Nitrogen-containing heteroaromatic ring degradation agent as well as preparation method and application thereof

Abstract

The invention belongs to the field of medicines, and particularly relates to a nitrogen-containing heteroaromatic ring degradation agent as well as a preparation method and application thereof. Particularly, the invention relates to a compound as shown in a general formula (I), a preparation method thereof and a pharmaceutical composition containing the compound, the invention also relates to the application of the compound in preparation of medicines for treating or preventing autoimmune diseases, inflammatory diseases, cancers, viral diseases, neurodegenerative diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplantation-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases and the like. The invention also relates to the application of the medicine for treating diseases related to cell death or cardiovascular diseases. Wherein each substituent in the general formula (I) is as defined in the specification.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a nitrogen-containing heteroaromatic ring degradation agent and a preparation method and application thereof. Background Art

[0002] Interleukin 1 receptor kinase 4 (IRAK4) is a serine / threonine-specific protein kinase, a member of the tyrosine kinase (TLK) family, and a key node in the innate immune response involving interleukin-1, 18, 33 receptors and Toll-like receptors. After extracellular signaling molecules bind to interleukin receptors or Toll-like receptors, they recruit to form a MyD88:IRAK4:IRAKl / 2 multiprotein complex, leading to IRAK1 / 2 phosphorylation, mediating a series of downstream signal transductions, thereby activating p38, JNK and NF-kB signaling pathways, and ultimately leading to the expression of pro-inflammatory cytokines. Clinical pathological studies have shown that individuals with IRAK4 mutations have a protective effect against chronic lung disease and inflammatory bowel disease. IRAK4 deficiency itself is not lethal, and individuals can survive to adulthood, and the risk of infection decreases with age. Therefore, IRAK4 has become an important therapeutic target and has attracted widespread research and development interest.

[0003] Proteolysis Targeting Chimeria (PROTAC) is a technology different from traditional small molecule inhibitors. Traditional small molecule inhibitors usually need to act on the active site of the target protein to inhibit its activity, while PROTAC is a heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein through a connecting chain, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and E3 ubiquitin ligase in vivo, brings the target protein and E3 ubiquitin ligase closer to form a ternary complex, and after ubiquitination of the target protein, it degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared with traditional small molecule inhibitors, PROTAC only needs to bring the target protein and E3 ubiquitin ligase closer to degrade the substrate. This mode of action allows this technology to be applied to some undruggable targets. On the other hand, since the target protein can be released after being degraded to continue to participate in the degradation process of the next protein, this degradation with catalytic effect allows a smaller PROTAC drug dose to achieve efficient degradation. On the other hand, traditional small molecule inhibitors are prone to drug resistance, often because of point mutations, which make the small molecule inhibitors lose their inhibitory effect on the target, while PROTAC can directly degrade the target protein, which can avoid the drug resistance caused by point mutations to a certain extent. Therefore, compared with traditional small molecule inhibitors, the use of PROTAC technology for the development of new drug small molecules has high advantages and feasibility, and is expected to become the next generation of promising new drugs.

[0004] Therefore, it is necessary to develop novel IRAK4 inhibitors and PROTAC drugs for E3 ubiquitin ligases for the treatment of IRAK4-related diseases. Summary of the invention

[0005] The present invention provides a compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound is as shown in formula (I):

[0006]

[0007] in:

[0008] R and R' are each independently selected from R d or And R and R' are not the same as R d or

[0009] Ring A is selected from 4-8 membered heterocyclylene;

[0010] Ring B is selected from 8-12 membered bicyclic heteroarylene;

[0011] Ring C is selected from 5-6 membered monocyclic heteroaryl, 8-12 membered bicyclic heteroaryl or 5-6 membered heterocyclyl;

[0012] M and W are each independently selected from a bond, -O-, -NR 3 -、-CR 1 R 2 -, -C(O)-, -S-, -S(O)-, -S(O) 2 -、-CR 1 R 2 -O-, -CR 1 R 2 NR 3 -、-(CR 1 R 2 ) 2 -or-CR 1 R 2 -S-;

[0013] M 1 Select from N or CR 4 ;

[0014] M 2 Select from N or CR 5 ;

[0015] M 3 Select from N or CR 6 ;

[0016] R 3 is selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0017] R 1 , R 2 , R 4 , R 5 and R 6 Each is independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0018] Or, R 1 and R 2 Together with the atoms to which it is attached, it forms a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group may be further substituted with one or more substituents selected from halogen, hydroxy, alkyl or alkoxy;

[0019] L 1 Selected from -Ak1-Cy1-Ak2-Cy2-Ak3-,

[0020] Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH 2 ) n-, -O-, -S-, -C(O)- or -NH-; the -(CH 2 ) n - and -NH-, which may optionally be further substituted;

[0021] Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group or a heterocyclylene group; the cycloalkylene group and the heterocyclylene group may be further substituted;

[0022] n is selected from 1, 2, 3 or 4;

[0023] L 2 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-;

[0024] L 3 Selected from a bond, -NH-, -S-, -O-, -CH 2 -、-CH 2 CH 2 -, -C(O)NH-, -NHC(O)-, or -C(O)-;

[0025] R a , R b , R c and R d Each independently selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, haloalkyl, -P(O)R 1 R 2 , alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic group may be further substituted with one or more substituents selected from halogen, hydroxy, alkyl, alkoxy, haloalkyl, and haloalkoxy;

[0026] Or, any R a Connected to any carbon atom on ring A to form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group may be further substituted;

[0027] Or, L 1 With R b connected to form a cycloalkyl or heterocyclic group;

[0028] Or, any two R c Connected to form a cycloalkyl group or a heterocyclic group, the cycloalkyl group and the heterocyclic group may be further substituted;

[0029] x, y and z are each independently selected from 0, 1, 2 or 3.

[0030] In a preferred embodiment of the present invention, the compound described above is further represented by formula (II):

[0031]

[0032] Where: M 4 is selected from N or CH; n1 and n2 are each independently selected from 0, 1 or 2.

[0033] In a preferred embodiment of the present invention, R mentioned above is selected from R d When R' is selected from or,

[0034] The R is selected from When R' is selected from R d .

[0035] In a preferred embodiment of the present invention, the ring B mentioned above is selected from indazolyl, benzimidazolyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl or pyrimidoimidazolyl;

[0036] Preferably, the Selected from

[0037] Alternatively, the ring C is selected from pyridyl, phenyl, pyridonyl, benzimidazolyl, pyridazinonyl, pyrazolopyrimidinyl, pyrimidopyrazolyl, pyridopyrrolyl, pyrimidinyl, pyrimidopyrrolyl or pyridopyrazolyl;

[0038] Preferably, the Selected from

[0039] In a preferred embodiment of the present invention, the above-mentioned L 1 -Cy1-Ak2-; wherein Cy1 is selected from a bond, cyclobutylene, cyclopentylene, cyclohexylene, piperidinylene or piperazinylene, wherein the cyclobutylene, cyclopentylene, cyclohexylene, piperidinylene and piperazinylene are optionally further substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, C 1-3 Haloalkyl or C 1-3 is substituted by a haloalkoxy substituent; wherein Ak2 is selected from -(CH 2 ) n -;

[0040] Preferably, the L 1 Selected from -cyclohexylene-(CH 2 ) n -、-piperidinyl-(CH 2 ) n - or piperazinyl-(CH2 ) n -; n is selected from 1, 2, 3 or 4;

[0041] Alternatively, the L 2 is selected from -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-;

[0042] Alternatively, the L 3 Selected from a bond, -NH-, -S-, -O-, -CH 2 -、-CH 2 CH 2 -, -C(O)NH-, -NHC(O)- or -C(O)-.

[0043] In a preferred embodiment of the present invention, the compound of the present invention is as shown in formula (III):

[0044]

[0045] Where: M 5 CH or N; R a , R b , R c , M, M 1 , W, x, and As defined above.

[0046] In a preferred embodiment of the present invention, R a , R b , R c and R d Each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, -P(O)R 1 R 2 , C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, hydroxyl C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; the C 3-4 Cycloalkyl and 3-4 membered heterocyclic groups, optionally further substituted with halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 is substituted by one or more substituents in a haloalkoxy group;

[0047] Or, R 1 , R 2 , R 4 , R 5 and R 6Each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group;

[0048] Or, R 3 Selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

[0049] In a preferred embodiment of the present invention, the compound of the present invention is further represented by formula (IV):

[0050]

[0051] in:

[0052] W is selected from -O-, -S-, -C(O)-, -S(O) 2 -、-CR 1 R 2 -or-NR 3 -;

[0053] M is selected from -O-, -S-, -C(O)-, -S(O) 2 -、-CR 1 R 2 -or-NR 3 -;

[0054] R b Selected from C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -P(O)R 1 R 2 , C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; the C 3-4 Cycloalkyl and 3-4 membered heterocyclic groups, optionally further substituted with halogen, hydroxyl or C 1-3 Alkyl substitution;

[0055] R c Selected from C 1-3 Haloalkyl;

[0056] R 1 and R 2 Each independently selected from hydrogen, hydroxy, halogen or C 1-3 alkyl;

[0057] R3 Selected from C 1-3 alkyl.

[0058] In a preferred embodiment of the present invention, the R b Selected from Methoxy,

[0059] In a preferred embodiment of the present invention, the R c Selected from -CF 3 .

[0060] In a preferred embodiment of the present invention, the R 1 and R 2 Each is independently selected from hydrogen, hydroxy, F or methyl.

[0061] In a preferred embodiment of the present invention, the R 3 Selected from methyl.

[0062] In a preferred embodiment of the present invention, the compound described above is selected from the following compounds:

[0063]

[0064]

[0065] The present invention also relates to a compound of formula (A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0066]

[0067] Where: R a1 is selected from hydrogen, an amino protecting group or a bond; M 2 、M 3 、M 4 ,M,W,R,R',R a , x, n1 and n2 are as defined above; when R a1 When selected from the bond, M of the formula A 4 Covalently linked to other moieties.

[0068] The present invention also provides a use of the compound of formula (A) as a binding portion of an E3 ubiquitin ligase for preparing a drug for protein degradation targeting chimera (PROTAC); the use at least comprises:

[0069] (1) connecting the compound of formula (A) and formula (C) via a covalent bond to form a compound of formula II;

[0070]

[0071] And / or, (2) the protein degradation targeting chimera (PROTAC) drug contains a binding portion for an E3 ubiquitin ligase as shown in formula (A).

[0072] In a preferred embodiment of the present invention, the covalent bond can be formed by reacting an amino group with an aldehyde group.

[0073] The present invention also relates to a compound represented by general formula (B), its stereoisomers or pharmaceutically acceptable salts thereof:

[0074]

[0075] in:

[0076] The PTM is selected from a drug or a derivative thereof that binds to a target protein;

[0077] L 1 、M 2 、M 3 、M 4 ,M,W,R,R',R a , x, n1 and n2 are as defined above.

[0078] In a preferred embodiment of the present invention, the PTM mentioned above is selected from drugs or derivatives thereof that act on AR, ER, kinase, phosphatase, MDM2, proteins of human BET bromodomain, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular growth factor, receptors or proteins related to immunosuppression, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease or acyl protein thioesterase 1 and / or acyl protein thioesterase 2; preferably, the PTM mentioned above is selected from drugs or derivatives thereof that act on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEEI, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, Mtor, AR, ER, PDE, SRC, MDM2, RAF, IRAK4, STAT3 and c-Myc.

[0079] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective dose of the compound represented by each general formula described above, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0080] The present invention also provides a preferred embodiment, involving the use of the compounds described in the general formulae and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of drugs for treating or preventing IRAK4-mediated diseases.

[0081] The present invention also provides a preferred embodiment, involving the use of the compounds of the general formula and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of drugs for treating or preventing autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death or cardiovascular diseases.

[0082] The present invention also relates to a method for treating or preventing an IRAK4-mediated disease, which comprises administering to a mammal an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate thereof; the IRAK4-mediated disease is selected from autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death or cardiovascular diseases.

[0083] Detailed description of the invention

[0084] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0085] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, and the like, and various branched isomers thereof, and the like.

[0086] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 4 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0087] The term "cycloalkylene" refers to a cycloalkyl group in which one hydrogen atom is further substituted. Non-limiting examples include cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene and the like.

[0088] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but not including the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 4 to 8 ring atoms; most preferably, it contains 3 to 4 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include oxetanyl, azetidinyl, azepanyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which the 5- to 20-membered monocyclic rings share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) of heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. Non-limiting examples of spiro heterocyclic groups include: The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, and one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) of heteroatoms, and the remaining ring atoms are carbon. The heterocyclyl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl ring, non-limiting examples of which include: wait.

[0089] The term "heterocyclylene" refers to a heterocyclyl group in which at least one hydrogen atom is further substituted. The definition of heterocyclyl is the same as above, and non-limiting examples thereof include: oxirane, oxetane, oxolanyl, oxhexane, aziridine, aziridine, azidoyl, aziridine, piperidinyl, piperazinyl, wait.

[0090] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably phenyl.

[0091] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably a 5-8-membered monoheteroaryl or an 8-14-membered diheteroaryl, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl or a 9-membered diheteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl, etc., preferably pyridoimidazolyl and pyrimidoimidazolyl.

[0092] The term "heteroarylene" means that at least one hydrogen atom of a heteroaryl group is further substituted, and the definition of heteroaryl group is the same as described above.

[0093] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0094] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0095] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0096] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -C(CH 3 ) 2 (OH).

[0097] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0098] Unless otherwise specified, the chiral carbon in the compounds of the present invention is in R configuration or S configuration.

[0099] The cis- and trans-isomers of the cyclic compounds in the present invention are marked as follows: when there are two or more substituents on the ring, the lowest-ranked one is selected as the reference group, and "r (reference substituent)" is added before its position to express it, and "c (cis-)" or "t (trans-)" is used before the positions of the remaining substituents to indicate their stereological relationship with the "reference group". Named: 4-t-bromo-4-methylcyclohexyl-1-r-amine.

[0100] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atoms in the example compounds of the present invention may also be replaced by deuterium atoms.

[0101] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0102] The substituent in the "optionally further substituted" of the present invention is selected from deuterium, halogen, cyano, hydroxyl, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein halogen, cyano, hydroxyl, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are as defined above.

[0103] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0104] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity. The pharmaceutically acceptable salt is selected from organic salts or inorganic salts. DETAILED DESCRIPTION

[0105] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0106] The starting materials and reagents used in the examples of the present invention are known and can be purchased on the market, or can be synthesized by methods known in the art. For example, compounds 1-7 in the present invention can be prepared by referring to the method disclosed in WO2020264499A1.

[0107] The compounds of the present invention are prepared by the following reaction route:

[0108]

[0109] Where: M 5 CH or N; R a , R b , R c , M, W, x, and As defined above;

[0110] Step 1: Synthesis of Compound III-2

[0111] Add 1,4-dioxane hydrochloride solution to compound III-1 at room temperature, stir and react for 1 hour. Monitor the reaction by liquid quality control until it is complete. Concentrate the residue under reduced pressure to obtain compound III-2.

[0112] Step 2: Synthesis of Compound III

[0113] An organic base and compound III-3 were added to a tetrahydrofuran solution of compound III-2 at room temperature, and the reaction was stirred for 1 hour. Then, a reductive amination reagent was added and the reaction was stirred for 1 hour. The reaction was completed by liquid chromatography-mass spectrometry monitoring, and the crude product was purified by high-efficiency preparative liquid phase to obtain compound III.

[0114] Example

[0115] Synthesis of intermediates 1-4 and 1-5

[0116]

[0117] Step 1: Synthesis of Compound 1-3

[0118] Under nitrogen protection, cesium fluoride (2.4 g, 15.8 mmol), water (8 mL) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (257 mg, 0.394 mmol) were added to the solution of compound 1-1 (3 g, 7.9 mmol) and compound 1-2 (40 mL, 517 mmol). After the addition was completed, the system was stirred at 80 degrees Celsius for 1 hour. The reaction was completed by liquid quality monitoring. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3*30 mL). The organic phases were combined, backwashed with saturated brine (2*10 mL), and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure and purified by preparative chromatography plate, ethyl acetate / petroleum ether (0-50%) to obtain compound 1-3 (4 g). LCMS: (ESI, m / z): 491.1 [M-100] + .

[0119] Step 2: Synthesis of compounds 1-4 and 1-5

[0120] A 10 mL isopropanol solution of compound 1-3 (500 mg, 0.846 mmol) was added to the autoclave, followed by palladium carbon (10 wt%, (1 g, 9.4 mmol)) and palladium hydroxide / carbon (20 wt%, (1 g, 7.1 mmol). The nitrogen was replaced, hydrogen (30 Psi) was introduced and reacted at room temperature for 24 hours. Celite was then added for filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, ethyl acetate / petroleum ether (0-20%) to obtain compound 1-4 (75 mg, 22%) and compound 1-5 (150 mg, 43%) as a white solid.

[0121] LCMS(1-4):(ESI,m / z):343.1[M-56] + .LCMS(1-5):(ESI,m / z):413.1[MH] - .

[0122] Synthesis of intermediate 3-3

[0123]

[0124] Use raw materials 3-1 Replace 1-1 Referring to the synthesis method of compound 1-4, compound 3-3 5-(2,6-dioxopiperidin-3-yl)-3H-spiro[1-benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (100 mg, 48.17%) was obtained. LCMS: (ESI, m / z): 399.00 [MH] - .

[0125] Synthesis of Intermediate 36-3

[0126]

[0127] Use raw material 36-2 Replace 1-1 Referring to the synthesis method of compound 1-4, compound 36-4 was obtained to obtain 3-(3H-spiro[1,4-benzodioxin-2,3'-pyrrolidine]-7-ylpiperidine-2,6-dione (20 mg, 70.79%) as a pale yellow solid. LCMS: (ESI, m / z): 303.40 [M+1] + .

[0128] Example 1 Preparation of Compound 1

[0129] N-[6-(2-Hydroxypropan-2-yl)-2-[(1r,4t)-4-(2-[5-(2,6-dioxopiperidin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl]ethylcyclohexyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (1)

[0130]

[0131] Step 1: Synthesis of Compound 1-6

[0132] Compound 1-4 (70 mg, 0.176 mmol) was added to 1,4-dioxane hydrochloride solution (1.5 mL) at room temperature and stirred for 1 h. The reaction was completed by liquid chromatography-mass spectrometry monitoring. The residue was concentrated under reduced pressure to obtain compound 1-6 (45 mg).

[0133] LCMS: (ESI, m / z): 299.1 [M+H] + .

[0134] Step 2: Synthesis of Compound 1

[0135] To a solution of compound 1-6 (20 mg, 0.067 mmol) in tetrahydrofuran (1 mL) at room temperature, N,N-diisopropylethylamine (26 mg, 0.2 mmol) and compound 1-7 (33 mg, 0.067 mmol) were added. After stirring for 1 h, sodium triacetylborohydride (36 mg, 0.17 mmol) was added and stirred for 1 h. The reaction was completed by liquid chromatography-mass spectrometry. The crude product was purified by high performance liquid chromatography to obtain compound 1 (2.1 mg) under the following conditions (column: XBridge BEH Shield RP18 5 μm, 30 mm*150 mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: 38% B to 58% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 8.38). LCMS: (ESI, m / z): 771.4 [M+H] + .

[0136] 1 H NMR (400MHz, DMSO) δ12.36(s,1H),10.79(s,1H),8.71(s,1H),8.45(d,J=7.8Hz,1H),8.39-8.34(m,2 H),8.16(d,J=7.8Hz,1H),7.57(s,1H),7.13(d,J=7.5Hz,1H),7.02(s,1H),6.94(d,J=8.1Hz,1H),5. 93(s,1H),4.42(s,1H),3.78(dd,J=4.8,11.1Hz,1H),2.75-2.70(m,4H),2.69-2.64(m,4H),2.34-2. 32(m,6H),2.16-2.09(m,3H),1.95-1.87(m,4H),1.62(s,6H),1.59-1.53(s,4H),1.59-1.53(m,3H).

[0137] Example 2 Preparation of Compound 2

[0138] N-[6-(2-Hydroxypropan-2-yl)-2-[(1r,4t)-4-(2-[5-(2,6-dioxopiperidin-3-yl)-3-hydroxy-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl]ethylcyclohexyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide (2)

[0139]

[0140] Step 1: Synthesis of Compound 2-1

[0141] Zinc bromide (283 mg, 1.26 mmol) was added to a solution of compound 1-5 (130 mg, 0.32 mmol) in hexafluoroisopropanol (2 mL) at room temperature. After stirring overnight, the reaction was completed by liquid chromatography-mass spectrometry. The residue was concentrated under reduced pressure to obtain compound 2-1 (80 mg). LCMS: (ESI, m / z): 315.2 [M+H] + .

[0142] Step 2: Synthesis of Compound 2

[0143] N, N-diisopropylethylamine (74 mg, 0.57 mmol) was added to a solution of compound 2-1 (60 mg, 0.19 mmol) in tetrahydrofuran (2 mL) at room temperature, and compound 1-7 (93 mg, 0.191 mmol) was stirred for 1 h. Then, sodium triacetylborohydride (101 mg, 0.48 mmol) was added at 0 degrees Celsius, and the solution was stirred for 2 h. The reaction was completed by liquid chromatography-mass spectrometry. The crude product was purified by high performance liquid chromatography to obtain compound 2 (19.8 mg, 13.12%) under the following conditions (chromatographic column: Sunfire C18 5 μm, 30 mm*150 mm; mobile phase A: water (0.1% formic acid), mobile phase B: acetonitrile; flow rate: 60 mL / min; gradient: from 15% B to 36% B in 10 min; wavelength: 254 nm / 220 nm; RT1 (min): 9.02). LCMS: (ESI, m / z): 787.3 [M+H] + .

[0144] 1H NMR (400MHz, DMSO) δ12.36 (s, 1H), 10.81 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 7.7Hz, 1H), 8.42-8.36 (m ,2H),8.16(d,J=7.8Hz,1H),7.57(s,1H),7.18-7.09(m,2H),7.03(d,J=7.7Hz,1H),5.93(s,1H),5. 20(d,J=6.5Hz,1H),4.56(d,J=3.7Hz,1H),4.48-4.35(m,1H),3.84(dd,J=5.0,10.8Hz,1H),2.87( d,J=15.8Hz,1H),2.78-2.69(m,2H),2.64-2.58(m,1H),2.46-2.36(m,3H),2.25-2.09(m,6H),2.09 -2.00(m,2H),1.98-1.83(m,4H),1.83-1.66(m,2H),1.62(s,6H),1.50-1.34(m,4H),1.28-1.13(m,3H).

[0145] Example 3 Preparation of Compound 3

[0146]

[0147] Use raw materials 3-3 Replace 1-4 Referring to the synthesis method of compound 1, N-[6-(2-hydroxy-2-propyl)-2-[(1r, 4r)-4-(2-[5-(2,6-dioxopiperidin-3-yl)-3H-spiro[1-benzofuran-2,4'-piperidin]-1'-yl]ethylcyclohexyl]indazol-5-yl]-6-trifluoromethylpyridine-2-carboxamide (Compound 3, 16.9 mg, 16.14%) was obtained under the following conditions (chromatographic column specifications: Kinetex 5um EVO C18, 30mm*150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 40% B to 60% B in 7 minutes; detection wavelength: UV 254nm / 220nm; retention time (min): 6.22). LCMS: (ESI, m / z): 773.10 [M+H] + .

[0148] 1 H NMR: (400MHz, DMSO-d 6,ppm)δ12.36(s,1H),10.77(s,1H),8.71(s,1H),8.45(d,J=7.8Hz,1H),8.40-8.33(m,1H),8.16(d,J=7.8Hz,1H),7.57(s,1H ),7.02(s,1H),6.91(d,J=8.2Hz,1H),6.68(d,J=8.2Hz,1H),5.93(s,1H),4.42(t,J=11.6Hz,1H),3.74(dd,J=4.9,11.2Hz,1 H),2.98(s,2H),2.71-2.62(m,1H),2.62-2.52(m,2H),2.45(t,J=4.3Hz,1H),2.44-2.31(m,4H),2.17-2.08(m,3H),2.05-1. 97(m,1H),1.91(d,J=11.0Hz,4H),1.87-1.80(m,2H),1.79-1.71(m,2H),1.62(s,6H),1.47-1.38(m,3H),1.24-1.13(m,2H).

[0149] Example 4 Preparation of Compound 36

[0150]

[0151] Use raw materials 36-4 Replace 1-6 Referring to the synthesis method of compound 1, N-[6-(2-hydroxypropan-2-yl)-2-[(1r,4r)-4-(2-[7-(2,6-dioxopiperidin-3-yl)-3H-spiro[1,4-benzodioxazine-2,3'-pyrrolidine]-1'-yl]ethylcyclohexyl]indazol-5-yl]-6-(trifluoromethyl)pyridine-2-carboxamide compound 36 (2.7 mg) was obtained under the following conditions (chromatographic column specifications: XBridge BEH Shield RP18 5um, 30mm*150mm; mobile phase A: water (10 mmol per liter ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; gradient: from 49% B to 63% B in 9 minutes; wavelength: UV 254 nm / 220 nm; retention time (min): 6.77). LCMS: (ESI, m / z): 775.55 [M+1] + .

[0152] 1 H NMR (400 MHz, DMSO-d 6,ppm)δ12.37(s,1H),10.80(s,1H),8.71(s,1H),8.46(d,J=7.6Hz,1H),8.42-8.33(m,2H),8.17(d,J= 7.8Hz,1H),7.58(s,1H),6.85(d,J=8.4Hz,1H),6.73(s,1H),6.69(d,J=8.1Hz,1H),5.95(s,1H),4.42( t,J=11.0Hz,1H),4.09(d,J=11.0Hz,1H),4.01(d,J=11.4Hz,1H),3.75(dd,J=4.6,11.4Hz,1H),2.76- 2.59(m,6H),2.28-2.05(m,4H),2.04-1.80(m,8H),1.62(s,6H),1.47-1.39(m,3H),1.25-1.16(m,2H).

[0153] The synthetic route described above was used to obtain the following compound:

[0154]

[0155]

[0156]

[0157] Biological test evaluation

[0158] The present invention is further described and explained in conjunction with the test examples below, but these examples are not intended to limit the scope of the present invention. Test Example 1 Detection of the degradation level of HiBiT-IRAK4 protein in K562 IRAK4-HiBiT cells after co-incubation with the compound of the present invention

[0159] Experimental reagents, equipment and consumables:

[0160] Nano-Glo Lytic Detection Assay, purchased from Promega;

[0161] EnVision, purchased from PerkinElmer;

[0162] Cell line name: K562 IRAK4-HiBiT stable cell line (can stably express IRAK4-HiBiT fusion protein) was constructed by Shanghai Runnuo Biotechnology Co., Ltd., where the K562 cell line was purchased from ATCC and the culture medium was IMDM + 10% FBS + 1% P / S (volume percentage, where FBS is fetal bovine serum, P / S is Penicillin-Streptomycin, an antibiotic solution of 1:1 mixed penicillin and streptomycin (10,000 units / mL)).

[0163] Experimental steps:

[0164] Cell culture: K562 IRAK4-HiBiT cells were cultured at 37°C and passaged every 2-3 days at a seeding density of 200,000 cells / mL.

[0165] IRAK4-HiBiT protein degradation assay:

[0166] Step 1: Cell seeding and compound treatment

[0167] 1. Use DMSO to prepare a 10 mM compound stock solution, and use the Bravo automated liquid handling platform to prepare a 1000-fold working concentration compound solution (the highest working concentration is 10 μM, 3.162-fold dilution, and a total of 10 concentration gradients).

[0168] 2. Transfer 40 nL of compound working solution to a 384-well plate and add an equal volume of DMSO to the positive control wells.

[0169] 3. Add 20 μL of culture medium to each well and shake for 10 minutes.

[0170] 4. Add 20 μL K562 IRAK4-HiBiT cell suspension (6000 cells / well) to each well and add an equal volume of culture medium to the negative control well.

[0171] 5. Spin the plate at 1000 rpm for 1 minute.

[0172] 6. Incubate at 37°C, 5% CO 2 Incubate in a CO2 incubator for 2 or 6 hours.

[0173] Step 2: HiBiT Lytic Experiment

[0174] 1 Allow the plate to equilibrate at room temperature for 30 minutes.

[0175] 2. Add 20 μL Nano-Glo HiBiT Lytic reagent (trade name: HiBiT LyticDetection Reagent) and protect from light.

[0176] 3. Place the plate on an orbital shaker at 300 rpm for 5 minutes.

[0177] 4. Incubate at room temperature for 10 minutes.

[0178] 5. Envision reads the luminescence value.

[0179] 6. Calculate and process data. Degradation degree % = (negative control - experimental well) / (negative control - positive control) * 100%; Use XL-fit software to fit the degradation curve using 4Parameter Logistic Model to obtain Relative DC 50 (nM) and Absolute DC 50 (nM) value.

[0180] The experimental results are shown in Table 1:

[0181] Table 1

[0182]

[0183] Note: NA: Not tested.

[0184] The other compounds of the present invention were tested by referring to the experimental method to obtain the Relative DC of the compounds of the present invention. 50 The value of (nM) is between 0.01 and 100. The Relative DC 50 The value of (nM) is less than 100; the Absolute DC 50 The value of (nM) is between 0.01 and 100. The Absolute DC 50 The value of (nM) is less than 100.

[0185] Experimental conclusion:

[0186] The compound of the present invention has good degradation activity on IRAK4 protein.

[0187] Test Example 2 Study on the pharmacokinetic behavior of the compound of the present invention in rats

[0188] Experimental drugs: Compounds of the present invention, homemade.

[0189] Experimental protocol:

[0190] Three healthy SD rats (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), male, weighing 180-250g, were intravenously injected with 1 mg / kg of the compound, with a dosing volume of 2 ml / kg. The compound was prepared using 5% DMSO+10% Solutol+85% Saline (w / v), and the animals were not fasted before the experiment.

[0191] Three healthy SD rats (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), male, weighing 180-250g, were given 5mg / kg of the compound by gavage, with a dosing volume of 10ml / kg. The compound was prepared with 5% DMSO+10% Solutol+85% Saline (w / v), and the animals were not fasted before the experiment.

[0192] Blood was collected from the vein at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after intravenous administration and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after oral administration. About 0.25mL of each sample was collected, and heparin sodium was used for anticoagulation. After blood samples were collected, they were placed on ice and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8℃). The concentration of the compound in plasma was determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored in a -80℃ refrigerator before analysis. The pharmacokinetic parameters were calculated using Phoenix WinNonlin8.2.0 based on the blood drug concentration data at different time points. The experimental results are shown in Table 2:

[0193] Table 2

[0194]

[0195] The experimental results show that the compound of the present invention has a high plasma exposure in rodent SD rats and has good pharmacokinetic properties.

Claims

1. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound is shown in formula (I): in: R and R' are each independently selected from R d or And R and R' are not the same as R d or Ring A is selected from 4-8 membered heterocyclylene; Ring B is selected from 8-12 membered bicyclic heteroarylene; Ring C is selected from 5-6 membered monocyclic heteroaryl, 8-12 membered bicyclic heteroaryl or 5-6 membered heterocyclyl; M and W are each independently selected from a bond, -O-, -NR3-, -CR1R2-, -C(O)-, -S-, -S(O)-, -S(O)2-, -CR1R2-O-, -CR1R2NR3-, -(CR1R2)2- or -CR1R2-S-; M1 is selected from N or CR4; M2 is selected from N or CR5; M3 is selected from N or CR6; R3 is selected from hydrogen, deuterium, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; R1, R2, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxy, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; Alternatively, R1 and R2 together with the atoms to which they are attached form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group may be further substituted with one or more substituents selected from halogen, hydroxy, alkyl or alkoxy; L1 is selected from -Ak1-Cy1-Ak2-Cy2-Ak3-, Ak1, Ak2 and Ak3 are each independently selected from a bond, -(CH2) n -, -O-, -S-, -C(O)- or -NH-; said -(CH2) n - and -NH-, which may optionally be further substituted; Cy1 and Cy2 are each independently selected from a bond, a cycloalkylene group or a heterocyclylene group; the cycloalkylene group and the heterocyclylene group may be further substituted; n is selected from 1, 2, 3 or 4; L2 is selected from a bond, -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-; L3 is selected from a bond, -NH-, -S-, -O-, -CH2-, -CH2CH2-, -C(O)NH-, -NHC(O)- or -C(O)-; R a , R b , R c and R d Each is independently selected from hydrogen, deuterium, halogen, hydroxyl, alkyl, haloalkyl, -P(O)R1R2, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl or heterocyclic group; the cycloalkyl and heterocyclic group may be further substituted with one or more substituents selected from halogen, hydroxyl, alkyl, alkoxy, haloalkyl, haloalkoxy; Or, any R a Connected to any carbon atom on ring A to form a cycloalkyl group or a heterocyclic group, wherein the cycloalkyl group and the heterocyclic group may be further substituted; Or, L1 and R b connected to form a cycloalkyl or heterocyclic group; Or, any two R c Connected to form a cycloalkyl group or a heterocyclic group, the cycloalkyl group and the heterocyclic group may be further substituted; x, y and z are each independently selected from 0, 1, 2 or 3.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by formula (II): Wherein: M4 is selected from N or CH; n1 and n2 are each independently selected from 0, 1 or 2.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R is selected from R d When R' is selected from or, The R is selected from When R' is selected from R d .

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring B is selected from indazolyl, benzimidazolyl, pyridotriazolyl, pyridopyrazolyl, pyridoimidazolyl or pyrimidoimidazolyl; Preferably, the Selected from Alternatively, the ring C is selected from pyridyl, phenyl, pyridonyl, benzimidazolyl, pyridazinonyl, pyrazolopyrimidinyl, pyrimidopyrazolyl, pyridopyrrolyl, pyrimidinyl, pyrimidopyrrolyl or pyridopyrazolyl; Preferably, the Selected from 5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The L1 is selected from -Cy1-Ak2-; the Cy1 is selected from a bond, cyclobutylene, cyclopentylene, cyclohexylene, piperidinylene or piperazinylene, the cyclobutylene, cyclopentylene, cyclohexylene, piperidinylene and piperazinylene are optionally further substituted by 1 to 4 deuterium, halogen, hydroxyl, cyano, oxo, C 1-3 Alkyl, hydroxyl C 1-3 Alkyl, C 1-3 Alkoxy, C 3-4 Cycloalkyl, 3-4 membered heterocyclic group, C 1-3 Haloalkyl or C 1-3 Substituted by a haloalkoxy substituent; wherein Ak2 is selected from -(CH2) n -; Preferably, L1 is selected from -cyclohexylene-(CH2)n-, -piperidinylene-(CH2)n- or -piperazinylene-(CH2)n-; n is selected from 1, 2, 3 or 4; Alternatively, L2 is selected from -NH-C(O)-, -C(O)-NH-, -NH-C(S)- or -C(S)-NH-; Alternatively, L3 is selected from a bond, -NH-, -S-, -O-, -CH2-, -CH2CH2-, -C(O)NH-, -NHC(O)- or -C(O)-.

6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R a , R b , R c and R d Each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, -P(O)R1R2, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, hydroxyl C 1-3 Alkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; the C 3-4 Cycloalkyl and 3-4 membered heterocyclic groups, optionally further substituted with halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 is substituted by one or more substituents in a haloalkoxy group; Alternatively, R1, R2, R4, R5 and R6 are each independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; Alternatively, R3 is selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group.

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is further represented by general formula (IV): in: W is selected from -O-, -S-, -C(O)-, -S(O)2-, -CR1R2- or -NR3-; M is selected from -O-, -S-, -C(O)-, -S(O)2-, -CR1R2- or -NR3-; R b Selected from C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, -P(O)R1R2, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; the C 3-4 Cycloalkyl and 3-4 membered heterocyclic groups, optionally further substituted with halogen, hydroxyl or C 1-3 Alkyl substitution; R c Selected from C 1-3 Haloalkyl; R1 and R2 are each independently selected from hydrogen, hydroxy, halogen or C 1-3 alkyl; R3 is selected from C 1-3 alkyl.

8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds: 。 9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. Use of the compound according to any one of claims 1 to 8, its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating or preventing an IRAK4-mediated disease.

11. The use according to claim 10, characterized in that The disease is selected from an autoimmune disease, an inflammatory disease, cancer, a viral disease, a neurodegenerative disease, a genetic disorder, a hormone-related disease, a metabolic disorder, a disease related to organ transplantation, an immunodeficiency disorder, a destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, or a cardiovascular disease.

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