Irak4 degrader and uses thereof

Abstract

This invention relates to an IRAK4 degrading agent and its uses. This degrading agent can be used to treat or prevent diseases such as cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to an IRAK4 degrading agent and its uses. Background Technology

[0002] IRAK4 (interleukin-1 receptor-associated kinase 4) is a serine / threonine protein kinase and a key mediator in the innate immune response, playing a particularly important role in the Toll-like receptor (TLR) and IL-1R signaling pathways. IRAK4 initiates the inflammatory response by forming a Myddosome complex with MYD88 and IRAK2, thereby activating the downstream NF-κB pathway.

[0003] As a key mediator of NF-κB-regulated inflammatory signaling, IRAK4 is associated with various diseases, including autoimmune and inflammatory conditions such as atopic dermatitis, hidradenitis suppurativa, rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Therefore, IRAK4 has become an important target for the treatment of these diseases. PROTAC (protein degradation-targeting chimera) targeting IRAK4 is an emerging drug development strategy aimed at treating inflammatory and tumor diseases by degrading the IRAK4 protein. It utilizes the ubiquitin-proteasome system (UPS) to degrade the target protein, thereby eliminating the kinase activity of IRAK4, potentially leading to comprehensive therapeutic effects and showing broad application prospects. Summary of the Invention

[0004] On the one hand, the present invention provides compounds of formula (I), their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, their acceptable salts of deuterated derivatives, their prodrugs, their hydrates or solvates thereof. (I); Among them, one of E1 and E2 is -C(=O)-, and the other is -NR. c -; R 1a R 1c Together with the atoms attached to both, they form an 8-20 membered heterocycle, which is optionally substituted by m² R² groups; each R² group is independently selected from halogen, cyano, nitro, hydroxyl, amino, C, ... 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; the amino group, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Substituents of aryl or 5-10 heteroaryl groups; each m2 is independently 0, 1, 2 or 3; Each R 1b Selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10Substituents of aryl or 5-10 heteroaryl groups; each m1 is independently selected as 0, 1 or 2; Cy1 has any of the structures in the table below. This indicates a connection to E2. It represents a connection with L;

[0005] L has the structure of the following formula (III): (III); Each of n4, n5, n6, n7, n8, and n9 can be independently chosen as 0, 1, 2, or 3, with at least one of n5, n7, and n9 being non-zero, and the following conditions must be met: (1) When n4≠0 and n6≠0, n5≠0; (2) When n6≠0 and n8≠0, ​​n7≠0; (3) When n4≠0 and n8≠0, ​​at least one of n5 and n7 is not 0; Each Cy3, Cy4, and Cy5 is independently selected from a 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring containing 0-3 heteroatoms, optionally selected by one or more of halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substituents of alkyl acyl groups, amino groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 The alkyl acyl group is optionally surrounded by one or more elements selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substitution of the alkyl acyl group; Each L1, each L2, and each L3 is independently selected from -(CR a R b ) n11 -、-(CR a R b ) n10 -O-(CR a R b )n10 -、-(CR a R b ) n10 -S-(CR a R b ) n10 -、-(CR a R b ) n10 -C(O)-(CR a R b ) n10 -、-(CR a R b ) n10 -N(R a )-(CR a R b ) n10 -、-(CR a R b ) n10 -C≡C-(CR a R b ) n10 -、-(CR a R b ) n10 -C=C-(CR a R b ) n10 -;-(CR a R b ) n11 -、-(CR a R b ) n10 -O-(CR a R b ) n10 -、-(CR a R b ) n10 -S-(CR a R b ) n10 -、-(CR a R b ) n10 -C(O)-(CR a R b ) n10 -、-(CR a R b ) n10 -N(R a )-(CR a R b ) n10 -、-(CR a R b ) n10 -C≡C-(CRa R b ) n10 -、-(CR a R b ) n10 -C=C-(CR a R b ) n10 -Optionally selected from one or more of the following groups: halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substituents of the alkyl acyl group; each R a and each R b Each is independently selected from H, halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group; each n 10 Each is independently 0, 1, 2, 3, or 4; n 11 It can be 1, 2, 3, or 4; Degron has a structure with any one of the following terms: (IV-1), (IV-2), (IV-3), (IV-4);

[0006] In equation (IV-1), A6 and A7 are each independently selected from -C(O)- and -NR. c -or-C(R) c )2-; In equation (IV-2), A8 and A9 are each independently selected from -C(O)- and -NR. c -or-C(R) c )2-, and A8 and A9 are not both -C(O)-; In formula (IV-3), A 10 A 11 A 12 A 13 A 14 It exists under any of the following conditions: (1) It is a double bond. It is a single key. It is a double bond, A 10 A 13 and A 14 All are -C-, A 11 -C(R) c )2- or -NRc -, A 12 For -CR c -or -N-; (2) It is a double bond. It is a single key. A is a single bond. 10 and A 14 All are -C-, A 13 For -CR c -or -N-, A 11 and A 12 Each independently is -C(R) c )2- or -NR c -; (3) It is a single key. It is a double bond. It is a double bond, A 10 For -C-, A 11 and A 12 Each independently as -CR c -or -N-, A 13 For -C-, A 14 For -CR c -or -N-; (4) It is a single key. It is a double bond. A is a single bond. 10 For -C-, A 11 For -CR c -or -N-, A 12 -C(R) c )2- or -NR c -, A 13 and A 14 Each independently as -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 2 nitrogen atoms; (5) It is a single key. It is a single key. It is a double bond, A 10 For -CR c -or -N-, A 11 -C(R) c )2- or -NR c -, A 12 For -CR c -or -N-; A 13 For -C-, A14 For -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 2 nitrogen atoms; (6) It is a single key. It is a single key. A is a single bond. 10 For -CR c -or -N-, A 11 -C(R) c )2-、-NR c -or-C(O)-, A 12 -C(R) c )2-、-NR c -or-C(O)-, A 13 For -CR c -or -N-, A 14 For -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 3 nitrogen atoms; In formula (IV-4), A 15 A 16 and A 17 Each is independently selected from -CH- or -N-, and A 15 A 16 and A 17 It contains at most 2 nitrogen atoms; A 18 L4 represents -N- or -CH-; L4 represents chemical bonds, -O-, or -NR. d -or-C(O)-NR d -; Each R c Each is independently selected from H, halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Each R d Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups; Each R4 group is independently selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C1-6 Haloalkyl; m4 is 0, 1, 2 or 3.

[0007] In some implementations, R 1a R 1c Together with the atoms attached to both, they form an 8-20 membered oxygen-containing heterocycle, which is optionally substituted by m² R² groups; each R² group is independently selected from halogen, cyano, nitro, hydroxyl, amino, C... 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; the amino group, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Substituents of aryl or 5-10 heteroaryl groups; each m2 is independently 0, 1, 2 or 3.

[0008] In some implementations, R 1a R 1c Together with the atoms attached to them, they form 8-20 member heterocycles containing oxygen heteroatoms and alkynyl groups.

[0009] In some implementations, one of E1 and E2 is -C(=O)- and the other is -NH-.

[0010] In some embodiments, the compound has the structure of formula (I-1): .

[0011] In some implementations, each R 1b Each is independently selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylidene, cyclopropylpropylpropene.

[0012] In some embodiments, each R2 is independently selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -Se-, -Se-CH3, -Se-CH2CH3, -CH2-Se-CH2CH3, -CH2-Se-CH3, -CH2CH2-Se-CH2CH3, vinyl, propenyl, butenyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, -C(CH3)2(OH), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2.

[0013] In some embodiments, the Degron of formula (IV-1) has the structure of any of the following formulas:

[0014] In some embodiments, the Degron of formula (IV-2) has the structure of any of the following formulas:

[0015] In some embodiments, the Degron of formula (IV-3) has the structure of any of the following formulas:

[0016] In some embodiments, the Degron of formula (IV-4) has the structure of any of the following formulas:

[0017] In some embodiments, the Degron has a structure of any of the following formulas:

[0018] Preferably, the Degron has a structure of any of the following formulas:

[0019] In some embodiments, each R4 is independently selected from F, Cl, Br, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, preferably independently selected from F, Cl, Br, methyl, -CCl3 or -CF3.

[0020] In some implementations, each R c Each of the following is independently selected from H, F, Cl, Br, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, preferably each independently selected from H, F, Cl, Br, methyl, -CCl3 or -CF3.

[0021] In some implementations, each R d Each of the following is independently selected from H, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, preferably each of the following is independently selected from H, methyl, -CCl3, -CF3, -CHCl2 or -CHF2.

[0022] In some implementations, each R a and each R b Each is independently selected from H, F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, 1-propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, formyl, or acetyl.

[0023] In some implementations, each R a and each R b Each is independently selected from H, F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, 1-propynyl, methoxy, ethoxy, formyl, or acetyl.

[0024] In some implementations, each n 10 Each can be 0, 1, 2, or 3 independently.

[0025] In some embodiments, each L1, each L2, and each L3 is independently selected from methylene, ethylene, propylene, -O-, -C≡C-, -C(O)-, -NH-, and -N(CH3)-.

[0026] In some implementations, n4 is 0.

[0027] In some embodiments, each Cy3, each Cy4, and each Cy5 is independently selected from 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered rings containing 0-3 heteroatoms, which are optionally substituted by one or more substituents selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, and propyl; the heteroatoms are selected from N, S, O, or Se; Preferably, each Cy3, each Cy4, and each Cy5 is independently selected from any of the structures in the following list, which are optionally substituted by one or more substituents selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, and propyl:

[0028] In some implementations, L is selected from any of the following structures:

[0029]

[0030]

[0031] , ; , .

[0032] In some embodiments, the compounds of the present invention are as follows:

[0033] The above compounds can be used as IRAK4 degrading agents to treat or prevent IRAK4-related diseases.

[0034] On the other hand, the present invention provides a pharmaceutical composition comprising the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of its deuterated derivative, its prodrug, its hydrate or solvate thereof; and at least one pharmaceutically acceptable excipient.

[0035] On the other hand, the present invention provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, its acceptable salt of its deuterated derivative, its prodrug, its hydrate or solvate thereof; or the use of the aforementioned pharmaceutical composition in the preparation of a medicament for treating or preventing diseases related to IRAK4.

[0036] In some implementations, diseases associated with IRAK4 include, but are not limited to: cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, cell death-related conditions, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases.

[0037] In some embodiments, the cancers or proliferative diseases include brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck or head tumors, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated tumor, papillary tumor, seminoma, melanoma, ABCDLBC L, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, chronic lymphocytic leukemia, smoldering indolent multiple myeloma, leukemia, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary exudative lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, or plasmacytoma or intravascular large B-cell lymphoma.

[0038] In some embodiments, the neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, ischemic or traumatic brain injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, and neurodegenerative diseases caused by organ transplantation or graft-versus-host disease.

[0039] In some embodiments, the inflammatory disease is an eye disease, such as eye allergy, conjunctivitis, dry eye syndrome or vernal conjunctivitis, or a disease affecting the nose, including allergic rhinitis.

[0040] In some embodiments, the diseases include, but are not limited to: hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenic purpura, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stephen Johnson syndrome, idiopathic stomatitis, idiopathic inflammatory bowel disease, irritable bowel syndrome, celiac disease, periostitis of the dental root, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcomatosis, vernal conjunctivitis-keratitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospirosis-related nephropathy, glaucoma, retinal disease, aging, headache, pain Pain, complex regional pain syndrome, cardiomegaly, muscular atrophy, catabolism, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmentosa, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reactions, systemic allergic reactions, sinusitis, silica-induced diseases, COPD, lung disease, cystic fibrosis, liver fibrosis, kidney fibrosis, alcoholic fatty liver disease, non-alcoholic fatty liver disease, cardiac fibrosis, psoriasis, Crohn's disease, inflammatory bowel disease, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease.Diseases, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonleinpurpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis media, pancreatitis Patient inflammation, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, localized pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, herpetic dermatitis, sclerosis, leukoderma, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, foliaceous pemphigus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryptothermal protein-related syndrome, or osteoarthritis.

[0041] In another aspect, the present invention provides a method for treating or preventing diseases associated with IRAK4, the method comprising administering to the subject a therapeutically effective amount of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, an acceptable salt of its deuterated derivative, its prodrug, its hydrate or solvate thereof; or a pharmaceutical composition comprising the above substances.

[0042] In another aspect, the present invention provides the use of the aforementioned compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt, its acceptable salt of the stereoisomer, its deuterated derivative, its prodrug, its hydrate, or its solvate; or the use of the pharmaceutical composition of the present invention described above in the treatment or prevention of IRAK4-related diseases. IRAK4-related diseases include, but are not limited to: cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases.

[0043] definition Unless otherwise stated, "The wavy line represents the location of the broken bond, that is, the location where it connects to the adjacent structure. In the definitions of structural segments L, Cy1, Cy3, Cy4, and Cy5, a substituent may have two..." The statement “”, without any special limitation, indicates that either end of the substituent can be connected to the corresponding structure in formula (I). Unless otherwise specified, such as in Cy1 where the order of connection is specifically defined.

[0044] Unless otherwise stated, the term "halogen" as used interchangeably herein refers to fluorine, chlorine, bromine, or iodine. Preferred halogen groups include -F, -Cl, and -Br.

[0045] Unless otherwise stated, the term "alkyl" as used herein includes saturated monovalent hydrocarbon groups having a straight chain or branched chain. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, and 2-methylpentyl, etc. Similarly, C 1-6 C in alkyl 1-6 Alkyl groups are defined as groups that identify straight or branched chains having 1, 2, 3, 4, 5, or 6 carbon atoms. Common alkyl abbreviations include: Me(-CH3), Et(-CH2CH3), iPr(-CH(CH3)2), nPr(-CH2CH2CH3), n-Bu(-CH2CH2CH2CH3) or i-Bu(-CH2CH(CH3)2).

[0046]

[0047]

[0048]

[0049] The term "alkoxy" refers to an oxygen ether formed from the aforementioned alkyl group, wherein the oxygen is attached to the substituted structure, including but not limited to -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)2.

[0050] The term "alkoxyalkyl" refers to a substituent formed by replacing an alkyl group with an alkoxy group. In some embodiments, alkoxyalkyl refers to -C 1-6 Alkylene-OC 1-6 Alkyl. In some embodiments, alkoxyalkyl refers to -C 1-3 Alkylene-OC 1-3Alkyl groups. The above alkoxyalkyl groups include, but are not limited to, -CH2OCH3, -CH2CH2OCH3, -CH2CH2O CH2CH3, etc.

[0051] Unless otherwise stated, the term "haloalkoxy" as used herein refers to the aforementioned alkoxy group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkoxy group is interchangeably -C 1-6 Halogenated alkoxy or halogenated C 1-6 alkoxy group, where -C 1-6 Halogenated alkoxy or halogenated C 1-6 C in alkoxy 1-6 This indicates that the total number of carbon atoms in the alkoxy group is 1 to 6. In some embodiments, -C 1-6 The haloalkoxy group can be substituted with 1, 2, 3, 4, 5, or 6 -F, -Cl, or -Br (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy); preferably -C 1-3 The haloalkoxy group is -OCF3.

[0052] Unless otherwise stated, the term "haloalkoxyalkyl" as used herein refers to the aforementioned alkoxyalkyl group substituted with one or more (1, 2, 3, 4, 5, or 6) halogens (-F, -Cl, or -Br). In some embodiments, the haloalkoxyalkyl group is interchangeably -C 1-6 Halogenated alkoxyalkyl or halogenated C 1-6 alkoxyalkyl, wherein, -C 1-6 Halogenated alkoxyalkyl or halogenated C 1-6 C in alkoxyalkyl 1-6 This indicates that the total number of carbon atoms in the alkoxy group is 1 to 6. In some embodiments, -C 1-6 The haloalkoxyalkyl group can be substituted with 1, 2, 3, 4, 5 or 6 -F, -Cl or -Br (methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexoxy).

[0053] Unless otherwise stated, the term "alkanoyl" as used herein refers to a group formed by the oxidation of a carbon atom in the aforementioned alkyl group, such as -CH(=O), -C(=O)CH3, -C(=O)CH2CH3, -C(=O)CH2CH2CH3, -C(=O)CH(CH3)3, etc.

[0054] Unless otherwise stated, the terms "aryl" or "aromatic ring" as used herein refer to an unsubstituted or substituted monocyclic or polycyclic aromatic ring system containing only a carbon ring atom. Preferred aryl groups are 6-10 membered aromatic ring systems, either monocyclic or bicyclic. Phenyl and naphthyl are preferred aryl groups.

[0055] Unless otherwise stated, the term "unsaturated heterocycle" as used herein can refer to an unsaturated ring in a non-aromatic ring system containing heteroatoms or an aromatic ring containing heteroatoms.

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064] This invention aims to include all atomic isotopes present in the compounds of this invention. An isotope is an atom having the same atomic number but different mass numbers. By way of general example and not limitation, isotopes of hydrogen include deuterium and tritium. Hydrogen isotopes can be represented as 1H (hydrogen), 2H (deuterium), and 3H (tritium). They are also commonly represented as D (deuterium) and T (tritium). In this invention, CD3 represents methyl, where all hydrogen atoms are deuterium. Carbon isotopes include 13C and 14C. Using suitable isotopically labeled reagents instead of unlabeled reagents, the isotopically labeled compounds of this invention can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described herein.

[0065] Unless otherwise stated, the term "deuterated derivative" as used herein refers to a compound having the same chemical structure as the reference compound, but in which one or more hydrogen atoms are replaced by deuterium atoms ("D"). It will be appreciated that variations in the abundance of natural isotopes can occur in synthetic compounds depending on the source of the chemical materials used in the synthesis. The concentration of naturally abundant stable hydrogen isotopes is small and insignificant compared to the degree of stable isotopic substitution in the deuterated derivatives described herein.

[0066] When the compounds of the present invention have tautomers, the present invention includes any possible tautomers and their pharmaceutically acceptable salts and mixtures thereof, unless otherwise specifically stated.

[0067] Therefore, the pharmaceutical compositions of the present invention may include pharmaceutically acceptable carriers and compounds or pharmaceutically acceptable salts. Compounds of Formula I or their pharmaceutically acceptable salts may also be included in the pharmaceutical composition in combination with one or more other therapeutically active compounds.

[0068]

[0069]

[0070] Typically, dosage levels of approximately 0.001 mg / kg to approximately 150 mg / kg body weight per day are used to treat the above-mentioned conditions, or approximately 0.05 mg to approximately 7 g per patient per day. For example, administering approximately 0.001 to 50 mg of the compound per kilogram of body weight per day, or approximately 0.05 mg to approximately 3.5 g of the compound per kilogram of body weight per day, can be effective in treating cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases.

[0071] However, it should be understood that the specific dosage level for any particular patient will depend on a variety of factors, including age, weight, general health condition, sex, diet, timing of administration, route of administration, excretion rate, combination of drugs, and the severity of the specific disease being treated.

[0072] Unless the context otherwise indicates, when a value is expressed as “approximately” X or “about” X, the specified value of X shall be understood to be accurate to ±10%, preferably ±5%, ±2%. Detailed Implementation

[0073] The compounds of this invention can be synthesized from commercially available reagents using the synthetic methods and reaction schemes described herein. The examples outlining specific synthetic routes are intended to provide guidance to synthetic chemists in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed within the technical skill and judgment of those skilled in the art.

[0074] Example The following examples are provided to better illustrate the invention. Unless otherwise explicitly stated, all parts and percentages are by weight, and all temperatures are in degrees Celsius.

[0075] Preparation of Intermediate 1

[0076] 7-Bromo-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (2.2 g, 9.734 mmol, 1.0 eq) was dissolved in ultradry THF (50 mL), and under N2 protection, LiHMDS (29.2 mL, 29.203 mmol, 3 eq, 1 M THF solution) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. 3-Bromopiperidin-2,6-dione (3.7 g, 19.469 mmol, 2.0 eq) was dissolved in THF (20 mL) and added to the reaction mixture at 0 °C, and the mixture was stirred at 70 °C for 15 h. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the ethyl acetate layer was washed with salt, dried over anhydrous sodium sulfate, and purified by rotary evaporation with silica gel in a normal phase. Approximately 10% ethyl acetate was used to give intermediate 1-1 (0.6 g, 18% yield), [M+H]. + [M+H+2] + =338.0, 340.0.

[0077] Intermediate 1-1 (600 mg, 1.78 mmol, 1.0 eq), tert-butyl 4-(prop-2-yn-1-yloxy)piperidin-1-carboxylate (638.27 mg, 2.67 mol, 1.5 eq), Pa(PPh3)2Cl2 (249.97 g, 0.35 mmol, 0.2 eq), CuI 67.65 g, 0.35 mmol, 0.2 eq), Cs2CO3 (2321.66 g, 7.12 mmol, 4 eq), and 4A.MS (600 mg) were weighed into a 100 mL double-necked flask. Under N2 protection, 20 mL of ultra-dry DMF was added, and the mixture was stirred at 80 °C for 2 h. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the ethyl acetate layer was washed with salt, dried over anhydrous sodium sulfate, and then purified by rotary evaporation with silica gel in a normal phase. Approximately 60% ethyl acetate was used to give intermediate 1-2 (500 mg, 56% yield), [M+H-56]. + =441.2.

[0078] Intermediates 1-2 (200 mg, 0.403 mmol, 1.0 eq) were dissolved in DCM (4 mL), and TFA (1 mL) was added. The mixture was stirred at 25 °C for 1 h. After the reaction was complete, the solution was concentrated to give intermediate 1 (150 mg, 93% yield), [M+H]. + =397.5.

[0079] Preparation of intermediate 2

[0080] Compound A (10.0 g, 29.58 mmol, 1.0 eq) and triethylamine (21 mL, 147.90 mmol, 5.0 eq) were dissolved in ultradry dichloromethane (100 mL), and tert-butyldimethylchlorosilane (6.78 g, 44.37 mmol, 1.5 eq) was added. The mixture was stirred at room temperature for 16 h. After the reaction was complete, the solution was concentrated and purified by silica gel chromatography, normal phase column chromatography, and petroleum ether-ethyl acetate system to give intermediate 2-1 (12.6 g, 92.9% yield), [M+H]. + [M+H+2] + =453.2, 455.2.

[0081] Intermediate 2-1 (12.6 g, 27.86 mmol, 1.0 eq) was dissolved in ultradry tetrahydrofuran (150 mL) under nitrogen protection and stirred at 0 °C for 0.5 h. Then, 2 M isopropyl magnesium chloride tetrahydrofuran solution (8.4 mL, 16.72 mmol, 0.6 eq) was slowly added dropwise, and the mixture was stirred at 0 °C for 0.5 h. Next, 2.5 M n-butyllithium n-hexane solution (13.4 mL, 33.44 mmol, 1.2 eq) was slowly added dropwise, and the mixture was stirred at 0 °C for 1.5 h. Then, excess carbon dioxide gas was slowly introduced, and the mixture was stirred at 0 °C for 1 h. Finally, the mixture was brought to room temperature and stirred for 1 h. After the reaction was complete, the reaction mixture was quenched with 400 mL of NH4Cl solution and extracted with ethyl acetate (150 mL x 3). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification was performed using a normal-phase column and a dichloromethane-methanol system to give intermediate 2-2 (4.5 g, 38.6% yield), [M+H]. + =419.3.

[0082] Intermediate 2-2 (3.83 g, 9.16 mmol, 1.0 eq), ammonium chloride (1 g, 11.91 mmol, 1.3 eq), and N,N-diisopropylethylamine (16.3 mL, 91.6 mmol, 10.0 eq) were dissolved in DMF (40 mL) and stirred at 25 °C for 2 h. 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate (1.54 g, 13.74 mmol, 1.5 eq) was added, and the mixture was stirred overnight at 25 °C. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the EA layer was washed with brine, dried over anhydrous Na₂SO₄, and purified by dry stirring with silica gel in a normal phase to give intermediate 2-3 (1.4 g, 36.6% yield), [MH]. - =417.1.

[0083] Intermediate 2-3 (1.2 g, 2.9 mmol, 1.0 eq) was dissolved in 1 M boron trichloride dichloromethane solution (30 mL) and stirred at 25 °C for 16 h. After the reaction was complete, the mixture was purified by dry stirring with silica gel under normal phase to give intermediate 2-4 (0.8 g, 95.5% yield), [M+H]. + =290.1.

[0084] 1,5-Pentanediol (12.7 mL, 1.22 mmol, 1.2 eq) was dissolved in ultradry tetrahydrofuran (500 mL) under nitrogen protection. Potassium tert-butoxide (12.9 g, 1.52 mmol, 1.5 eq) was added at 20 °C, followed by stirring for 0.5 h. Then, 3-bromopropyne (12 g, 1.02 mmol, 1.0 eq) was slowly added dropwise, and the mixture was stirred at 20 °C for 16 h. After the reaction was complete, the reaction mixture was quenched by adding saturated sodium chloride solution (60 mL), and the pH was adjusted to 3–5 with 1 M hydrochloric acid. The mixture was then extracted with dichloromethane (100 mL x 6). The combined organic layers were washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by normal-phase column chromatography gave intermediate 2-5 (5.2 g, 36.2% yield), [M+H]. + =143.1.

[0085] Intermediate 2-5 (1.42 g, 9.99 mmol, 1.0 eq), 1-bromo-3-iodobenzene (3.1 g, 10.99 mmol, 1.1 eq), Pd(PPh3)2Cl2 (351 mg, 0.49 mmol, 0.05 eq), CuI (191 mg, 0.99 mmol, 0.1 eq), and triethylamine (14 mL, 99.92 mmol, 10.0 eq) were dissolved in ultradry tetrahydrofuran (20 mL) and stirred at room temperature for 16 h. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the EA layer was washed with salt, dried over anhydrous Na2SO4, and purified by dry stirring with silica gel in a normal phase to give intermediate 2-6 (1.6 g, 54.0% yield). Intermediate 2-6 (1.43 g, 4.83 mmol, 1.0 eq), triethylamine (2.01 mL, 14.49 mmol, 3.0 eq), and N,N-dimethylaminopyridine (60 mg, 0.48 mmol, 0.1 eq) were dissolved in 30 mL of ultradry dichloromethane (24133055). p-Toluenesulfonyl chloride (1.01 g, 5.32 mmol, 1.1 eq) was added, and the mixture was stirred at room temperature for 16 h. After the reaction was complete, the solution was concentrated and purified by silica gel chromatography, normal-phase column chromatography, and a petroleum ether-ethyl acetate system to give intermediate 2-7 (1.4 g, 64.4% yield), [M+H]. + [M+H+2] + =451.1, 453.1.

[0086] Cesium carbonate (646 mg, 1.98 mmol, 1.5 eq) was added to an ultradry DMF (25 mL) solution of intermediate 2-4 (0.381 g, 1.32 mmol, 1.0 eq) with stirring at room temperature, followed by stirring the reaction mixture at 60 °C for 1 h. Then, intermediate 2-7 (0.624 g, 1.39 mmol, 1.05 eq) was added, and the reaction mixture was stirred at 60 °C for 16 h. After the reaction was complete, the solid was filtered off, and the mixture was purified by dry stirring with silica gel in a normal phase to give intermediate 2-8 (0.24 g, 32.0% yield). [M+H] + [M+H+2] + =568.3, 570.3.

[0087] Intermediate 2-8 (0.292 g, 0.51 mmol, 1.0 eq), Pd2(dba)3 (48 mg, 0.05 mmol, 0.1 eq), XantPhos (60 mg, 0.10 mmol, 0.2 eq), and sodium tert-butoxide (150 mg, 1.56 mmol, 3.0 eq) were dissolved in ultradry 1,4-dioxane (40 mL) under nitrogen protection and stirred at 60 °C for 16 h. After the reaction was complete, the solid was filtered off, and the solution was evaporated to dryness to give intermediate 2-9 (0.351 g, 140.0% yield). [M+H] + =488.7.

[0088] Intermediate 2-9 (351 mg, 0.7 mmol, 1.0 eq) was dissolved in DCM (60 mL), and Dysmartin oxidant (594 mg, 1.4 mmol, 2.0 eq) was added. The mixture was stirred at 25 °C for 4 h. After the reaction was complete, the solid was filtered off, and the solution was evaporated to dryness to give intermediate 2 (0.342 g, 100.0% yield). [M+H] + =486.3.

[0089] Example 1 Preparation of Compound 1

[0090] Intermediate 2 (61 mg, 0.125 mmol, 1.0 eq), intermediate 1 (75 mg, 0.1375 mmol, 1.1 eq), and N,N-diisopropylethylamine (0.21 mL, 1.25 mmol, 10.0 eq) were dissolved in 1,2-dichloroethane (5 mL), ultradry methanol (0.5 mL), and ultradry N,N-dimethylformamide (0.5 mL), and stirred at 25 °C for 1 h. NaBH(OAc)3 (53 mg, 0.25 mmol, 2.0 eq) was added, and the mixture was stirred at 25 °C for 16 h. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the EA layer was washed with brine, dried over anhydrous Na2SO4, dissolved in methanol, filtered, purified by HPLC, and lyophilized to give compound 1 (1 mg, 0.925% yield), [M+2H]. 2+ =867.2. Compound 1: 1 H NMR (400 MHz, DMSO- d 6) δ 11.13 (s, 1H), 10.09 (s, 1H), 8.77(s, 1H), 8.44 (s, 1H), 7.23 – 7.19 (m, 1H), 7.17 – 6.97 (m, 7H), 5.46 – 5.40(m, 1H), 4.56 (s, 2H), 4.49 – 4.42 (m, 1H), 4.36 (s, 2H), 4.09 (s, 2H), 3.74– 3.64 (m, 8H), 2.28 – 2.15 (m, 5H), 2.12 – 1.86 (m, 15H), 1.77 – 1.68 (m,4H), 1.62 – 1.54 (m, 3H). Example 2 Preparation of compound 2

[0091] Intermediate 2 (177 mg, 0.35 mmol, 1.0 eq), INT-11 (133 mg, 0.3883 mmol, 1.1 eq), and N,N-diisopropylethylamine (0.6 mL, 3.53 mmol, 10.0 eq) were dissolved in 1,2-dichloroethane (10 mL), ultradry methanol (1 mL), and ultradry N,N-dimethylformamide (1 mL), and stirred at 25 °C for 1 h. NaBH(OAc)3 (150 mg, 0.706 mmol, 2.0 eq) was added, and the mixture was stirred at 25 °C for 16 h. After the reaction was complete, ethyl acetate and purified water were added. The product was extracted, the EA layer was washed with brine, dried over anhydrous Na2SO4, dissolved in methanol, filtered, purified by HPLC, and lyophilized to give compound 2 (16 mg, 55.9% yield), [M+2H]. 2+ =813.1. Compound 2: 1 H NMR (400 MHz, DMSO- d 6) δ 11.09 (s, 1H), 10.10 (s, 1H), 8.44(s, 1H), 7.95 (d, J = 7.7 Hz, 1H), 7.51 – 7.33 (m, 3H), 7.17 – 6.98 (m, 4H), 6.93 (d, J = 8.2 Hz, 1H), 5.41 – 5.29 (m, 1H), 4.48 – 4.29 (m, 3H), 4.09 (s,2H), 3.71 (t, J = 7.6 Hz, 2H), 3.02 – 2.93 (m, 2H), 2.18 (t, 4H), 2.08 – 1.87(m, 10H), 1.80 – 1.56 (m, 11H), 1.24 (s, 4H), 1.13 (d, J = 13.2 Hz, 2H). Activity test of the compound IRAK4 THP1 cell degradation activity assay Compound-treated cell protein samples were collected and seeded into 12-well cell culture plates. Each well was inoculated with 2 mL of THP-1 cell suspension at a cell density of 3 × 10⁻⁶ cells / well. 6Cells per well; cell plates were incubated overnight at 37°C in a 5% CO2 incubator until cells adhered properly. Then, DMSO stock solution of the test compound was added to ensure a final concentration of 0.5–5000 nM. After 24 hours of incubation, cells were digested and collected into 2 mL centrifuge tubes, centrifuged at 1000 rpm and 4°C for 5 minutes. Cell aggregates were washed once with 1×DPBS and resuspended in 60 μL of RIPA lysis buffer (Beyotime, P0013B) containing a protease inhibitor mixture (ThermoFisher, 78446). After standing on ice for 30 minutes, the plates were centrifuged at 14000g and 4°C for 10 minutes. The supernatant was used for Western blotting to detect IRAK4 protein levels.

[0092] Protein concentration determination: The protein concentration of cell lysates was quantified using the BCA protein analysis kit. Albumin standards at different concentrations were prepared, including 2,000 ug / mL, 1,500 ug / mL, 1,000 ug / mL, 750 ug / mL, 500 ug / mL, 250 ug / mL, 125 ug / mL, and 25 ug / mL. The BCA working reagent was prepared by mixing BCA reagent A and reagent B at a 50:1 ratio. 200 μL of the BCA working reagent was added to 25 μL of BCA standard or cell lysate in a microplate and thoroughly mixed on a plate shaker for 30 seconds. After incubation at 37°C for 30 minutes, the absorbance of the sample at 562 nm was measured using a multi-plate reader.

[0093] Western blot analysis: 5X protein loading buffer was added to the protein lysate at a ratio of 1:5 and incubated at 100°C for 10 minutes. For Western blot analysis, 40 μg of total protein was resolved in a 10% SDS-PAG gel (Epizyme, PG212) with 1× electrophoresis buffer (Epizyme, PS105). The protein was transferred to a PVDF membrane using a wet transfer system. The PVDF membrane was then blocked in 5% skim milk at room temperature for 1 hour, followed by overnight incubation at 4°C with primary antibody IRAK4 rabbit polyclonal antibody (Abcam, ab5985) and HRP-conjugated GAPDH rabbit monoclonal antibody (ABclonal, AC054). The membrane was washed three times with 1×TBST, and then incubated with the IRAK4 rabbit polyclonal antibody and secondary antibody Goat Anti-Rabbit IgG-HRP (Ab-mart, M21002S) at room temperature for 1 hour. The membrane was washed three times with 1×TBST, and proteins were detected using ECL chemiluminescence buffer (Thermo Fisher, 34577). Western blot images were obtained using a multifunction image workstation. Analysis was performed using ImageJ software. Data are reported as IRAK4 signals relative to GAPDH signals, normalized to DMSO-treated controls, and protein degradation inhibition rates were calculated.

[0094] The DC50 curve was fitted using the software Graphpad Prism 8.0 and the calculation formulas XY-analysis / Nonlinear regression (curve fit) / Dose response-Inhibition / log (inhibitor) vs. response-Variable slope (four parameters) were employed to calculate the DC value. 50 value.

[0095] The test results are shown in Table 1 below.

[0096] Table 1. Data on IRAK4 cell degradation activity

[0097] Mouse pharmacokinetics study The aim of this study was to evaluate the pharmacokinetic properties of compounds in ICR mice (male, male) following a single dose (10 mg / kg, PO). Three mice were used per group for each compound. Mice were treated with a single oral dose of 10 mg / kg of the compound. Blood samples were collected from each mouse at 0.25, 0.5, 1, 4, and 8 hours post-administration. Whole blood samples were placed in tubes containing EDTA-K2, inverted several times, and then centrifuged at 6000 rpm, 4°C for 15 minutes to obtain plasma. Plasma samples were stored at -75 ± 15°C until analysis. The concentrations of the compounds in the plasma samples were determined using LC-MS / MS. The results are shown in Table 2 below.

[0098] Table 2. Pharmacokinetic parameters of the compound at an oral dose of 10 mg / kg

[0099] It should be understood that if this invention references any prior art publications, such reference does not imply an admission that such publication is part of common general knowledge in the field in any country.

[0100] All publicly available texts, patents, patent applications, and published patent applications used in this article are incorporated herein by reference in their entirety.

[0101] Although the invention has been described in considerable detail by way of illustration and examples for purposes of clarity, it will be apparent to those skilled in the art that certain minor changes and modifications will be apparent. Therefore, the description and examples should not be construed as limiting the scope of the invention.

Claims

1. Compounds of formula (I), their stereoisomers, their deuterated derivatives, their pharmaceutically acceptable salts, pharmaceutically acceptable salts of their stereoisomers, acceptable salts of their deuterated derivatives, their prodrugs, their hydrates or solvates thereof, （I）； in, One of E1 and E2 is -C(=O)-, and the other is -NR. c -; R 1a R 1c Together with the atoms attached to both, they form an 8-20 membered heterocycle, which is optionally substituted by m² R² groups; each R² group is independently selected from halogen, cyano, nitro, hydroxyl, amino, C, ... 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl; the amino group, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 Cycloalkyl, 4-8 membered heterocyclic groups, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, -(C 1-3 Alkylene) 0-3 -Se-(C 1-3 Alkyl), C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Substituents of aryl or 5-10 heteroaryl groups; each m2 is independently 0, 1, 2 or 3; Each R 1b Selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl; the amino group, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 2-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Aryl or 5-10 heteroaryl groups are optionally surrounded by one or more groups selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group, C 3-8 cycloalkyl, 4-8 membered heterocyclic, C 6-10 Substituents of aryl or 5-10 heteroaryl groups; each m1 is independently selected as 0, 1 or 2; Cy1 has any of the structures in the table below. This indicates a connection to E2. It represents a connection with L; L has the structure of the following formula (III): (III); Each of n4, n5, n6, n7, n8, and n9 can be independently chosen as 0, 1, 2, or 3, with at least one of n5, n7, and n9 being non-zero, and the following conditions must be met: (1) When n4≠0 and n6≠0, n5≠0; (2) When n6≠0 and n8≠0, ​​n7≠0; (3) When n4≠0 and n8≠0, ​​at least one of n5 and n7 is not 0; Each Cy3, Cy4, and Cy5 is independently selected from a 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered ring containing 0-3 heteroatoms, optionally selected by one or more of halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substituents of alkyl acyl groups, amino groups, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 The alkyl acyl group is optionally surrounded by one or more elements selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substitution of the alkyl acyl group; Each L1, each L2, and each L3 are each independently selected from -(CR a R b ) n11 -, -(CR a R b ) n10 -O-(CR a R b ) n10 -, -(CR a R b ) n10 -S-(CR a R b ) n10 -, -(CR a R b ) n10 -C(O)-(CR a R b ) n10 -, -(CR a R b ) n10 -N(R a )-(CR a R b ) n10 -, -(CR a R b ) n10 -C≡C-(CR a R b ) n10 -, -(CR a R b ) n10 -C=C-(CR a R b ) n10 -; -(CR a R b ) n11 -, -(CR a R b ) n10 -O-(CR a R b ) n10 -, -(CR a R b ) n10 -S-(CR a R b ) n10 -, -(CR a R b ) n10 -C(O)-(CR a R b ) n10 -, -(CR a R b ) n10 -N(R a )-(CR a R b ) n10 -、-(CR a R b ) n10 -C≡C-(CR a R b ) n10 -、-(CR a R b ) n10 -C=C-(CR a R b ) n10 -Optionally selected from one or more of the following groups: halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Substituents of the alkyl acyl group; each R a and each R b Each is independently selected from H, halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkyl group; each n 10 Each is independently 0, 1, 2, 3, or 4; n 11 It can be 1, 2, 3, or 4; Degron has a structure with any one of the following terms: (IV-1), (IV-2), (IV-3), (IV-4); In equation (IV-1), A6 and A7 are each independently selected from -C(O)- and -NR. c -or-C(R) c )2-; In equation (IV-2), A8 and A9 are each independently selected from -C(O)- and -NR. c -or-C(R) c )2-, and A8 and A9 are not both -C(O)-; In formula (IV-3), A 10 A 11 A 12 A 13 A 14 It exists under any of the following conditions: (1) It is a double bond. It is a single key. It is a double bond, A 10 A 13 and A 14 All are -C-, A 11 -C(R) c )2- or -NR c -, A 12 For -CR c -or -N-; (2) It is a double bond. It is a single key. A is a single bond. 10 and A 14 All are -C-, A 13 For -CR c -or -N-, A 11 and A 12 Each independently is -C(R) c )2- or -NR c -; (3) It is a single key. It is a double bond. It is a double bond, A 10 For -C-, A 11 and A 12 Each independently as -CR c -or -N-, A 13 For -C-, A 14 For -CR c -or -N-; (4) It is a single key. It is a double bond. A is a single bond. 10 For -C-, A 11 For -CR c -or -N-, A 12 -C(R) c )2- or -NR c -, A 13 and A 14 Each independently as -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 2 nitrogen atoms; (5) It is a single key. It is a single key. It is a double bond, A 10 For -CR c -or -N-, A 11 -C(R) c )2- or -NR c -, A 12 For -CR c -or -N-; A 13 For -C-, A 14 For -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 2 nitrogen atoms; (6) It is a single key. It is a single key. A is a single bond. 10 For -CR c -or -N-, A 11 -C(R) c )2-、-NR c -or-C(O)-, A 12 -C(R) c )2-、-NR c -or-C(O)-, A 13 For -CR c -or -N-, A 14 For -CR c - or -N-, and A 10 A 11 A 12 A 13 and A 14 It contains at most 3 nitrogen atoms; In formula (IV-4), A 15 A 16 and A 17 Each is independently selected from -CH- or -N-, and A 15 A 16 and A 17 It contains at most 2 nitrogen atoms; A 18 L4 represents -N- or -CH-; L4 represents chemical bonds, -O-, or -NR. d -or-C(O)-NR d -; Each R c Each is independently selected from H, halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups; Each R d Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Halogenated alkyl groups; Each R4 group is independently selected from halogen, cyano, nitro, hydroxyl, amino, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 Haloalkyl; m4 is 0, 1, 2 or 3.

2. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... The compound has the structure of the following formula (I-1): 。 3. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, its acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... Each R 1b Each is independently selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -NH(CH3), -N(CH3)2, -N(CH2CH3)2, -N(CH2CH3)(CH3), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, cyclopropylmethylene, cyclopropylethylidene, cyclopropylpropylpropene; Preferably, each R2 is independently selected from F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -Se-, -Se-CH3, -Se-CH2CH3, -CH2-Se-CH2CH3, -CH2-Se-CH3, -CH2CH2-Se-CH2CH3, vinyl, propenyl, butenyl, ethynyl, 1-propynyl, 1-butynyl, 2-butynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, propoxymethylene, isopropoxymethylene, -C(CH3)2(OH), -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2.

4. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... The Degron has a structure of any of the following forms: 。 5. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... Each R4 is independently selected from F, Cl, Br, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, -OCH3, -OCH2CH3, -OCH(CH3)2, preferably independently selected from F, Cl, Br, methyl, -CCl3 or -CF3; Preferably, each R c Each of the following is independently selected from H, F, Cl, Br, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, preferably independently selected from H, F, Cl, Br, methyl, -CCl3 or -CF3; Preferably, each R d Each of the following is independently selected from H, methyl, ethyl, propyl, isopropyl, -CCl3, -CF3, -CHCl2, -CHF2, -CH2CCl3, -CH2CF3, -CH2CHCl2, -CH2CHF2, -CH2CH2CCl3, -CH2CH2CF3, -CH(CCl3)2, -CH(CF3)2, preferably each of the following is independently selected from H, methyl, -CCl3, -CF3, -CHCl2 or -CHF2.

6. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... Each R a and each R b Each is independently selected from H, F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, 1-propynyl, methoxy, ethoxy, propoxy, isopropoxy, methoxymethylene, ethoxymethylene, formyl, or acetyl. Preferably, each R a and each R b Each is independently selected from H, F, Cl, Br, cyano, nitro, hydroxyl, amino, methyl, ethyl, propyl, vinyl, propenyl, ethynyl, 1-propynyl, methoxy, ethoxy, formyl, or acetyl. Preferably, each n 10 Each can be independently 0, 1, 2, or 3; Preferably, each L1, each L2, and each L3 is independently selected from methylene, ethylene, propylene, -O-, -C≡C-, -C(O)-, -NH-, and -N(CH3)-. Preferably, n4 is 0.

7. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... L is selected from any of the following structures: ； ， 。 8. The compound, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of the stereoisomer, an acceptable salt of the deuterated derivative, its prodrug, its hydrate, or its solvate, as described in claim 1, is characterized in that... The compound includes the following: 。 9. A pharmaceutical composition comprising the compound according to any one of claims 1-8, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, a pharmaceutically acceptable salt of its stereoisomer, an acceptable salt of its deuterated derivative, its prodrug, its hydrate or solvate thereof; and at least one pharmaceutically acceptable excipient.

10. The use of a compound according to any one of claims 1-8, its stereoisomer, its deuterated derivative, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, an acceptable salt of its deuterated derivative, its prodrug, its hydrate or solvate thereof; or the use of the pharmaceutical composition according to claim 9 in the preparation of a medicament for treating or preventing diseases related to IRAK4; Preferably, the disease includes: Cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, hereditary diseases, hormone-related diseases, metabolic diseases, organ transplant-related diseases, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular diseases, or CNS diseases.

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