Spiro compounds and their uses

Abstract

According to the present invention, there are provided a new compound having a binding action with the E3 ligase protein CRBN, and use of this compound in the preparation of a drug for treating cell abnormal proliferation diseases.

Description

[Technical Field]

[0001] This invention relates to the field of medical technology, and more specifically to a novel ligand compound for binding to a spiroring cereblon E3 ubiquitin ligase protein. [Background technology]

[0002] Protein degradation is a highly regulated and essential process for maintaining cellular homeostasis. Selective identification and removal of damaged, misfolded, or excess proteins occurs through the ubiquitin-proteasome pathway (UPP). The UPP is characterized by its ATP-dependent, efficient, and highly selective removal of defective proteins. Its catalytic component is the E3 ubiquitin ligase, which first requires the replenishment of the protein to be degraded. PROTACs technology is designed based on the UPP principle, identifying the target protein by appropriately chemically linking the target protein's ligand to the E3 ligase's ligand, enhancing the E3 ligase's ability to bind to the target protein, and forcing the degradation of the target protein by targeting ubiquitination. It features low catalytic requirements, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules covalently bind to terminal lysine residues via E3 ubiquitin ligase, thereby labeling proteins and enabling proteasome degradation. The proteins are digested into small peptides, and ultimately broken down into amino acids, which then function as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical conditions, including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease, and cancer.

[0004] Cereblon is a thalidomide-binding protein that is part of the E3 ubiquitin ligase protein complex and functions as a substrate receptor that selectively acts on ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene and forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), karin 4A (CUL4A), and karin 1 regulator (ROCI). This complex can ubiquitinize a range of proteins, although the specific mechanism is unknown. Cereblon is a commonly used E3 ligase known to be used in PROTAC technology.

[0005] This invention provides a novel spiro compound. This compound can function as an effective CRBN ligand and can also synthesize a corresponding proteolytic chimeric molecule, the PROTAC bifunctional compound, which can be applied to the treatment of various medical conditions, particularly abnormal cell proliferation. [Overview of the Initiative]

[0006] The present invention provides a compound represented by the following formula I, its stereoisomer, its deuterated compound, or a pharmaceutically acceptable salt thereof. [ka] Equation I During the ceremony, ==O indicates the presence or absence of oxygen substitution. Ring A is selected from 3-12 membered cycloalkyl groups, 4-12 membered heterocycloalkyl groups, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings, where the cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring are further divided into one, two, three, or four independent R groups. A1 It may be replaced by, Each R A1 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and =CR. A2 R A3 , -C 1~6 Alkyl alkyl group, -C2~6 an alkenyl group, -C 2~6 an alkynyl group, -C1-6 haloalkyl group, -C2-6 haloalkenyl group, -C2-6 haloalkynyl group, -C 0~4 alkylene-OR A2 、-C 0~4 alkylene-OC(O)R A2 、-C 0~4 alkylene-SR A2 、-C 0~4 alkylene-S(O)2R A2 、-C 0~4 alkylene-S(O)R A2 、-C 0~4 alkylene-S(O)2NR[[ID=]26] A2 R A3 、-C 0~4 alkylene-S(O)NR A2 R A3 、-C 0~4 alkylene-C(O)R A2 、-C 0~4 alkylene-C(O)OR A2 、-C 0~4 alkylene-C(O)NR A2 R A3 、-C 0~4 alkylene-NR A2 R A3 、-C 0~4 alkylene-NR A2 C(O)R A3 、-C 0~4 alkylene-NR A2 S(O)2R A3 、-C 0~4 alkylene-NR A2 S(O)R A3 、-C 0~4 alkylene-(3-10 membered cycloalkyl group), -C 0~4 alkylene-(4-10 membered heterocycloalkyl group), -C 0~4 alkylene-(6-10 membered aromatic ring), -C 0~4 selected from alkylene-(5-10 membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, heteroaromatic ring may be further substituted by one, two, three, or four independent R A4 and, Each R A4 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR A2 R A3 , -C 1~6 alkyl group, -C 2~6 alkenyl group, -C 2~6 alkynyl group, -C 1~6 haloalkyl group, -C 2~6 haloalkenyl group, -C 2~6 haloalkynyl group, -C 0~4 alkylene-OR A2 , -C 0~4 alkylene-OC(O)R A2 , -C 0~4 alkylene-SR A2 , -C 0~4 alkylene-S(O)2R A2 , -C 0~4 alkylene-S(O)R A2 , -C 0~4 alkylene-S(O)2NR A2 R A3 , -C 0~4 alkylene-S(O)NR A2 R A3 , -C 0~4 alkylene-C(O)R A2 , -C 0~4 alkylene-C(O)OR A2 , -C 0~4 alkylene-C(O)NR A2 R A3 , -C 0~4 alkylene-NR A2 R A3 , -C 0~4 alkylene-NR A2 C(O)R A3 , -C 0~4 alkylene-NR A2 S(O)²R A3 , -C 0~4 alkylene-NR A2 S(O)R A3 selected from, R A2 R A3 is independently hydrogen, -C 1-6 alkyl group, -C 2~6 alkenyl group, -C2~6 an alkynyl group, -C 1~6 a halogenated alkyl group, -C 2~6 a halogenated alkenyl group, -C 2~6 selected from a halogenated alkynyl group, R 2 is independently hydrogen, halogen, a cyano group, a nitro group, =O, =S, =CR 21 R 22 、-C 1~6 an alkyl group, -C 2~6 an alkenyl group, -C 2~6 an alkynyl group, -C 1~6 a halogenated alkyl group, -C 2~6 a halogenated alkenyl group, -C 2~6 a halogenated alkynyl group, -C 0~4 alkylene-OR 21 、-C 0~4 alkylene-OC(O)R 21 、-C 0~4 alkylene-SR 21 、-C 0~4 alkylene-S(O)2R 21 、-C 0~4 alkylene-S(O)R 21 、-C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further divided into one, two, three, or four independent groups. 23 Therefore, substitution is acceptable. Each R 23 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and =CR. 21 R 22 , -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 0~4 Alkilen-OR 21 , -C 0~4 Alkylene-OC(O)R 21 , -C 0~4 Alkilen-SR 21 , -C 0~4 Alkilen-S(O)2R 21 , -C 0~4 Alkylene-S(O)R 21 , -C 0~4 Alkylene-S(O)2NR 21 R 22 , -C 0~4 Alkylene-S(O)NR 21 R 22 , -C 0~4 Alkylene-C(O)R 21 , -C 0~4 Alkylene-C(O)OR 21 , -C 0~4 Alkylene-C(O)NR 21 R 22 , -C 0~4 Alkilen-NR 21 R 22 , -C 0~4 Alkilen-NR21 C(O)R 22 , -C 0~4 Alkilen-NR 21 S(O)2R 22 , -C 0~4 Alkilen-NR 21 S(O)R 22 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. 26 It may be replaced by, R 21 , R 22 These are hydrogen and -C, respectively, independently. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 1~4 Alkilen-OR 24 , -C 1~4 Alkylene-OC(O)R 24 , -C 1~4 Alkilen-SR 24 , -C 1~4 Alkilen-S(O)2R 24 , -C 1~4 Alkylene-S(O)R 24 , -C 1~4 Alkylene-S(O)2NR 24 R 25 , -C 1~4 Alkylene-S(O)NR 24 R 25 , -C 1~4 Alkylene-C(O)R 24 , -C 1~4 Alkylene-C(O)OR 24 , -C 1~4 Alkylene-C(O)NR24 R 25 , -C 1~4 Alkilen-NR 24 R 25 , -C 1~4 Alkilen-NR 24 C(O)R 25 , -C 1~4 Alkilen-NR 24 S(O)2R 25 , -C 1~4 Alkilen-NR 24 S(O)R 25 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. 26 It may be replaced by, Each R 26 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and =CR. 24 R 25 , -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 0~4 Alkilen-OR 24 , -C 0~4 Alkylene-OC(O)R 24 , -C 0~4 Alkilen-SR 24 , -C 0~4 Alkilen-S(O)2R 24 , -C 0~4 Alkylene-S(O)R 24 , -C 0~4 Alkylene-S(O)2NR 24 R 25 , -C 0~4 Alkylene-S(O)NR24 R 25 , -C 0~4 Alkylene-C(O)R 24 , -C 0~4 Alkylene-C(O)OR 24 , -C 0~4 Alkylene-C(O)NR 24 R 25 , -C 0~4 Alkilen-NR 24 R 25 , -C 0~4 Alkilen-NR 24 C(O)R 25 , -C 0~4 Alkilen-NR 24 S(O)2R 25 , -C 0~4 Alkilen-NR 24 S(O)R 25 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. 27 It may be replaced by, R 24 , R 25 These are hydrogen and -C, respectively, independently. 1-6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Selected from alkynyl halogenated groups, Each R 27 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6Alkenyl halide group, -C 2~6 Selected from alkynyl halogenated groups.

[0007] Furthermore, ring A is, [ka] These rings are selected from and further divided into one, two, three, or four independent R A1 It may be substituted by. In formula I, R bonded to ring A 2 The carbonyl group can be bonded to any of the substituted positions on the A ring.

[0008] Preferably, each R A1 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. 1~3 Alkyl alkyl group, -C 1~3 Selected from alkyl halogens.

[0009] Furthermore, ring A is, [ka] Selected from.

[0010] Preferably, the R 2 These are hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 0~4 Alkilen-OR 21 , -C 0~4 Alkylene-OC(O)R 21 , -C 0~4 Alkylene-C(O)R 21 , -C 0~4 Alkylene-C(O)OR 21 , -C 0~4 Alkylene-C(O)NR 21 R 22, -C 0~4 Alkilen-NR 21 R 22 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. 23 It may be replaced by, Each R 23 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 0~4 Alkilen-OR 21 , -C 0~4 Alkylene-OC(O)R 21 , -C 0~4 Alkylene-C(O)R 21 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. 26 It may be replaced by, R 21 , R 22 These are hydrogen and -C, respectively, independently. 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 1~4 Alkilen-OR 24 , -C 1~4 Alkylene-OC(O)R 24 , -C 1~4 Alkylene-C(O)R 24 , -C 1~4 Alkylene-C(O)OR 24 , -C 1~4 Alkylene-C(O)NR 24 R 25 , -C 1~4 Alkilen-NR 24 R 25 , -C 1~4 Alkilen-NR 24 C(O)R 25 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene-(5-10 membered heteroaromatic ring), where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further divided into one, two, three, or four independent R groups. 26 It may be replaced by, Each R 26 These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and =CR. 24 R 25 , -C 1~6 Alkyl alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, -C 1~6 Halogenated alkyl groups, -C 2~6 Alkenyl halide group, -C 2~6 Alkynyl halide group, -C 0~4 Alkilen-OR 24 , -C 0~4 Alkylene-OC(O)R 24 , -C 0~4 Alkylene-C(O)R 24 , -C 0~4Alkylene-C(O)OR 24 , -C 0~4 Alkylene-C(O)NR 24 R 25 , -C 0~4 Alkilen-NR 24 R 25 , -C 0~4 Alkilen-NR 24 C(O)R 25 , -C 0~4 Alkylene-(3-10 membered cycloalkyl group), -C 0~4 Alkylene-(4-10 member heterocycloalkyl group), -C 0~4 Alkylene-(6-10 member aromatic ring), -C 0~4 Selected from alkylene (5-10 membered heteroaromatic rings), R 24 , R 25 These are hydrogen and -C, respectively, independently. 1-3 Selected from alkyl groups and C1-C3 halogenated alkyl groups.

[0011] Furthermore, R 2 is -C(O)NR 21 R 22 , -C(O)R 21 , -C 0~2 Alkilen-NR 21 R 22 , -C(O)OR 21 Selected from, R 21 , R 22 These are hydrogen and -C, respectively, independently. 1~3 Alkyl alkyl group, -C 0~1 Alkylene-(6-membered aromatic ring), -C 0~1 Alkylene is selected from -(10-membered heteroaromatic ring), -(4-6 membered heterocycloalkyl group), and -(3-6 membered cycloalkyl group), where the aromatic ring, heteroaromatic ring, heterocycloalkyl group, and cycloalkyl group can be further divided into one, two, three, or four independent R groups. 26 It may be replaced by, Each R 26 These are hydrogen and -C, respectively, independently. 1~3 Alkyl group, -(4-6 member heterocycloalkyl group), -C(O)R 24 , -C(O)OR24 -OC(O)R 24 Selected from, R 24 The group is selected from hydrogen, methyl, and ethyl groups.

[0012] More specifically, R 2 is hydrogen, [ka] Selected from.

[0013] In some specific embodiments of the present invention, the compound is, specifically, [ka] That is the case.

[0014] The present invention provides for the use of any of the above-mentioned compounds, their stereoisomers, their deuterated compounds, or pharmaceutically acceptable salts thereof in the preparation of pharmaceutical compositions for treating diseases related to abnormal cell proliferation.

[0015] Furthermore, the aforementioned disease is cancer.

[0016] The present invention further provides the use of any of the above compounds, their stereoisomers, their deuterated compounds, or pharmaceutically acceptable salts thereof in the preparation of a target protein degradation agent.

[0017] Furthermore, the use of the aforementioned compound, its stereoisomer, its deuterated compound, or a pharmaceutically acceptable salt thereof as an intermediate in the preparation of a target protein degradation agent is provided.

[0018] Furthermore, the aforementioned target proteolytic agent is a drug that degrades proteins via the E3 ligase CRBN.

[0019] The compounds and derivatives provided in the present invention may be named according to the nomenclature of IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstract Service, Columbus, Ohio).

[0020] Definitions of terms used in this invention: Unless otherwise specified, the first definition provided for a base or term in this specification applies throughout this specification. Any terms not specifically defined in this specification will be understood by those skilled in the art based on the content and context of this invention.

[0021] "Substitution" means that a hydrogen atom within a molecule is replaced by another atom or molecule. "Substitution" also means that a lone pair of electrons on an atom within a molecule is replaced by "=O", "=S", etc.

[0022] "Further substitutions may occur" means that substitutions may or may not occur, and whether or not substitutions occur, they are included herein.

[0023] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, prefix C a ~ b The term "alkyl" refers to any alkyl group containing a to b carbon atoms. For example, C1-C4 alkyl groups refer to alkyl groups containing 1 to 4 carbon atoms.

[0024] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of constituent atoms. For example, a C1-6 alkyl group refers to an alkyl group having 1 to 6 constituent atoms, for example, 1 to 4 constituent atoms. Alkyl groups may be linear or branched. Typical branched alkyl groups have one, two, or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Examples of alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as C1-6 alkoxys.

[0025] The term "alkylene" as used in this invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of constituent atoms. a ~ b Alkylene refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and linear hydrocarbyl groups. For example, "C 1~6 "Alkylene" includes methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Therefore, for example, the term "propylene" has the following structure: [ka] This can be illustrated by the following structure: Similarly, the term "dimethylbutylene" can be used, for example, in the structure shown below: [ka] This can be illustrated by any of the following. Furthermore, the term "(C1-6) alkylene" is intended to include its branched hydrocarbyl group, for example, cyclopropylmethylene, as shown in the following structure: [ka] This can be illustrated by the following: Also, for example, C 0~4An alkylene group can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-), a C3 alkylene group, or a C4 alkylene group. C0 alkylene means that there is no group present, and the groups are linked in the form of chemical bonds. For example, A-C0 alkylene-B means AB, that is, groups A and B are directly linked via a chemical bond.

[0026] "Alkenyl" refers to a linear or branched hydrocarbon group having a predetermined number of carbon atoms, 2 to 6 or 2 to 4 carbon atoms in some embodiments, and at least one vinyl unsaturated moiety (>C=C<). For example, C a~b The term "alkenyl" refers to an alkenyl group having a to b carbon atoms, and is intended to include, for example, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0027] In this invention, the term "alkenylene group" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valencies. For example, the (C3-C6) alkenylene group includes >C=CH-CH2-, -CH-CH=CH-CH2-, and so on.

[0028] "Alkynyl" refers to a straight-chain monovalent hydrocarbon group or a branched-chain monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl" is also intended to include hydrocarbyl groups having one triple bond and one double bond. For example, C 2~6 Alkinyl is intended to include ethinyl, propynyl, etc.

[0029] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0030] "Alkyl halide" and "halogen-substituted alkyl" refer to a case where one or more hydrogen atoms in the alkyl group are substituted by halogens. For example, "C 1~4 "Alkyl halide" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms.

[0031] In this invention, "-OR", "-NRR", etc., refer to a configuration in which the R group is bonded to an oxygen atom or a nitrogen atom by a single bond.

[0032] In this invention, the oxygen atom in "-C(O)R", "-S(O)2R", etc., is bonded to a carbon atom or sulfur atom by a double bond, and the R group is bonded to an oxygen atom or sulfur atom by a single bond.

[0033] In this invention, "cycloalkyl group" and "cycloalkane" refer to saturated or partially saturated cyclic groups having multiple carbon atoms, lacking ring heteroatoms, and having a monocycle or multiple rings (including condensed, cross-linked, spiro, and adamantane systems). For polycyclic systems containing aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl group" (e.g., 5,6,7,8-tetralin-5-yl) is applied when the bonding site is located at a non-aromatic carbon atom. The term "cycloalkyl group" includes cycloalkenyls, such as cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. For example, [ka] Adamantyl is [ka] This includes, but is not limited to, the following:

[0034] The terms "heterocycle," "heterocycloalkyl," and "heterocycloalkane" as used in this invention refer to saturated or non-aromatic unsaturated rings containing at least one heteroatom. Here, a heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Typically, this refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 9 ring atoms, containing 1, 2, or 3 ring heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring refers to one consisting of two rings sharing two ring atoms, meaning that the bridge separating the two rings is a single bond or a chain consisting of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyls include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidine-3-yl, tetrahydrofuryl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, [ka] These include thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples of bicyclic saturated heterocycloalkyls include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, [ka] This includes: Examples of partially unsaturated heterocycloalkyls include dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl.

[0035] The terms "spiroheterocyclyl" and "spiroheterocycle" are interchangeable and refer to a non-aromatic saturated or non-aromatic unsaturated ring system having two monorings sharing one carbon atom. It consists of a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus. For example, a "5-12 membered spiroheterocycle" refers to a spiroheterocycle having 5-12 ring atoms, of which 1, 2, or 3 are heteroatoms.

[0036] A "bridged ring or bridged cyclic group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures that share two non-adjacent atoms. Specific examples include: [ka] This includes, but is not limited to, the following:

[0037] The terms "bridged heterocyclyl" and "bridged heterocycle" are interchangeable and refer to saturated or unsaturated cyclic groups formed by two or more cyclic structures sharing two non-adjacent atoms, consisting of a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples include: [ka] This includes, but is not limited to, the following:

[0038] As used in this invention, "aromatic ring" and "aryl" refer to an aromatic hydrocarbon group having 5 to 20 carbon atoms. "Aaryl" typically refers to a monocyclic, bicyclic, or tricyclic aryl group having multiple carbon atoms. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent that may be a single aromatic ring or a condensed group of aromatic rings. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0039] In this invention, "heteroaromatic ring" and "heteroaromatic ring group" refer to an unsaturated ring of the aromatic group containing at least one heteroatom, where the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Aromatic group heterocycles generally include aromatic monocyclic or bicyclic hydrocarbons containing multiple ring atoms, one or more of which are heteroatoms selected from O, N, and S. It is preferable that there are 1 to 3 heteroatoms. Heterocyclic aryls include, for example, pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzothienyl, benzopyranyl, benzothiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0040] "Stereoisomers" include enantiomers and diastereomers. The "deuterated compound" of the present invention means that one or more hydrogen atoms in the molecule or group are replaced by deuterium atoms, and the proportion of deuterium atoms is greater than the amount of deuterium present in nature.

[0041] The term "pharmaceutically acceptable" means that the carrier, vehicle, diluent, excipient and / or the salt formed is generally chemically or physically compatible with the other components constituting the pharmaceutical dosage form and physiologically compatible with the receptor.

[0042] The terms “salt” and “pharmaceutically acceptable salt” refer to acidic and / or basic salts formed between the above-mentioned compounds or their stereoisomers and inorganic and / or organic acids and bases, including zwitterionic salts (intramolecular salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compounds. These salts can also be obtained by appropriately mixing the above-mentioned compounds or their stereoisomers with a certain amount of acid or base (e.g., equivalent). These salts may form a precipitate in solution and be collected by filtration, or recovered after evaporation of the solvent, or by reacting in an aqueous medium and then freeze-drying. The salts described in the present invention may be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoric acid, phosphate, acetate, propionate, succinate, oxalate, malate, butanediate, fumarate, maleate, tartrate, or trifluoroacetate of the compounds.

[0043] Clearly, according to the above-described content of the present invention, various other forms of modifications, substitutions, or alterations can be made in accordance with the general technical knowledge and common means of the art, without departing from the above-described basic technical idea of ​​the present invention. [Modes for carrying out the invention]

[0044] The above-described content of the present invention will be further explained below with reference to examples. However, this should not be interpreted as meaning that the scope of the subject matter of the present invention is limited to the examples. All techniques performed based on the above-described content of the present invention fall within the scope of the present invention.

[0045] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Energy Chemical, Chengdu Kelong Chemical, Accela ChemBio Co., Ltd, and J&K Scientific.

[0046] The abbreviations for the reagents described in the examples are as follows: DIPEA: N,N-diisopropylethylamine HATU:2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate DIPEA: N,N-diisopropylethylamine HATU:2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate HOBT: 1-hydroxybenzotriazole DMSO: Dimethyl sulfoxide LC-MS: High-performance liquid chromatography-mass spectrometry NaCl: Sodium Chloride MPLC: Preparative Medium Pressure Liquid Chromatography EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Pd(OAc)2: Palladium acetate DMF: N,N-dimethylformamide AIBN: Azobisisobutyronitrile NBS: N-bromosuccinimide BPO: Benzoyl peroxide

[0047] Unless otherwise specified in the examples, the reaction was carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution was an aqueous solution. Unless otherwise specified in the examples, the reaction temperature was room temperature. Room temperature of 20°C to 30°C was the most suitable reaction temperature. Unless otherwise specified in the examples, M was moles / liter.

[0048] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was 10 -6The values ​​are expressed in ppm. NMR was measured using nuclear magnetic spectrometers (Bruker Avance III 400 and Bruker Avance 600). The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (methanol-d4), with tetramethylsilane (TMS) as the internal standard. LC-MS measurements were performed using a Shimadzu LC-MS 2020 (ESI) liquid chromatography-mass spectrometer. HPLC measurements were performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reverse-phase preparative chromatograph. Thin-layer chromatography silica gel plates were either Yantai Huanghai's HSGF254 or Qingdao's GF254 silica gel plates, and the thin-layer chromatography specification for product separation and purification was 0.4 mm to 0.5 mm. For column chromatography, Yantai Huanghai's Silica Gel 200 to 300 mesh silica gel was generally used as the support.

[0049] Example 1: Preparation of Compound A1 [ka]

[0050] Step 1: Preparation of Compound A-3 [ka] Compound A-2 (50.00 mg, 211.65 μmol), DIPEA (132.25 mg, 0.80 mmol, 178.06 μL), HATU (250.96 mg, 0.66 mmol), and dichloromethane (2 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0°C, compound A-1 (86.29 mg, 1.06 mmol) was added, and the mixture was reacted for 0.5 hours with stirring under ice bath conditions. The reaction was then quenched (under LC-MS monitoring), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, evaporated the solvent to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A-3 (crude).

[0051] Step 2: Preparation of Compound A-4 [ka] Compound A-3 (crude), sodium hydroxide (47.95 mg, 854.50 mmol), tetrahydrofuran (4 mL), and water (2 mL) were added sequentially to a 50 mL reaction flask. The reaction was allowed to proceed at room temperature with stirring for 8 hours. The reaction was then quenched (under LC-MS monitoring), the pH of the system was adjusted to 6.0-7.0 with 1 N hydrochloric acid solution, and the reaction mixture was concentrated to obtain compound A-4 (crude), which was then used directly in the next reaction.

[0052] Step 3: Synthesis of Compound A1 [ka] Compound A-4 (8.70 mg, 34.90 μmol), EDCI (13.33 mg, 69.80 μmol), HOBT (9.43 mg, 69.80 μmol), DIPEA (11.28 mg, 87.25 μmol, 15.20 μL), and DMSO (1 mL) were added sequentially to a 50 mL reaction flask. After reacting at room temperature for 10 minutes, compound A-5 (4.89 mg, 34.90 μmol) was added, and the mixture was reacted at room temperature with stirring for 1 hour. The reaction was then quenched (under LC-MS monitoring), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, evaporated the solvent to dryness, concentrated under reduced pressure, and purified compound A1 by MPLC (2.30 mg, 6.20 μmol, 17.12% yield, purity 81.1%). LC-MS:C 18 H 18 N3O4S,[M+H]+372.1;found 372.2.1H NMR(400MHz,Methanol-d4)δ7.98-7.95(m,2H),7.54-7.49(m,2H),4.44-4.05(m,4H),3.21(s,3H),3.13(s,3H),3.03-2.99(m,2H)

[0053] Compounds A2-A11 were obtained by following the same procedure as for the synthesis of compound A1, except that starting material 1 shown in Table 1 below was used instead of compound A-1, and starting material 2 was used instead of compound A-2. [Table 1] TIFF0007856847000020.tif255166TIFF0007856847000021.tif255169TIFF0007856847000022.tif45170

[0054] Example 2: Preparation of Compound A16 [ka]

[0055] Step 1: Synthesis of Compound A12 [ka] Compounds A-16 (20.00 mg, 112.23 μmol), A-5 (15.73 mg, 112.23 μmol), EDCI (42.87 mg, 224.46 μmol), and pyridine (2 mL) were sequentially added to a 50 mL reaction flask. The mixture was reacted for 0.5 hours under ice bath conditions with stirring. The reaction was then quenched (under LC-MS monitoring), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, purified by MPLC, evaporated to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A12 (10.00 mg, 33.30 μmol, 29.67% yield, 99.9% purity). LC-MS:C 15 H 13 N2O3S,[M+H] + 301.1; found 301.2. 1 H NMR(600MHz,DMSO-d6)δ11.29(s,1H),8.04(d,J=7.8Hz,1H),7.96(d,J=7.8Hz,1H),7.86(s,1H),7. 51-7.44(m,2H),4.71(d,J=9.0Hz,1H),4.61(d,J=9.0Hz,1H),4.25(m,1H),4.11(m,1H),3.03(s,2H)

[0056] Compounds A13 and A14 were obtained by following the synthesis method for compound A12, except that starting material 1 shown in Table 2 was used instead of compound A-16.

[0057] [Table 2]

[0058] Example 3: Preparation of Compound A15 [ka]

[0059] Step 1: Synthesis of Compound A-20 [ka] Compound A-19 (155.00 mg, 0.75 mmol), DIPEA (132.25 mg, 1.00 mmol, 178.06 μL), HATU (250.96 mg, 0.66 mmol), and dichloromethane (2 mL) were added sequentially to a 50 mL reaction flask. After the reaction system temperature dropped to 0°C, compound A-1 (190.00 mg, 0.75 mmol) was added, and the mixture was reacted for 0.5 hours with stirring under ice bath conditions. The reaction was then quenched (under LC-MS monitoring), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, evaporated the solvent to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A-20 (100.00 mg, crude).

[0060] Step 2: Synthesis of Compound A-21 [ka] Under nitrogen gas protection, A-20 (117.00 mg, 0.50 mmol), sodium carbonate (91.00 mg, 1.00 mmol), Mo(CO)6 (169.30 mg, 0.75 mmol), Pd(OAc)2 (9.6 mg, 0.05 mmol), and Bu3PBF4 (24.73 mg, 0.10 mmol) were dissolved in DMF / H2O (10 mL, 1:1). After heating at 85°C for 2 hours, the solvent was evaporated to dryness, and the product was purified by MPLC to obtain A-21 (70.00 mg, 70.35%).

[0061] Step 3: Synthesis of Compound A15 [ka] Compounds A-21 (20.00 mg, 100.39 μmol), A-5 (14.07 mg, 100.39 μmol), EDCI (19.17 mg, 100.39 μmol), and pyridine (2 mL) were sequentially added to a 50 mL reaction flask. The reaction was carried out for 0.5 hours under ice bath conditions with stirring. The reaction was then quenched (monitored by LC-MS), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, purified by MPLC, evaporated to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A15 (5.00 mg, 15.56 μmol, 15.50% yield, 99.9% purity). LC-MS:C 14 H 16 N3O4S,[M+H] + 322.1; found 322.1. 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),7.72(d,J=5.2Hz,1H),7.21(d,J=5.2Hz,1H),4.39-4.10(m,3H),4.00(m,1H),3.08-2.76(m,8H)

[0062] Example 4: Preparation of Compound A16 [ka]

[0063] Step 1: Synthesis of Compound A-23 [ka] Compound A-22 (500.00 mg, 2.64 mmol), DMAP (322.83 mg, 2.64 mmol), and Boc2O (8.64 g, 39.64 mmol) were added sequentially to a 50 mL reaction flask. The reaction was carried out overnight at room temperature with stirring, and after the solvent was evaporated to dryness, A-23 was obtained by purification using MPLC (700.00 mg, 2.42 mmol, 91.56% yield).

[0064] Step 2: Synthesis of Compound A-24 [ka] Compound A-23 (700.00 mg, 2.42 mmol), NBS (452.15 mg, 2.54 mmol), AIBN (79.46 mg, 483.88 μmol), and carbon tetrachloride (7 mL) were added sequentially to a 50 mL reaction flask. The mixture was reacted overnight under reflux, and after evaporating the solvent to dryness, A-24 was obtained by purification using MPLC (700.00 mg, 1.90 mmol, 78.57% yield).

[0065] Step 3: Synthesis of Compound A-25 [ka] Compounds A-1 (36.73 mg, 814.73 μmol), A-24 (100.00 mg, 271.58 μmol), potassium carbonate (187.39 mg, 1.36 mmol), and DMF (2 mL) were added sequentially to a 50 mL reaction flask. After stirring at 60°C for 2 hours, the mixture was purified by MPLC to obtain A-25 (50.00 mg, 150.42 μmol, 55.39% yield).

[0066] Step 4: Synthesis of Compound A-26 [ka] Compound A-25 (50.00 mg, 150.42 μmol), sodium hydroxide (60.17 mg, 1.50 mmol), and MeOH / H2O (2 mL, 1:1) were added sequentially to a 50 mL reaction flask. The mixture was stirred under reflux for 2 hours, the pH was adjusted by adding 1 M aqueous HCl, the solvent was evaporated to dryness, and the compound was purified by MPLC to obtain A-26 (45.00 mg, 141.35 μmol, 93.97% yield).

[0067] Step 5: Synthesis of Compound A-27 [ka] Compound A-26 (45.00 mg, 141.35 μmol) was dissolved in hydrochloric acid / dioxane (2 mL). After stirring at room temperature for 2 hours, the solvent was evaporated to dryness to obtain A-27 (30.00 mg, 137.46 μmol, 97.25% yield).

[0068] Step 6: Synthesis of Compound A16

Chemical Structure

[0069] Compound A17 was obtained by operating according to the synthesis method of Compound A16, except that the raw materials shown in Table 3 below were used instead of Compound A-22.

[0070]

Table 3

[0071] Example 5: Preparation of Compound A18 [ka]

[0072] Step 1: Synthesis of Compound A-30 [ka] Compounds A-29 (1.00 g, 5.20 mmol), A-1 (703.57 mg, 15.61 mmol), EDCI (2.99 g, 15.61 mmol), and pyridine (10 mL) were added sequentially to a 25 mL reaction flask. The mixture was reacted for 0.5 hours under ice bath conditions with stirring, then the reaction was quenched (monitored by LC-MS), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined the organic phases, dried the organic phases over anhydrous sodium sulfate, purified by MPLC, evaporated the solvent to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A-30 (1.13 g, 5.15 mmol, 99.05% yield).

[0073] Step 2: Synthesis of Compound A-31 [ka] Compound A-30 (100.00 mg, 455.99 μmol), BPO (22.09 mg, 91.20 μmol), NBS (85.22 mg, 478.79 μmol), and DCM (5 mL) were added sequentially to a 25 mL reaction flask. The mixture was stirred overnight and purified by MPLC to obtain A-31 (115.00 mg, 385.65 μmol, 84.57% yield).

[0074] Step 3: Synthesis of Compound A18 [ka] Compounds A-31 (45.00 mg, 150.91 μmol), A-5 (21.15 mg, 150.91 μmol), sodium bicarbonate (63.38 mg, 754.53 μmol), and DMF (1 mL) were sequentially added to a 25 mL reaction flask. The mixture was stirred overnight at room temperature, and A18 was obtained by purification using MPLC (17.85 mg, 49.94 μmol, 33.09% yield, 98.1% purity). LC-MS:C 18 H 21 N4O3,[M+H] + 341.2; found 341.1 1 H NMR(400MHz,DMSO-d6)δ7.53(m,1H),7.42(dd,J=6.6,2.4Hz,1H),7.14(m,2H),4. 17(d,J=8.3Hz,2H),4.01(d,J=9.2Hz,2H),3.78(s,2H),2.97(s,2H),2.22(s,6H)

[0075] Example 6: Preparation of Compound A19 [ka]

[0076] Step 1: Synthesis of Compound A-33 [ka] Compound A-32 (500.00 mg, 2.85 mmol), HATU (1.08 g, 2.85 mmol), DIPEA (368.88 mg, 2.85 mmol, 497.14 μL), and dichloromethane (10 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred in an ice bath for 20 minutes, and then A-1 (128.67 mg, 2.85 mmol) was added. After stirring at room temperature for 1 hour, the solvent was evaporated to dryness, and the mixture was purified by MPLC to obtain A-33 (500.00 mg, 2.47 mmol, 86.62% yield).

[0077] Step 2: Synthesis of Compound A-34 [ka] Compound A-33 (500.00 mg, 2.47 mmol), phosphorus oxychloride (1.13 g, 7.41 mmol) and DMF (15 mL) were sequentially added to a 50 mL reaction flask. The mixture was stirred at room temperature for 2 hours and purified by MPLC to obtain A-34 (430.00 mg, 1.88 mmol, 75.62%).

[0078] Step 3: Synthesis of Compound A-35

Chemical Structure

[0079] Step 4: Synthesis of Compound A19

Chemical Structure

[0080] Example 7: Preparation of Compound A20 [ka]

[0081] Step 1: Synthesis of Compound A-37 [ka] Compound A-36 (410.00 mg, 2.33 mmol), HATU (1.06 g, 2.79 mmol), DIPEA (902.37 mg, 6.98 mmol, 1.22 mL), and dichloromethane (10 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred in an ice bath for 20 minutes, and A-1 (128.67 mg, 2.85 mmol) was added. After stirring at room temperature for 1 hour, the solvent was evaporated to dryness, and the mixture was purified by MPLC to obtain A-37 (397.00 mg, 1.95 mmol, 83.93% yield).

[0082] Step 2: Synthesis of Compound A-38 [ka] Compound A-37 (560.00 mg, 2.76 mmol), NBS (637.54 mg, 3.58 mmol), AIBN (22.62 mg, 137.77 μmol), and chlorobenzene (10 mL) were added sequentially to a 50 mL reaction flask. The mixture was reacted overnight under reflux, and after evaporating the solvent to dryness, it was purified by MPLC to obtain A-38 (449.00 mg, 1.59 mmol, 57.76% yield).

[0083] Step 3: Synthesis of Compound A-40 [ka] Compounds A-38 (449.00 mg, 1.59 mmol), A-39 (478.13 mg, 6.37 mmol), and DMF (5 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred overnight at room temperature and purified by MPLC to obtain A-40 (187.00 mg, 860.88 μmol, 54.09% yield).

[0084] Step 4: Synthesis of Compound A-41 [ka] Compound A-40 (187.00 mg, 860.88 μmol), sodium dihydrogen phosphate (381.26 mg, 2.44 mmol), hydrogen peroxide ( 35.14 mg, 1.03 mmol) and sodium chlorite (174.59 mg, 1.12 mmol) were dissolved in acetonitrile / water (10 mL). The mixture was stirred overnight at room temperature, and after evaporating the solvent to dryness, it was purified by MPLC to obtain A-41 (140.00 mg, 600.29 μmol, 69.73% yield).

[0085] Step 5: Synthesis of Compound A20 [ka] Compounds A-41 (30.00 mg, 128.63 μmol), A-5 (18.03 mg, 128.63 μmol), EDCI (25.47 mg, 128.63 μmol), and pyridine (3 mL) were sequentially added to a 25 mL reaction flask. The reaction was carried out for 0.5 hours under ice bath conditions with stirring. The reaction was then quenched (monitored by LC-MS), extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL), combined with the organic phase, dried over anhydrous sodium sulfate, purified by MPLC, evaporated to dryness, and concentrated under reduced pressure to remove the solvent and obtain compound A20 (8.00 mg, 22.51 μmol, 17.50% yield, 99.1% purity). LC-MS:C 18 H 18 N3O5,[M+H]+ 355.1; found 355.2 1 H NMR(400MHz,DMSO-d6)δ11.23(s,1H),7.78(d,J=7.6Hz,1H),7.72(d,J=8.4Hz,1H),7. 50(t,J=7.6Hz,1H),7.42(t,J=7.6Hz,1H),4.35-3.93(m,4H),3.07(m,6H),2.96(m,2H)

[0086] The technical effects of the present invention will be explained using the following test examples.

[0087] Test Example 1: Detection of compound inhibition of CRBN / DDB1 activity (FRET)

[0088] 1. Experimental materials and reagents Microplate reader (BMG PHERAstar FSX), ECHO (LABCYTE Echo 665), microplate thermostat (Hangzhou Ruicheng Instruments Co., Ltd.), disodium hydrogen phosphate (Sigma), bovine serum albumin (Sigma), Anti-6His-Tb crypate Gold (CISBIO), CRBN / DDB1 protein (HitGen), 384-well plate (Grenier Bio-one).

[0089] 2. Experimental Method The compound's dry powder was dissolved in DMSO, and the compound was serially diluted using ECHO. This was then added to a 384-well plate, and the final concentration of DMSO in the entire reaction system (10.0 μL) was adjusted to 1.0%, with an equal volume of DMSO added as a control.

[0090] The CRBN / DDB1 protein was diluted to twice the required final concentration (5.0 nM) using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, and pH 7.0 buffer. 5.0 μL of the diluted CRBN / DDB1 protein was aspirated and added to a 384-well plate containing the compound. The plate was centrifuged at 1000 rpm for 1 minute, and then pre-incubated in a microplate incubator at 25°C and 250 rpm for 15 minutes. Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analogs were diluted to twice the required final concentration using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, and pH 7.0 buffer. The final concentration of Anti-6His-Tb crypate Gold was 0.2 nM, and the final concentration of the FITC-labeled thalidomide analog was 50.0 nM, obtaining a mixture of Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analog. 5.0 μL of the Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analog mixture was aspirated, added to a 384-well plate, centrifuged at 1000 rpm for 1 minute, and then incubated in a microplate incubator at 25°C and 250 rpm for 30 minutes. After the reaction was complete, the fluorescence signal values ​​in the 384-well plate were read using a microplate reader (Ex=337nm; Em=520 / 490nm).

[0091] 3. Data Analysis The solvent group (containing 5.0 nM CRBN / DDB1, 0.2 nM Anti-6His-Tb crypate Gold, 50.0 nM FITC-labeled thalidomide analog, and 1.0% DMSO) was used as a negative control, and the reaction buffer group (containing 0.2 nM Anti-6His-Tb crypate Gold, 50.0 nM FITC-labeled thalidomide analog, and 1.0% DMSO) was used as a blank control.

[0092] The residual activity percentage for each concentration was calculated using the following formula. Residual activity (%)=100%×(Flu化合物群 -Flu ブランク対照 ) / (Flu 陰性対照 -Flu ブランク対照 ) Subsequently, the dose-effect curve was fitted using GraphPad 6.0 to obtain IC. 50 The value was calculated.

[0093] Table 1: Compounds and CRBN / DDB1 protein inhibition table [Table 4]

[0094] Here, + represents 200 μM > IC 50 >100μM indicates ++, where 100μM >IC 50 >10μM indicates +++, and +++ indicates 10μM >IC 50 >1μM indicates ++++, and 1μM >IC 50 >0.1μM indicates ++++, IC 50 This indicates a concentration of <0.1 μM.

[0095] Test Example 2: ITC (Isothermal Titration Calorimetry) Detection of Binding Between Compound and CRBN / DDB1 1. Experimental materials and reagents Disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), Tween20 (Sigma), dimethyl sulfoxide (Sigma), desalting column (Thermo Scientific, #89882), microplate reader (BMG PHERAstar FSX), CRBN / DDB1 protein (HitGen), MicroCal PEAQ-ITC (Malvern).

[0096] 2. Experimental Method 6.1 mL of 200 mM disodium hydrogen phosphate aqueous solution and 3.9 mL of 200 mM sodium dihydrogen phosphate aqueous solution were mixed to obtain a 200 mM PB buffer (pH 7.0). 600 μL of the 200 mM PB buffer and 3 μL of 10% Ethanol 20 aqueous solution were added to 5397 μL of deionized water and mixed uniformly to obtain a pH 7.0 detection buffer.

[0097] Using the prepared detection buffer described above, the desalting column Zeba TM Following the instructions in the Spin Desalting Columns instructions (Thermo Scientific, #89882), perform buffer replacement in the protein preservation solution, and after replacement, measure the OD of the protein solution using a microplate reader (BMG PHERAstar FSX). 280nm The UV absorption was measured, and the concentration after substitution was calculated. Based on the measured concentration, the protein was diluted to 10 μM with detection buffer, and DMSO was added until the final concentration was 1% and the total volume was 300 μL. After short centrifugation at room temperature, the solution was stored until use.

[0098] The dry powder of the compound was dissolved in DMSO, and the compound was further diluted to 100 μM with the above detection buffer, adjusting the DMSO concentration to 1% and total volume 100 μL. At room temperature, this compound solution was centrifuged at 15,000 rpm for 5 minutes, and then at least 75 μL of the supernatant was taken and stored until use.

[0099] The MicroCal PEAQ-ITC ITC instrument was cleaned according to the instrument's program, and after cleaning, the cleanliness and condition of the instrument were detected by a droplet experiment. When titrating the sample, the protein sample was added to the sample cell, and the compound solution was added to the titrator. The instrument temperature was set to 25°C, the Reference Power (ucal / s) to 5.00, the feedback model to "High", and the stirring speed to 750 rpm. A total of 19 drops were titrated, and when titrating the remaining 18 drops (excluding the first drop), 2 μL / 4 s was used each time, with a 150-second equilibration between drops. After the titration was complete, the instrument was cleaned. The droplet experiment was performed again to ensure good cleanliness and condition of the instrument. Subsequently, a control titration was performed, the compound was prepared as described above, added to the titrator, and 300 μL of 1% DMSO-containing detection buffer was prepared separately and added to the sample cell. The instrument parameters were set in the same way as above, and the titration was performed.

[0100] 3. Data Analysis Using the analysis software of the ITC instrument itself, a fitting was performed in "one set of sites" mode, and after subtracting the background according to the control experiment, reaction-related parameters such as N, KD, δH, δG, and δS were obtained.

[0101] Table 2: Compound binding table to CRBN / DDB1 protein [Table 5]

[0102] As can be seen from the above experiments, compound A of the examples of the present invention has good CRBN binding ability and inhibitory effect, and can be applied to the treatment of diseases related to CRBN activity abnormalities.

Claims

1. A compound represented by the following formula I, its stereoisomer, its deuterated compound, or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 Equation I (In the formula, == O represents the presence or absence of oxygen substitution, Ring A is selected from 3-12 membered cycloalkyl groups, 4-12 membered heterocycloalkyl groups, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings, and the cycloalkyl group, heterocycloalkyl group, aromatic ring, or heteroaromatic ring bonded to R2 may have one, two, three, or four independent R2s. Ａ１ It may be replaced by, Each R Ａ１ is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR Ａ２ , -C ０～４ alkylene - OC(O)R Ａ２ , -C ０～４ alkylene - SR Ａ２ , -C ０～４ alkylene - S(O) ２ R Ａ２ , -C ０～４ alkylene - S(O)R Ａ２ , -C ０～４ alkylene - S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ alkylene - S(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - C(O)R Ａ２ , -C ０～４ alkylene - C(O)OR Ａ２ , -C ０～４ alkylene - C(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ C(O)R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O) ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O)R Ａ３ , -C ０～４ alkylene - (3 - 10 member cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. Ａ４ It may be replaced by, Each R Ａ４ is independently hydrogen, a halogen, a cyano group, a nitro group, =O, =S, =CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR Ａ２ , -C ０～４ alkylene - OC(O)R Ａ２ , -C ０～４ alkylene - SR Ａ２ , -C ０～４ alkylene - S(O) ２ R Ａ２ , -C ０～４ alkylene - S(O)R Ａ２ , -C ０～４ alkylene - S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ alkylene - S(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - C(O)R Ａ２ , -C ０～４ alkylene - C(O)OR Ａ２ , -C ０～４ alkylene - C(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ C(O)R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O) ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O)R Ａ３ selected from R Ａ２ , R Ａ３ These are hydrogen and -C, respectively, independently. １－６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Selected from alkynyl halogenated groups, R ２ These are independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２１ R ２２ , -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２１ , -C ０～４ Alkylene-OC(O)R ２１ , -C ０～４ Alkilen-SR ２１ , -C ０～４ Alkylene-S(O) ２ R ２１ , -C ０～４ Alkylene-S(O)R ２１ , -C ０～４ Alkylene-S(O) ２ NR ２１ R ２２ , -C ０～４ Alkylene-S(O)NR ２１ R ２２ , -C ０～４ Alkylene-C(O)R ２１ , -C ０～４ Alkylene-C(O)OR ２１ , -C ０～４ Alkylene-C(O)NR ２１ R ２２ , -C ０～４ Alkylene-NR ２１ R ２２ , -C ０～４ Alkylene-NR ２１ C(O)R ２２ , -C ０～４ Alkylene-NR ２１ S(O) ２ R ２２ , -C ０～４ Alkylene-NR ２１ S(O)R ２２ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２３ It may be replaced by, Each R ２３ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２１ R ２２ , -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２１ , -C ０～４ Alkylene-OC(O)R ２１ , -C ０～４ Alkilen-SR ２１ , -C ０～４ Alkylene-S(O) ２ R ２１ , -C ０～４ Alkylene-S(O)R ２１ , -C ０～４ Alkylene-S(O) ２ NR ２１ R ２２ , -C ０～４ Alkylene-S(O)NR ２１ R ２２ , -C ０～４ Alkylene-C(O)R ２１ , -C ０～４ Alkylene-C(O)OR ２１ , -C ０～４ Alkylene-C(O)NR ２１ R ２２ , -C ０～４ Alkylene-NR ２１ R ２２ , -C ０～４ Alkylene-NR ２１ C(O)R ２２ , -C ０～４ Alkylene-NR ２１ S(O) ２ R ２２ , -C ０～４ Alkylene-NR ２１ S(O)R ２２ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２６ It may be replaced by, R ２１ , R ２２ These are hydrogen and -C, respectively, independently. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C １～４ Alkylene-OR ２４ , -C １～４ Alkylene-OC(O)R ２４ , -C １～４ Alkilen-SR ２４ , -C １～４ Alkylene-S(O) ２ R ２４ , -C １～４ Alkylene-S(O)R ２４ , -C １～４ Alkylene-S(O) ２ NR ２４ R ２５ , -C １～４ Alkylene-S(O)NR ２４ R ２５ , -C １～４ Alkylene-C(O)R ２４ , -C １～４ Alkylene-C(O)OR ２４ , -C １～４ Alkylene-C(O)NR ２４ R ２５ , -C １～４ Alkylene-NR ２４ R ２５ , -C １～４ Alkylene-NR ２４ C(O)R ２５ , -C １～４ Alkylene-NR ２４ S(O) ２ R ２５ , -C １～４ Alkylene-NR ２４ S(O)R ２５ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２６ It may be replaced by, Each R ２６ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２４ R ２５ , -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２４ , -C ０～４ Alkylene-OC(O)R ２４ , -C ０～４ Alkilen-SR ２４ , -C ０～４ Alkylene-S(O) ２ R ２４ , -C ０～４ Alkylene-S(O)R ２４ , -C ０～４ Alkylene-S(O) ２ NR ２４ R ２５ , -C ０～４ Alkylene-S(O)NR ２４ R ２５ , -C ０～４ Alkylene-C(O)R ２４ , -C ０～４ Alkylene-C(O)OR ２４ , -C ０～４ Alkylene-C(O)NR ２４ R ２５ , -C ０～４ Alkylene-NR ２４ R ２５ , -C ０～４ Alkylene-NR ２４ C(O)R ２５ , -C ０～４ Alkylene-NR ２４ S(O) ２ R ２５ , -C ０～４ Alkylene-NR ２４ S(O)R ２５ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２７ It may be replaced by, R ２４ , R ２５ These are hydrogen and -C, respectively, independently. １－６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Selected from alkynyl halogenated groups, Each R ２７ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ (Selected from alkynyl halogenated groups.)

2. Ring A is, 【Chemistry 2】 A ring is selected from the rings represented by , and these rings are further divided into one, two, three, or four independent R Ａ１ The compound according to claim 1, characterized in that it may be substituted by

3. Each R Ａ１ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. １～３ Alkyl alkyl group, -C １～３ The compound according to claim 2, characterized in that it is selected from alkyl halogens.

4. Ring A is, 【Transformation 3】 The compound according to claim 1, characterized by being selected from among.

5. R ２ These are hydrogen, halogen, cyano group, nitro group, =O, =S, -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２１ , -C ０～４ Alkylene-OC(O)R ２１ , -C ０～４ Alkylene-C(O)R ２１ , -C ０～４ Alkylene-C(O)OR ２１ , -C ０～４ Alkylene-C(O)NR ２１ R ２２ , -C ０～４ Alkylene-NR ２１ R ２２ ;-C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２３ It may be replaced by, Each R ２３ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, and -C. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２１ , -C ０～４ Alkylene-OC(O)R ２１ , -C ０～４ Alkylene-C(O)R ２１ ;-C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２６ It may be replaced by, R ２１ , R ２２ These are hydrogen and -C, respectively, independently. １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C １～４ Alkylene-OR ２４ , -C １～４ Alkylene-OC(O)R ２４ , -C １～４ Alkylene-C(O)R ２４ , -C １～４ Alkylene-C(O)OR ２４ , -C １～４ Alkylene-C(O)NR ２４ R ２５ , -C １～４ Alkylene-NR ２４ R ２５ , -C １～４ Alkylene-NR ２４ C(O)R ２５ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylene (5-10 membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further consist of one, two, three, or four independent R groups. ２６ It may be replaced by, Each R ２６ These are, independently, hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２４ R ２５ , -C １～６ Alkyl alkyl group, -C ２～６ Alkenyl group, -C ２～６ Alkynyl group, -C １～６ Alkyl halogenated compounds, -C ２～６ Alkenyl halogen group, -C ２～６ Alkynyl halogenated group, -C ０～４ Alkylene-OR ２４ , -C ０～４ Alkylene-OC(O)R ２４ , -C ０～４ Alkylene-C(O)R ２４ , -C ０～４ Alkylene-C(O)OR ２４ , -C ０～４ Alkylene-C(O)NR ２４ R ２５ , -C ０～４ Alkylene-NR ２４ R ２５ , -C ０～４ Alkylene-NR ２４ C(O)R ２５ , -C ０～４ Alkylene-(3-10 membered cycloalkyl group), -C ０～４ Alkylene-(4-10 member heterocycloalkyl group), -C ０～４ Alkylene-(6-10 membered aromatic ring), -C ０～４ Selected from alkylenes (5-10 membered heteroaromatic rings), R ２４ , R ２５ These are hydrogen and -C, respectively, independently. １－３ Alkyl alkyl group, -C １～３ Selected from halogenated alkyl groups A compound according to claim 1 or 4, a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof.

6. R ２ is -C(O)NR ２１ R ２２ , -C(O)R ２１ , -C ０～２ Alkylene-NR ２１ R ２２ , -C(O)OR ２１ Selected from, R ２１ , R ２２ These are hydrogen and -C, respectively, independently. １～３ Alkyl alkyl group, -C ０～１ Alkylene-(six-membered aromatic ring),-C ０～１ Alkylene is selected from -(10-membered heteroaromatic ring), -(4-6 membered heterocycloalkyl group), and -(3-6 membered cycloalkyl group), and the aromatic ring, heteroaromatic ring, heterocycloalkyl group, and cycloalkyl group may further be one, two, three, or four independent R ２６ It may be replaced by, Each R ２６ These are hydrogen and -C, respectively, independently. １～３ Alkyl alkyl group, -(4-6 member heterocycloalkyl group), -C(O)R ２４ , -C(O)OR ２４ , -OC(O)R ２４ Selected from, R ２４ The group is selected from hydrogen, methyl, and ethyl groups. The compound according to feature 5.

7. R ２ is hydrogen, 【Chemistry 4】 The compound according to claim 6, characterized by being selected from among.

8. The aforementioned compound, 【Transformation 5】 A compound according to any one of claims 1 to 7, characterized by being selected from among.

9. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for treating a disease related to abnormal cell proliferation.

10. The use according to claim 9, characterized in that the disease is cancer.

11. Use of a compound according to any one of claims 1 to 8, a stereoisomer thereof, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof in the production of a targeted protein degradation agent.

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