Spiro compounds and uses

Abstract

The invention provides a novel compound which has a binding effect with E3 ligase protein CRBN, and application of the novel compound in preparation of a medicine for treating cell abnormal proliferation diseases.

Description

Spirocyclic compounds and uses Technical Field

[0001] The present invention belongs to the field of medicine, and in particular relates to a novel ligand compound bound to a spirocyclic cereblon E3 ubiquitin ligase protein. Background Art

[0002] Protein degradation is a highly regulated process that is essential for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is responsible for removing defective proteins and is ATP-dependent, highly efficient and highly selective. Its catalytic part is the ubiquitination E3 ligase, but it needs to first recruit the protein to be degraded. PROTACs technology is designed based on the UPP principle. The target protein ligand and the ligand of the E3 ligase are connected with a suitable chemical bond, so that the target protein can be recognized and the binding ability of the ligase E3 to the target protein can be enhanced, thereby targeting ubiquitination to force degradation of the target protein, and it has the characteristics of catalytic quantity, high efficiency and high selectivity.

[0003] Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligases tags proteins for proteasomal degradation, where they are digested into small peptides and ultimately into their constituent amino acids, which serve as building blocks for new proteins. Defective proteasomal 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 and part of the E3 ubiquitin ligase protein complex. It acts as a substrate receptor to select ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene. Cereblon, along with damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of Cullin-1 (ROCI), form an E3 ubiquitin ligase complex that ubiquitinates a range of proteins, though the specific mechanism remains unclear. Cereblon is currently known to be a commonly used E3 ligase in PROTACs technology.

[0005] The present invention discloses a novel class of spirocyclic compounds that can serve as effective CRBN ligands and further can be used to synthesize corresponding PROTACs bifunctional compounds that can target protein degradation chimeras, which can be used to treat various medical conditions, especially abnormal cell proliferation.

[0006] Summary of the Invention

[0007] The present invention provides a compound represented by Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0008] in,

[0009] Indicates the presence or absence of oxygen substitution;

[0010] Ring A is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally replaced by one, two, three or four independent R A1 replace;

[0011] Each R A1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-NRA2 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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R A4 replace;

[0012] Each R A4 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 RA3 、-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 ;

[0013] R A2 、R A3 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0014] R 2 independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-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 、-C0～4 Alkylene-NR 21 R 22 、-C 0～4 Alkylene-NR 21 C(O)R 22 、-C 0～4 Alkylene-NR 21 S(O)2R 22 、-C 0～4 Alkylene-NR 21 S(O)R 22 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 23 replace;

[0015] Each R 23 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-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)NR21 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)2R 22 、-C 0～4 Alkylene-NR 21 S(O)R 22 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0016] R 21 、R 22 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 1～4 Alkylene-OR 24 、-C 1～4 Alkylene-OC(O)R 24 、-C 1～4 Alkylene-SR 24 、-C 1～4 Alkylene-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 Alkylene-NR 24 R 25 、-C 1～4 Alkylene-NR 24 C(O)R 25 、-C 1～4 Alkylene-NR 24 S(O)2R 25 、-C 1～4 Alkylene-NR 24 S(O)R 25 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0017] Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 24 、-C 0～4 Alkylene-OC(O)R 24 、-C 0～4 Alkylene-SR 24 、-C 0～4 Alkylene-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)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)2R 25 、-C 0～4 Alkylene-NR 24 S(O)R 25 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein the alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace;

[0018] R 24 、R 25 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl;

[0019] Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

[0020] Furthermore,

[0021] Ring A is selected from Wherein, the ring selected from the group consisting of A and B may be further optionally replaced by one, two, three or four independent R A1 Substitution: R2 and the carbonyl group connected to Ring A in Formula I can be connected to any substitutable position of Ring A.

[0022] Preferably, each R A1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0023] Furthermore,

[0024] Ring A is selected from

[0025] As a preference,

[0026] The R 2 Selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 23 replace;

[0027] Each R 23 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0028] R 21 、R 22 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace;

[0029] Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring);

[0030] R 24 、R 25 are independently selected from hydrogen, -C 1-3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0031] Further,

[0032] R 2 Selected from -C(O)NR 21 R 22 、-C(O)R 21 、-C 0～2 Alkylene-NR 21 R 22 、-C(O)OR 21 ;

[0033] R 21 、R 22are independently selected from hydrogen, -C 1～3 Alkyl, -C 0～1 Alkylene-(6-membered aromatic ring), -C 0～1 Alkylene-(10-membered heteroaromatic ring), -(4- to 6-membered heterocycloalkyl), -(3- to 6-membered cycloalkyl), wherein the aromatic ring, heteroaromatic ring, heterocycloalkyl, and cycloalkyl may be further optionally replaced by one, two, three, or four independent R 26 replace;

[0034] Each R 26 are independently selected from hydrogen, -C 1～3 Alkyl, -(4- to 6-membered heterocycloalkyl), -C(O)R 24 、-C(O)OR 24 、-OC(O)R 24 ;

[0035] R 24 Selected from hydrogen, methyl, ethyl.

[0036] More specifically,

[0037] R 2 Selected from hydrogen,

[0038] In some specific embodiments of the present invention, the compound is specifically:

[0039] The present invention also provides the use of any of the above-mentioned compounds, or their stereoisomers, or their deuterated compounds, or their pharmaceutically acceptable salts in the treatment of diseases related to abnormal cell proliferation.

[0040] Furthermore, the disease is cancer.

[0041] The present invention also provides use of any of the above-mentioned compounds, or stereoisomers thereof, or deuterated compounds thereof, or pharmaceutically acceptable salts thereof in the preparation of targeted protein degradation drugs.

[0042] Furthermore, provided is the use of the compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of a targeted protein degradation drug.

[0043] Furthermore, the targeted protein degradation drug is a drug that relies on the E3 ligase CRBN for protein degradation.

[0044] The compounds and derivatives provided herein can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0045] Definitions of terms used in the present invention: Unless otherwise stated, the initial definitions provided for groups or terms in this document apply to the groups or terms throughout the specification; for terms that are not specifically defined herein, they should be given the meaning that a person skilled in the art would give them based on the disclosure and context.

[0046] "Substitution" refers to the replacement of a hydrogen atom in a molecule by another different atom or molecule. "Substitution" can also refer to the replacement of a lone pair of electrons in an atom in a molecule by "=O", "=S", etc.

[0047] "May be further optionally substituted" means that "substitution" may but need not occur, and the description includes cases where it occurs or does not occur.

[0048] The minimum and maximum carbon atom content in a hydrocarbon group is indicated by a prefix, for example, the prefix C a～b Alkyl refers to any alkyl group containing from "a" to "b" carbon atoms. Thus, for example, "C 1～4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms.

[0049] "Alkyl" refers to a saturated hydrocarbon chain having the specified number of member atoms. For example, C 1～6 Alkyl refers to an alkyl group having 1 to 6 member atoms, for example 1 to 4 member atoms. The alkyl group can be straight or branched. Representative branched alkyl groups have one, two or three branches. The alkyl group may be optionally substituted with one or more substituents as defined herein. Alkyl includes 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 also be part of other groups, such as C 1～6 Alkoxy.

[0050] The "alkylene" mentioned in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of carbon atoms. a～b "Alkylene" refers to an alkylene group having a to b carbon atoms. Alkylene groups include branched and straight chain hydrocarbon groups. For example, "C 1～6 The term "alkylene" is intended to include methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, and the like. Thus, the term "propylene" can be exemplified by the following structures: Likewise, the term "dimethylbutylene" can be exemplified, for example, by any of the following structures: In addition, the term “(C 1～6 )alkylene" is intended to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which can be exemplified by the following structure: For example, -C0～4 The alkylene group can be a C0 alkylene group, a C1 alkylene group (e.g., -CH2-), a C2 alkylene group (e.g., -CH2CH2-, etc.), a C3 alkylene group, or a C4 alkylene group; a C0 alkylene group means that the group here does not exist and is connected in the form of a chemical bond, such as A-C0 alkylene-B means AB, that is, the A group and the B group are directly connected by a chemical bond.

[0051] "Alkenyl" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms and 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 Alkenyl refers to an alkenyl group having a to b carbon atoms and is intended to include, for example, ethenyl, propenyl, isopropenyl, 1,3-butadienyl, and the like.

[0052] As used herein, "alkenylene" refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond, and two unsaturated valences. For example, (C3-C6)alkenylene includes >C=CH-CH2-, -CH-CH=CH-CH2-, and the like.

[0053] "Alkynyl" refers to a straight or branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also intended to include those hydrocarbon groups having one triple bond and one double bond. For example, (C2-C6)alkynyl is intended to include ethynyl, propynyl, and the like.

[0054] "Halogen" is fluorine, chlorine, bromine or iodine.

[0055] "Halogen alkyl" or "halogen substituted alkyl" means that the hydrogen atoms in the alkyl group may be substituted by one or more halogen atoms. 1～4 The halogenalkyl group refers to an alkyl group containing 1 to 4 carbon atoms in which hydrogen atoms are substituted by one or more halogen atoms.

[0056] The "-OR", "-NRR" and the like described in the present invention refer to that the R group is connected to the oxygen atom or nitrogen atom via a single bond.

[0057] The oxygen atom in "-C(O)R", "-S(O)2R" and the like described in the present invention is connected to the carbon atom or sulfur atom by a double bond, and the R group is connected to the oxygen atom or sulfur atom by a single bond.

[0058] The "cycloalkyl" and "cycloalkane" described in the present invention refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no ring heteroatoms and having a single ring or multiple rings (including fused, bridged, spiro and adamantane systems). For polycyclic systems with aromatic and non-aromatic rings without ring heteroatoms, the term "cycloalkyl" (for example, 5,6,7,8,-tetrahydronaphthalene-5-yl) is applicable when the point of attachment is at a non-aromatic carbon atom. The term "cycloalkyl" includes cycloalkenyl groups such as cyclohexenyl. Examples of cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. For example Adamantyl groups include, but are not limited to, the following structures:

[0059] The "heterocycle", "heterocycloalkyl" and "heterocycloalkane" described in the present invention refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. It usually refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with multiple ring atoms, preferably a monovalent saturated or partially unsaturated monocyclic or bicyclic ring system with 3 to 9 ring atoms, which contains 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Bicyclic means composed of two rings with two ring atoms in common, that is, the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl are oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1-thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxazepanyl. Examples of bicyclic saturated heterocycloalkyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, tetrahydro-pyridyl or dihydropyranyl.

[0060] "Spiroheterocyclyl" and "spiroheterocycle" are used interchangeably and refer to a non-aromatic saturated ring or a non-aromatic unsaturated ring system having two monocyclic rings sharing a common carbon atom, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "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.

[0061] "Bridged ring or bridged ring group" refers to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples include but are not limited to:

[0062] "Bridged heterocyclic group" and "bridged heterocycle" are used interchangeably and refer to a saturated or unsaturated cyclic group formed by two or more cyclic structures sharing two non-adjacent atoms, which is composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples include, but are not limited to:

[0063] As used herein, "aromatic ring" or "aryl" refers to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aromatic groups having 5 to 20 carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0064] As used herein, "heteroaromatic ring" or "heteroaromatic ring group" refers to an aromatic unsaturated ring containing at least one heteroatom; a heteroatom includes nitrogen, oxygen, sulfur, or the like. It is typically an aromatic monocyclic or bicyclic hydrocarbon ring containing multiple ring atoms, one or more of which is selected from O, N, and S. Preferably, there are one to three heteroatoms. Examples of heteroaromatic ring groups include pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolyl, benzothiophenyl, benzofuranyl, benzothiophenyl, benzopyranyl, benzothiapyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, and benzoxazolyl.

[0065] "Stereoisomers" include enantiomers and diastereomers;

[0066] The "deuterated compound" of the present invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0067] The term "pharmaceutically acceptable" means that a carrier, vehicle, diluent, excipient, and / or formed salt is generally chemically or physically compatible with the other ingredients that make up a pharmaceutical dosage form and physiologically compatible with the receptor.

[0068] The terms "salt" and "pharmaceutically acceptable salt" refer to acidic and / or basic salts of the above-mentioned compounds or their stereoisomers, formed with inorganic and / or organic acids and bases, and also include zwitterionic salts (inner salts), and also include quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final isolation and purification of the compound. They can also be obtained by mixing the above-mentioned compound, or its stereoisomers, with a certain amount of acid or base appropriately (e.g., equivalent amounts). These salts may form a precipitate in the solution and be collected by filtration, or be recovered after evaporation of the solvent, or be obtained by freeze-drying after reaction in an aqueous medium. The salts described in the present invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluorides, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates or trifluoroacetates of the compound.

[0069] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made. BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION

[0070] The following further describes the above content of the present invention in detail through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention.

[0071] 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 Anaiji Chemical, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0072] The reagents described in the examples are abbreviated as follows: DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HOBT: 1-hydroxybenzotriazole; DMSO: dimethyl sulfoxide; LC-MS: liquid chromatography-mass spectrometry; NaCl: sodium chloride; MPLC: medium pressure preparative 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.

[0073] Unless otherwise specified, reactions were conducted under a nitrogen atmosphere. Unless otherwise specified, solutions in the examples are aqueous solutions. Unless otherwise specified, reactions were conducted at room temperature. Room temperature is the most suitable reaction temperature, ranging from 20°C to 30°C. Unless otherwise specified, M is moles per liter.

[0074] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10-6 (ppm). NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 600 nuclear magnetic resonance spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and 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 use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications used for thin layer chromatography separation and purification products are 0.4mm-0.5mm. Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0075] Example 1. Preparation of Compound A1

[0076] Step 1. Preparation of compound A-3

[0077] 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 to a 50 mL reaction flask in sequence. After the temperature of the reaction system dropped to 0°C, compound A-1 (86.29 mg, 1.06 mmol) was added. The reaction was stirred for 0.5 hours under ice bath conditions and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solvent was removed by concentration under reduced pressure to obtain compound A-3 (crude product).

[0078] Step 2: Preparation of Compound A-4

[0079] 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 stirred at room temperature for 8 hours and then quenched (LC-MS monitoring). The pH value of the system was adjusted to 6.0-7.0 with 1N hydrochloric acid solution. The reaction solution was concentrated to obtain compound A-4 (crude), which was directly used in the next reaction.

[0080] Step 3. Synthesis of Compound A1

[0081] Compound A-4 (8.70 mg, 34.90 μmol), EDCI (13.33 mg, 69.80 μmol), HOBT (9.43 mg, 69.80 μmol), and DIPEA (11.28 mg, 87.25 μmol, 15.20 μL) were added to a 50 mL reaction vial in sequence. After the reaction was allowed to proceed at room temperature for 10 minutes, compound A-5 (4.89 mg, 34.90 μmol) was added. The reaction was stirred at room temperature for 1 hour and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the mixture was concentrated under reduced pressure. The resultant compound A1 (2.30 mg, 6.20 μmol, 17.12% yield, 81.1% purity) was analyzed by MPLC. 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).

[0082] Referring to the synthesis method of compound A1, compound A2-A11 can be obtained by replacing compound A-1 with raw material 1 in the following table 1, and replacing compound A-2 with raw material 2, while keeping other raw materials and operation methods unchanged.

[0083] Example 2. Preparation of Compound A16

[0084] Step 1. Synthesis of Compound A12

[0085] Compound 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 added sequentially to a 50 mL reaction flask. The reaction was stirred on ice for 0.5 h and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. The solvent was removed by concentration under reduced pressure to obtain compound A12 (10.00 mg, 33.30 μmol, 29.67% yield, purity 99.9%). 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),7.5 1-7.44(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).

[0086] Referring to the synthesis method of compound A12, replacing compound A-16 with starting material 1 in Table 2 below, and keeping the other starting materials and procedures unchanged, compounds A13 and A14 can be obtained.

[0087] Example 3. Preparation of Compound A15

[0088] Step 1. Synthesis of Compound A-20

[0089] 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 to a 50 mL reaction flask in sequence. After the temperature of the reaction system dropped to 0°C, compound A-1 (190.00 mg, 0.75 mmol) was added. The reaction was stirred in an ice bath for 0.5 hours and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated, and the solvent was removed by concentration under reduced pressure to obtain compound A-20 (100.00 mg, crude product).

[0090] Step 2: Synthesis of Compound A-21

[0091] Under nitrogen, 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 two hours, the solvent was evaporated to dryness. The product was purified by MPLC to afford A-21 (70.00 mg, 70.35%).

[0092] Step 3. Synthesis of Compound A15

[0093] Compound 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 added sequentially to a 50 mL reaction flask. The mixture was stirred on ice for 0.5 h before being quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. The solvent was removed by concentration under reduced pressure to obtain compound A15 (5.00 mg, 15.56 μmol, 15.50% yield, purity 99.9%). LC-MS: C 14 H 16 N3O4S, [M+H] + 322.1;found 322.1. 1H 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).

[0094] Example 4. Preparation of Compound A16

[0095] Step 1. Synthesis of Compound A-23

[0096] To a 50 mL reaction flask, 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. The reaction was stirred at room temperature overnight. The solvent was evaporated and purified by MPLC to afford A-23 (700.00 mg, 2.42 mmol, 91.56% yield).

[0097] Step 2: Synthesis of Compound A-24

[0098] 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 reaction was refluxed overnight, and the solvent was evaporated to dryness. The product was purified by MPLC to afford A-24 (700.00 mg, 1.90 mmol, 78.57% yield).

[0099] Step 3. Synthesis of Compound A-25

[0100] Compound 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 two hours, A-25 (50.00 mg, 150.42 μmol, 55.39% yield) was obtained by MPLC purification.

[0101] Step 4. Synthesis of Compound A-26

[0102] To a 50 mL reaction flask, 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. The mixture was stirred at reflux for two hours. 1 M aqueous HCl was added to adjust the pH, and the solvent was evaporated to dryness. MPLC analysis yielded A-26 (45.00 mg, 141.35 μmol, 93.97% yield).

[0103] Step 5. Synthesis of Compound A-27

[0104] Compound A-26 (45.00 mg, 141.35 μmol) was dissolved in hydrochloric acid / dioxane (2 mL). The mixture was stirred at room temperature for two hours, and the solvent was evaporated to dryness to yield A-27 (30.00 mg, 137.46 μmol, 97.25% yield).

[0105] Step 6. Synthesis of Compound A16

[0106] Compound A-27 (45.00 mg, 206.18 μmol), A-5 (28.89 mg, 206.18 μmol), EDCI (78.97 mg, 412.37 μmol) and pyridine (2 mL) were added sequentially to a 25 mL reaction flask. The reaction was stirred on ice for 0.5 h and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. The solvent was removed by concentration under reduced pressure to obtain compound A16 (8.60 mg, 25.27 μmol, 12.25% yield, purity 98.1%). 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).

[0107] Referring to the synthesis method of compound A16, the raw materials in Table 3 below are used to replace compound A-22. Other raw materials and operation methods remain unchanged to obtain compound A17.

[0108] Example 5. Preparation of Compound A18

[0109] Step 1. Synthesis of Compound A-30

[0110] Compound 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 reaction was stirred for 0.5 h under ice bath conditions and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated. The solvent was removed by concentration under reduced pressure to obtain compound A-30 (1.13 g, 5.15 mmol, 99.05% yield).

[0111] Step 2: Synthesis of Compound A-31

[0112] To a 25 mL reaction vial, 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. The mixture was stirred overnight and purified by MPLC to afford A-31 (115.00 mg, 385.65 μmol, 84.57% yield).

[0113] Step 3. Synthesis of Compound A18

[0114] Compound 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 added to a 25 mL reaction flask in sequence. The mixture was stirred at room temperature overnight and purified by MPLC to obtain A18 (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 1H 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).

[0115] Example 6. Preparation of Compound A19

[0116] Step 1. Synthesis of Compound A-33

[0117] To a 50 mL reaction flask, 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 in sequence. The mixture was stirred in an ice-water bath for 20 minutes, and then A-1 (128.67 mg, 2.85 mmol) was added. After stirring at room temperature for one hour, the solvent was evaporated and purified by MPLC to afford A-33 (500.00 mg, 2.47 mmol, 86.62% yield).

[0118] Step 2. Synthesis of Compound A-34

[0119] Compound A-33 (500.00 mg, 2.47 mmol), phosphorus oxychloride (1.13 g, 7.41 mmol), and DMF (15 mL) were added sequentially to a 50 mL reaction flask. The mixture was stirred at room temperature for two hours and purified by MPLC to afford A-34 (430.00 mg, 1.88 mmol, 75.62%).

[0120] Step 3. Synthesis of Compound A-35

[0121] Compound A-34 (430.00 mg, 1.88 mmol), sodium dihydrogen phosphate (381.26 mg, 2.44 mmol), hydrogen peroxide (76.70 mg, 2.26 mmol), and chlorous acid (238.00 mg, 2.63 mmol) were dissolved in acetonitrile / water (10 mL). The mixture was stirred overnight at room temperature, the solvent was evaporated, and the product was purified by MPLC to afford A-35 (300.00 mg, 1.22 mmol, 64.89% yield).

[0122] Step 4. Synthesis of Compound A19

[0123] Compound A-35 (8.54 mg, 60.91 μmol), A-1 (15.00 mg, 60.91 μmol), EDCI (23.27 mg, 121.82 μmol), and pyridine (2 mL) were added sequentially to a 25 mL reaction flask. The reaction was stirred on ice for 0.5 h before being quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. The solvent was removed by concentration under reduced pressure to obtain compound A19 (5.50 mg, 14.93 μmol, 24.51% yield, 98.4% purity). LC-MS: C 19 H 21 N4O4, [M+H] + 369.2; found 369.2 1 H NMR (600MHz, DMSO-d6) δ11.19(s,1H),7.69(d,J=8.4Hz,1H),7.59(d,J=8.4Hz,1H),7.31(t,J=7.8Hz ,1H),7.23(t,J=7.8Hz,1H),4.25-3.94(m,4H),3.71(s,3H),3.08(s,3H),2.97(s,2H),2.91(s,3H).

[0124] Example 7. Preparation of Compound A20

[0125] Step 1. Synthesis of Compound A-37

[0126] To a 50 mL reaction flask, 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 in sequence. The mixture was stirred in an ice-water bath for 20 minutes, and then A-1 (128.67 mg, 2.85 mmol) was added. After stirring at room temperature for one hour, the solvent was evaporated and purified by MPLC to afford A-37 (397.00 mg, 1.95 mmol, 83.93% yield).

[0127] Step 2: Synthesis of Compound A-38

[0128] 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 reaction was refluxed overnight, and the solvent was evaporated and purified by MPLC to obtain A-38 (449.00 mg, 1.59 mmol, 57.76% yield).

[0129] Step 3. Synthesis of Compound A-40

[0130] Compound 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 afford A-40 (187.00 mg, 860.88 μmol, 54.09% yield).

[0131] Step 4. Synthesis of Compound A-41

[0132] 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. The solvent was evaporated and purified by MPLC to afford A-41 (140.00 mg, 600.29 μmol, 69.73% yield).

[0133] Step 5. Synthesis of Compound A20

[0134] Compound 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 added sequentially to a 25 mL reaction vial. The reaction was stirred on ice for 0.5 h and then quenched (LC-MS monitoring). The mixture was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, purified by MPLC, and the solvent was evaporated to dryness. The solvent was removed by concentration under reduced pressure to obtain compound A20 (8.00 mg, 22.51 μmol, 17.50% yield, purity 99.1%). 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),7.5 0(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).

[0135] The present invention illustrates the technical effects of the present invention through the following test examples:

[0136] Experimental Example 1: Detection of Compound Inhibition of CRBN / DDB1 Activity (FRET)

[0137] 1. Experimental materials and reagents

[0138] Microplate reader (BMG PHERAstar FSX), ECHO (LABCYTE Echo 665), microplate constant temperature oscillator (Hangzhou Ruicheng Instrument Co., Ltd.), disodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), bovine serum albumin (Sigma), Anti-6His-Tb crypate Gold (CISBIO), CRBN / DDB1 protein (HitGen), 384-well plate (Grenier Bio-one).

[0139] 2. Experimental methods

[0140] The compound powder was dissolved in DMSO, graded diluted using ECHO, and added to a 384-well reaction plate to make the final concentration of DMSO in the entire reaction system (10.0 μL) 1.0%. An equal amount of DMSO was added as a control.

[0141] CRBN / DDB1 protein was diluted to twice the desired final concentration (5.0 nM) using 20 mM sodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH 7.0 buffer. 5.0 μL of the diluted CRBN / DDB1 protein was added to a 384-well reaction plate containing the compound. The plate was centrifuged at 1000 rpm for 1 minute and then pre-incubated on a microplate incubator at 25°C, 250 rpm for 15 minutes. Anti-6His-Tb crypate Gold and FITC-labeled thalidomide analogs were diluted to twice the desired final concentration using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH 7.0 buffer. The final concentration of Anti-6His-Tb crypate Gold was 0.2 nM, and the final concentration of FITC-labeled thalidomide analogs was 50.0 nM to obtain an Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analog mixture. 5.0 μL of the Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analog mixture was added to a 384-well reaction plate, centrifuged at 1000 rpm for 1 minute, and then placed on a microplate thermostat shaker at 25°C, 250 rpm, and incubated for 30 minutes. After the reaction was completed, the fluorescence signal value (Ex=337 nm, Em=520 / 490 nm) in the 384-well reaction plate was read with a microplate reader.

[0142] 3. Data Analysis

[0143] The vehicle 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.

[0144] Calculate the percentage of remaining activity at each concentration using the following formula:

[0145] Remaining activity (%) = 100% × (Flu 化合物组 -Flu 空白对照 ) / (Flu 阴性对照 -Flu 空白对照 )

[0146] GraphPad 6.0 was then used to fit the dose-effect curve and calculate the IC 50 value.

[0147] Table 1: Compounds and CRBN / DDB1 protein inhibition

[0148] Where, + represents 200 μM > IC 50 >100μM, ++ represents 100μM>IC 50 >10μM, +++ represents 10μM >IC 50 >1μM, ++++ means 1μM>IC 50 >0.1μM, ++++ represents IC 50 <0.1 μM.

[0149] Experimental Example 2: ITC (Isothermal Titration Calorimetry) Detection of Compound Binding to CRBN / DDB1

[0150] 1. Experimental materials and reagents

[0151] Sodium hydrogen phosphate (Sigma), sodium dihydrogen phosphate (Sigma), Tween 20 (Sigma), dimethyl sulfoxide (Sigma), desalting column (Thermo Scientific, #89882), microplate reader (BMG PHERAstar FSX), CRBN / DDB1 protein (HitGen), MicroCal PEAQ-ITC (Malvern).

[0152] 2. Experimental methods

[0153] Mix 6.1 mL of 200 mM sodium dihydrogen phosphate (NaHPO) and 3.9 mL of 200 mM sodium dihydrogen phosphate (NaHPO) to create 200 mM PB buffer (pH 7.0). Add 600 μL of 200 mM PB buffer and 3 μL of 10% Tween 20 to 5397 μL of deionized water and mix thoroughly to create a pH 7.0 assay buffer.

[0154] Use the above-prepared detection buffer to desalt the column Zeba TM The protein storage solution was buffered according to the instructions of Spin Desalting Columns (Thermo Scientific, #89882). After replacement, the protein solution was measured at OD using a microplate reader (BMG PHERAstar FSX). 280nm Measure the UV absorbance at the target site and calculate the post-displacement concentration. Based on the measured concentration, dilute the protein to 10 μM in assay buffer and add DMSO to a final concentration of 1% in a total volume of 300 μL. Centrifuge briefly at room temperature and set aside.

[0155] Dissolve the compound powder in DMSO, then dilute the compound to 100 μM in the assay buffer above, adjusting the DMSO concentration to 1% in a total volume of 100 μL. Centrifuge the compound solution at 15,000 rpm for 5 minutes at room temperature, and remove at least 75 μL of the supernatant for later use.

[0156] Clean the MicroCal PEAQ-ITC ITC instrument according to the instrument procedures. After cleaning, perform a water drop test to verify instrument cleanliness and condition. For sample titration, add the protein sample to the sample cell and the compound solution to the titrator. Set the instrument temperature to 25°C, the Reference Power (ucal / s) to 5.00, the feedback mode to "High," and the stirring speed to 750 rpm. Perform a total of 19 drops, excluding the discarded first drop. The remaining 18 drops are titrated at a rate of 2 uL / 4 s, with a 150 s equilibration between drops. After the titration, clean the instrument. Perform the water drop test again to ensure instrument cleanliness and condition. Then, perform a control titration. Prepare the compound as above and add it to the titrator. Separately, prepare 300 uL of assay buffer containing 1% DMSO and add it to the sample cell. Set the instrument parameters as above and perform the titration.

[0157] 3. Data Analysis

[0158] The ITC instrument's own analysis software was used to perform fitting in the "one set of sites" mode. After deducting the background from the control experiment, reaction-related parameters such as N, KD, δH, δG, and δS were obtained.

[0159] Table 2: Binding of compounds to CRBN / DDB1 protein

[0160] The above experiments show that compound A of the examples of the present invention has good CRBN binding ability and inhibitory effect, and can be effectively used for the treatment of diseases related to abnormal CRBN activity.

Claims

1. A compound represented by Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, Indicates the presence or absence of oxygen substitution; Ring A is selected from 3-12 membered cycloalkyl, 4-12 membered heterocycloalkyl, 6-10 membered aromatic ring, 5-10 membered heteroaromatic ring; wherein, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring can be further optionally replaced by one, two, three or four independent R A1 replace; Each R A1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R A4 replace; Each R A4 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR A2 R A3 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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 ; R A2 、R A3 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; R 2 independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-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 Alkylene-NR 21 R 22 、-C 0～4 Alkylene-NR 21 C(O)R 22 、-C 0～4 Alkylene-NR 21 S(O)2R 22 、-C 0～4 Alkylene-NR 21 S(O)R 22 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 23 replace; Each R 23 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 21 R 22 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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-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 Alkylene-NR 21 R 22 、-C 0～4 Alkylene-NR 21 C(O)R 22 、-C 0～4 Alkylene-NR 21 S(O)2R 22 、-C 0～4 Alkylene-NR 21 S(O)R 22 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; R 21 、R 22 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 1～4 Alkylene-OR 24 、-C 1～4 Alkylene-OC(O)R 24 、-C 1～4 Alkylene-SR 24 、-C 1～4 Alkylene-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)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)2R 25 、-C 1～4 Alkylene-NR 24 S(O)R 25 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -C 0～4 Alkylene-OR 24 、-C 0～4 Alkylene-OC(O)R 24 、-C 0～4 Alkylene-SR 24 、-C 0～4 Alkylene-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)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)2R 25 、-C 0～4 Alkylene-NR 24 S(O)R 25 、-C 0～4 Alkylene-(3-10 membered cycloalkyl), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 27 replace; R 24 、R 25 are independently selected from hydrogen, -C 1-6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl; Each R 27 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl.

2. The compound according to any one of claim 1, characterized in that: Ring A is selected from Wherein, the ring selected from the group consisting of A and B may be further optionally replaced by one, two, three or four independent R A1 replace.

3. The compound according to any one of claim 2, characterized in that: Each R A1 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl.

4. The compound according to any one of claim 1, characterized in that: Ring A is selected from 5. The compound according to any one of claims 1 or 4, characterized in that: R 2 Selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 23 replace; Each R 23 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; R 21 、R 22 are independently selected from hydrogen, -C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5-10 membered heteroaromatic ring); wherein, alkylene, cycloalkyl, heterocycloalkyl, aromatic ring, heteroaromatic ring may be further optionally replaced by one, two, three or four independent R 26 replace; Each R 26 are independently selected from hydrogen, halogen, cyano, nitro, =O, =S, =CR 24 R 25 、-C 1～6 Alkyl, -C 2～6 Alkenyl, -C 2～6 Alkynyl, halogen-substituted-C 1～6 Alkyl, halogen-substituted -C 2～6 Alkenyl, halogen-substituted-C 2～6 Alkynyl, -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), -C 0～4 Alkylene-(4-10 membered heterocycloalkyl), -C 0～4 Alkylene-(6-10 membered aromatic ring), -C 0～4 Alkylene-(5- to 10-membered heteroaromatic ring); R 24 、R 25 are independently selected from hydrogen, -C 1-3 Alkyl, halogen-substituted -C 1～3 alkyl.

6. The compound according to any one of claim 5, characterized in that: R 2 Selected from -C(O)NR 21 R 22 、-C(O)R 21 、-C 0～2 Alkylene-NR 21 R 22 、-C(O)OR 21 ; R 21 、R 22 are independently selected from hydrogen, -C 1～3 Alkyl, -C 0～1 Alkylene-(6-membered aromatic ring), -C 0～1 Alkylene-(10-membered heteroaromatic ring), -(4- to 6-membered heterocycloalkyl), -(3- to 6-membered cycloalkyl), wherein the aromatic ring, heteroaromatic ring, heterocycloalkyl, and cycloalkyl may be further optionally replaced by one, two, three, or four independent R 26 replace; Each R 26 are independently selected from hydrogen, -C 1～3 Alkyl, -(4- to 6-membered heterocycloalkyl), -C(O)R 24 、-C(O)OR 24 、-OC(O)R 24 ; R 24 Selected from hydrogen, methyl, ethyl.

7. The compound according to any one of claim 6, characterized in that: R 2 Selected from hydrogen, 8. The compound according to any one of claims 1 to 7, characterized in that: The compound is specifically:

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

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

11. Use of the compound according to any one of claims 1 to 8, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a drug for targeted protein degradation.

12. Use of the compound according to any one of claims 1 to 8, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of a targeted protein degradation drug.