Fused ring compounds and their uses

Abstract

The present invention provides a compound represented by the following formula (I), which has binding activity to CRBN, an E3 ligase protein, and use of the compound in the manufacture of a therapeutic agent for an abnormal cell proliferation disorder. JPEG2026505431000026.jpg5759

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and specifically to novel spirocyclic ligand compounds that have the ability to bind to cereblon E3 ubiquitin ligase protein. [Background technology]

[0002] Protein degradation is a highly regulated process essential for maintaining cellular homeostasis. The ubiquitin-proteasome pathway (UPP) selectively identifies and removes damaged, misfolded, or excess proteins. The UPP, which is responsible for removing abnormal proteins, is ATP-dependent, highly efficient, and highly selective. Its catalytic component is a ubiquitination E3 ligase. However, the protein to be degraded must first be recruited. PROTACs technology, designed based on the UPP principle, utilizes appropriate chemical bonds between target protein ligands and E3 ligase ligands to identify the target protein, enhance the binding ability of the ligase E3 to the target protein, and then ubiquitinate the target protein for forced degradation. These technologies offer advantages such as high catalytic yield, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules are covalently attached to terminal lysine residues via E3 ubiquitin ligases to target proteins for degradation by the proteasome. The proteins are then degraded into small peptides and ultimately into their constituent amino acids, which are used as building blocks for new proteins. Defective proteasomal degradation has been 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 and part of the E3 ubiquitin ligase protein complex, functioning 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), cullin-4A (CUL4A), and regulator of cullin-1 (ROCI). This complex can ubiquitinate a range of proteins, but its specific mechanism of action remains unknown. Cereblon is currently known as an E3 ligase commonly used in PROTACs technology.

[0005] The present invention discloses novel spirocyclic compounds that are effective as CRBN ligands and can be used to synthesize bifunctional PROTACs (proteolysis targeting chimeras) that act as corresponding proteolysis targeting chimeras, which can be used to treat various diseases, particularly abnormal cell proliferation. Summary of the Invention

[0006] According to the present invention, there is provided a compound represented by formula (I), or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: [ka] [In the formula, R 1 is hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4 alkylene groups-(5- to 10-membered heteroaromatic rings); Ring A is selected from the group consisting of a 4- to 12-membered heterocycloalkyl group and a 5- to 10-membered heteroaromatic ring (provided that the heterocycloalkyl group and the heteroaromatic ring may further optionally be selected from the group consisting of 1, 2, 3, or 4 independent R A1 may be substituted by); Each R A1 are each independently hydrogen, halogen, cyano group, nitro group, =O, =S, or =CR A2 R A3 , -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR A2 , -C 0~4 Alkylene group -OC(O)R A2 , -C 0~4 Alkylene group -SR A2 , -C 0~4 Alkylene group -S(O)R A2 , -C 0~4 Alkylene group -S(O)R A2 , -C 0~4 Alkylene group -S(O)NR A2 R A3 , -C 0~4 Alkylene group -S(O)NR A2 R A3 , -C 0~4 Alkylene group -C(O)R A2 , -C 0~4 Alkylene group -C(O)OR A2 , -C 0~4 Alkylene group -C(O)NR A2 R A3 , -C 0~4 Alkylene group -NR A2 R A3, -C 0~4 Alkylene group -NR A2 C(O)R A3 , -C 0~4 Alkylene group -NR A2 S(O)2R A3 , -C 0~4 Alkylene group -NR A2 S(O)R A3 , -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4 alkylene group-(5- to 10-membered heteroaromatic ring) (provided that the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R A4 may be substituted by); Each R A4 are each independently hydrogen, halogen, cyano group, nitro group, =O, =S, or =CR A2 R A3 , -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR A2 , -C 0~4 Alkylene group -OC(O)R A2 , -C 0~4 Alkylene group -SR A2 , -C 0~4 Alkylene group -S(O)R A2 , -C 0~4 Alkylene group -S(O)R A2 , -C 0~4 Alkylene group -S(O)NR A2 R A3 , -C 0~4 Alkylene group -S(O)NR A2 R A3 , -C0~4 Alkylene group -C(O)R A2 , -C 0~4 Alkylene group -C(O)OR A2 , -C 0~4 Alkylene group -C(O)NR A2 R A3 , -C 0-4 Alkylene group -NR A2 R A3 , -C 0-4 Alkylene group -NR A2 C(O)R A3 , -C 0-4 Alkylene group -NR A2 S(O)2R A3 , -C 0-4 Alkylene group -NR A2 S(O)R A3 Selected from the group consisting of: R A2 and R A3 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 alkynyl groups; R 2 represents hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 21 R 22 , -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR 21 , -C 0~4 Alkylene group -OC(O)R 21 , -C 0~4 Alkylene group -SR 21 , -C 0~4 Alkylene group -S(O)R 21 , -C0~4 Alkylene group -S(O)R 21 , -C 0~4 Alkylene group -S(O)NR 21 R 22 , -C 0~4 Alkylene group -S(O)NR 21 R 22 , -C 0~4 Alkylene group -C(O)R 21 , -C 0~4 Alkylene group -C(O)OR 21 , -C 0~4 Alkylene group -C(O)NR 21 R 22 , -C 0~4 Alkylene group -NR 21 R 22 , -C 0~4 Alkylene group -NR 21 C(O)R 22 , -C 0~4 Alkylene group -NR 21 S(O)2R 22 , -C 0~4 Alkylene group -NR 21 S(O)R 22 , -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4 alkylene group-(5- to 10-membered heteroaromatic ring) (provided that the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R 23 may be substituted by); Each R 23 are each independently hydrogen, halogen, cyano group, nitro group, =O, =S, or =CR 21 R 22 , -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR 21 , -C 0~4 Alkylene group -OC(O)R 21 , -C 0~4 Alkylene group -SR 21 , -C 0~4 Alkylene group -S(O)R 21 , -C 0~4 Alkylene group -S(O)R 21 , -C 0~4 Alkylene group -S(O)NR 21 R 22 , -C 0~4 Alkylene group -S(O)NR 21 R 22 , -C 0~4 Alkylene group -C(O)R 21 , -C 0~4 Alkylene group -C(O)OR 21 , -C 0~4 Alkylene group -C(O)NR 21 R 22 , -C 0~4 Alkylene group -NR 21 R 22 , -C 0~4 Alkylene group -NR 21 C(O)R 22 , -C 0~4 Alkylene group -NR 21 S(O)2R 22 , -C 0~4 Alkylene group -NR 21 S(O)R 22 , -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4 alkylene group-(5- to 10-membered heteroaromatic ring) (provided that the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R 26 may be substituted by); R 21and R 22 are each independently hydrogen, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR 24 , -C 0~4 Alkylene group -OC(O)R 24 , -C 0~4 Alkylene group -SR 24 , -C 0~4 Alkylene group -S(O)R 24 , -C 0~4 Alkylene group -S(O)R 24 , -C 0~4 Alkylene group -S(O)NR 24 R 25 , -C 0~4 Alkylene group -S(O)NR 24 R 25 , -C 0~4 Alkylene group -C(O)R 24 , -C 0~4 Alkylene group -C(O)OR 24 , -C 0~4 Alkylene group -C(O)NR 24 R 25 , -C 0~4 Alkylene group -NR 24 R 25 , -C 0~4 Alkylene group -NR 24 C(O)R 25 , -C 0~4 Alkylene group -NR 24 S(O)2R 25 , -C 0~4 Alkylene group -NR 24 S(O)R 25 , -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4alkylene group-(5- to 10-membered heteroaromatic ring) (provided that the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R 26 may be substituted by); Each R 26 are each independently hydrogen, halogen, cyano group, nitro group, =O, =S, or =CR 24 R 25 , -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 Alkynyl group, -C 0~4 Alkylene group -OR 24 , -C 0~4 Alkylene group -OC(O)R 24 , -C 0~4 Alkylene group -SR 24 , -C 0~4 Alkylene group -S(O)R 24 , -C 0~4 Alkylene group -S(O)R 24 , -C 0~4 Alkylene group -S(O)NR 24 R 25 , -C 0~4 Alkylene group -S(O)NR 24 R 25 , -C 0~4 Alkylene group -C(O)R 24 , -C 0~4 Alkylene group -C(O)OR 24 , -C 0~4 Alkylene group -C(O)NR 24 R 25 , -C 0~4 Alkylene group -NR 24 R 25 , -C 0~4 Alkylene group -NR 24 C(O)R 25 , -C 0~4 Alkylene group -NR 24 S(O)2R 25, -C 0~4 Alkylene group -NR 24 S(O)R 25 , -C 0~4 Alkylene group -(3-10 membered cycloalkyl group), -C 0~4 Alkylene group -(4-10 membered heterocycloalkyl group), -C 0~4 Alkylene group -(6- to 10-membered aromatic ring), -C 0~4 alkylene group-(5- to 10-membered heteroaromatic ring) (provided that the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R 27 may be substituted by); R 24 and R 25 are each independently hydrogen, -C 1-6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 alkynyl groups; Each R 27 are each independently hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~6 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~6 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 alkynyl groups].

[0007] Preferably, R 1 is hydrogen, -C 1~3 Specifically, R 1 is selected from the group consisting of hydrogen, a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0008] Preferably, R 2is hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~3 Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~3 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 alkynyl groups. Specifically, R 2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, =O, =S, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0009] Preferably, ring A is selected from the group consisting of a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group further optionally comprises 1, 2, 3, or 4 independent R A1 may be substituted by

[0010] In some preferred embodiments, ring A is selected from the group consisting of a 5-membered nitrogen-containing heterocycloalkyl group, a 6-membered nitrogen-containing heterocycloalkyl group, wherein the heterocycloalkyl group further optionally contains 1, 2, 3, or 4 independent R A1 may be substituted by

[0011] In some preferred embodiments, ring A is selected from the group consisting of a 5-membered nitrogen-containing heterocycloalkyl group, a 6-membered nitrogen-containing heterocycloalkyl group, and the nitrogen-containing heterocycloalkyl group contains 1 or 2 nitrogen atoms, preferably 2 nitrogen atoms, wherein the heterocycloalkyl group further optionally contains 1, 2, 3, or 4 independent R A1 may be substituted by

[0012] Each R A1 are each independently hydrogen, halogen, cyano group, nitro group, =O, -C 1~3Alkyl group, -C 2~6 Alkenyl group, -C 2~6 Alkynyl group, halogen-substituted -C 1~3 Alkyl groups, halogen-substituted -C 2~6 Alkenyl group, halogen-substituted -C 2~6 alkynyl groups. Specifically, each R A1 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, nitro, =O, methyl, ethyl, n-propyl, isopropyl, vinyl, ethynyl, monofluoromethyl, difluoromethyl, and trifluoromethyl.

[0013] More specifically, the ring A is [ka] is.

[0014] Preferably, the compound is as represented by formula (IIA), formula (IIB), or formula (IIC): [ka] (In the formula, [ka] represents a single bond or a double bond, and the substituent R 1 , R.A. 1 and R 2 The definition of is as described above.

[0015] In some specific embodiments of the invention, the compound is specifically one of the following: [ka] .

[0016] The present invention further provides the use of the aforementioned compound, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with abnormal cell proliferation.

[0017] Furthermore, the disease is cancer.

[0018] The present invention further provides use of the aforementioned compound, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a targeted protein degradation drug.

[0019] The present invention further provides use of the aforementioned compound, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as an intermediate in the production of a targeted protein degradation drug.

[0020] The compounds and derivatives in the present invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) naming systems.

[0021] Unless otherwise specified, the initial definition of a group or term in this specification applies throughout the present specification. Terms not specifically defined in this specification should be given the meaning that a person skilled in the art can give based on the disclosure and context.

[0022] "Substitution" means that a hydrogen atom in a molecule is replaced with another atom or molecule. "Substitution" can also mean that a lone electron pair of an atom in a molecule is replaced with "=O", "=S", etc.

[0023] The phrase "may further be optionally substituted" means that "substitution" may occur but is not necessarily required, and the present specification includes both cases where substitution occurs and cases where it does not occur.

[0024] The minimum and maximum number of carbon atoms in the hydrocarbon group are indicated by prefixes, e.g., the prefix C a~b The alkyl group represents an alkyl group containing any number of carbon atoms from "a" to "b". 1~4 "Alkyl group" refers to an alkyl group containing 1 to 4 carbon atoms.

[0025] "Alkyl group" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C 1~6 An alkyl group refers to an alkyl group containing 1 to 6, e.g., 1 to 4, member atoms. The alkyl group may be straight-chained or branched. Representative branched-chain alkyl groups have one, two, or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. 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. The alkyl group may be part of another group, such as, for example, C 1~6 Examples include alkoxy groups.

[0026] In the present invention, the term "alkylene group" refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. a~b The term "alkylene group" refers to an alkylene group having a to b carbon atoms. The alkylene group includes branched and straight chain hydrocarbon groups. For example, "C 1~6 The term "alkylene group" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene group" refers to a group having the following structure: [ka] Similarly, the term "dimethylbutylene group" can be exemplified by, for example, the following structure: [ka] Furthermore, the term "(C 1~6 The term "alkylene group" is intended to include branched chain hydrocarbon groups such as cyclopropylmethylene groups, and includes the following structures: [ka] For example, -C 0~4 The alkylene group may 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. A C0 alkylene group means that there is no group present and the group is connected in the form of a chemical bond. For example, A-C0 alkylene group-B refers to AB, that is, the A group and the B group are directly connected by a chemical bond.

[0027] "Alkenyl group" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms, in some embodiments 2 to 6 carbon atoms or 2 to 4 carbon atoms, and having at least one site of vinyl unsaturation (>C=C<). For example, C a-b The alkenyl group refers to an alkenyl group having a to b carbon atoms, and includes, for example, a vinyl group, a propenyl group, an isopropenyl group, a 1,3-butadienyl group, and the like.

[0028] As used herein, the term "alkenyl group" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated chemical valences. For example, (C3-C6) alkenylene groups include >C=CH-CH2-, -CH-CH=CH-CH2-, etc.

[0029] An "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing at least one triple bond. The term "alkynyl group" is intended to include hydrocarbon groups having one triple bond and one double bond. For example, a (C2-C6)alkynyl group is intended to include ethynyl, propynyl, and the like.

[0030] "Halogen" is fluorine, chlorine, bromine, or iodine.

[0031] The terms "halogen alkyl group" and "halogen-substituted alkyl group" refer to an alkyl group in which one or more hydrogen atoms can be substituted with halogen atoms. For example, C 1-4 A halogenalkyl group refers to an alkyl group having 1 to 4 carbon atoms in which one or more hydrogen atoms have been substituted with halogen atoms.

[0032] In the present invention, "-OR", "-NRR", etc. mean that the R group is connected to an oxygen atom or a nitrogen atom via a single bond.

[0033] In the present invention, the oxygen atom in "-C(O)R", "-S(O)R", etc. means that it is connected to a carbon atom or a sulfur atom via a double bond, and the R group is connected to the oxygen atom or the sulfur atom via a single bond.

[0034] In the present invention, the terms "cycloalkyl group" and "cycloalkane group" refer to saturated or partially saturated cyclic groups having multiple carbon atoms, no cycloheteroatom, and monocyclic or polycyclic rings (including fused rings, bridged rings, spiro rings, and adamantane rings). For polycyclic systems having aromatic and non-aromatic rings without cycloheteroatoms, the term "cycloalkyl group" (e.g., 5,6,7,8-tetrahydronaphthalen-5-yl) is applicable when the linking site is located at a non-aromatic carbon atom. The term "cycloalkyl group" includes cycloalkenyl groups such as cyclohexenyl groups. Illustrative examples of cycloalkyl groups include adamantyl groups, cyclopropyl groups, cyclobutyl groups, cyclohexyl groups, cyclopentyl groups, cyclooctyl groups, cyclopentenyl groups, and cyclohexenyl groups. Examples of cycloalkyl groups containing polybicycloalkyl ring systems include bicyclohexyl groups, bicyclopentyl groups, and bicyclooctyl groups, such as [ka] Adamantyl groups include the following structures: [ka] This includes, but is not limited to:

[0035] In the present invention, the terms "heterocycle," "heterocycloalkyl group," and "heterocycloalkane group" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom. Here, heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Typically, they refer 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 cycloheteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Bicyclic means composed of two rings that share two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of 1 or 2 ring atoms. Illustrative examples of monocyclic saturated heterocycloalkyl groups include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxopyrrolidin-3-yl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, [ka] Examples of bicyclic saturated heterocycloalkyl include 8-azabicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl, [ka] Examples of the partially unsaturated heterocycloalkyl group include a dihydrofuranyl group, an imidazolinyl group, a tetrahydropyridinyl group, and a dihydropyranyl group.

[0036] The terms "spiroheterocyclic group" and "spiroheterocycle" may be used interchangeably and refer to a non-aromatic saturated or unsaturated ring system having two monocyclic rings that share one carbon atom, and which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, a "5- to 12-membered spiroheterocycle" refers to a spiroheterocycle having 5 to 12 ring atoms, of which 1, 2, or 3 ring atoms are heteroatoms.

[0037] The term "bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more ring structures sharing two non-adjacent atoms, and specific examples thereof include: [ka] These include, but are not limited to:

[0038] The terms "bridged heterocyclic group" and "bridged heterocycle" may be used interchangeably and refer to a saturated or unsaturated cyclic group in which two or more ring structures share two non-adjacent atoms, and are composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples include: [ka] These include, but are not limited to:

[0039] In the present invention, the terms "aromatic ring" and "aryl group" refer to an aromatic hydrocarbon group having multiple carbon atoms. An aryl group is typically a monocyclic, bicyclic, or tricyclic aromatic group having 5 to 20 carbon atoms. The term "aryl group" as used herein refers to an aromatic substituent having a single aromatic ring or multiple condensed aromatic rings. Non-limiting examples include a phenyl group, a naphthyl group, and a tetrahydronaphthyl group.

[0040] In the present invention, the term "heteroaromatic ring" or "heteroaromatic ring group" refers to an aromatic unsaturated ring containing at least one heteroatom. The heteroatom may be a nitrogen atom, an oxygen atom, a sulfur atom, or the like. Typically, the heteroaromatic ring is an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, at least one of which is selected from O, N, and S. Preferably, the heteroaromatic ring has 1 to 3 heteroatoms. Examples of heterocycloaryl groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothienyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiapyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0041] "Stereoisomer" includes enantiomers and diastereomers.

[0042] In the present invention, the term "deuterated compound" refers to a molecule or group in which one or more hydrogen atoms have been replaced with deuterium atoms, and the proportion of deuterium atoms therein is greater than the abundance of deuterium in nature.

[0043] The term "pharmaceutically acceptable" means that the carrier, carrier, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up the pharmaceutical formulation and is physiologically compatible with the receptor.

[0044] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts formed by the compound or its stereoisomer with inorganic and / or organic acids or inorganic and / or organic bases, including zwitterionic salts (internal salts) and quaternary ammonium salts such as alkylammonium salts. These salts can be obtained directly from the final isolation and purification of the compound. They can also be obtained by mixing the compound or its stereoisomer with an appropriate amount of acid or base (e.g., equivalent amounts). These salts can be precipitated in a solution and recovered by filtration, recovered by evaporating the solvent, or prepared by reaction in an aqueous medium followed by lyophilization. The salts of the present invention can be hydrochloride, sulfate, citrate, benzenesulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate, or trifluoroacetate salts of the compound.

[0045] Obviously, the above content of the present invention may be modified, substituted or changed in various other forms in accordance with common technical common sense and conventional means in the art without departing from the above basic technical spirit of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0046] The above content of the present invention will be described in more detail below by specific embodiments using examples. However, it should not be understood that the scope of the above subject matter of the present invention is limited to the following examples. All technologies realized based on the above content of the present invention are within the scope of the present invention.

[0047] The known starting materials in the present invention can be synthesized by methods known in the art or purchased from companies such as Energy Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and J&K Scientific.

[0048] The abbreviations for the reagents described in the examples are as follows: EDCI: carbodiimide; DMF: N,N-dimethylformamide; ACN: acetonitrile.

[0049] Unless otherwise specified in the examples, reactions were carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, solutions refer to aqueous solutions. Unless otherwise specified in the examples, reaction temperatures were room temperature. Room temperature is the most suitable reaction temperature, and is 20°C to 30°C. Unless otherwise specified in the examples, M is moles per liter.

[0050] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was 10 -6 The values ​​are shown in ppm. NMR measurements were performed using nuclear magnetic resonance spectrometers (Bruker Avance III 400 and Bruker Avance 600) with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methol-d4) as solvents, and tetramethylsilane (TMS) as an internal standard. LC-MS measurements were performed using a Shimadzu LC-MS 2020 liquid chromatograph mass spectrometer (ESI). HPLC measurements were performed using a Shimadzu LC-20A high-pressure liquid chromatograph. MPLC (medium-pressure preparative chromatography) measurements were performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography silica gel plates were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm. For column chromatography, Yantai Yellow Sea silica gel 200-300 mesh silica gel was generally used as the carrier. [Example]

[0051] Preparation of Compound A1 [ka]

[0052] Step 1: Synthesis of compound A-3 A-1 (3.9 g, 20.61 mmol), A-2 (9.24 g, 41.22 mmol), cesium carbonate (13.43 g, 41.22 mmol), and DMF (50 mL) were added to a 100 mL reaction flask. The reaction was heated at 100 °C overnight until completion. Water was then added to quench the reaction, followed by extraction with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the reaction product was evaporated to dryness. The resulting mixture was purified by MPLC to give A-3 (4.1 g, 12.33 mmol, 59.84% yield).

[0053] Step 2: Synthesis of compound A-4 A-3 (4.0 g, 12.03 mmol) and dichloromethane (10 mL) were added to a 50 mL reaction flask, and 10 mL of HCl / dioxane (4 M) was added dropwise. After stirring at room temperature for 1 hour, the solvent was evaporated to dryness to give A-4 (2.6 g, 11.19 mmol, 93.02% yield).

[0054] Step 3: Synthesis of compound A-5 A-4 (2.6 g, 11.19 mmol), sodium methoxide (5.82 g, 107.79 mmol), and methanol (20 mL) were added to a 50 mL reaction flask. The reaction was heated at 65 °C overnight until completion. The solvent was then evaporated to dryness, and the reaction product was purified by MPLC to give A-5 (1.8 g, 9.67 mmol, 86.36% yield).

[0055] Step 4: Synthesis of compound A-6 A-5 (500 mg, 2.69 mmol), sodium hydride (96.66 mg, 4.03 mmol), and DMF (15 mL) were added to a 50 mL reaction flask. After stirring at room temperature for 30 minutes, iodomethane (457.55 mg, 3.22 mmol) was added. After stirring at room temperature overnight, the reaction was quenched by adding water and extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give A-6 (500 mg, 2.50 mmol, 93.00% yield).

[0056] Step 5: Synthesis of Compound A-7 A-6 (300 mg, 1.50 mmol) and DMF (5 mL) were added to a 50 mL reaction flask. Phosphorus oxychloride (344.59 mg, 2.25 mmol) was slowly added at 0 °C, and the mixture was heated to 60 °C and allowed to react overnight. After evaporating the solvent to dryness, the reaction product was purified by MPLC to give A-7 (250 mg, 1.10 mmol, 73.11% yield).

[0057] Step 6: Synthesis of Compound A-8 A-7 (100 mg, 438.12 μmol), sodium dihydrogen phosphate (78.86 mg, 657.19 μmol), hydrogen peroxide (60.00 μL), and ACN / HO (4:1, 3 mL) were added to a 50 mL reaction flask. Sodium chlorite (102.52 mg, 657.19 μmol) was added at 0 °C, and the mixture was warmed to room temperature and stirred for 3 h. The reaction solution was filtered, and the solvent was evaporated to dryness to give A-8 (90 mg, 368.48 μmol, 84.10% yield).

[0058] Step 7: Synthesis of Compound A1 A-8 (45 mg, 184.24 μmol), A-9 (25.82 mg, 184.24 μmol), EDCI (70.64 mg, 368.48 μmol), and pyridine (2 mL) were added to a 50 mL reaction flask. The reaction was allowed to proceed overnight at room temperature, and the resulting mixture was purified by MPLC to give A1 (10.00 mg, 27.29 μmol, 14.81% yield, 99.6% purity). 1H NMR (400 MHz, DMSO-d6) δ 7.64 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.40-7.36 (m, 1H), 7.24-7.20 (m, 1H), 4.43 - 4.32 (m, 2H), 4.27 (d, J = 10.0 Hz, 1H), 4.08 (d, J = 10.0 Hz, 1H), 4.00 (d, J = 8.8 Hz, 1H), 3.90 (d, J = 8.8 Hz, 1H), 3.87 - 3.79 (m, 2H), 3.09 (s, 3H), 3.08 - 2.84 (m, 2H). LC-MS: [M+H] + C 19 H 19 N4O 4, 367.14, found:367.1. HPLC > 99%. [Example]

[0059] Preparation of Compounds B1-B5 [ka]

[0060] Step 1: Synthesis of compound B-2 B-1 (5.00 g, 31.03 mmol), thionyl chloride (9.24 g, 41.22 mmol), and dichloromethane (25 mL) were added to a 100 mL reaction flask. The reaction was heated at 90 °C for 3 hours until completion. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give crude product B-2 (5.60 g).

[0061] Step 2: Synthesis of compound B-4 B-2 (5.60 g, 31.18 mmol), B-3 (3.28 g, 62.36 mmol), triethylamine (6.31 g, 62.36 mmol), and dichloromethane (20 mL) were added to a 50 mL reaction flask. The mixture was stirred at room temperature for 1 hour until the reaction was complete. After distillation under reduced pressure, the product was separated and purified by silica gel chromatography (petroleum ether:ethyl acetate = 3:1) to obtain a pale yellow solid, B-4 (4.50 g, 18.12 mmol, 58.13% yield).

[0062] Step 3: Synthesis of compound B-5 B-4 (2.50 g, 10.07 mmol) and DMF (5 mL) were added to a 50 mL reaction flask and added dropwise to phosphorus oxychloride (3.09 g, 20.14 mmol) dissolved in 15 mL of DMF. The mixture was stirred at room temperature for 1 hour until the reaction was complete. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give crude product B-5 (2.80 g).

[0063] Step 4: Synthesis of compound B-6 B-5 (2.76 g, 10.00 mmol), 2-methyl-2-butene (3.51 g, 50.00 mmol), sodium dihydrogen phosphate (50.00 mmol), and acetonitrile / tetrahydrofuran / water mixed solvent (20 mL) were added to a 50 mL reaction flask, and sodium dihydrogen phosphate (50.00 mmol) was added dropwise at 0 °C. The reaction was stirred at room temperature for 12 hours until the reaction was complete. The reaction mixture was adjusted to pH 6.0 and extracted with ethyl acetate (50 mL × 3). The organic phase was washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude product B-6 (2.00 g).

[0064] Step 5: Synthesis of compound B-7 B-6 (2.00 g, 6.84 mmol) was added to a 50 mL reaction flask and dissolved in 20 mL of HCl / dioxane (4 M). The reaction was stirred at 70 °C for 3 h until completion. After evaporation of the solvent to dryness, the reaction product was purified by MPLC to give B-7 (0.30 g, 1.31 mmol, 19.21% yield).

[0065] Step 6: Synthesis of Compound B1 TCFH (7.58 mg, 210.34 μmol) and NMI (350.56 μmol) were added to a 15 mL reaction flask and dissolved in 5 mL of DMF at 0 °C for 0.2 h. After activating, B-7 (40.00 mg, 175.28 μmol) and B-8 (24.56 mg, 175.28 μmol) were added at room temperature and the reaction was allowed to proceed for 2 h until completion. The solvent was then evaporated to dryness, and the reaction product was purified by MPLC to give B1 (6.90 mg, 19.46 μmol, 11.10% yield, 98.8% purity). 1 H NMR (600 MHz, DMSO-d6) δ 11.20 (s, 1H), 11.00 (d, J = 5.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 5.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 6.77 (t, J = 5.6 Hz, 1H), 4.36-3.83 (m, 4H), 3.06 and 3.03 (s, 1H), 2.90 and 2.87 (s, 1H). LC-MS: [M+H] + C 18 H 14 N4O 4, 351.1, found: 351.2. HPLC > 98%.

[0066] Step 7: Synthesis of Compound B-9 B-7 (0.20 g, 0.88 mmol), iodomethane (0.37 g, 2.64 mmol), and DMF (4 mL) were added to a 15 mL reaction flask, and sodium hydride (63.10 mg, 2.63 mmol) was slowly added at 0 °C. The reaction was stirred at room temperature for 2 hours until completion. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to give crude product B-9 (0.22 g).

[0067] Step 8: Synthesis of compound B-10 B-9 (220.00 mg, 858.52 μmol) and a methanol / water mixture (8 mL) were added to a 15 mL reaction flask, and sodium hydroxide (103.02 mg, 2.58 mmol) was slowly added. The mixture was stirred at 50 °C for 2 hours until the reaction was complete. The reaction solution was adjusted to pH 6.0 and extracted with ethyl acetate (50 mL × 3). The organic phase was then washed with concentrated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to dryness to obtain crude product B-10 (150.00 mg).

[0068] Step 9: Synthesis of Compound B2 TCFH (8.93 mg, 247.70 μmol) and NMI (412.83 μmol) were added to a 15 mL reaction flask, dissolved in 3 mL of DMF, and activated at 0 °C for 0.2 h. B-10 (50.00 mg, crude product) and B-8 (28.93 mg, 206.42 μmol) were then added at room temperature. The reaction was allowed to proceed for 2 h at room temperature until the reaction was complete. The solvent was then evaporated to dryness, and the reaction product was purified by MPLC to give B2 (26.60 mg, 71.98 μmol, 34.87% yield, 98.6% purity). 1H NMR (600 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 5.9 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.55-7.33 (m, 2H), 7.02 (d, J = 5.9 Hz, 1H), 4.32-3.85 (m, 4H), 3.21 (s, 1H), 3.07 and 3.04 (s, 1H), 2.91 and 2.88 (s, 1H). LC-MS: [M+H] + C 19 H 17 N4O 4, 365.1, found: 365.1. HPLC > 98%.

[0069] By referring to the synthesis methods of compounds B1 and B2, compounds B3, B4, and B5 were obtained without changing the other raw materials or operating methods, except that the raw materials shown in column 3 of the table below were used instead of compound B-3.

[0070] [Table 1-1] [Table 1-2]

[0071] In the present invention, the technical effects of the present invention will be explained through the following test examples. Test Example 1

[0072] Detection of inhibitory effects of compounds on CRBN / DDB1 activity (FRET method) 1. Experimental materials and reagents The following equipment was used: a microplate reader (BMG PHERAstar FSX), an ECHO (LABCYTE Echo 665), a thermostatic microplate oscillator (Hangzhou Ruicheng Instrument Co., Ltd.), disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), bovine serum albumin (Sigma), anti-6His-Tb Cryptogold (CISBIO), CRBN / DDB1 protein (HitGen), and a 384-well plate (Grenier Bio-one).

[0073] 2. Experimental Method The compound powder was dissolved in DMSO so that the final DMSO concentration in the entire reaction system (10.0 μL) was 1.0%, and the solution was serially diluted with ECHO and injected into a 384-well reaction plate. As a control, an equal amount of DMSO was added.

[0074] 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, and 0.08% bovine serum albumin, pH 7.0 buffer. 5.0 μL of the diluted CRBN / DDB1 protein was aspirated and dispensed into a 384-well reaction plate containing the compound. The plate was centrifuged at 1000 rpm for 1 minute, then placed in a microplate incubator and pre-incubated at 25°C and 250 rpm for 15 minutes. Next, anti-6His-Tb Cryptogold and the FITC-labeled thalidomide analog were diluted twice to the required final concentrations using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, and 0.08% bovine serum albumin, pH 7.0 buffer, to obtain a final concentration of 0.2 nM anti-6His-Tb Cryptogold and 50.0 nM FITC-labeled thalidomide analog. 5.0 μL of this mixture was aspirated and dispensed into a 384-well reaction plate. The plate was centrifuged at 1000 rpm for 1 minute, then placed in a microplate thermostat and incubated at 250 rpm for 30 minutes at 25°C. After the reaction was complete, the fluorescence signal (Ex = 337 nm, Em = 520 / 490 nm) in the 384-well reaction plate was read using a microplate reader.

[0075] 3. Data Analysis A solvent group (CRBN / DDB1 5.0 nM, anti-6His-Tb Cryptogold 0.2 nM, FITC-labeled thalidomide analog 50.0 nM, containing 1.0% DMSO) was used as a negative control, and a reaction buffer group (anti-6His-Tb Cryptogold 0.2 nM, FITC-labeled thalidomide analog 50.0 nM, containing 1.0% DMSO) was used as a blank control.

[0076] The percentage of residual activity at 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 )

[0077] Dose-effect curves were then fitted using GraphPad 6.0 to determine IC 50 The value was calculated.

[0078] [Table 2]

[0079] As is clear from the above experimental data, the compounds of the present invention have a good inhibitory effect on the CRBN / DDB1 protein and may be a novel class of CRBN inhibitors. Alternatively, the compounds of the present invention can be used to synthesize bifunctional PROTACs compounds that are effective as CRBN ligands and also function as corresponding proteolysis-inducing chimeric molecules.

Claims

1. A compound represented by the following formula (I), or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, R １ is hydrogen, -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene groups -(5- to 10-membered heteroaromatic rings); Ring A is selected from the group consisting of a 4- to 12-membered heterocycloalkyl group and a 5- to 10-membered heteroaromatic ring (provided that the heterocycloalkyl group and the heteroaromatic ring may further optionally be selected from the group consisting of 1, 2, 3, or 4 independent R Ａ１ and optionally substituted by Each R Ａ１ are each independently hydrogen, halogen, a cyano group, a nitro group, ═O, ═S, or ═CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR Ａ２ , -C ０～４ Alkylene group -OC(O)R Ａ２ , -C ０～４ Alkylene group -SR Ａ２ , -C ０～４ Alkylene group -S(O) ２ R Ａ２ , -C ０～４ Alkylene group -S(O)R Ａ２ , -C ０～４ Alkylene group -S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -S(O)NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -C(O)R Ａ２ , -C ０～４ Alkylene group -C(O)OR Ａ２ , -C ０～４ Alkylene group -C(O)NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -NR Ａ２ C(O)R Ａ３ , -C ０～４ Alkylene group -NR Ａ２ S (O) ２ R Ａ３ , -C ０～４ Alkylene group -NR Ａ２ S(O)R Ａ３ , -C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene group-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R Ａ４ and optionally substituted by Each R Ａ４ are each independently hydrogen, halogen, a cyano group, a nitro group, ═O, ═S, or ═CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR Ａ２ , -C ０～４ Alkylene group -OC(O)R Ａ２ , -C ０～４ Alkylene group -SR Ａ２ , -C ０～４ Alkylene group -S(O) ２ R Ａ２ , -C ０～４ Alkylene group -S(O)R Ａ２ , -C ０～４ Alkylene group -S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -S(O)NR Ａ２ R Ａ３ , -C ０～４ Alkylene group -C(O)R Ａ２ , -C ０～４ Alkylene group -C(O)OR Ａ２ , -C ０～４ Alkylene group -C(O)NR Ａ２ R Ａ３ , -C ０－４ Alkylene group -NR Ａ２ R Ａ３ , -C ０－４ Alkylene group -NR Ａ２ C(O)R Ａ３ , -C ０－４ Alkylene group -NR Ａ２ S (O) ２ R Ａ３ , -C ０－４ Alkylene group -NR Ａ２ S(O)R Ａ３ selected from the group consisting of: R A２ and R Ａ３ are each independently hydrogen, —C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ alkynyl groups; R ２ represents hydrogen, halogen, cyano group, nitro group, ═O, ═S, ═CR ２１ R ２２ , -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR ２１ , -C ０～４ Alkylene group -OC(O)R ２１ , -C ０～４ Alkylene group -SR ２１ , -C ０～４ Alkylene group -S(O) ２ R ２１ , -C ０～４ Alkylene group -S(O)R ２１ , -C ０～４ Alkylene group -S(O) ２ NR ２１ R ２２ , -C ０～４ Alkylene group -S(O)NR ２１ R ２２ , -C ０～４ Alkylene group -C(O)R ２１ , -C ０～４ Alkylene group -C(O)OR ２１ , -C ０～４ Alkylene group -C(O)NR ２１ R ２２ , -C ０～４ Alkylene group -NR ２１ R ２２ , -C ０～４ Alkylene group -NR ２１ C(O)R ２２ , -C ０～４ Alkylene group -NR ２１ S (O) ２ R ２２ , -C ０～４ Alkylene group -NR ２１ S(O)R ２２ , -C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene group-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R ２３ and optionally substituted by Each R ２３ are each independently hydrogen, halogen, a cyano group, a nitro group, ═O, ═S, or ═CR ２１ R ２２ , -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR ２１ , -C ０～４ Alkylene group -OC(O)R ２１ , -C ０～４ Alkylene group -SR ２１ , -C ０～４ Alkylene group -S(O) ２ R ２１ , -C ０～４ Alkylene group -S(O)R ２１ , -C ０～４ Alkylene group -S(O) ２ NR ２１ R ２２ , -C ０～４ Alkylene group -S(O)NR ２１ R ２２ , -C ０～４ Alkylene group -C(O)R ２１ , -C ０～４ Alkylene group -C(O)OR ２１ , -C ０～４ Alkylene group -C(O)NR ２１ R ２２ , -C ０～４ Alkylene group -NR ２１ R ２２ , -C ０～４ Alkylene group -NR ２１ C(O)R ２２ , -C ０～４ Alkylene group -NR ２１ S (O) ２ R ２２ , -C ０～４ Alkylene group -NR ２１ S(O)R ２２ , -C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene group-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R ２６ and optionally substituted by R ２１ and R ２２ are each independently hydrogen, —C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR ２４ , -C ０～４ Alkylene group -OC(O)R ２４ , -C ０～４ Alkylene group -SR ２４ , -C ０～４ Alkylene group -S(O) ２ R ２４ , -C ０～４ Alkylene group -S(O)R ２４ , -C ０～４ Alkylene group -S(O) ２ NR ２４ R ２５ , -C ０～４ Alkylene group -S(O)NR ２４ R ２５ , -C ０～４ Alkylene group -C(O)R ２４ , -C ０～４ Alkylene group -C(O)OR ２４ , -C ０～４ Alkylene group -C(O)NR ２４ R ２５ , -C ０～４ Alkylene group -NR ２４ R ２５ , -C ０～４ Alkylene group -NR ２４ C(O)R ２５ , -C ０～４ Alkylene group -NR ２４ S (O) ２ R ２５ , -C ０～４ Alkylene group -NR ２４ S(O)R ２５ , -C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene group-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R ２６ and optionally substituted by Each R ２６ are each independently hydrogen, halogen, a cyano group, a nitro group, ═O, ═S, or ═CR ２４ R ２５ , -C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ Alkynyl group, —C ０～４ Alkylene group -OR ２４ , -C ０～４ Alkylene group -OC(O)R ２４ , -C ０～４ Alkylene group -SR ２４ , -C ０～４ Alkylene group -S(O) ２ R ２４ , -C ０～４ Alkylene group -S(O)R ２４ , -C ０～４ Alkylene group -S(O) ２ NR ２４ R ２５ , -C ０～４ Alkylene group -S(O)NR ２４ R ２５ , -C ０～４ Alkylene group -C(O)R ２４ , -C ０～４ Alkylene group -C(O)OR ２４ , -C ０～４ Alkylene group -C(O)NR ２４ R ２５ , -C ０～４ Alkylene group -NR ２４ R ２５ , -C ０～４ Alkylene group -NR ２４ C(O)R ２５ , -C ０～４ Alkylene group -NR ２４ S (O) ２ R ２５ , -C ０～４ Alkylene group -NR ２４ S(O)R ２５ , -C ０～４ alkylene group -(3- to 10-membered cycloalkyl group), -C ０～４ alkylene group -(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene group -(6- to 10-membered aromatic ring), -C ０～４ alkylene group-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further optionally have 1, 2, 3, or 4 independent R ２７ and optionally substituted by R ２４ and R ２５ are each independently hydrogen, —C １－６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ alkynyl groups; Each R ２７ are each independently hydrogen, halogen, cyano group, nitro group, ═O, ═S, or —C １～６ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～６ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ alkynyl groups].

2. R １ is hydrogen, -C １～３ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl groups.

3. R ２ represents hydrogen, halogen, cyano group, nitro group, ═O, ═S, -C １～３ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～３ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ 2. The compound of claim 1, wherein the alkynyl group is selected from the group consisting of:

4. Ring A is selected from the group consisting of a 5-membered heterocycloalkyl group, a 6-membered heterocycloalkyl group, wherein said heterocycloalkyl group further optionally has 1, 2, 3, or 4 independent R Ａ１ and optionally substituted by Each R Ａ１ are each independently hydrogen, halogen, cyano group, nitro group, ═O, —C １～３ alkyl group, -C ２～６ Alkenyl group, —C ２～６ Alkynyl group, halogen-substituted —C １～３ alkyl group, halogen-substituted —C ２～６ Alkenyl group, halogen-substituted —C ２～６ 2. The compound of claim 1, wherein the alkynyl group is selected from the group consisting of:

5. Ring A is 【Chemistry 2】 5. The compound of claim 4, wherein: 【Request Item 6】 【Chemistry 3】 (In the formula, 【Chemistry 4】 represents a single bond or a double bond, and the substituent R １ , R Ａ１ and R ２ are defined as in claim 1) The compound according to claim 1, characterized in that it is represented by formula (IIA), formula (IIB), or formula (IIC). 【Request Item 7】 【Chemistry 5】 The compound according to any one of claims 1 to 6, characterized in that it is represented by any one of the above chemical formulas.

8. Use of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with abnormal cell proliferation.

9. 9. The use according to claim 8, wherein the disease is cancer.

10. Use of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a targeted protein degradation drug.

11. Use of the compound according to any one of claims 1 to 7, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, as an intermediate in the production of a targeted protein degradation drug.

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