Spiro compound and application thereof

Abstract

The invention provides a spiro compound which is shown in a formula I and has a binding effect with E3 ligase protein CRBN, and application of the spiro compound in preparation of a medicine for treating cell abnormal proliferation diseases. # imgabs0 #

Description

Spirocyclic compounds and uses thereof 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] 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;

[0010] 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-NRA2 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;

[0011] 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)RA3 、-C 0～4 Alkylene-NR A2 S(O)2R A3 、-C 0～4 Alkylene-NR A2 S(O)R A3 ;

[0012] 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;

[0013] 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 、 -C0～4 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;

[0014] 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-NR21 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;

[0015] 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-NR24 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;

[0016] 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 R25 、-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;

[0017] 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;

[0018] 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.

[0019] Preferably, the A ring is selected from a 10-membered nitrogen-containing aromatic heterocycle.

[0020] Further,

[0021] The A ring is selected from The B ring is a 6-membered nitrogen-containing aromatic heterocycle. 2 and N atoms can be connected to any substitutable position of the above-mentioned A ring; preferably, R 2The N atom can be attached to any substitutable position of the above-mentioned B ring.

[0022] Preferably,

[0023] The A ring 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 In formula I, R connected to ring A 2 and the N atom may be attached to any substitutable position of the above-mentioned A ring;

[0024] As a preference,

[0025] Each R A1 are independently selected from hydrogen, halogen, -NR A2 R A3 、-OR A2 、-C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl;

[0026] R A2 、R A3 are independently selected from hydrogen, methyl, ethyl and propyl.

[0027] As a preference,

[0028] The A ring is selected from

[0029] As a preference,

[0030] 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;

[0031] 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;

[0032] 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 、-C1～4 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;

[0033] 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);

[0034] R 24 、R 25 are independently selected from hydrogen, -C 1-3 Alkyl, halogen-substituted -C 1～3 alkyl.

[0035] As a preference,

[0036] The R 2 Selected from hydrogen, -C(O)NR 21 R 22 、-C(O)R 21 、-C 0～2 Alkylene-NR 21 R 22 、-C(O)OR 21 、-OR 21 ;

[0037] 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;

[0038] 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 ;

[0039] R 24 Selected from hydrogen, methyl, ethyl, propyl.

[0040] Further,

[0041] The R 2 Selected from hydrogen, hydroxyl,

[0042] In some specific embodiments of the invention, the compound represented by formula I of the present invention is specifically:

[0043] The present invention also provides the use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of treatment for diseases related to abnormal cell proliferation.

[0044] Furthermore, the disease is cancer.

[0045] The present invention also provides use of the above-mentioned compound, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a targeted protein degradation drug.

[0046] The present invention also provides the use of the above-mentioned 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.

[0047] 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.

[0048] 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.

[0049] "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.

[0050] "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.

[0051] 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.

[0052] "Alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. For example, C1-6 alkyl refers to an alkyl group having 1 to 6 member atoms, such as 1 to 4 member atoms. Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may optionally be 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. Alkyl groups can also be part of other groups, such as C1-6 alkoxy.

[0053] 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: Furthermore, the term "(C1-6)alkylene" is intended to include such branched chain hydrocarbyl groups as cyclopropylmethylene, which can be exemplified by the following structure: For example, -C0~4 alkylene can be C0 alkylene, C1 alkylene (for example, -CH2-), C2 alkylene (for example, -CH2CH2-, etc.), C3 alkylene or C4 alkylene; C0 alkylene 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.

[0054] "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.

[0055] 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.

[0056] "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.

[0057] "Halogen" is fluorine, chlorine, bromine or iodine.

[0058] "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.

[0059] 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.

[0060] 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.

[0061] 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:

[0062] 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.

[0063] "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.

[0064] "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:

[0065] "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:

[0066] 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.

[0067] 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.

[0068] "Stereoisomers" include enantiomers and diastereomers;

[0069] 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.

[0070] 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.

[0071] 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.

[0072] 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. DETAILED DESCRIPTION

[0073] 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.

[0074] 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.

[0075] Unless otherwise specified in the examples, the reaction was carried out under nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Room temperature is the most suitable reaction temperature, which is 20°C. □ ~30℃ □ Unless otherwise specified in the examples, M refers to moles per liter.

[0076] 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 AvanceIII 400 and Bruker Avance 600 nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (Methol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS measurements were performed using a Shimadzu liquid chromatography-mass spectrometer.

[0077] HPLC analysis was performed using a Shimadzu LC-MS 2020 (ESI). A Shimadzu LC-20A high-pressure liquid chromatograph was used. A Gilson GX-281 reverse-phase preparative chromatograph was used for MPLC (medium-pressure preparative chromatography). Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used for thin-layer chromatography. Thin-layer chromatography separation and purification products were performed using 0.4 mm to 0.5 mm silica gel. Column chromatography typically used Yantai Huanghai 200-300 mesh silica gel as the carrier.

[0078] The reagents described in the examples are abbreviated as follows: Pd2(dba)3: trisdibenzylideneacetone dipalladium; DIPEA: N,N-diisopropylethylamine; DMSO: dimethyl sulfoxide; AcOH: acetic acid; Sphos: 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl; LC-MS: liquid chromatography-mass spectrometry; NaCl: sodium chloride; MPLC: medium pressure liquid chromatography; TMEDA: tetramethylethylenediamine.

[0079] Example 1. Preparation of Compound A1

[0080] Step 1. Preparation of compound A-3

[0081] Compound A-1 (100.00 mg, 502.42 μmol), A-2 (22.65 mg, 502.42 μmol), and DIPEA (194.80 mg, 1.51 mmol, 262.53 μL) were added to a 50 mL reaction flask in sequence and dissolved in 5 mL of tetrahydrofuran. The reaction was allowed to react at room temperature for 15 hours (monitored by LC-MS). The reaction solution was then extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and concentrated under reduced pressure to remove the solvent to obtain compound A-3 (crude product), which was then purified by MPLC to obtain compound A-3 (86.00 mg, 414.14 μmol, 82.43% yield).

[0082] Step 2: Synthesis of Compound A1

[0083] Compound A-3 (28.00 mg, 134.84 μmol), A-4 (18.90 mg, 134.84 μmol), AcOH (2 mL) and DMSO (2 mL) were added to a 50 mL reaction flask in sequence. The mixture was stirred at 100°C for 2 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, and the solvent was evaporated to dryness. The mixture was concentrated under reduced pressure and analyzed by MPLC. Compound A1 (4.00 mg, 12.85 μmol, 9.53% yield, 99.9% purity) was obtained. LC-MS: C 16 H 18 N6O2,[M+H] + :312.1,found 312.2. 1 H NMR (600MHz, DMSO-d6) δ7.95 (dd, J=8.5, 1.4Hz, 1H), 7.53 (ddd, J=8.5, 6.8, 1.4Hz, 1H), 7.37 (dd, J=8.4, 1.2Hz, 1H), 7.09 (ddd, J=8.4, 6.8, 1.2Hz, 1H), 4.23 (d, J=8.6Hz, 2H), 4.02 (d, J=8.6Hz, 2H), 3.24 (s, 6H), 3.04 (s, 2H).

[0084] Referring to the synthesis method of compound A1, compound A2 can be obtained by replacing compound A-2 with raw material 1 in the table below and keeping other raw materials and operation methods unchanged.

[0085] Example 2. Preparation of Compound A3

[0086] Step 1. Synthesis of Compound A3

[0087] Compound A-6 (20.00 mg, 110.75 μmol), A-4 (15.52 mg, 110.75 μmol), DIPEA (42.94 mg, 332.24 μmol, 57.87 μL) and DMSO (2 mL) were added to a 50 mL reaction flask in sequence. The mixture was stirred at 150°C for 15 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, and the solvent was evaporated to dryness. The organic phases were concentrated under reduced pressure and analyzed by MPLC. Compound A3 (8.00 mg, 28.14 μmol, 25.14% yield, purity 99.1%) was obtained. LC-MS: C 14 H 13 N4O3,[M+H] + :285.1,found 285.2. 1 H NMR (400MHz, Methanol-d4) δ 8.02 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.49-7.23 (m, 2H), 4.54 (d, J = 9.5 Hz, 2H), 4.33 (d, J = 9.5 Hz, 2H), 3.02 (s, 2H).

[0088] Referring to the synthesis method of compound A3, compound A4 can be obtained by replacing compound A-6 with raw material 1 in the table below and keeping other raw materials and operation methods unchanged.

[0089] Example 3. Preparation of Compound A5

[0090] Step 1. Preparation of Compound A-9

[0091] Compound A-8 (150.00 mg, 753.63 μmol), A-4 (34.95 mg, 753.63 μmol), and DIPEA (292.20 mg, 1.51 mmol, 262.53 μL) were added to a 50 mL reaction flask in sequence and dissolved in 8 mL of tetrahydrofuran. The reaction system was reacted at room temperature for 12 hours (monitored by LC-MS). The reaction solution was then extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and concentrated under reduced pressure to remove the solvent to obtain compound A-9 (crude product), which was then purified by MPLC to obtain compound A-9 (100.00 mg, 481.40 μmol, 63.90% yield).

[0092] Step 2: Synthesis of Compound A5

[0093] Compound A-9 (20.00 mg, 66.07 μmol), A-2 (2.98 mg, 66.07 μmol), AcOH (2 mL) and DMSO (2 mL) were added to a 50 mL reaction flask in sequence. The mixture was stirred at 100°C for 15 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, and the solvent was evaporated to dryness. The mixture was concentrated under reduced pressure and analyzed by MPLC. Compound A5 (2.20 mg, 7.07 μmol, 10.70% yield, purity 99.9%) was obtained. LC-MS: C 16 H 18 N5O2,[M+H] + :312.1,found 312.2. 1 H NMR(400MHz,DMSO-d6)δ11.65and 11.37(s,2H),8.16-7.68(m,3H),7.45-7.40(m,1H),5.08-4.88(m,2H),4.61-4.26(m,2H),3.25(s,6H),3.08(s,2H).

[0094] Referring to the synthesis method of compound A5, compound A6 and A7 can be obtained by replacing compound A-2 with raw material 1 in the table below and keeping other raw materials and operation methods unchanged.

[0095] Example 4. Preparation of Compound A8

[0096] Step 1. Preparation of Compound A-13

[0097] Compound A-12 (300.00 mg, 1.51 mmol), A-2 (271.91 mg, 6.03 mmol), and potassium carbonate (1.25 g, 9.04 mmol) dissolved in 10 mL of N-methylpyrrolidone were added sequentially to a 50 mL reaction flask. The reaction system was heated at 180 ° C for 4 hours (LC-MS monitoring). Then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and concentrated under reduced pressure to remove the solvent to obtain compound A-13 (crude product), which was then purified by MPLC to obtain compound A-13 (170.00 mg, 818.65 μmol, 54.31% yield).

[0098] Step 2: Synthesis of Compound A8

[0099] Compound A-13 (100.00 mg, 481.56 μmol), A-4 (80.98 mg, 577.87 μmol), cesium carbonate (313.98 mg, 963.12 μmol), Sphos (19.74 mg, 48.16 μmol) and Pd2(dba)3 (22.03 mg, 24.08 μmol) were added to a 50 mL reaction flask in sequence and dissolved in 1,4-dioxane (5 mL). The mixture was stirred at 120°C in an airtight state for 2 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 to dryness, and concentrated under reduced pressure. The product was analyzed by preparative MPLC. Compound A8 (1.50 mg, 4.82 μmol, 1.00% yield, 92.0% purity) was obtained. LC-MS: C 16 H 18 N5O2,[M+H] + :312.1,found 312.2. 1 H NMR (400MHz, DMSO-d6) δ 8.17-8.03 (m, 1H), 7.97-7.79 (m, 3H), 4.51 (d, J = 8.4Hz, 2H), 4.33 (d, J = 8.4Hz, 2H), 3.11 (s, 2H), 2.92 (s, 6H).

[0100] Example 5. Preparation of Compound A9

[0101] Step 1. Preparation of Compound A-15

[0102] Compound A-14 (398.00 mg, 2.00 mmol), A-2 (90.15 mg, 2.00 mmol), and DIPEA (516.88 mg, 4.00 mmol, 696.60 μL) dissolved in 8 mL DMSO were added sequentially to a 50 mL reaction flask. The reaction system was heated at 80 ° C for 10 hours (LC-MS monitoring). Then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and concentrated under reduced pressure to remove the solvent to obtain compound A-15 (crude product), which was then purified by MPLC to obtain compound A-15 (300.00 mg, 1.44 mmol, 72.25% yield).

[0103] Step 2: Synthesis of Compound A9

[0104] Compound A-15 (120.00 mg, 577.87 μmol), A-4 (121.47 mg, 866.81 μmol), cesium carbonate (379.08 mg, 1.16 mmol), Sphos (23.69 mg, 57.79 μmol) and Pd2(dba)3 (26.44 mg, 28.89 μmol) were added to a 50 mL reaction flask in sequence and dissolved in 1,4-dioxane (3 mL). The mixture was stirred at 140°C in an airtight state for 4 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 mixture was concentrated under reduced pressure. The mixture was analyzed by preparative MPLC. Compound A9 (19.50 mg, 59.00 μmol, 10.21% yield, 94.2% purity) was obtained. LC-MS: C 16 H 18 N5O2,[M+H] + :312.1,found 312.1. 1 H NMR (400MHz, DMSO-d6) δ11.22(s,1H),7.86-7.50(m,2H),7.45-7.11(m,2H),4.30(d,J=9.0Hz,2H),4.14(d,J=9.0Hz,2H),3.02(s,2H),2.50(s,6H).

[0105] Referring to the synthesis method of compound A9, compound A10 can be obtained by replacing compound A-2 with raw material 1 in the table below and keeping other raw materials and operation methods unchanged.

[0106] Example 6. Preparation of Compounds A11 and A12

[0107] Step 1. Preparation of Compound A-16

[0108] Compound A-14 (100.00 mg, 2.00 mmol), A-4 (70.41 mg, 502.42 μmol), and DIPEA (194.80 mg, 1.51 mmol, 262.54 μL) were added to a 50 mL reaction flask in sequence and dissolved in 5 mL of acetonitrile. The reaction system was heated at 80 ° C for 15 hours (LC-MS monitoring). Then the reaction solution was extracted with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was evaporated and concentrated under reduced pressure to remove the solvent to obtain compound A-16 (crude product), which was then purified by MPLC to obtain compound A-16 (120.00 mg, 396.41 μmol, 78.90% yield).

[0109] Step 2: Synthesis of Compound A11

[0110] Compound A-16 (20.00 mg, 66.07 μmol) and 6M HCl (66.07 μmol) were added to a 50 mL reaction flask in sequence, dissolved in water (2 mL), and stirred in an airtight environment at 100°C for 2 hours before quenching the reaction (LC-MS monitoring). Extraction was completed with saturated NaCl solution (10 mL) and ethyl acetate (3×20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness. After concentration under reduced pressure, the compound A-11 (8.00 mg, 28.14 μmol, 42.60% yield, purity 90.0%) was analyzed by preparative MPLC. LC-MS: C 14 H 13 N4O3,[M+H] + :285.1,found 285.2. 1 H NMR (400MHz, Methanol-d4) δ7.59-7.38(m,1H),7.35-7.06(m,3H),4.60-4.40(m,4H),3.12(s,2H).

[0111] Step 3. Synthesis of Compound A12

[0112] Compound A-16 (20.00 mg, 66.07 μmol), AcOH (660.69 μmol), Zn (660.69 μmol) and TMEDA (76.77 mg, 660.69 μmol) were added to a 50 mL reaction flask in sequence and dissolved in ethanol (3 mL). The mixture was stirred at 45°C in an airtight state for 15 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, and the solvent was evaporated to dryness. The organic phases were concentrated under reduced pressure and analyzed by preparative MPLC. Compound A12 (2.00 mg, 7.46 μmol, 11.28% yield, 91.2% purity) was obtained. LC-MS: C 14 H 13 N4O2,[M+H] + :269.1,found 269.1. 1 H NMR (400MHz, DMSO-d6) δ 11.27 (s, 1H), 8.37 (s, 1H), 8.00-7.30 (m, 4H), 4.40 (d, J = 8.8Hz, 2H), 4.24 (d, J = 8.8Hz, 2H), 3.07 (s, 2H).

[0113] The present invention illustrates the technical effects of the present invention through the following test examples:

[0114] Experimental Example 1: Detection of Compound Inhibition of CRBN / DDB1 Activity (FRET)

[0115] 1. Experimental materials and reagents

[0116] 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).

[0117] 2. Experimental methods

[0118] 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.

[0119] Use 20mM disodium hydrogen phosphate, 20mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH 7.0 buffer to dilute the CRBN / DDB1 protein to twice the desired final concentration (5.0nM). Pipette 5.0μL of the diluted CRBN / DDB1 protein into a 384-well reaction plate to which the compound has been added. Centrifuge at 1000rpm for 1 minute, and then place on a microplate constant temperature shaker at 25°C, 250rpm, and preincubate 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.

[0120] 3. Data Analysis

[0121] 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.

[0122] Calculate the percentage of remaining activity at each concentration using the following formula:

[0123] Remaining activity (%) = 100% × (Flu 化合物组 -Flu 空白对照 ) / (Flu 阴性对照 -Flu 空白对照 )

[0124] GraphPad 6.0 was then used to fit the dose-effect curve and calculate the IC 50 value.

[0125] Table 1: Compounds and CRBN / DDB1 protein inhibition Where, + represents 200 μM > IC 50 >100μM, ++ represents 100μM>IC 50 >10 μM, +++ represents 10 μM > IC 50 >1μM, ++++ represents IC 50 <1 μM.

Claims

1. A compound represented by Formula I, or a stereoisomer thereof, or a deuterated compound thereof, or a pharmaceutically acceptable salt thereof: in, 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 claim 1, characterized in that: The A ring is selected from a 10-membered nitrogen-containing aromatic heterocycle.

3. The compound according to claim 2, characterized in that: The A ring is selected from The B ring is a 6-membered nitrogen-containing aromatic heterocycle.

4. The compound according to any one of claim 1, characterized in that: The A ring 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.

5. The compound according to claim 4, characterized in that: Each R A1 are independently selected from hydrogen, halogen, -NR A2 R A3 、-OR A2 、-C 1～3 Alkyl, halogen-substituted -C 1～3 alkyl; R A2 、R A3 are independently selected from hydrogen, methyl, ethyl and propyl.

6. The compound according to any one of claims 1 to 5, characterized in that: The A ring is selected from 7. The compound according to claim 1, 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.

8. The compound according to claim 7, characterized in that: R 2 Selected from hydrogen, -C(O)NR 21 R 22 、-C(O)R 21 、-C 0～2 Alkylene-NR 21 R 22 、-C(O)OR 21 、-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, propyl.

9. The compound according to claim 8, characterized in that: The R 2 Selected from hydrogen, hydroxyl, 10. The compound according to any one of claims 1 to 9, characterized in that: The compound is specifically:

11. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the treatment of diseases related to abnormal cell proliferation.

12. The use according to claim 11, characterized in that: The disease is cancer.

13. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt in the preparation of a drug for targeted protein degradation.

14. Use of the compound according to any one of claims 1 to 10, or its stereoisomer, or its deuterated compound, or its pharmaceutically acceptable salt as an intermediate in the preparation of a drug for targeted protein degradation.

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