Spiro compound and its use

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and specifically to a ligand compound for binding to a novel spirocyclic cereblon E3 ubiquitin ligase protein.

Background Art

[0002] The degradation of proteins is a highly regulated and essential process for maintaining cellular homeostasis. The selective identification and removal of damaged, misfolded, or excessive proteins are carried out through the ubiquitin-proteasome pathway (UPP). UPP is characterized by removing defective proteins, being ATP-dependent, efficient, and highly selective. Its catalytic part is the E3 ubiquitin ligase, but it is necessary to supplement the protein that needs to be degraded first. PROTACs technology is designed based on the UPP principle. By binding the ligand of the target protein and the ligand of the E3 ligase with an appropriate chemical bond, it can identify the target protein, enhance the binding ability of the ligase E3 to the target protein, target ubiquitination to force the degradation of the target protein, and has the characteristics of low catalytic amount, high efficiency, and high selectivity.

[0003] Multiple ubiquitin molecules covalently bind to the terminal lysine residue through the E3 ubiquitin ligase, thereby marking the protein for degradation by the proteasome. The protein is digested into small peptides and finally decomposed into amino acids, which function as components of new proteins. Degradation by defective proteasomes is related to various clinical symptoms such as Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular diseases, and cancer.

[0004] Cereblon is a thalidomide-binding protein that is part of the E3 ubiquitin ligase protein complex and functions as a substrate receptor that selectively acts on ubiquitinated proteins. Cereblon is a protein encoded by the human CRBN gene and forms an E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), cullin 4A (CUL4A), and regulator of cullins 1 (ROC1). This complex can ubiquitinate a series of proteins, but the specific mechanism is unknown. Cereblon is a commonly used E3 ligase known to be used in PROTAC technology.

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

Summary of the Invention

[0006] The present invention provides a compound represented by the following formula I, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts.

Chemical Formula

[0007] Furthermore, ring A is

Chemical formula

[0008] Preferably, each R A1 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~3 alkyl group, -C 1~3 alkyl halide group.

[0009] Furthermore, ring A is

Chemical formula

[0010] Preferably, the said R 2 is hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~6 alkyl group, -C 2~6 alkenyl group, -C 2~6 alkynyl group, -C 1~6 alkyl halide group, -C 2~6 alkenyl halide group, -C 2~6 alkynyl halide group, -C 0~4 alkylene - OR 21 , -C 0~4 alkylene - OC(O)R 21 , -C 0~4 alkylene - C(O)R 21 , -C 0~4 alkylene - C(O)OR 21 , -C 0~4 alkylene - C(O)NR 21 R 22, -C 0~4 alkylene - NR 21 R 22 , -C 0~4 alkylene - (3 - to 10 - membered cycloalkyl group), -C 0~4 alkylene - (4 - to 10 - membered heterocycloalkyl group), -C 0~4 alkylene - (6 - to 10 - membered aromatic ring), -C 0~4 alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from these, where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may each be further substituted by one, two, three, or four independent R 23 groups, each R 23 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, -C 1~6 alkyl group, -C 2~6 alkenyl group, -C 2~6 alkynyl group, -C 1~6 halogenated alkyl group, -C 2~6 halogenated alkenyl group, -C 2~6 halogenated alkynyl group, -C 0~4 alkylene - OR 21 , -C 0~4 alkylene - OC(O)R 21 , -C 0~4 alkylene - C(O)R 21 , -C 0~4 alkylene - (3 - to 10 - membered cycloalkyl group), -C 0~4 alkylene - (4 - to 10 - membered heterocycloalkyl group), -C 0~4 alkylene - (6 - to 10 - membered aromatic ring), -C 0~4 alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from these, where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may each be further substituted by one, two, three, or four independent R 26 groups, R 21 R 22 is independently hydrogen, -C 1~6 alkyl group, -C 2~6 alkenyl group, -C 2~6 alkynyl group, -C 1~6an alkyl halide group, -C 2~6 an alkenyl halide group, -C 2~6 an alkynyl halide group, -C 1~4 alkylene - OR 24 、-C 1~4 alkylene - OC(O)R 24 、-C 1~4 alkylene - C(O)R 24 、-C 1~4 alkylene - C(O)OR 24 、-C 1~4 alkylene - C(O)NR 24 R 25 、-C 1~4 alkylene - NR 24 R 25 、-C 1~4 alkylene - NR 24 C(O)R 25 、-C 0~4 alkylene - (3 - to 10 - membered cycloalkyl group), -C 0~4 alkylene - (4 - to 10 - membered heterocycloalkyl group), -C 0~4 alkylene - (6 - to 10 - membered aromatic ring), -C 0~4 alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from these, where the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R 26 ; each R 26 is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR 24 R 25 、-C 1~6 alkyl group, -C 2~6 alkenyl group, -C 2~6 alkynyl group, -C 1~6 alkyl halide group, -C 2~6 alkenyl halide group, -C 2~6 alkynyl halide group, -C 0~4 alkylene - OR 24 、-C 0~4 alkylene - OC(O)R 24 、-C 0~4 alkylene - C(O)R 24 、-C 0~4alkylene-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- to 10-membered cycloalkyl group), -C 0~4 alkylene-(4- to 10-membered heterocycloalkyl group), -C 0~4 alkylene-(6- to 10-membered aromatic ring), -C 0~4 alkylene-(5- to 10-membered heteroaromatic ring), selected from R 24 、R 25 each independently is hydrogen, -C 1-3 alkyl group, -C1-3 haloalkyl group.

[0011] Furthermore, R 2 is selected from -C(O)NR 21 R 22 、-C(O)R 21 、-C 0~2 alkylene-NR 21 R 22 、-C(O)OR 21 selected from R 21 、R 22 each independently is hydrogen, -C 1~3 alkyl group, -C 0~1 alkylene-(6-membered aromatic ring), -C 0~1 alkylene-(10-membered heteroaromatic ring), -(4- to 6-membered heterocycloalkyl group), -(3- to 6-membered cycloalkyl group), where the aromatic ring, heteroaromatic ring, heterocycloalkyl group, cycloalkyl group may be further substituted by one, two, three, or four independent R 26 s, each R 26 independently is hydrogen, -C 1~3 alkyl group, -(4- to 6-membered heterocycloalkyl group), -C(O)R 24 、-C(O)OR24 、 -OC(O)R 24 selected from R 24 is selected from hydrogen, methyl group, and ethyl group.

[0012] More specifically, R 2 is hydrogen,

Chemical formula

[0013] In some specific embodiments of the present invention, the compound is specifically

Chemical formula

[0014] According to the present invention, there is provided the use of any one of the above compounds, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts in the preparation of a pharmaceutical composition for treating diseases associated with abnormal cell proliferation.

[0015] Furthermore, the disease is cancer.

[0016] According to the present invention, there is further provided the use of any one of the above compounds, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts in the preparation of a target proteolytic agent.

[0017] Furthermore, there is provided the use of the above compound, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts as an intermediate in the preparation of a target proteolytic agent.

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

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

[0020] Definition of terms used in the present invention: Unless otherwise specified, the first definition provided for a group or term in this specification applies to the group or term throughout this specification. For terms not specifically defined in this specification, those skilled in the art can recognize their meanings based on the content and context of the present invention.

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

[0022] "Optionally further substituted" means that "substitution" may or may not occur, and whether "substitution" occurs or not, it is included in this specification.

[0023] The minimum and maximum contents of carbon atoms in a hydrocarbon group are indicated by a prefix. For example, the prefix C a ~ b Alkyl refers to any alkyl containing "a" to "b" carbon atoms. Thus, for example, C1-4 alkyl refers to an alkyl containing 1 to 4 carbon atoms.

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

[0025] "Alkylene" as described in the present invention refers to a divalent saturated aliphatic hydrocarbon group having a specified number of constituent atoms. C a ~ b "Alkylene" refers to an alkylene group having from a to b carbon atoms. The alkylene group includes branched and linear hydrocarbyl groups. For example, "C 1~6 alkylene" includes methylene, ethylene, propylene, 2-methylpropylene, dimethylethylene, pentylene, etc. Thus, for example, the term "propylene" has the following structure:

Chemical formula

Chemical formula

Chemical formula

[0026] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having a predetermined number of carbon atoms, in some embodiments 2 to 6 or 2 to 4 carbon atoms, and having at least one vinyl unsaturation site (>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, vinyl, propenyl, isopropenyl, 1,3-butadienyl, etc.

[0027] The "alkenylene group" referred to in the present invention refers to a hydrocarbon chain having 2 to 10 carbon atoms, at least one double bond and two unsaturated valences. For example, a (C3-C6) alkenylene group includes >C=CH-CH2-, -CH-CH=CH-CH2-, etc.

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

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

[0030] "Halogenated alkyl", "halogen-substituted alkyl" means that one or more hydrogen atoms in the alkyl are substituted by halogens. For example, "C 1~4 "Halogenated alkyl" refers to an alkyl in which one or more hydrogen atoms are substituted by one or more halogen atoms.

[0031] In the present invention, "-OR", "-NRR", etc. indicate that the R group is bonded to an oxygen atom or a nitrogen atom by a single bond.

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

[0033] In the present invention, the "cycloalkyl group" and "cycloalkane" refer to a saturated or partially saturated cyclic group having a plurality of carbon atoms, no ring heteroatoms, and having a single ring or a plurality of rings (including fused, bridged, spiro and adamantane systems). For a polycyclic system containing an aromatic ring and a non-aromatic ring without ring heteroatoms, when the bonding site is located at a non-aromatic carbon atom, the term "cycloalkyl group" (for example, 5,6,7,8-tetralin-5-yl) is applicable. The term "cycloalkyl group" includes cycloalkenyl, for example, cyclohexenyl. Examples of cycloalkyl groups include adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl and cyclohexenyl. Examples of cycloalkyl groups including polybicycloalkyl ring systems include bicyclohexyl, bicyclopentyl, bicyclooctyl, etc. For example,

Chemical formula

Chemical formula

[0034] As used herein, the terms "heterocyclic ring", "heterocycloalkyl" and "heterocycloalkane" of the present invention refer to a saturated or non-aromatic unsaturated ring containing at least one heteroatom. Here, the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. Generally, it refers to a monocyclic or bicyclic ring system that is monovalent, saturated or partially unsaturated and has a plurality of ring atoms, preferably a monovalent, saturated or partially unsaturated monocyclic or bicyclic ring system having 3 to 9 ring atoms, containing 1, 2 or 3 ring heteroatoms selected from N, O and S, and the remaining ring atoms being carbon. The term "bicyclic" refers to a structure consisting of two rings sharing two ring atoms, that is, the bridge separating the two rings is a single bond or a chain consisting of one or two ring atoms. Examples of monocyclic saturated heterocycloalkyl include oxetanyl, azetidinyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuryl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, [Chemical formula] , thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl or oxaazepanyl. Examples of bicyclic saturated heterocycloalkyl include 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, [Chemical formula] are included. Examples of partially unsaturated heterocycloalkyl include dihydrofuranyl, imidazolinyl, tetrahydropyridyl or dihydropyranyl.

[0035] "Spiroheterocyclyl" and "spiroheterocyclic ring" can be used interchangeably and refer to a non-aromatic saturated or non-aromatic unsaturated ring system having two monocyclic rings sharing one carbon atom. It is composed of a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus. For example, "5- to 12-membered spiroheterocyclic ring" refers to a spiroheterocyclic ring having 5 to 12 ring atoms, among which 1, 2, or 3 ring atoms are heteroatoms.

[0036] "Bridged ring or bridged ring-type group" refers to a saturated or unsaturated ring-type group formed by two or more cyclic structures sharing two non-adjacent atoms. Specific examples thereof include

Chem.

[0037] "Bridged heterocyclyl" and "bridged heterocyclic ring" can be 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 a carbon atom and a heteroatom selected from nitrogen, oxygen, sulfur, and phosphorus. Specific examples thereof include

Chem.

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

[0039] As used herein, the terms "heteroaromatic ring" and "heteroaromatic group" refer to an aromatic unsaturated ring containing at least one heteroatom, where the heteroatom refers to a nitrogen atom, an oxygen atom, a sulfur atom, etc. An aromatic heterocyclic ring generally includes an aromatic monocyclic or bicyclic hydrocarbon containing a plurality of ring atoms, one or more of which are heteroatoms selected from O, N, and S. It is preferred that there are 1 to 3 heteroatoms. Heterocyclic aryl represents, for example, pyridyl, indolyl, quinoxalinyl, quinolyl, isoquinolinyl, benzothienyl, benzofuranyl, benzothienyl, benzothienyl, benzopyranyl, benzothiopyranyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, oxadiazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl.

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

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

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

[0043] Obviously, according to the above content of the present invention, without departing from the above basic technical idea of the present invention, various other forms of modification, substitution or change can also be made in accordance with general technical knowledge and general means in the art.

Embodiments for Carrying Out the Invention

[0044] The above content of the present invention will be further described in detail by examples below. However, this should not be construed as meaning that the scope of the above subject matter of the present invention is limited to the examples. All techniques carried out based on the above content of the present invention belong to the scope of the present invention.

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

[0046] The abbreviations of the reagents described in the examples are as follows. DIPEA: N,N-Diisopropylethylamine HATU: 2-(7-Azabenzotriazole)-N,N,N’,N’-tetramethylurea hexafluorophosphate DIPEA: N,N-Diisopropylethylamine HATU: 2-(7-Azabenzotriazole)-N,N,N’,N’-tetramethylurea hexafluorophosphate HOBT: 1-Hydroxybenzotriazole DMSO: Dimethyl sulfoxide LC-MS: Liquid chromatography-mass spectrometry NaCl: Sodium chloride MPLC: Medium pressure liquid chromatography for preparative use EDCI: 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride Pd(OAc)2: Palladium acetate DMF: N,N-Dimethylformamide AIBN: Azobisisobutyronitrile NBS: N-Bromosuccinimide BPO: Benzoyl peroxide

[0047] Unless otherwise specified in the examples, the reactions were carried out under a nitrogen atmosphere. Unless otherwise explained in the examples, the solutions were aqueous solutions. Unless otherwise specified in the examples, the reaction temperature was room temperature. The room temperature of 20 °C to 30 °C was the most suitable reaction temperature. Unless otherwise explained in the examples, M was in mol / liter.

[0048] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR shift (δ) was 10 -6It was shown in units of (ppm). NMR was measured using nuclear magnetic resonance apparatuses (AvanceIII 400 of Bruker and Avance 600 of Bruker). The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (methanol-d4), and the internal standard was tetramethylsilane (TMS). LC-MS measurement was performed using a liquid chromatography mass spectrometer (Shimadzu LC-MS 2020 (ESI)) of Shimadzu Corporation. HPLC measurement was performed using a high-pressure liquid chromatograph (Shimadzu LC-20A) of Shimadzu Corporation. MPLC (medium-pressure preparative chromatography) was performed using a GX-281 reversed-phase preparative chromatograph of Gilson. The thin-layer chromatography silica gel plate was HSGF254 of Yantai Huanghai or GF254 silica gel plate of Qingdao, and the specifications of thin-layer chromatography for the separation and purification of the product were 0.4 mm to 0.5 mm. Generally, for column chromatography, silica gel of 200 to 300 mesh of Yantai Huanghai was used as the carrier.

[0049] Example 1: Preparation of Compound A1

Chemical formula

[0050] Step 1: Preparation of Compound A-3

Chemical formula

[0051] Step 2: Preparation of compound A-4

Chemical formula

[0052] Step 3: Synthesis of compound A1

Chemical formula

[0053] Compound A2 - A11 were obtained by operating in the same manner as the synthesis method of compound A1, except that starting material 1 shown in Table 1 below was used instead of compound A-1 and starting material 2 was used instead of compound A-2.

Table 1

[0054] Example 2: Preparation of Compound A16

Chemical formula

[0055] Step 1: Synthesis of Compound A12

Chemical formula

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

[0057]

Table 2

[0058] Example 3: Preparation of Compound A15

Chemical formula

[0059] Step 1: Synthesis of Compound A-20

Chemical formula

[0060] Step 2: Synthesis of compound A-21

Chemical formula

[0061] Step 3: Synthesis of compound A15

Chemical formula

[0062] Example 4: Preparation of Compound A16

Chemical Structure

[0063] Step 1: Synthesis of Compound A-23

Chemical Structure

[0064] Step 2: Synthesis of Compound A-24

Chemical Structure

[0065] Step 3: Synthesis of compound A-25

Chemical formula

[0066] Step 4: Synthesis of compound A-26

Chemical formula

[0067] Step 5: Synthesis of compound A-27

Chemical formula

[0068] Step 6: Synthesis of Compound A16

Chemical Structure

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

[0070]

Table 3

[0071] Example 5: Preparation of Compound A18

Chem.

[0072] Step 1: Synthesis of Compound A-30

Chem.

[0073] Step 2: Synthesis of Compound A-31

Chem.

[0074] Step 3: Synthesis of Compound A18

Chem.

[0075] Example 6: Preparation of compound A19

Chemical formula

[0076] Step 1: Synthesis of compound A-33

Chemical formula

[0077] Step 2: Synthesis of compound A-34

Chemical formula

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

Chemical formula

[0079] Step 4: Synthesis of compound A19

Chemical formula

[0080] Example 7: Preparation of Compound A20

Chemical Structure

[0081] Step 1: Synthesis of Compound A-37

Chemical Structure

[0082] Step 2: Synthesis of Compound A-38

Chemical Structure

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

[0084] Step 4: Synthesis of Compound A-41 [Chemical formula] 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. After evaporating the solvent to dryness, it was purified by MPLC to obtain A-41 (140.00 mg, 600.29 μmol, 69.73% yield).

[0085] Step 5: Synthesis of Compound A20 [Chemical formula] 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 sequentially added to a 25 mL reaction flask. The reaction was carried out for 0.5 h with stirring under ice bath conditions, and then the reaction was quenched (monitored by LC-MS). After extraction 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, the solvent was evaporated to dryness, and concentrated under reduced pressure to remove the solvent 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 1H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.78 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 4.35 - 3.93 (m, 4H), 3.07 (m, 6H), 2.96 (m, 2H)

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

[0087] Test Example 1: Detection of Inhibition of Compounds against CRBN / DDB1 Activity (FRET)

[0088] 1. Experimental Materials and Reagents Microplate reader (BMG PHERAstar FSX), ECHO (LABCYTE Echo 665), microplate thermostatic shaker (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).

[0089] 2. Experimental Method Dissolve the compound dry powder in DMSO, serially dilute the compound using ECHO, add it to a 384-well plate, and make the final concentration of DMSO in the whole reaction system (10.0 μL) 1.0%, and add an equal amount of DMSO as a control.

[0090] Dilute the CRBN / DDB1 protein to twice the required final concentration (5.0 nM) using 20 mM disodium hydrogen phosphate, 20 mM sodium dihydrogen phosphate, 0.08% bovine serum albumin, pH 7.0 buffer. Pipette 5.0 μL of the diluted CRBN / DDB1 protein, add it to a 384-well plate with the compound added, centrifuge at 1000 rpm for 1 minute, then place it in a microplate thermostatic shaker and pre-incubate at 25 °C and 250 rpm for 15 minutes. Dilute Anti-6His-Tb crypate Gold and the thalidomide analog labeled with FITC to twice the required 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 is 0.2 nM, and the final concentration of the thalidomide analog labeled with FITC is 50.0 nM to obtain an Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analog mixture. Pipette 5.0 μL of the Anti-6His-Tb crypate Gold / FITC-labeled thalidomide analog mixture, add it to a 384-well plate, centrifuge at 1000 rpm for 1 minute, then place it in a microplate thermostatic shaker and incubate at 25 °C and 250 rpm for 30 minutes. After the reaction is completed, read the fluorescence signal value in the 384-well plate using a microplate reader (Ex = 337 nm; Em = 520 / 490 nm).

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

[0092] Calculate the percentage of residual activity at each concentration using the following formula. Residual activity (%) = 100% × (Flu化合物群 -Flu ブランク対照 ) / (Flu 陰性対照 -Flu ブランク対照 ) After that, the dose-effect curve was fitted by GraphPad 6.0 to calculate the IC 50 value.

[0093] Table 1: Inhibition Table of Compounds and CRBN / DDB1 Protein

Table 4

[0094] Here, + indicates 200 μM > IC 50 > 100 μM, ++ indicates 100 μM > IC 50 > 10 μM, +++ indicates 10 μM > IC 50 > 1 μM, ++++ indicates 1 μM > IC 50 > 0.1 μM, ++++ indicates IC 50 < 0.1 μM.

[0095] Test Example 2: Detection of ITC (Isothermal Titration Calorimetry) of the Binding between Compounds and CRBN / DDB1 1. Experimental Materials and Reagents Disodium 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).

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

[0097] Using the prepared detection buffer above, desalting column Zeba TM According to the instructions of Spin Desalting Columns instructions (Thermo Scientific, #89882), buffer replacement was performed on the protein storage solution. After replacement, the OD of the protein solution was measured by a microplate reader (BMG PHERAstar FSX) 280nm at ultraviolet absorption, and the concentration after replacement was calculated. Based on the measured concentration, the protein was diluted to 10 uM with the detection buffer, and DMSO was added until the final concentration was 1% and the total volume was 300 uL. After short centrifugation at room temperature, it was stored until use.

[0098] The dry powder of the compound was dissolved in DMSO, and the compound was further diluted to 100 uM with the above detection buffer, and DMSO was adjusted to a final concentration of 1% and a total volume of 100 uL. At room temperature, this compound solution was centrifuged at 15000 rpm for 5 minutes, and then at least 75 uL of the supernatant was taken and stored until use.

[0099] The ITC instrument MicroCal PEAQ-ITC was cleaned according to the instrument's program. After cleaning, the cleanliness and condition of the instrument were detected by a water drop experiment. When titrating the sample, the protein sample was added into the sample cell, and the compound solution was added into the titrator. The instrument temperature was set to 25 °C, the Reference Power (ucal / s) was 5.00, the feedback model was "High", and the stirring speed was 750 rpm. A total of 19 drops of titration were performed. When titrating the remaining 18 drops other than the first drop, 2 uL / 4 s was added each time, and equilibration was performed for 150 seconds between drops. After the titration was completed, the instrument was cleaned. The water drop experiment was performed again to ensure good cleanliness and condition of the instrument. Then, the titration of the control experiment was performed. The compound was prepared as above and added into the titrator. Separately, 300 uL of the 1% DMSO-containing detection buffer was prepared and added into the sample cell. The instrument parameters were set the same as above and titrated.

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

[0101] Table 2: Binding table of compounds and CRBN / DDB1 proteins

Table 5

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

Claims

1. A compound represented by the following formula I, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts. 【Chemical 1】 Formula I (In the formula, ==O represents the presence or absence of oxygen substitution, Ring A is selected from a 3- to 12-membered cycloalkyl group, a 4- to 12-membered heterocycloalkyl group, a 6- to 10-membered aromatic ring, and a 5- to 10-membered heteroaromatic ring, and the cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent Rs Ａ１ and may be substituted by Each R Ａ１ is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR Ａ２ , -C ０～４ alkylene - OC(O)R Ａ２ , -C ０～４ alkylene - SR Ａ２ , -C ０～４ alkylene - S(O) ２ R Ａ２ , -C ０～４ alkylene - S(O)R Ａ２ , -C ０～４ alkylene - S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ alkylene - S(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - C(O)R Ａ２ , -C ０～４ alkylene - C(O)OR Ａ２ , -C ０～４ alkylene - C(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ C(O)R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O) ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O)R Ａ３ , -C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ Alkylene-(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene-(6- to 10-membered aromatic ring), -C ０～４ Selected from alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R Ａ４ groups, Each R Ａ４ is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR Ａ２ R Ａ３ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR Ａ２ , -C ０～４ alkylene - OC(O)R Ａ２ , -C ０～４ alkylene - SR Ａ２ , -C ０～４ alkylene - S(O) ２ R Ａ２ , -C ０～４ alkylene - S(O)R Ａ２ , -C ０～４ alkylene - S(O) ２ NR Ａ２ R Ａ３ , -C ０～４ alkylene - S(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - C(O)R Ａ２ , -C ０～４ alkylene - C(O)OR Ａ２ , -C ０～４ alkylene - C(O)NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ C(O)R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O) ２ R Ａ３ , -C ０～４ alkylene - NR Ａ２ S(O)R Ａ３ selected from R Ａ２ 、 R Ａ３ are each independently hydrogen, -C １－６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, and are selected from R ２ is independently hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２１ R ２２ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR ２１ , -C ０～４ alkylene - OC(O)R ２１ , -C ０～４ alkylene - SR ２１ , -C ０～４ alkylene - S(O) ２ R ２１ , -C ０～４ alkylene - S(O)R ２１ , -C ０～４ alkylene - S(O) ２ NR ２１ R ２２ , -C ０～４ alkylene - S(O)NR ２１ R ２２ , -C ０～４ alkylene - C(O)R ２１ , -C ０～４ alkylene - C(O)OR ２１ , -C ０～４ alkylene - C(O)NR ２１ R ２２ , -C ０～４ alkylene - NR ２１ R ２２ , -C ０～４ alkylene - NR ２１ C(O)R ２２ , -C ０～４ alkylene - NR ２１ S(O) ２ R ２２ , -C ０～４ alkylene - NR ２１ S(O)R ２２ , -C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene-(6- to 10-membered aromatic ring), -C ０～４ selected from alkylene-(5- to 10-membered heteroaromatic ring), and the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R ２３ and may be substituted by Each R ２３ is, independently of one another, hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２１ R ２２ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR ２１ , -C ０～４ alkylene - OC(O)R ２１ , -C ０～４ alkylene - SR ２１ , -C ０～４ alkylene - S(O) ２ R ２１ , -C ０～４ alkylene - S(O)R ２１ , -C ０～４ alkylene - S(O) ２ NR ２１ R ２２ , -C ０～４ alkylene - S(O)NR ２１ R ２２ , -C ０～４ alkylene - C(O)R ２１ , -C ０～４ alkylene - C(O)OR ２１ , -C ０～４ alkylene - C(O)NR ２１ R ２２ , -C ０～４ alkylene - NR ２１ R ２２ , -C ０～４ alkylene - NR ２１ C(O)R ２２ , -C ０～４ alkylene - NR ２１ S(O) ２ R ２２ , -C ０～４ alkylene - NR ２１ S(O)R ２２ , -C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ Alkylene-(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene-(6- to 10-membered aromatic ring), -C ０～４ Selected from alkylene-(5- to 10-membered heteroaromatic ring), wherein the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R ２６ and may be substituted by R ２１ 、R ２２ each independently represents hydrogen, -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, -C 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) ２ R ２４ 、 - C １～４ alkylene - S(O)R ２４ 、 - C １～４ alkylene - S(O) ２ NR ２４ R ２５ 、 - C １～４ alkylene - S(O)NR ２４ R ２５ 、 - C １～４ alkylene - C(O)R ２４ 、 - C １～４ alkylene - C(O)OR ２４ 、 - C １～４ alkylene - C(O)NR ２４ R ２５ 、 - C １～４ alkylene - NR ２４ R ２５ 、 - C １～４ alkylene - NR ２４ C(O)R ２５ 、 - C １～４ alkylene - NR ２４ S(O) ２ R ２５ 、 - C １～４ alkylene - NR ２４ S(O)R ２５ 、 - C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene - (6 - to 10 - membered aromatic ring), -C ０～４ Selected from alkylene-(5- to 10-membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may further be substituted by one, two, three, or four independent Rs ２６ and may be substituted by Each R ２６ is, independently of one another, hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２４ R ２５ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR ２４ , -C ０～４ alkylene - OC(O)R ２４ , -C ０～４ alkylene - SR ２４ , -C ０～４ alkylene - S(O) ２ R ２４ , -C ０～４ alkylene - S(O)R ２４ , -C ０～４ alkylene - S(O) ２ NR ２４ R ２５ , -C ０～４ alkylene - S(O)NR ２４ R ２５ , -C ０～４ alkylene - C(O)R ２４ , -C ０～４ alkylene - C(O)OR ２４ , -C ０～４ alkylene - C(O)NR ２４ R ２５ , -C ０～４ alkylene - NR ２４ R ２５ , -C ０～４ alkylene - NR ２４ C(O)R ２５ , -C ０～４ alkylene - NR ２４ S(O) ２ R ２５ , -C ０～４ alkylene - NR ２４ S(O)R ２５ , -C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ Alkylene-(4- to 10-membered heterocycloalkyl group), -C ０～４ Alkylene-(6- to 10-membered aromatic ring), -C ０～４ Selected from alkylene-(5- to 10-membered heteroaromatic ring), the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent Rs ２７ and may be substituted by R ２４ 、 R ２５ are each independently hydrogen, -C １－６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, and are selected from Each R ２７ is independently selected from hydrogen, halogen, cyano group, nitro group, =O, =S, -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group. )

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

3. Each R Ａ１ is independently hydrogen, halogen, cyano group, nitro group, =O, =S, -C １～３ alkyl group, -C １～３ alkyl halide group, and the compound according to claim 2, characterized in that it is selected from the group consisting of

4. Ring A is [Chemical Formula 3] The compound according to claim 1, characterized in that it is selected from

5. R ２ is hydrogen, halogen, cyano group, nitro group, =O, =S, -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, -C ０～４ alkylene - OR 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 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene - (6 - to 10 - membered aromatic ring), -C ０～４ alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from them. The alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R ２３ ; and Each R ２３ is, independently of one another, hydrogen, halogen, cyano group, nitro group, =O, =S, -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, -C ０～４ alkylene - OR ２１ , -C ０～４ alkylene - OC(O)R ２１ , -C ０～４ alkylene - C(O)R ２１ ; -C ０～４ alkylene - (3 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene - (6 - to 10 - membered aromatic ring), -C ０～４ alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from these; the alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R ２６ and may be substituted by R ２１ 、R ２２ each independently represents hydrogen, -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ haloalkyl group, -C ２～６ haloalkenyl group, -C ２～６ haloalkynyl group, -C 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 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene - (6 - to 10 - membered aromatic ring), -C ０～４ alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from these. The alkylene group, cycloalkyl group, heterocycloalkyl group, aromatic ring, and heteroaromatic ring may be further substituted by one, two, three, or four independent R ２６ groups, Each R ２６ is independently selected from hydrogen, halogen, cyano group, nitro group, =O, =S, =CR ２４ R ２５ , -C １～６ alkyl group, -C ２～６ alkenyl group, -C ２～６ alkynyl group, -C １～６ halogenated alkyl group, -C ２～６ halogenated alkenyl group, -C ２～６ halogenated alkynyl group, -C ０～４ alkylene - OR 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 - to 10 - membered cycloalkyl group), -C ０～４ alkylene - (4 - to 10 - membered heterocycloalkyl group), -C ０～４ alkylene - (6 - to 10 - membered aromatic ring), -C ０～４ alkylene - (5 - to 10 - membered heteroaromatic ring), and is selected from R ２４ and R ２５ are each independently selected from hydrogen, -C １－３ alkyl group, -C １～３ haloalkyl group The compound according to claim 1 or claim 4, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts, characterized in that

6. R ２ is selected from -C(O)NR ２１ R ２２ -C(O)R ２１ -C ０～２ alkylene-NR ２１ R ２２ -C(O)OR ２１ and is selected from R ２１ 、R ２２ are each independently hydrogen, -C １～３ alkyl group, -C ０～１ alkylene-(6-membered aromatic ring), -C ０～１ alkylene-(10-membered heteroaromatic ring), -(4-6-membered heterocycloalkyl group), -(3-6-membered cycloalkyl group), and the aromatic ring, heteroaromatic ring, heterocycloalkyl group, and cycloalkyl group may be further substituted by one, two, three, or four independent R ２６ and may be substituted by Each R ２６ is independently hydrogen, -C １～３ alkyl group, -(4-6 membered heterocycloalkyl group), -C(O)R ２４ , -C(O)OR ２４ , -OC(O)R ２４ and is selected from R ２４ is selected from hydrogen, a methyl group, and an ethyl group The compound according to claim 5, characterized in that

7. R ２ is hydrogen, 【Chemical Formula 4】 The compound according to claim 6, characterized in that it is selected from

8. The compound is 【Chemical Formula 5】 The compound according to any one of claims 1 to 7, characterized in that it is selected from

9. Use of the compound according to any one of claims 1 to 8, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts, in the preparation of a pharmaceutical composition 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, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts, as a protein in the manufacture of a target protease.

12. Use of the compound according to any one of claims 1 to 8, its stereoisomers, its deuterated compounds, or its pharmaceutically acceptable salts, as an intermediate protein in the manufacture of a target protease.

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