embodiments, the pharmaceutical agent can be formulated using an oily base or an ointment to form a semi-solid composition having a desired shape. In addition to the pharmaceutical agent, these semi-solid compositions can contain a dissolved and / or suspended bactericide, a preservative, and / or a buffer system. The petrolatum component that can be included can be any paraffin in the viscosity range from mineral oil incorporating isobutylene, colloidal silica, or stearate to paraffin wax. The absorbent base can be used together with an oil-based system. Additives can include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohol, low HLB (hydrophilic-lipophilic balance) emulsifiers, and various ionic and non-ionic surfactants), either alone or in combination.

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

[0376] Inserts, transdermal patches, dressings or articles can include a mixture or coating of polymers that provide release of the pharmaceutical agent at a constant rate over a long period of time. In some embodiments, the article, transdermal patch or insert can include a water-soluble pore-forming agent such as polyethylene glycol (PEG) that can be mixed 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 caused using pH changes. These rate-controlling polymers can be applied using a continuous coating film during the processes of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets containing the active ingredient that are compressed to form solid biodegradable inserts.

[0378] Polymeric formulations can also be utilized to provide controlled or sustained release. Biodegradable polymers described in the art can be used. By way of example, sustained release gels and compounds can be incorporated into a polymeric matrix such as a hydrophobic polymer matrix. Examples of polymeric matrices include microparticles. The microparticles can be microspheres and the core can be of a material different from the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, 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 thereof of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrix can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0379] Typically, kits are provided having one or more unit doses of one of the agents described herein in oral or injectable dosages. Such kits can include a container containing the unit dose, a package insert providing information describing the use and attendant benefits of the drug in the treatment of the disease, and, optionally, an instrument or device for delivery of the composition. Methods of treatment

[0380] In one aspect, the present disclosure provides compounds that inhibit the KRas G12 mutant. In some cases, the method can inhibit the activity of the KRas G12 mutant in a cell. In some cases, inhibiting the activity of the KRas G12 mutant in a cell involves contacting a cell in which inhibition of the activity of the KRas G12 mutant is desired with an effective amount of a compound of formula (I), formula (II), formula (II * ), formula (III), or a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof. In some cases, the contacting is in vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to bringing together the indicated moieties in an in vitro system or in an in vivo system. For example, "contacting" the KRas G12D and / or other G12 mutants with the compounds provided herein includes administering the compounds provided herein to an individual or patient, such as a human, having the KRas G12D and / or other G12 mutants, and introducing, for example, the compounds provided herein into a sample containing a cell preparation or a purified preparation containing the KRas G12D and / or other G12 mutants. In some cases, the cells in which inhibition of the activity of the KRas G12D and / or other G12 mutants is desired are contacted with an effective amount of a compound of formula (I) or formula (II) or formula (II *)Contact with 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 unwanted cell proliferation resulting from enhanced activity of KRas G12D and / or other G12 mutants in cells. The cells can be contacted in a single dose or multiple doses according to a specific treatment regimen that produces the desired negative modulation of KRas G12D and / or other G12 mutants. The ability of the compound to bind to KRas G12D and / or other G12 mutants can be monitored in vitro using well-known methods.

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

[0382] In another aspect, a method of treating cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of formula (I), formula (II), formula (II * ), formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof is provided. The compositions and methods provided herein are for the treatment of a therapeutically effective amount of a compound of formula (I), formula (II), formula (II *) Administering to a patient in need thereof a compound of formula (III), any one of its pharmaceutically acceptable salts, or a pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt, which can be used for the treatment of KRas G12D and / or other G12 mutant-related cancers in the patient. In some cases, the KRas G12D and / or other G12 mutant-related cancers are lung cancers. The compositions and methods provided herein can be used for the treatment of a variety of cancers, including tumors such as lung cancer, prostate cancer, breast cancer, brain cancer, skin cancer, cervical cancer, testicular cancer, etc. More specifically, the cancers that can be treated by the compositions and methods of the present invention include, but are not limited to, cancer types and sarcomas of astrocytes, breast, cervix, colorectal, endometrium, esophagus, stomach, head and neck, hepatocytes, pharynx, lung, mouth, ovary, prostate and thyroid. More specifically, these compounds are: Heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondroid hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (cancer types, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIPoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyosarcoma); Urogenital 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, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bile duct: gallbladder carcinoma, ampulla carcinoma, cholangiocarcinoma;Bone: Osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulosarcoma), multiple myeloma, malignant giant cell tumor, osteochondroma (osteochronfroma) (cartilaginous exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumor; Nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, Paget's disease), meninges (meningioma, meningosarcoma, gliosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pinealoma), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal nerve fibroma, meningioma, glioma, sarcoma); Gynecology: Uterus (endometrial cancer), cervix (cervical cancer, pre-tumor cervical dysplasia), ovary (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer type), granulosa cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (fetal rhabdomyosarcoma), fallopian tube (cancer type); 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 nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; and Adrenal gland: It can be used to treat neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the concentration and the route of administration to the patient will vary depending on the cancer being treated. The compound, its pharmaceutically acceptable salts, and pharmaceutical compositions containing such compounds and salts may also be co-administered with other anti-neoplastic compounds, for example, chemotherapy, or used in combination with other treatments, for example, radiation or surgical intervention, as an adjunct before or after surgery.;

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

[0384] For use in the treatment of cancer, 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 also provided herein.

[0385] For use in the inhibition of KRas G12D and / or other G12 mutants, 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 also provided herein.

[0386] For use in the treatment of a KRas G12D and / or other G12 mutant-related disease or disorder, a compound of formula (I), formula (II), formula (III) as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is also provided herein.

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

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

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

[0390] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising: (a) determining that the cancer is associated with a KRas G12D mutation and / or other G12 mutants (e.g., KRas G12D and / or other G12 mutant-related cancer), for example, determined using an assay or kit approved by a regulatory authority, such as an assay or kit approved by the FDA; and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (II), Formula (II * ), Formula (III), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

[0392] Compositions containing the compounds described herein can be administered for prophylactic and / or therapeutic treatment. In therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. The amount effective for this use depends on the severity and course of the disease or condition, previous therapy, the health state, weight and response of the patient to the drug, and the judgment of the physician administering the treatment.

[0393] In prophylactic applications, a composition containing a compound described herein is administered to a patient who is susceptible to, or 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 status, weight, etc. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder or condition, previous therapies, the patient's health status and response to the drug, and the judgment of the treating physician.

[0394] If the patient's condition does not improve, at the discretion of the physician, administration of the compound may be chronic, i.e., over a long period including the entire life of the patient, to alleviate, or otherwise control or limit, the symptoms of the patient's disease or condition.

[0395] Once improvement of the patient's condition occurs, a maintenance dose is administered if necessary. Thereafter, the dosage or frequency of administration, or both, can be reduced as a function of the symptoms to a level at which the improved disease, disorder or condition is maintained. However, the patient may require long-term intermittent treatment upon recurrence of any symptoms.

[0396] The amount of a given agent corresponding to such an amount will vary depending on factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, etc., but nevertheless can be determined in a manner recognized in the art 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. However, generally, the dosage used for the treatment of adult humans is typically in the range of about 0.02 to about 5000 mg per day, and in some embodiments, about 1 to about 1500 mg per day. The desired dosage may conveniently be presented as a single dose, or as divided doses administered simultaneously (or over a short period), 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 forms suitable for single administration of precise dosages. In unit dosage forms, the formulation is divided into unit dosages containing appropriate amounts of one or more compounds. The unit dosage may be in the form of a package containing a distinct quantity of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. An aqueous suspension composition can be packaged in a non-resealable container for a single dose. Alternatively, a multiple-dose resealable container can be used, in which case it is typical to include a preservative in the composition. By way of mere example, a parenteral injection formulation can be presented in a unit dosage form including, but not limited to, an ampoule, or a multiple-dose container with a preservative added.

[0398] The toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of LD 50 (the dose lethal to 50% of the population) and ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio between LD 50 and ED 50 . Compounds showing a high therapeutic index are preferred. Data obtained from cell culture assays and animal studies can be used in formulating the dosage range for use in humans. The dosage of such compounds preferably lies within a range of circulating concentrations that includes the ED 50 with minimal toxicity. The dosage may vary within this range depending on 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 can be selected from the groups described elsewhere herein. Bifunctional compound

[0400] In some embodiments, the compounds herein can be employed to selectively eliminate the over-activated KRas signaling induced by KRas mutations by directly binding to the mutant KRas protein, either by stabilizing its GDP-bound form (inactive form) or by blocking the interaction between the GTP-bound form and its downstream target proteins. In some embodiments, another approach is by a bifunctional molecule called a proteolysis targeting chimera (PROTAC) (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 hijacks the proteolysis mechanism in cells and exploits the substrate specificity of an E3 ligase (such as VHL, CRBN or IAP), which can bind to both the mutant KRas protein and the E3 ligase, create an interaction between these two proteins, and induce KRas degradation.

[0401] A bifunctional compound composed of a target protein (i.e., KRAS G12D) binding moiety and an E3 ubiquitin ligase binding moiety is disclosed herein, 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, the use of the compounds disclosed herein in preparations for degrading target protein compounds by using chemical modifications of the compounds disclosed herein is disclosed herein. In some cases, the target protein binding moiety is derived from a compound of formula (I), formula (II), formula (II * ), or 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. By way of example, the compounds of the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the field of synthetic organic chemistry or variations thereof 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 should of course not be construed as limiting its scope in any way.

Examples

[0404] The following synthetic schemes are provided for illustrative purposes only and not by way of limitation. The following examples illustrate various methods for making the compounds described herein. It is understood that one of ordinary skill in the art may be able to make these compounds by similar methods or by combining other methods known to one of ordinary skill in the art. It is also understood that one of ordinary skill in the art can make them in a manner similar to that 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, synthesized according to sources known to one of ordinary skill in the art, or prepared as described herein.

[0405] This disclosure provides a process for preparing the compounds described herein (described in more detail below, as will be described). General Scheme

Chemical formula

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

Chemical formula

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

Chemical formula

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

[0409] Ethyl 4-chloro-6-methyl-2-(methylthio)pyrimidine-5-carboxylate can be deprotonated with LDA or LiHMDS at -78 °C in THF. 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. The R3 of IIB-d can be introduced via reductive amination or alkylation. Treatment of IIB-d with R1 can provide IIB-e in the presence of a base such as DIEA in DCM. 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) [Chemistry]

[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) were 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 indicated that the reaction was complete. The reaction mixture was concentrated under vacuum. 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 under vacuum. The residue was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to afford 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 a...

Claims

1. A compound of formula (II): 【Chemical Formula 601】 or a pharmaceutically acceptable salt thereof wherein: M is selected from O, and NR ３ and is selected from; R １ is selected from 7- to 10-membered heterocycles, each of which is halogen, -B(OR ２０ ), -OR ２ , -SR ２０ , -S(O) ２０ (R ２ ), -S(O) ２０ N(R ２ ), -S(O)N(R ２０ ), -S(O)R ２ (=NR ２０ ), -NR ２ S(O) ２０ R ２０ , -C(O)N(R ２０ ), -C(=NR ２０ )N(R ２０ ), -C(O)NR ２０ OR ２０ , -N(R ２０ )C(O)R ２０ , -N(R ２０ )C(O)N(R ２０ ), -N(R ２ )C(O)OR ２０ , -N(R ２０ ), -C(O)R ２０ , -C(O)OR ２ , -OC(O)R ２０ , -OC(O)N(R ２０ ), -NO ２０ , =O, =N(R ２０ ), =NO(R ２ ), -CN, -NHCN, C ２ alkyl-N(R ２０ ), C ２０ aminoalkyl, C １～６ alkoxy, C ２０ hydroxyalkyl, C ２ cyanoalkyl, C １～６ haloalkyl, C １～６ alkyl-SO １～６ R １～６ , C １～６ alkyl, C １～６ alkyl-SO ２ R ２０ , C １～６ alkyl, C ２～６ alkyl-SO ２～６ R ３ , C １２ alkyl, C ３ alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３ -C １２ Optionally substituted with one or more substituents independently selected from carbocycles and 5- to 12-membered heterocycles, said C ３ -C １２ The carbocycles and 5- to 12-membered heterocycles are each independently optionally substituted with one or more R １＊ ; and are each independently optionally substituted accordingly; Each R １＊ is independently selected from halogen, -B(OR ２０ ), -OR ２ , -SR ２０ , -S(O) ２０ (R ２ ), -S(O) ２０ N(R ２ ), -S(O)N(R ２０ ), -S(O)N(R ２ ), -S(O)R ２０ (=NR ２ ), -NR ２０ S(O) ２０ R ２０ , -C(O)N(R ２ ), -C(O)NR ２０ OR ２０ , -N(R ２ C(O)R ２０ , -N(R ２０ )C(O)N(R ２０ ), -N(R ２０ )C(O)OR ２０ , -N(R ２０ ), -C(O)R ２ , -C(O)OR ２０ , -OC(O)R ２０ , -OC(O)N(R ２０ ), -NO ２ , =O, =N(R ２０ ), =NO(R ２０ ), -CN, -NHCN, C ２０ alkyl-N(R ２０ ), C ２ aminoalkyl, C ２ alkoxy, C ２０ hydroxyalkyl, C ２０ cyanoalkyl, C １～６ alkyl-N(R ２０ ), C ２ alkyl, C １～６ alkenyl, C １～６ alkynyl, and C １～６ is independently selected from C １～６ -C １～６ -C １～６ -C ２～６ -C ２～６ -C ３ -C １２ carbocyclic rings; Y is O; R ２ is selected from -L-N(R ２１ ), and -L-heterocyclic ring, and the heterocyclic ring moiety of the -L-heterocyclic ring is optionally substituted with one or more R ２ ; ６ and optionally substituted with Each L is hydroxy, C １ -C ４ hydroxyalkyl, C １ -C ４ alkyl, C ３ -C ６ an alkylene independently selected from one or more substituents selected from a carbocyclic ring and a 3- to 8-membered heterocyclic ring, optionally substituted with C １ -C ４ wherein said C ３ -C ６ carbocyclic ring and 3- to 8-membered heterocyclic ring are each optionally substituted with one or more substituents selected from halogen, -OH, -NO ２ , =O, =S, -CN, C １～６ aminoalkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, and C １～６ haloalkyl, optionally substituted; optionally, two substituents on the same carbon atom of L together form a C ３ -C ６ carbocyclic ring or 3- to 8-membered heterocyclic ring, said C ３ -C ６ carbocyclic ring and 3- to 8-membered heterocyclic ring are each optionally substituted with one or more substituents selected from halogen, -OH, -NO ２ , =O, =S, -CN, C １～６ aminoalkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, and C １～６ haloalkyl, optionally substituted; R ３ is selected from hydrogen, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C １～６ alkyl-N(R ２０ ) ２ , C １～６ aminoalkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, C １～６ cyanoalkyl, C １～６ haloalkyl, C １～６ alkoxyalkyl, C ３～１２ is selected from a carbocyclic ring and a 3- to 12-membered heterocyclic ring, and the C ３～１２ carbocyclic ring and the 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from 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 is optionally substituted with one or more substituents independently selected from a carbocyclic ring and a 3- to 12-membered heterocyclic ring; n is selected from 0 to 2; Each R ４ is independently selected from C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, oxo, hydroxyl, halogen, C ３～１２ carbocyclic ring, and 3- to 12-membered heterocyclic ring, and the C １ -C ６ alkyl, C ３～１２ carbocyclic ring, and 3- to 12-membered heterocyclic ring are each optionally substituted with one or more substituents independently selected from cyano, halogen, -OR ５ , and -N(R ５ )([[]]ID=21 ２ ); Each R ５ is independently selected from hydrogen and C １ ~C ６ alkyl; Each R ６ is halogen, hydroxy, C １ to C ３ hydroxyalkyl, C １ to C ３ alkyl, oxo, C １ to C ３ haloalkyl, C １ to C ３ alkoxy, cyano, =CH ２ =NO-C １ to C ３ alkyl, C １ to 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 to C ３ alkyl-substituted pyrazolyl, tert-butyldimethylsilyloxyCH ２ -、-N(R ５ ) ２ (C １ to C ３ alkoxy)C １ to C ３ alkyl-、(C １ to C ３ alkyl)C(=O)、oxo、(C １ to C ３ haloalkyl)C(=O)-、-SO ２ F、(C １ to C ３ alkoxy)C １ to C ３ alkoxy、-CH ２ OC(O)N(R ５ ) ２ 、-CH ２ NHCOOC １ to C ６ alkyl、-CH ２ NHCON(R ５ ) ２ 、-CH ２ NHCOC １ to C ６ alkyl、-CH ２ (pyrazolyl), -CH ２ NHS0 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, -O-C １ ~C ３ alkyl, and -CH ２ heterocycle are each independently selected from, -NHC(O)phenyl and -OC(O)NH(C １ ~C ３ alkyl)(C １ ~C ３ alkyl)phenyl, the phenyl of which is optionally substituted with one or more substituents selected from -C(O)H and OH, the alkyl of -O-C １ ~C ３ alkyl is optionally substituted with a substituent selected from heterocycle, oxo and hydroxy; the heterocycle of -CH ２ 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 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 carbocyclic ring, and one or more substituents independently selected from 3- to 12-membered heterocyclic rings, optionally substituted C １～６ alkyl, C ３～１２ carbocyclic ring, and 3- to 12-membered heterocyclic rings, independently selected; Each R ２１ is hydrogen; and each of them is 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 a carbocyclic ring, and a C optionally substituted with one or more substituents independently selected from 3- to 12-membered heterocyclic rings １～６ alkyl, C ３～１２ a carbocyclic ring, and a 3- to 12-membered heterocyclic ring, independently selected; B is selected from a heterocyclic ring and a carbocyclic ring, and the heterocyclic ring and the carbocyclic ring are 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)halo C １ ~C ３ alkyl-, C １～６ alkyl-N(R ２０ ) ２ , C ３ ~C １２ carbocyclic ring and one or more substituents independently selected from 5- to 12-membered heterocyclic rings are each optionally substituted, and the C ３ ~C １２ carbocyclic ring and 5- to 12-membered heterocyclic rings are halogen, -OH, -NO ２ , -NH ２ , =O, =S, -CN, C １～６ alkyl-N(R ２０ ) ２ and C １～６ aminoalkyl, C １～６ alkoxy, C １～６ hydroxyalkyl, and C １～６ optionally substituted with one or more substituents selected from haloalkyl].

2. R １ The compound or salt according to claim 1, wherein R is selected from 10-membered heterocyclic rings optionally substituted.

3. R １ is 【Chemical Formula 602】 and 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)NR ２０ OR 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 optionally substituted with one or more substituents independently selected from 5- to 12-membered heterocycles, said 5- to 12-membered heterocycles being optionally substituted with one or more substituents selected from halogen, -OR ２０ 、and C １～６ alkyl, the compound or salt according to claim 2.

4. R １ is 【Chemical Formula 603】 【Chemical Formula 604】 【Chemical Formula 605】 The compound or salt according to claim 3, selected from

5. R １ is 【Chemical Formula 606】 【Chemical Formula 607】 The compound or salt according to claim 4, selected from

6. R １ is 【Chemical Formula 608】 【Chemical Formula 609】 The compound or salt according to claim 5, selected from

7. R １ is 【Chemical 610】 The compound or salt according to claim 6, wherein

8. R １ is 【Chemical 611】 The compound or salt according to claim 1, wherein

9. R １ The compound or salt according to claim 1, wherein R is selected from 7- to 8-membered bridged heterocyclic rings optionally substituted.

10. R １ is 【Chemical Formula 612】 The compound or salt according to claim 9, selected from

11. R １ is 【Chemical 613】 The compound or salt according to claim 1, selected from and each of which is optionally substituted

12. R １ is 【Chemical 614】 The compound or salt according to claim 11, selected from

13. The compound or salt according to claim 1, wherein M is O

14. The compound or salt according to claim 1, wherein M is NMe

15. B is an 8- to 15-membered fused heterocyclic ring optionally substituted and a C ８ to C １５ selected from fused carbocyclic rings, each of which is halogen, -NH ２ , C １ to C ３ alkyl, hydroxy, =O, cyano, C １ to C ３ alkoxy, C １ to C ３ hydroxyalkyl, and C ２ to C ４ optionally substituted with one or more substituents independently selected from alkynyl, the compound or salt according to claim 1.

16. B is 【Chemical 615】 The compound or salt according to claim 15, selected from

17. B is 【Chemical 616】 The compound or salt according to claim 16, selected from

18. R ２ is a -L-heterocyclic ring, and one or more R ６ are optionally substituted, and each R ６ is halogen, hydroxy, C １ to C ３ alkyl, -N(R ５ ), -S(O) ２ (R ５ ), -OC(O)N(R ５ ) ２ =CH ２ oxo, =NO-C １ to C ３ alkyl, -CH ２ OC(O)heterocyclic ring, -CH ２ heterocyclic ring, -CH ２ OC(O)N(R ５ ) ２ and -O-C １ to C ３ alkyl is independently selected from, and the alkyl of -O-C １ to C ３ alkyl is optionally substituted with a substituent selected from a heterocyclic ring, oxo, and hydroxy, the compound or salt according to claim 1.

19. Each L is unsubstituted C １ ~C ４ alkylene, 【Chemical 617】 The compound or salt according to claim 18, independently selected from

20. Y - R ２ is 【Chemical Formula 618】 The compound or salt according to claim 19, selected from

21. Y - R ２ is 【Chemical 619】 The compound or salt according to claim 1, wherein

22. Y - R ２ is 【Chemical 620】 The compound or salt according to claim 1, wherein

23. The compound is 【Chemical 621】 【Chemical Formula 622】 【Chemical Formula 623】 【Chemical Formula 624】 【Chemical Formula 625】 【Chemical Formula 626】 【Chemical Formula 627】 The compound or salt according to claim 1, selected from or a salt of any one thereof

24. The compound is 【Chemical Formula 628】 【Chemical Formula 629】 【Chemical Formula 630】 【Chemical 631】 【Chemical 632】 The compound or salt according to claim 1, selected from or a salt of any one thereof

25. The compound is 【Chemical Formula 633】 【Chemical Formula 634】 【Chemical 635】 The compound or salt according to claim 1, selected from or a salt of any one thereof

26. A pharmaceutical composition comprising the compound or salt according to claim 1 and a pharmaceutically acceptable excipient

27. A pharmaceutical composition according to claim 26 for treating a disease or disorder, wherein the disease or disorder is cancer, and the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer, or the cancer is tumor cancer

28. The compound is 【Chemical 636】 The compound or salt according to claim 1, or a salt thereof

29. The compound is 【Chemical 637】 or a salt thereof, the compound or salt according to claim 1.

30. The compound is 【Chemical 638】 or a salt thereof, the compound or salt according to claim 1.

31. The compound is 【Chemical 639】 or a salt thereof, the compound or salt according to claim 1.

32. The compound is 【Chemical 640】 or a salt thereof, the compound or salt according to claim 1.

33. The compound is 【Chemical Formula 641】 or a salt thereof, the compound or salt according to claim 1.

34. The compound is 【Chemical Formula 642】 or a salt thereof, the compound or salt according to claim 1.

35. The compound is 【Chemical Formula 643】 or a salt thereof, the compound or salt according to claim 1.

36. The compound is 【Chemical Formula 644】 or a salt thereof, the compound or salt according to claim 1.

37. The compound is 【Chemical 645】 or a salt thereof, the compound or salt according to claim 1.

38. The compound is 【Chemical 646】 or a salt thereof, the compound or salt according to claim 1.

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