Indazole derivatives, their preparation methods and applications

Abstract

A class of indazole derivatives targeting the degradation of IRAK4 kinase protein, their preparation methods and applications are provided. Specifically, it relates to the compounds of formula I, their preparation methods, their pharmaceutical compositions and applications, wherein Ra, Rb, Rc, Rd, Re, n, ring A, ring B, L, ring C, X, W are as defined in the specification. The compounds can significantly degrade the IRAK4 kinase protein in cells and can be used to prepare drugs for treating and / or preventing related diseases or disorders mediated by IRAK4, such as cancer, immune diseases and inflammatory diseases.

Description

[0001] Technical Field: The present invention belongs to the field of pharmaceuticals. Specifically, the present invention relates to indazole derivatives targeting IRAK4 protein degradation, their preparation methods, and their use in the preparation of drugs for treating and / or preventing IRAK4-mediated related diseases or disorders, such as cancer, immune diseases, and inflammatory diseases.

[0002] Background Art: Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine / threonine-specific protein kinase with biologically important kinase activity and plays an important role in activating the immune system. Studies have shown that IRAK4 is a key factor downstream of the interleukin (IL)-1β family receptors (including IL-1R, IL-18R, IL-33R, IL-36R) and Toll-like receptor (TLR) signaling pathways. Mice lacking IRAK4 and patients lacking IRAK4 do not respond to TLR (except TLR3) and IL-1β family stimuli (Suzuki, Suzuki et al., Nature, 2002; Davidson, Currie et al., The Journal of Immunology, 2006; Ku, von Bernuth et al., JEM, 2007; Kim, Staschke et al., JEM, 2007).

[0003] According to the involvement of MyD88, the TLR / IL-1β-mediated signaling pathway can be divided into the MyD88-dependent signaling pathway and the MyD88-independent pathway. Among them, the signal transduction pathways mediated by IL-1R and TLR2, TLR4, TLR7 / 8, TLR9 all rely on MyD88 as a regulator to activate the downstream inflammatory signaling pathway. After TLR / IL-1β binds to the ligand, it recruits the MyD88 molecule. MyD88 further recruits IRAK4 to the TLR / IL-1β complex through its N-terminal death domain, interacts with IRAK1 or IRAK2 and activates them (Kollewe, Mackensen et al., Journal of Biological Chemistry, 2004; Precious et al., J. Biol. Chem., 2009), thereby transmitting signals downstream to the E3 ubiquitin ligase TNF receptor-associated factor (TRAF6), activating the serine / threonine kinase TAK1, and further activating the NF-κB and MAPK signaling pathways (Wang, Deng et al., Nature, 2001), leading to the release of various inflammatory cytokines and anti-apoptotic molecules. The IRAK4-dependent TLR / IL-1β signaling pathway has been shown to be associated with a variety of diseases: such as multiple sclerosis, atherosclerosis, myocardial infarction, myocarditis (Valaperti, Nishii et al., Circulation, 2013), Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus (SLE), obesity (Ahmad, R., P. Shihab et al., Diabetology & Metabolic Syndrome, 2015), type 1 diabetes, rheumatoid arthritis, spondyloarthritis (especially psoriatic spondyloarthritis and Bekhterev's disease), lupus erythematosus, psoriasis, vitiligo, giant cell arteritis, chronic inflammatory bowel disease and viral diseases, such as HIV (human immunodeficiency virus), hepatitis virus (Staschke et al., The Journal of Immunology, 2009; Marquez et al., Ann Rheum Dis, 2014; Zambrano-Zaragoza et al., International Journal of Inflammation, 2014; Wang et al., Experimental and Therapeutic Medicine, 2015; Ciccia et al., Rheumatology, 2015);Skin diseases such as psoriasis, atopic dermatitis, Kindler's syndrome, bullous pemphigoid, allergic contact dermatitis, alopecia areata, acne inversa, and acne vulgaris; other inflammatory diseases such as allergies, Behçet's disease, gout, adult-onset Still's disease, pericarditis, and chronic inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, transplant rejection, and graft-versus-host reaction; gynecological diseases such as adenomyosis, dysmenorrhea, dyspareunia, and endometriosis, particularly pain associated with endometriosis and other endometriosis-related symptoms such as dysmenorrhea, dyspareunia, dysuria, and defecation difficulties (Akoum, Lawson et al., Human Reproduction, 2007; Allhorn, Boing et al., Reproductive Biology and Endocrinology, 2008; Lawson, Bourcier et al., Journal of Reproductive Immunology, 2008; Sikora, Mielczarek-Palacz et al., American Journal of Reproductive Immunology, 2012; Khan, Kitajima et al., Journal of Obstetrics and Gynaecology Research, 2013; Santulli, Borghese et al., Human Reproduction, 2013); eye diseases such as retinal ischemia, keratitis, allergic conjunctivitis, keratoconjunctivitis sicca, macular degeneration, and uveitis (Kaarniranta and Salminen, J Mol Med (Berl), 2009; Sun and Pearlman, Investigative Ophthalmology & Visual Science, 2009; Redfern and McDermott, Experimental Eye Research, 2010; Kezic, Taylor et al., J Leukoc Biol, 2011; Chang, McCluskey et al., Clinical & Experimental Ophthalmology, 2012; Guo, Gao et al., Immunol Cell Biol, 2012;Lee, Hattori et al., Investigative Ophthalmology & Visual Science, 2012; Qi, Zhao et al., Investigative Ophthalmology & Visual Science, 2014); fibrotic diseases such as liver fibrosis, myocarditis, primary biliary cirrhosis, cystic fibrosis (Zhao, Zhao et al., Scand J Gastroenterol, 2011; Benias, Gopal et al., Clin Res Hepatol Gastroenterol, 2012; Yang, L. and E. Seki, Front Physiol, 2012; Liu, Hu et al., Biochim Biophys Acta., 2015); chronic liver diseases, such as steatohepatitis, particularly non-alcoholic fatty liver disease (NAFLD) and / or non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis (ASH) (Nozaki, Saibara et al., Alcohol Clin Exp Res, 2004; Csak, T., A. Velayudham et al., Am J Physiol Gastrointest Liver Physiol, 2011; Miura, Kodama et al., Gastroenterology, 2010; Kamari, Shaish et al., J Hepatol, 2011; Ye, Li et al., Gut, 2012; Roh, Seki, J Gastroenterol Hepatol, 2013; Ceccarelli, S., V. Nobili et al., World J Gastroenterol, 2014; Miura, Ohnishi, World J Gastroenterol, 2014; Stojsavljevic, Palcic et al., World J Gastroenterol, 2014); cardiovascular diseases and neurological disorders, such as myocardial reperfusion injury, myocardial infarction, hypertension (Oyama, Blais et al., Circulation, 2004; Timmers, Sluijter et al., Circulation Research, 2008; Fang and Hu, MedSci Monit, 2011; Bijani, International Reviews of Immunology, 2012; Bomfim, Dos Santos et al., Clin Sci (Lond), 2012;Christia and Frangogiannis, European Journal of Clinical Investigation, 2013; Thompson and Webb, Clin Sci (Lond), 2013; Hernanz, Martínez-Revelles et al., British Journal of Pharmacology, 2015; Frangogiannis, Curr Opin Cardiol, 2015; Bomfim, Echem et al., Life Sciences, 2015), as well as Alzheimer's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Brough, Tyrrell et al., Trends in Pharmacological Sciences, 2011; Carty and Bowie, Biochemical Pharmacology, 2011; Denes, Kitazawa, Cheng et al., The Journal of Immunology, 2011; Lim, Kou et al., The American Journal of Pathology, 2011; Béraud and Maguire-Zeiss, Parkinsonism & Related Disorders, 2012; Denes, Wilkinson et al., Disease Models & Mechanisms, 2013; Noelker, Morel et al., Sci. Rep., 2013; Wang, Wang et al., Stroke, 2013; Xiang, Chao et al., Rev Neurosci, 2015; Lee, Lee et al., J Neuroinflammation, 2015); itching and pain (including acute, chronic, inflammatory, and neuropathic pain) such as hyperalgesia, allodynia, premenstrual pain, pain associated with endometriosis, postoperative pain, interstitial cystitis, CRPS (complex regional pain syndrome), trigeminal neuralgia, prostatitis, pain caused by spinal cord injury, inflammation-induced pain, low back pain, cancer pain, chemotherapy-related pain, HIV treatment-induced neuropathy, pain caused by burns, and chronic pain (Wolf, Livshits et al., Brain, Behavior, and Immunity, 2008; Kim, Lee et al., Toll-like Receptors: Roles in Infection and Neuropathology, 2009;del Rey, Apkarian et al., Annals of the New York Academy of Sciences, 2012; Guerrero, Cunha et al., European Journal of Pharmacology, 2012; Kwok, Hutchinson et al., PLoS ONE, 2012; Nicotra, Loram et al., Experimental Neurology, 2012; Chopra and Cooper, J Neuroimmune Pharmacol, 2013; David, Ratnayake et al., Neurobiology of Disease, 2013; Han, Zhao et al., Neuroscience, 2013; Liu and Ji, Pflugers Arch., 2013; Stokes, Cheung et al., Journal of Neuroinflammation, 2013; Zhao, Zhang et al., Neuroscience, 2013; Liu, Zhang et al., Cell Research, 2014; Park, Stokes et al., Cancer Chemother Pharmacol, 2014; Van der Watt, Wilkinson et al., BMC Infect Dis, 2014; Won, K.A., M.J. Kim et al., J Pain, 2014; Min, Ahmad et al., Photochem Photobiol., 2015; Schrepf, Bradley et al., Brain Behav Immun, 2015; Wong, L., J.D. Done et al., Prostate, 2015); Tumor diseases such as certain lymphomas: ABC-DLBCL (activated B-cell diffuse large B-cell lymphoma), mantle cell lymphoma, and Waldenström disease, as well as chronic lymphocytic leukemia, melanoma, pancreatic tumors, and hepatocellular carcinoma (Ngo, Young et al., Nature, 2011; Puente, Pinyol et al., Nature, 2011; Ochi, Nguyen et al., J Exp Med, 2012; Srivastava, Geng et al., Cancer Research, 2012; Treon, Xu et al., New England Journal of Medicine, 2012; Choi, Kim et al., Human Pathology, 2013;Liang, Chen et al., Clinical Cancer Research, 2013), ras-dependent tumors, breast cancer, ovarian cancer, colorectal cancer, head and neck cancer, lung cancer, prostate cancer.;

[0004] The regulation of the IRAK4-mediated signaling pathway is mainly related to its kinase function. However, there are also some reports indicating that in certain cell types, the signal regulation of IRAK4 on downstream processes is related to the non-kinase function of IRAK4. Cushing et al. showed that although the phosphorylation level of IRAK4 decreased in IL-1β-stimulated human skin fibroblasts, the pharmacological inhibition of IRAK4 did not lead to the inhibition of IL-6 and TNF-α. Supporting these results, in fibroblasts lacking IRAK4, compared with wild-type cells, the scaffolding function of IRAK4 is important for IL1 signaling, but its kinase function is redundant. At the same time, Chiang and his colleagues also showed that IRAK4 kinase activity is not necessary in human B cells, T cells, dendritic cells and monocytes, and siRNA gene excision also showed that IRAK4 has a scaffolding function in these cells. A variety of potent selective inhibitors against IRAK4 have been reported, such as CA-4948, BAY-1834845, BMS-986126 and PF-06650833, etc. These inhibitors can selectively inhibit the kinase activity of IRAK4 and are mainly used for the prevention and treatment of autoimmune diseases, inflammatory diseases and neoplastic diseases. However, on the one hand, because IRAK4 has the roles of a scaffolding protein and an active kinase, and on the other hand, traditional small molecule inhibitors are prone to drug resistance, therefore, only inhibiting the kinase activity of IRAK4 may not be sufficient to produce a therapeutic effect.

[0005] 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 heterobifunctional molecule. One end of it is a small molecule inhibitor that can recognize the target protein, and through a linker, the other end is an E3 ubiquitin ligase ligand that can recognize the E3 ubiquitin ligase. This bifunctional molecule recognizes the target protein and the E3 ubiquitin ligase in vivo, pulls the target protein and the E3 ubiquitin ligase closer to form a ternary complex, ubiquitinates the target protein, and then degrades the target protein through the ubiquitin-proteasome pathway in vivo. Compared with traditional small molecule inhibitors, on the one hand, PROTAC only needs to pull the target protein and the E3 ubiquitin ligase closer to degrade the substrate, and this mode of action enables this technology to be applied to some undruggable targets; on the other hand, since the PROTAC molecule can be released after the target protein is degraded and continue to participate in the degradation process of the next protein, this catalytic degradation effect enables a small dose of PROTAC drugs to achieve efficient degradation; on the other hand, traditional small molecule inhibitors are prone to drug resistance often because of point mutations, which makes the small molecule inhibitor lose its inhibitory effect on the target, while PROTAC can directly degrade the target protein and can avoid 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 small molecule drugs has high advantages and feasibility and is expected to become the next generation of very promising new drugs. PROTAC technology has also been applied to the modification of drugs for various targets, such as androgen receptor, estrogen protein receptor, BTK, etc. Several types of compounds targeting IRAK4 degradation are disclosed in US2019 / 0151295, US2019 / 0192688, WO2019 / 160915 and WO2020 / 113233, and more compounds targeting IRAK4 degradation are urgently to be developed. Summary of the Invention

[0006] Due to its large molecular weight, PK has become one of the main obstacles to the drug development of PROTAC. Therefore, compounds with good PK properties are given priority in drug development. The present invention provides a class of compounds with good degradation properties and PK properties.

[0007] The present invention provides compounds of formula I, and / or their stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and / or their pharmaceutically acceptable salts

[0008]

[0009] Wherein:

[0010] R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;

[0011] Ring A is a 6-10 membered aryl or 5-10 membered heteroaryl;

[0012] R d Each R is independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 cycloalkyl), C3-C6 cycloalkyl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl and heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxyl, and amino;

[0013] n is 1, 2, 3 or 4;

[0014] R e is hydrogen or C1-C6 alkyl;

[0015] R c is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0016] R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0017] Ring B is a 6-10 membered aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl or 3-12 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0018] Ring C is a 6-10 membered aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl or 3-12 membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0019] X is a bond, -O-, -NH-, -N(C1-C6 alkyl)-, -S-, -C═C-, -C≡C-, -C(O)-, -OC(O)-, -C(O)O-, -NHC(O)- or -C(O)NH-;

[0020] W is -CR g R h or -C(O);

[0021] R g 、R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;

[0022] L is -(CH2) j -, and one or more methylenes in the -(CH2) j - are optionally substituted with substituents selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -, -NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -, -NR 3’ S(O)2-, -NR 4’ S(O)2NR 3’ -, -CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’ C(O)O-, -OC(O)NR 3’ -, -C(O)NR 3’ -, -NR 3’ C(O)-, -NR4’ C(O)NR 3’ - is replaced by a group of -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, vinylene or ethynylene;

[0023] R 1’ 、R 2’ are each independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), 3-6 membered heterocycloalkyl, -O(3-6 membered heterocycloalkyl), -NH(C3-C6 cycloalkyl);

[0024] R 3’ 、R 4’ are each independently hydrogen or C1-C6 alkyl;

[0025] j is 1, 2, 3, 4, 5 or 6;

[0026] provided that the compound of formula I does not include the following compounds

[0027]

[0028] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts are compounds of formula II

[0029]

[0030] wherein said R a 、R b 、R c 、R d 、R e 、n, ring A, ring B, L, ring C, X, W are as defined above.

[0031] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, X is a bond.

[0032] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring B is a 3- to 8-membered monocyclic cycloalkyl, 7- to 12-membered spirocyclic cycloalkyl, 7- to 12-membered fused cycloalkyl, 3- to 8-membered monocyclic heterocycloalkyl containing 1 to 2 N heteroatoms, 7- to 12-membered fused heterocycloalkyl containing 1 to 2 N heteroatoms or 7- to 12-membered spiroheterocycloalkyl containing 1 to 2 N heteroatoms.

[0033] More preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring B is cyclohexane, piperidinyl or piperazinyl.

[0034] More preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring B is piperidinyl.

[0035] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring B is

[0036] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring C is a 3- to 8-membered monocyclic cycloalkyl, 7- to 12-membered spirocyclic cycloalkyl, 7- to 12-membered fused cycloalkyl, 3- to 8-membered monocyclic heterocycloalkyl containing 1 to 2 N heteroatoms, 7- to 12-membered fused heterocycloalkyl containing 1 to 2 N heteroatoms or 7- to 12-membered spiroheterocycloalkyl containing 1 to 2 N heteroatoms.

[0037] More preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring C is cyclohexane, piperidinyl, piperazinyl,

[0038] More preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring C is

[0039] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R a is hydrogen.

[0040] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, W is C(O).

[0041] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, ring A is phenyl or pyridyl.

[0042] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R d are each independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted by one or more groups selected from halogen, hydroxy, and amino.

[0043] More preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R d are each independently hydrogen, halogen or C1-C6 alkyl optionally substituted by one or more groups selected from F or hydroxy.

[0044] More preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R d is hydrogen, F, methyl, difluoromethyl, trifluoromethyl or 2-hydroxypropyl.

[0045] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, n is 1 or 2.

[0046] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R e is hydrogen.

[0047] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R c is hydrogen, -O(C1-C6 alkyl), -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, -O(C3-C6 cycloalkyl), -N(C3-C6 cycloalkyl), -O(3-6 membered heterocycloalkyl), -N(3-6 membered heterocycloalkyl), and the alkyl, cycloalkyl, heterocycloalkyl are optionally substituted by one or more groups independently selected from hydroxy, amino, halogen, cyano.

[0048] More preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R c is C1-C6 alkyl optionally substituted by one or more groups independently selected from hydroxy or halogen, C3-C6 cycloalkyl containing one or two N heteroatoms or -O(C1-C6 alkyl) optionally substituted by one or more groups independently selected from hydroxy or halogen.

[0049] More preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R c is difluoromethyl, hydroxypyrrolidinyl, 2-hydroxypropyl, methoxy, ethoxy or isopropoxy.

[0050] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R b is hydrogen or C1-C6 alkyl, and the alkyl is optionally substituted by one or more groups independently selected from hydroxy, amino, halogen, cyano.

[0051] Preferably, in certain embodiments of the present invention, the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, R b is hydrogen or methyl.

[0052] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, L is -(CH2)j -, one or more of the methylene groups in said -(CH2) j - are optionally replaced by a group selected from -NR 3’ -, -O-, -CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR 3’ -, -NR 3’ C(O)-; said R 1’ , R 2’ are each independently halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or -O(C1-C4 alkyl); said R 3’ , R 4’ are each independently hydrogen or methyl; j is 1, 2 or 3.

[0053] Preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, L is -(CH2) j -, and j is 1, 2 or 3.

[0054] More preferably, in certain embodiments of the present invention, for the compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salts, L is

[0055] In another preferred example, R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxy;

[0056] Ring A is a 6-10 membered aryl or a 5-10 membered heteroaryl;

[0057] R d are each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 cycloalkyl), C3-C6 cycloalkyl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl and heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxy, amino;

[0058] n is 1, 2, 3 or 4;

[0059] R e is hydrogen or C1-C6 alkyl;

[0060] R cis hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heteroalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heteroalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0061] R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heteroalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heteroalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0062] Ring B is a 6-10 membered aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl or a 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, cycloalkyl and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0063] Ring C is a 6-10 membered aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl or a 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, cycloalkyl and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0064] X is a bond;

[0065] W is -CR g R h or -C(O);

[0066] R g 、R hEach independently is hydrogen, a halogen, a C1-C4 alkyl group, a C1-C4 chloroalkyl group, a C1-C4 hydroxyalkyl group or a C3-C6 cycloalkyl group;

[0067] L is -(CH2) j -;

[0068] j is 1, 2, 3, 4, 5 or 6.

[0069] In another preferred example, R a is hydrogen, a halogen, a C1-C6 alkyl group or -O-(C1-C6 alkyl group), and the alkyl group is optionally substituted by a halogen or a hydroxy group;

[0070] Ring A is a 6-10 membered aryl group or a 5-10 membered heteroaryl group;

[0071] R d Each independently is hydrogen, a halogen, a cyano group, a C1-C6 alkyl group, -O-(C1-C6 alkyl group), -O-(C3-C6 cycloalkyl group), a C3-C6 cycloalkyl group or a 5-10 membered heteroaryl group, and the alkyl group, cycloalkyl group and heteroaryl group are optionally substituted by one or more groups selected from a halogen, a hydroxy group and an amino group;

[0072] n is 1, 2, 3 or 4;

[0073] R e is hydrogen or a C1-C6 alkyl group;

[0074] R c is hydrogen, -O-(C1-C6 alkyl group), -O-(C3-C8 cycloalkyl group), -O-(3-8 membered heterocycloalkyl group), -O-aryl group, -O-heteroaryl group, -N(C1-C6 alkyl) 1-2 、-NH(C3-C8 cycloalkyl group), -NH(3-8 membered heterocycloalkyl group), -NH aryl group, -NH heteroaryl group, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C3-C8 cycloalkyl group, a 3-8 membered heterocycloalkyl group, a 6-10 membered aryl group or a 5-10 membered heteroaryl group, and the alkyl group, cycloalkyl group, heterocycloalkyl group, aryl group and heteroaryl group are optionally substituted by one or more groups independently selected from a hydroxy group, an amino group, a halogen and a cyano group;

[0075] R b is hydrogen, -O-(C1-C6 alkyl group), -O-(C3-C8 cycloalkyl group), -O-(3-8 membered heterocycloalkyl group), -O-aryl group, -O-heteroaryl group, -N(C1-C6 alkyl) 1-2, -NH(C3-C8 cycloalkyl), -NH(3-8 membered heteroalkyl), -NH aryl, -NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, amino, halogen or cyano;

[0076] Ring B is 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0077] Ring C is 6-10 membered aryl, 5-10 membered heteroaryl, C3-C12 cycloalkyl or 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0078] X is a bond;

[0079] W is -CR g R h or -C(O);

[0080] R g 、R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;

[0081] L is -(CH2) j -, and one or more methylenes in the -(CH2) j - are optionally substituted by groups selected from -NR 3’ -, -O-, -S-, -S(O)-, -S(O)NR 3’ -, -NR 3’ S(O)-, -S(O)2-, -S(O)2NR 3’ -, -NR 3’ S(O)2-, -NR 4’ S(O)2NR 3’ -, -CR 1’ R 2’ -, -C(O)-, -C(O)O-, -OC(O)-, -NR 3’C(O)O-, -OC(O)NR 3’ -, -C(O)NR 3’ -, -NR 3’ C(O)-, -NR 4’ C(O)NR 3’ -, -P(O)-, -P(O)O-, -OP(O)-, -OP(O)O-, a vinylene or ethynylene group substitution;

[0082] R 1’ , R 2’ each independently is halogen, -OH, -NH2, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 cycloalkyl, -O(C3-C6 cycloalkyl), -NH(C3-C6 cycloalkyl), 3-6 membered heterocycloalkyl, -O(3-6 membered heterocycloalkyl), -NH(C3-C6 cycloalkyl);

[0083] R 3’ , R 4’ each independently is hydrogen or C1-C6 alkyl;

[0084] j is 1, 2, 3, 4, 5 or 6.

[0085] In another preferred embodiment, R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxy;

[0086] Ring A is a 6-10 membered aryl or 5-10 membered heteroaryl;

[0087] R d each independently is hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 cycloalkyl), C3-C6 cycloalkyl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl and heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxy, amino;

[0088] n is 1, 2, 3 or 4;

[0089] R e is hydrogen or C1-C6 alkyl;

[0090] R c is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2, -NH(C3-C8 cycloalkyl), -NH(3-8 membered heteroalkyl), -NH aryl, -NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, amino, halogen or cyano;

[0091] R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heteroalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heteroalkyl), -NH aryl, -NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heteroalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the alkyl, cycloalkyl, heteroalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxy, amino, halogen or cyano;

[0092] Ring B is 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0093] Ring C is 6-10 membered aryl, 5-10 membered heteroaryl, or 3-12 membered heteroalkyl containing 1-2 heteroatoms selected from N, O or S, and the aryl, heteroaryl, and heteroalkyl are optionally substituted by substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0094] X is a bond;

[0095] W is -CR g R h or -C(O);

[0096] R g 、R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;

[0097] L is -(CH2) j -;

[0098] j is 1, 2, 3, 4, 5 or 6.

[0099] In another preferred example, R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;

[0100] Ring A is a 6-10 membered aryl or 5-10 membered heteroaryl;

[0101] R d are each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 cycloalkyl), C3-C6 cycloalkyl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl and heteroaryl are optionally substituted by one or more groups selected from halogen, hydroxyl, amino;

[0102] n is 1, 2, 3 or 4;

[0103] R e is hydrogen or C1-C6 alkyl;

[0104] R c is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0105] R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, -O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NH-aryl, -NH-heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, and the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen or cyano;

[0106] Ring B is a 3- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, and the heterocycloalkyl is optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0107] Ring C is a 3- to 12-membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O or S, and the heterocycloalkyl is optionally substituted with substituents selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);

[0108] X is a bond;

[0109] W is -CR g R h or -C(O);

[0110] R g 、R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;

[0111] L is -(CH2) j -;

[0112] j is 1, 2, 3, 4, 5 or 6.

[0113] More preferably, in some embodiments of the present invention, the compound of formula I is selected from

[0114]

[0115]

[0116]

[0117] The present invention provides a method for preparing a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts.

[0118] The present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, diluent or excipient.

[0119] The present invention provides a method for degrading IRAK4 protein, which comprises contacting a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof with IRAK4 protein.

[0120] The compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof according to the present invention is used as a medicine for treating or preventing IRAK4-mediated diseases or disorders.

[0121] The compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof according to the present invention is used as a medicine for treating or preventing diseases or disorders mediated by TLR (except TLR3R) or IL-1β receptor family (including IL-1R, IL-18R, IL-33R, IL-36R).

[0122] The compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof according to the present invention is used as a medicine for treating or preventing IRAK4-mediated diseases or disorders, wherein the IRAK4-mediated diseases or disorders are MyD88-driven diseases or disorders.

[0123] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating or preventing IRAK4-mediated diseases or disorders.

[0124] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a medicine for treating or preventing diseases or disorders mediated by TLR (except TLR3R) or IL-1β receptor family (including IL-1R, IL-18R, IL-33R, IL-36R).

[0125] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing a disease or disorder regulated by IRAK4, wherein the IRAK4-mediated disease or disorder is a MyD88-driven disease or disorder.

[0126] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory 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, thrombin-induced platelet aggregation, liver diseases, pathological immunological conditions involving T cell activation, cardiovascular disorders or CNS disorders.

[0127] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating or preventing cancer or a proliferative disease, wherein the cancer or proliferative disease is brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric 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 multiforme, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck or head tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular carcinoma, undifferentiated tumor, papilloma, seminoma, melanoma, ABC DLBCL, 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 effusion lymphoma, Burkitt 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.

[0128] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing neurodegenerative diseases, said neurodegenerative diseases being Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, neurodegenerative diseases caused by organ transplantation or graft-versus-host disease.

[0129] The present invention provides the use of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating or preventing inflammatory diseases, said inflammatory diseases being ophthalmic diseases such as ocular allergy, conjunctivitis, dry eye or vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis; autoimmune blood disorders such as hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periapical osteitis, hyaline membrane disease of the lung, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Grave's disease, sarcoidosis, dry eye, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, vasculitis, interstitial cystitis, diverticulitis, glomerulonephritis, chronic granulomatous disease, endometriosis, leptospiral nephropathy, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolism, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma, acute lung injury, acute respiratory distress syndrome, eosinophilia, allergic reaction, anaphylaxis, sinusitis, ocular allergy, silica-induced diseases, COPD, lung diseases, cystic fibrosis, liver fibrosis, renal fibrosis, alcoholic fatty liver, non-alcoholic fatty liver, cardiac fibrosis, psoriasis, Crohn's disease, inflammatory bowel disease, acid-induced lung injury, pulmonary arterial hypertension, polyneuropathy, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, 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, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, focal pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome or osteoarthritis.

[0130] The present invention provides a method for treating or preventing an IRAK4-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof.

[0131] The present invention provides a method for treating or preventing an IRAK4-mediated disease or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof, wherein the IRAK4-mediated disease or disorder is a MyD88-driven disease or disorder.

[0132] The present invention provides a method for treating or preventing a disease or disorder mediated by TLR (except TLR3R) or the IL-1 receptor family (including IL-1R, IL-18R, IL-33R, IL-36R), comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts, or a pharmaceutical composition thereof.

[0133] The present invention provides a method for preparing a compound of formula I, and / or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts:

[0134] Method 1:

[0135]

[0136] Intermediate Int-a and intermediate Int-b undergo a substitution reaction under basic conditions to obtain the compound of formula I. The base is an inorganic base or an organic base, including but not limited to triethylamine, N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate. X1 is a halogen; preferably F. The R a 、R b 、R c 、R d 、R e 、n, ring A, ring B, L, ring C, X, W are as defined above.

[0137] Method 2:

[0138]

[0139] Intermediate Int-c and intermediate Int-d undergo reductive amination to obtain the compound of formula I. The reducing reagents for the reductive amination include but not limited to Pd / C, sodium borohydride, sodium cyanoborohydride, borane, sodium triacetoxyborohydride. Wherein L1 is -(CH2) j-1 ,the methylene group in the -(CH2) j -1 is as defined in L above and is optionally substituted by one or more groups. The R a 、R b 、R c 、R d 、R e 、n, ring A, ring B, ring C, X, W are as defined above.

[0140] Method 3:

[0141]

[0142] Intermediate Int-e and intermediate Int-f undergo reductive amination to obtain the compound of formula I. The reducing reagents for the reductive amination include but not limited to Pd / C, sodium borohydride, sodium cyanoborohydride, borane, sodium triacetoxyborohydride. Wherein L1 is -(CH2) j-1 ,the methylene group in the -(CH2) j-1 is as defined in L above and is optionally substituted by one or more groups. The R a 、R b 、R c 、R d 、R e 、n, ring A, ring B, ring C, X, W are as defined above.

[0143] Detailed description: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

[0144] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain or branched-chain alkyl groups; C1-C8 refers to an alkyl group containing 1 to 8 carbon atoms, such as 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, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or their various branched isomers; preferably C1-C6 alkyl; more preferably C1-C4 alkyl. The alkyl group may be substituted or unsubstituted.

[0145] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-11 cycloalkyl" refers to a cycloalkyl group containing 3 to 11 carbon atoms; "C3-C8 cycloalkyl" refers to a cycloalkyl group containing 3 to 8 carbon atoms; "C5-C10 cycloalkyl" refers to a cycloalkyl group containing 5 to 10 carbon atoms;

[0146] Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8 cycloalkyl; more preferably C3-C6 cycloalkyl.

[0147] Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between monocyclic rings. They may contain one or more double bonds, but no ring has a completely conjugated π electron system. Spirocycloalkyl groups are classified into monospirocycloalkyl, dispirocycloalkyl or polyspirocycloalkyl groups according to the number of spiro atoms shared between rings, preferably 7-12 membered dispirocycloalkyl groups. Non-limiting examples of spirocycloalkyl groups include:

[0148]

[0149] "Fused cycloalkyl" refers to a fully carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, where one or more rings may contain one or more double bonds, but no ring has a fully conjugated π - electron system. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl according to the number of constituent rings, and bicyclic fused cycloalkyl is preferred. Non - limiting examples of fused cycloalkyl include:

[0150]

[0151] "Bridged cycloalkyl" refers to a fully carbon polycyclic group in which any two rings share two non - directly - connected carbon atoms. They may contain one or more double bonds, but no ring has a fully conjugated π - electron system. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl according to the number of constituent rings. Non - limiting examples of bridged cycloalkyl include:

[0152]

[0153] The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, where the ring connected to the parent structure is cycloalkyl. Non - limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl can be optionally substituted or unsubstituted.

[0154] "Heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, where one or more ring atoms are selected from nitrogen, oxygen or S(O)r (where r is an integer 0, 1 or 2), but does not include the ring moiety of - O - O -, - O - S - or - S - S -, and the remaining ring atoms are carbon. "3 - 11 - membered heterocycloalkyl" refers to a ring group containing 3 to 11 ring atoms, "5 - 10 - membered heterocycloalkyl" refers to a ring group containing 5 to 10 ring atoms, "3 - 8 - membered heterocycloalkyl" refers to a ring group containing 3 to 8 ring atoms. Preferably, a "3 - 11 - membered heterocycloalkyl" containing 1 - 2 heteroatoms selected from N, O or S is preferred, and more preferably a 3 - 11 - membered heterocycloalkyl containing 1 or 2 N atoms.

[0155] Monocyclic heterocycloalkyl is preferably a 3 - 8 - membered monocyclic heterocyclic group containing 1 - 2 N heteroatoms; non - limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., and piperidinyl and piperazinyl are preferred.

[0156] Polycyclic heterocycloalkyl includes spiro, fused, and bridged heterocycloalkyl. "Spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which a single atom (called a spiro atom) is shared between monocyclic rings, where one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, 2), and the remaining ring atoms are carbon. They may contain one or more double bonds, but no ring has a fully conjugated π - electron system. Spirocycloalkyl is classified into monospiroheterocycloalkyl, dispiroheterocycloalkyl, or polyspiroheterocycloalkyl according to the number of spiro atoms shared between rings. Preferably, it is a saturated "3 - 11 - membered dispiroheterocycloalkyl" containing 1 - 2 heteroatoms selected from N, O, or S; more preferably, a saturated "7 - 12 - membered dispiroheterocycloalkyl" containing 1 or 2 N atoms. Non - limiting examples of spiroheterocycloalkyl include:

[0157]

[0158] "Fused heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but no ring has a fully conjugated π - electron system, where one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, 2), and the remaining ring atoms are carbon. It can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocycloalkyl according to the number of constituent rings. Preferably, it is a "3 - 11 - membered bicyclic fused heterocycloalkyl" containing 1 - 3 heteroatoms selected from N, O, or S; more preferably, a saturated "3 - 11 - membered bicyclic fused heterocycloalkyl" containing 1 or 2 N atoms. Non - limiting examples of fused heterocycloalkyl include:

[0159]

[0160] "Bridged heterocycloalkyl" refers to a polycyclic heterocycloalkyl group in which any two rings share two non - directly - connected atoms. They may contain one or more double bonds, but no ring has a fully conjugated π - electron system, where one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is an integer 0, 1, 2), and the remaining ring atoms are carbon. It can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl according to the number of constituent rings. Non - limiting examples of bridged heterocycloalkyl include:

[0161]

[0162] The heterocycloalkyl ring can be fused to an aryl, heteroaryl, or cycloalkyl ring, where the ring connected to the parent structure is heterocycloalkyl. Non - limiting examples include:

[0163] The heterocycloalkyl can be optionally substituted or unsubstituted.

[0164] "Aryl" refers to a polycyclic group that is a fully carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) and has a conjugated π electron system. "6-10 membered aryl" refers to a fully carbon aryl containing 6-10 carbons, such as phenyl and naphthyl; preferably phenyl. The aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is the aryl ring. Non-limiting examples include:

[0165] The aryl can be optionally substituted or unsubstituted.

[0166] "Heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, said heteroatoms including nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2), 5-6 membered heteroaryl refers to a heteroaromatic system containing 5-6 ring atoms, 5-10 membered heteroaryl refers to a heteroaromatic system containing 5-10 ring atoms, preferably 5-6 membered heteroaryl; more preferably 5-6 membered heteroaryl containing 1 or 2 N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazolyl, triazolyl, tetrazolyl, etc.; preferably pyridyl. The heteroaryl ring can be fused to an aryl, heterocycloalkyl or cycloalkyl ring, where the ring connected to the parent structure is the heteroaryl ring. Non-limiting examples include:

[0167] The heteroaryl can be optionally substituted or unsubstituted.

[0168] "Alkenyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. "C2-8 alkenyl" refers to a straight-chain or branched-chain alkenyl containing 2-8 carbons, including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc., preferably "C2-6 alkenyl", more preferably "C2-4 alkenyl". The alkenyl can be substituted or unsubstituted.

[0169] "Alkynyl" refers to an alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond. "C2-8 alkynyl" refers to a straight-chain or branched-chain alkynyl containing 2-8 carbons, including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, preferably "C2-6 alkynyl", more preferably "C2-4 alkynyl". The alkynyl can be substituted or unsubstituted.

[0170] "Subunit" refers to a divalent group, such as alkylene refers to a divalent alkyl group, alkenylene refers to a divalent alkenyl group, alkynylene refers to a divalent alkynyl group, cycloalkylene refers to a divalent cycloalkyl group, heteroalkylene refers to a divalent heteroalkyl group, arylene refers to a divalent aryl group, heteroarylene refers to a divalent heteroaryl group, and the alkyl, alkenyl, alkynyl, cycloalkyl, heteroalkyl, aryl, and heteroaryl groups are as defined above. The subunit may be optionally substituted or unsubstituted.

[0171] "Halogenated alkyl" refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine, or iodine atoms, where the alkyl group is as defined above. Non-limiting examples include difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.

[0172] "Hydroxyalkyl" refers to an alkyl group optionally substituted with one or more -OH groups, where the alkyl group is as defined above. Non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxyisopropyl.

[0173] "Cyano" refers to -CN.

[0174] "Amino" refers to -NH2.

[0175] "Hydroxy" refers to -OH.

[0176] "Carboxyl" or "carboxylic acid" refers to -COOH.

[0177] "Oxo" refers to the =O group.

[0178] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0179] "NMP" refers to N-methylpyrrolidone.

[0180] "IBX" refers to 2-iodoxybenzoic acid.

[0181] "DIEA" refers to N,N-diisopropylethylamine.

[0182] "STAB" refers to sodium triacetoxyborohydride.

[0183] "T3P" refers to 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphoric acid 2,4,6-trioxide.

[0184] "DPBS" refers to Dulbecco's phosphate buffered saline.

[0185] "Dess-Martin" refers to Dess-Martin periodinane.

[0186] "PBS" refers to phosphate buffered saline.

[0187] "SDS-PAGE" refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.

[0188] "PVDF" refers to polyvinylidene fluoride.

[0189] "Plural" means 2, 3, 4, 5, 6, etc., preferably fully substituted. For example, in the case of a methyl group, when plural halogens (such as F) are substituted, it may refer to trifluoromethyl F3C.

[0190] "Optionally" means that the subsequently described event or circumstance may but need not occur, and this description includes the cases where the event or circumstance occurs or does not occur. For example, "optionally alkyl-substituted heterocyclic alkyl group" means that the alkyl group may but need not be present, and this description includes the case where the heterocyclic alkyl group is substituted by an alkyl group and the case where the heterocyclic alkyl group is not substituted by an alkyl group.

[0191] "Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) what substitutions are possible or impossible without much effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0192] "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 the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient and thus exert its biological activity.

[0193] The present invention also provides pharmaceutically acceptable salts of the compounds of formula (I). The term "pharmaceutically acceptable salts" refers to acid addition salts or base addition salts of the compounds of the present invention that are relatively non-toxic. The acid addition salts are salts formed by the compounds of formula (I) of the present invention with suitable inorganic acids or organic acids, and these salts can be prepared during the final separation and purification process of the compounds, or can be prepared by reacting the purified compounds of formula (I) in their free base form with suitable organic acids or inorganic acids. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearate, lauryl silicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluene sulfonate, citrate, maleate, fumarate, succinate, tartrate, benzoate, mesylate, p-toluenesulfonate, gluconate, lactobionate, and lauryl sulfonate, etc. The base addition salts are salts formed by the compounds of formula (I) with suitable inorganic bases or organic bases, including salts formed with alkali metals, alkaline earth metals, quaternary ammonium cations, such as sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, tetramethylammonium salt, tetraethylammonium salt, etc.; amine salts include salts formed with ammonia (NH3), primary amines, secondary amines or tertiary amines, such as methylamine salt, dimethylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.

[0194] The compounds of the present invention or their pharmaceutically acceptable salts can be administered to mammals including humans, and can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (powder, ointment or drops), or intratumorally.

[0195] The dosage of the compounds of the present invention can be approximately 0.05 - 300 mg / kg body weight / day, preferably 10 - 300 mg / kg body weight / day, more preferably 10 - 200 mg / kg body weight / day.

[0196] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, etc. In these solid dosage forms, the compound of formula (I) of the present invention is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dibasic calcium phosphate, or mixed with the following components: (1) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol, silicic acid, etc.; (2) binders, such as hydroxypropylmethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, etc.; (3) humectants, such as glycerol, etc.; (4) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, etc.; (5) dissolution retardants, such as paraffin wax, etc.; (6) absorption accelerators, such as quaternary ammonium compounds, etc.; (7) wetting agents, such as cetyl alcohol, glycerol monostearate, etc.; (8) adsorbents, such as kaolin, etc.; and (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., or mixtures thereof. Buffering agents may also be included in capsules, tablets and pills.

[0197] Solid dosage forms such as tablets, dragees, capsules, pills and granules can be coated or microencapsulated with coating and shell materials such as enteric coatings and other materials well known in the art. They may contain opacifying agents, and the release of the active ingredient in such compositions can be delayed in a manner to release in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax substances. If necessary, the active ingredient can also be in the form of microcapsules with one or more of the above excipients.

[0198] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into liquid dosage forms for oral administration, including but not limited to pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, etc. In addition to the compound of formula (I) or its pharmaceutically acceptable salt as the active ingredient, the liquid dosage forms may contain inert diluents conventionally used in the art, such as water and other solvents, solubilizing agents and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc., or mixtures of these substances. In addition to these inert diluents, the liquid dosage forms of the present invention may also contain conventional adjuvants, such as wetting agents, emulsifying agents and suspending agents, sweetening agents, flavoring agents and fragrances, etc.

[0199] The suspending agents include, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan monolaurate, microcrystalline cellulose, aluminum monostearate, agar, etc., or mixtures of these substances.

[0200] The compounds of the present invention or their pharmaceutically acceptable salts can be formulated into dosage forms for parenteral injection, including but not limited to physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0201] The compounds of the present invention or their pharmaceutically acceptable salts can also be formulated into dosage forms for topical administration, including, for example, ointments, powders, suppositories, drops, sprays and inhalants, etc. The compound of formula (I) of the present invention or its pharmaceutically acceptable salt as the active ingredient is mixed together with a physiologically acceptable carrier and optionally a preservative, a buffer, or a propellant that may be required when necessary, under sterile conditions.

[0202] The present invention also provides a pharmaceutical composition which contains the compound of formula (I) of the present invention or its pharmaceutically acceptable salt as the active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent. When preparing the pharmaceutical composition, the compound of formula (I) of the present invention or its pharmaceutically acceptable salt is usually mixed with a pharmaceutically acceptable carrier, excipient or diluent.

[0203] The composition of the present invention can be formulated into conventional pharmaceutical preparations according to conventional preparation methods. For example, tablets, pills, capsules, powders, granules, emulsions, suspensions, dispersions, solutions, syrups, elixirs, ointments, drops, suppositories, inhalants, sprays, etc.

[0204] The compounds or their pharmaceutically acceptable salts of the present invention can be administered alone, or (if necessary) in combination with other pharmaceutically acceptable therapeutic agents, such as in combination with other anti-tumor drugs, anti-inflammatory drugs or autoimmune drugs. The components to be combined can be administered simultaneously or sequentially, in the form of a single preparation or in the form of different preparations. The combination can include not only the combination of the compound of the present invention and one other active agent, but also the combination of the compound of the present invention and two or more other active agents.

[0205] The present invention proves through IRAK4 kinase activity test experiments that the compound of formula I described in the present invention can effectively bind to the IRAK4 target protein or produce an inhibitory effect; it proves through Western-Blot that the compound of formula I described in the present invention can effectively and specifically degrade the IRAK4 protein in THP-1 cells; it proves through the study of the pharmacokinetic properties of mice that the compound of the present invention has low clearance rate, high plasma exposure, good oral bioavailability, and good pharmacokinetic properties; it proves through the degradation experiments of IKZF1 and IKZF3 in L363 cells that the compound of the present invention has good selectivity. The compound of formula I described in the present invention, and / or its stereoisomers, enantiomers, diastereoisomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and / or its pharmaceutically acceptable salts can effectively degrade the IRAK4 protein, thereby achieving the effect of preventing or treating diseases or disorders related to IRAK4. Specific Examples

[0206] The present invention will be further described in detail and completely below in conjunction with the examples, but it is by no means a limitation of the present invention, and the present invention is not only limited to the content of the examples. The starting materials in the examples of the present invention are known and can be purchased on the market, or can be synthesized by using or according to the methods known in the art. Without special instructions, the experimental methods without specific conditions in the examples of the present invention usually follow conventional conditions, or the conditions recommended by the raw material or commodity manufacturers.

[0207] Preparation Examples of Compound I

[0208] Intermediate 1: 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione

[0209]

[0210] To a solution of 4-fluorophthalic acid (5.52 g, 0.03 mol) in acetic acid (50 mL) was added 3-aminopiperidine-2,6-dione hydrochloride (5.0 g, 0.03 mol) and potassium acetate (8.8 g, 0.09). The reaction mixture was stirred at 120 °C overnight, the reaction mixture was concentrated under reduced pressure, the concentrate was diluted with water (100 mL), stirred at room temperature for 30 minutes, filtered, and the solid was washed with water (50 mL × 2). Dried under reduced pressure to obtain the product (6.0 g).

[0211] LC-MS: (ESI, m / z): [M-H] + = 277.1

[0212] 11H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 8.01 (dd, J = 8.2, 4.5 Hz, 1H), 7.85 (dd, J = 7.4, 2.1 Hz, 1H), 7.79 - 7.66 (m, 1H), 5.17 (dd, J = 12.8, 5.4 Hz, 1H), 2.90 (ddd, J = 17.0, 13.8, 5.4 Hz, 1H), 2.58 (dd, J = 24.5, 11.8 Hz, 2H), 2.20 - 2.01 (m, 1H).

[0213] Intermediate 2: N-(6-Methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0214] Step 1: Preparation of 2-Fluoro-4-methoxy-5-nitrobenzaldehyde

[0215]

[0216] Cesium carbonate (3.5 g, 10.8 mmol) and potassium iodide (1.85 g, 13.0 mmol) were added to a solution of 2-fluoro-4-hydroxy-5-nitrobenzaldehyde (2 g, 10.8 mmol) in N,N-dimethylformamide (20 ml). The reaction mixture was stirred at room temperature for 10 hours, water (30 ml) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the concentrate was purified by column chromatography to obtain 1.6 g of the target product 2-fluoro-4-methoxy-5-nitrobenzaldehyde.

[0217] LC-MS: (ES, m / z): [M + H] + = 200.1

[0218] Step 2: Preparation of 2-Azido-4-methoxy-5-nitrobenzaldehyde

[0219]

[0220] Sodium azide (1.06 g, 16.1 mmol) was added to a solution of 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1.6 g, 8.04 mmol) in dimethyl sulfoxide (20 ml). The reaction mixture was stirred at room temperature for 2 hours, then poured into ice water, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 1.7 g of a crude product, which was used directly in the next step without purification.

[0221] Step 3: Preparation of tert-Butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate

[0222]

[0223] A toluene (20 ml) solution of 2-azido-4-methoxy-5-nitrobenzaldehyde (1.7 g, 7.65 mmol) and tert-butyl 4-aminopiperidine-1-carboxylate (1.53 g, 7.65 mmol) was stirred at 100 °C for 2 h, cooled to room temperature, the reaction solution was concentrated, 50 ml of water was added, extracted with ethyl acetate, the organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, the organic phase was concentrated, and the concentrate was purified by column to obtain 1.72 g of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate.

[0224] LC-MS: (ES, m / z): [M+H] + = 377.2

[0225] Step 4: Preparation of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate

[0226]

[0227] Iron powder (2.85 g, 50.9 mmol) and ammonium chloride (0.13 g, 2.3 mmol) were added to an ethanol (20 ml) solution of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate (1.7 g, 4.5 mmol), and the reaction solution was reacted at 90 °C for 2 h. After the reaction solution was cooled to room temperature, it was filtered and concentrated to obtain 2.01 g of the target crude product, which was directly used in the next step of the reaction.

[0228] LC-MS: (ES, m / z): [M+H] + = 347.3

[0229] Step 5: Preparation of tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridin-2-carboxamido)-2H-indazol-2-yl)piperidine-1-carboxylate

[0230]

[0231] To a solution of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate (1.7 g, 4.9 mmol) in tetrahydrofuran, 6-(trifluoromethyl)picolonic acid (940 mg, 4.9 mmol) and N,N-diisopropylethylamine (1.9 g, 14.7 mmol) were added. Subsequently, T3P (1.5 g) was added, and the reaction mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, water was added, and the mixture was extracted three times with ethyl acetate. The organic phases were collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The concentrate was purified by column chromatography to obtain 1.78 g of the target product tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridin-2-ylamide)-2H-indazol-2-yl)piperidine-1-carboxylate.

[0232] LC-MS: (ES, m / z): [M+H] + = 520.2

[0233] Step 6: Preparation of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0234]

[0235] To a solution of tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridin-2-ylamide)-2H-indazol-2-yl)piperidine-1-carboxylate (435 mg, 0.795 mmol) in dichloromethane, trifluoroacetic acid (1 ml) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed by concentration under reduced pressure to obtain the crude product (500 mg). The crude product was directly used in the next step.

[0236] LC-MS: (ES, m / z): [M+H] + = 420.2

[0237] Step 7: Preparation of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)picolylamino)-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate

[0238]

[0239] To a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (1.0 g, 2.386 mmol) and tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (0.813 g, 3.581 mmol) in tetrahydrofuran (20 mL) was added STAB (1.518 g, 7.160 mmol). The reaction mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate (50 mL) and washed with water (2 × 50 mL) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to give 700 mg of the target yellow solid product.

[0240] LC-MS: (ESI, m / z): [M+H] + = 631.3

[0241] Step 8: Preparation of N-(6-methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0242]

[0243] A mixture of tert-butyl 4-(2-(4-(6-methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidin-1-yl)ethyl)piperidine-1-carboxylate (700 mg, 1.11 mmol) in hydrochloric acid / ethyl acetate (1 M, 20 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to give 650 mg of the target crude product as a yellow oil. The crude product was directly used in the next step.

[0244] LC-MS: (ESI, m / z): [M+H] + = 531.3

[0245] Intermediate 3: N-(6-methoxy-2-(1-(piperidin-4-ylmethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0246]

[0247] Intermediate 3 was synthesized by referring to the method of Intermediate 2.

[0248] LC-MS: (ESI, m / z): [M+H] + = 517.2.

[0249] Intermediate 4: N-(6-Methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0250] Step 1: Preparation of N-(2-(1-(2,2-Dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0251]

[0252] To a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide (750 mg, 1.79 mmol) and 2-bromo-1,1-dimethoxyethane (46 mg, 0.3 mmol) in acetonitrile (20 mL) was added potassium carbonate (1.235 g, 8.95 mmol) and potassium iodide (149 mg, 0.89 mmol). The reaction mixture was stirred at 80 °C overnight. The solvent was removed by concentration under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 500 mg of the target product as an oil.

[0253] LC-MS: (ESI, m / z): [M+H] + = 508.1

[0254] Step 2: Preparation of N-(6-Methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0255]

[0256] A mixture of N-(2-(1-(2,2-Dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide (500 mg, 0.99 mmol) in hydrochloric acid (4 mL) / dioxane (5 mL) was stirred at 50 °C overnight. The solvent was removed by concentration under reduced pressure, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by column chromatography to give 300 mg of the target product as an oil.

[0257] LC-MS: (ESI, m / z): [M+H] + = 462.1

[0258] Intermediate 5: N-(6-(2-Hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0259] Step 1: Preparation of methyl 5-nitro-1H-indazole-6-carboxylate

[0260]

[0261] At -10 °C, concentrated nitric acid (15 mL) was slowly added to a solution of methyl 1H-indazole-6-carboxylate (9.2 g, 0.052 mol) in concentrated sulfuric acid (20 mL). The reaction mixture was stirred at -10 °C for 2 h. The reaction mixture was poured into ice water, and the solid was filtered to obtain 10.8 g of the target crude product as a white solid. The crude product was directly used in the next step.

[0262] LC-MS: (ES, m / z): [M+H] + = 222.1

[0263] Step 2: Preparation of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate

[0264]

[0265] Potassium carbonate (11.1 g, 81.3 mmol) was added to a solution of methyl 5-nitro-1H-indazole-6-carboxylate (6 g, 27.12 mmol) and tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate (15.3 g, 43.5 mmol) in N,N-dimethylformamide (100 mL). The reaction mixture was stirred at 100 °C for 10 h. The reaction mixture was cooled to room temperature, water (50 ml) and ethyl acetate (100 ml) were added, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate (100 ml × 2). The organic layers were combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 2.01 g of the target product as a yellow solid.

[0266] LC-MS: (ES, m / z): [M+H] + = 405.2

[0267] Step 3: Preparation of methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate

[0268]

[0269] To a solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate (1.7 g, 4.5 mmol) in ethanol (20 ml) were added iron powder (2.85 g, 50.9 mmol) and ammonium chloride (0.13 g, 2.3 mmol). The reaction mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 2.01 g of the crude product as an oil. The crude product was directly used in the next step.

[0270] LC-MS: (ES, m / z): [M+H] + = 375.3

[0271] Step 4: Methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxylate

[0272]

[0273] To a mixture of methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate (170 mg, 0.45 mmol), 6-(trifluoromethyl)pyridine-2-carboxylic acid (86.8 mg, 0.45 mmol) and DIEA (88 mg, 0.68 mmol) in THF was added T3P (650 mg). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure. Water (20 mL) and ethyl acetate (20 mL) were added. The aqueous layer was separated and extracted with ethyl acetate (20 ml × 2). The organic layers were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 150 mg of the target product as a yellow solid.

[0274] LC-MS: (ES, m / z): [M+H] + = 548.3

[0275] Step 5: Preparation of tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidine-1-carboxylate

[0276]

[0277] To a solution of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazole-6-carboxylate (500 mg, 0.91 mmol) in tetrahydrofuran was added lithium chloride (192 mg, 4.57 mmol). The reaction solution was cooled to 0 °C, and then methylmagnesium bromide in tetrahydrofuran (3.04 ml, 1 M) was added. The reaction solution was stirred at room temperature for 12 h, quenched with aqueous ammonium chloride solution, and water (30 mL) and ethyl acetate (50 mL) were added. The aqueous layer was separated, and the organic layer was extracted with ethyl acetate (50 ml × 2). The combined organic layers were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 435 mg of the target white solid product.

[0278] LC-MS: (ES, m / z): [M+H] + = 548.3

[0279] Step 6: Preparation of N-(6-(2-Hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)pyridinecarboxamide

[0280]

[0281] A mixture of tert-butyl 4-(6-(2-hydroxypropan-2-yl)-5-(6-(trifluoromethyl)pyridinecarboxamido)-2H-indazol-2-yl)piperidine-1-carboxylate (435 mg, 0.79) in dichloromethane (3 mL) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h, and the solvent was removed by concentration under reduced pressure to obtain 500 mg of the target crude product as a yellow oil. The crude product was directly used in the next step.

[0282] LC-MS: (ES, m / z): [M+H] + = 448.2

[0283] Intermediate 6: 2-(4-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[0284] Step 1: Preparation of tert-butyl 4-(2,2-dimethoxyethyl)piperazine-1-carboxylate

[0285]

[0286] To a mixture of tert-butyl piperazine-1-carboxylate (2.0 g, 10.75 mmol), potassium carbonate (4.45 g, 32.26 mmol) and potassium iodide (892 mg, 5.38 mmol) in acetone (20 mL) was added 2-bromo-1,1-dimethoxyethane (3.63 g, 21.51 mmol). The reaction mixture was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (50 mL) and washed with water (50 mL * 2) and saturated brine (50 mL). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to give the desired product (2.2 g).

[0287] LC-MS: (ES, m / z): [M + H] + = 275.0.

[0288] Step 2: Preparation of 1-(2,2-dimethoxyethyl)piperazine

[0289]

[0290] A mixture of tert-butyl 4-(2,2-dimethoxyethyl)piperazine-1-carboxylate (2.2 g, 8.03 mmol) in hydrochloric acid / dioxane (4 M, 10 mL) solution was stirred at room temperature overnight. It was concentrated under reduced pressure to give a light yellow oily product (1.5 g, crude). The crude product was directly used for the next step.

[0291] Step 3: Preparation of 5-(4-(2,2-dimethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0292]

[0293] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (1.48 g, 5.36 mmol), 1-(2,2-dimethoxyethyl)piperazine (1.4 g, 8.05 mmol) and DIEA (4.15 g, 36.16 mmol) in NMP (10 mL) solution was reacted in a microwave reactor at 140 °C for 5 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 2). The organic phase was collected and washed with water (100 mL * 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to give the desired product (1.8 g).

[0294] LC-MS: (ESI, m / z): [M + H] + = 431.1.

[0295] Step 4: Preparation of 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde

[0296]

[0297] A mixture of 5-(4-(2,2-dimethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (1.8 g, 4.19 mmol) in trifluoroacetic acid / dichloromethane (5 mL / 5 mL) solution was stirred at room temperature for 60 h. The mixture was concentrated under reduced pressure, water was added, and the pH was adjusted to 8 with sodium bicarbonate (aqueous solution). The mixture was extracted with ethyl acetate (100 mL * 2). The organic phase was collected and washed with water (100 mL * 2) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to obtain the desired product (700 mg).

[0298] LC-MS: (ESI, m / z): [M+H] + = 285.0.

[0299] Intermediate 7: 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-2-methylpropanal

[0300]

[0301] Synthesized by referring to the method of Intermediate 6.

[0302] LC-MS: (ESI, m / z): [M+H] + = 413.2.

[0303] Intermediate 8: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0304] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione

[0305]

[0306] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (500 mg, 1.81 mmol), 2-(piperidin-4-yl)ethyl-1-ol (280, 2.17 mmol)) and DIEA (701 mg, 5.43 mmol) in NMP (5 mL) was reacted in a microwave reactor at 140 °C for 5 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 2). The organic phase was collected and washed with water (100 mL * 2) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to give the product (650 mg).

[0307] LC-MS: (ES, m / z): [M + H] + = 386.1.

[0308] Step 2: Preparation of 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde

[0309]

[0310] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3-dione (300 mg, 0.78 mmol) and IBX (436 mg, 1.56 mmol) in acetonitrile (6 mL) was stirred at 80 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL * 2). The organic phase was collected and washed with water (50 mL × 2) and saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The concentrate was purified by silica gel column chromatography to give the product (22 mg).

[0311] LC-MS: (ES, m / z): [M + H] + = 384.1.

[0312] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.69 (t, J = 1.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.6, 2.2 Hz, 1H), 5.06 (dd, J = 12.9, 5.4 Hz, 1H), 4.03 (dd, J = 10.3, 2.9 Hz, 2H), 3.04 - 2.82 (m, 3H), 2.65 - 2.52 (m, 2H), 2.41 (dd, J = 6.7, 1.6 Hz, 2H), 2.17 - 1.97 (m, 2H), 1.73 (d, J = 11.1 Hz, 2H), 1.2 - 1.18 (m, 2H).

[0313] Intermediate 9: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propanal

[0314]

[0315] Synthesized by referring to the method of Intermediate 8.

[0316] LC-MS: (ES, m / z): [M + H] + = 398.2.

[0317] Intermediate 10: 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidine-4-carbaldehyde

[0318]

[0319] Synthesized by referring to the method of Intermediate 8.

[0320] LC-MS: (ES, m / z): [M + H] + = 370.1.

[0321] Intermediate 11: 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2-methylpropanal

[0322]

[0323] Synthesized by referring to the method of Intermediate 8.

[0324] LC-MS: (ES, m / z): [M + H] + = 412.2.

[0325] Intermediate 12: 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0326] Step 1: Preparation of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate

[0327]

[0328] A mixture of 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (300 mg, 1.09 mmol), tert-butyl piperazine-1-carboxylate (203 mg, 1.09 mmol) and DIEA (422 mg, 3.27 mmol) in NMP (1 mL) was reacted at 140 °C for 5 h on a microwave reactor. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with dichloromethane (10 mL × 3). The combined organic phases were concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain the product (90 mg).

[0329] LC-MS: (ESI, m / z): [M+H] + = 788.2.

[0330] Step 2: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione

[0331]

[0332] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate (65 mg, 0.147 mmol) in dichloromethane (5 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure, and the concentrate was diluted with saturated aqueous sodium bicarbonate (5 mL) and extracted with dichloromethane (5 mL × 3). The combined organic phases were concentrated under reduced pressure to obtain the crude product (59 mg). The crude product was used directly in the next step without further purification.

[0333] LC-MS: (ESI, m / z): [M+H] + = 343.3.

[0334] Intermediate 13: 3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-3-methylbutanal

[0335]

[0336] Synthesized by referring to the method of Intermediate 8.

[0337] LC-MS: (ES, m / z): [M+H] + = 426.2.

[0338] Intermediate 14: 3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-methylbutanal

[0339]

[0340] Synthesized by referring to the method of Intermediate 6.

[0341] LC-MS: (ESI, m / z): [M+H] + = 427.2.

[0342] Intermediate 15: 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)acetaldehyde

[0343]

[0344] Synthesized by referring to the method of Intermediate 6.

[0345] LC-MS: (ESI, m / z): [M+H] + = 453.2.

[0346] Intermediate 16: 2-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)-2-methylpropanal

[0347]

[0348] Synthesized by referring to the method of Intermediate 6.

[0349] LC-MS: (ESI, m / z): [M+H] + = 481.2.

[0350] Intermediate 17: 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undecan-9-yl)-2-methylpropanal

[0351]

[0352] Synthesized by referring to the method of Intermediate 8.

[0353] LC-MS: (ESI, m / z): [M+H] + = 480.2.

[0354] Intermediate 18: 2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undecan-9-yl)acetaldehyde

[0355]

[0356] Synthesized by referring to the method of Intermediate 8.

[0357] LC-MS: (ESI, m / z): [M+H] + = 452.2.

[0358] Intermediate 19: 3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undecane-9-carbaldehyde

[0359]

[0360] Synthesized by referring to the method of Intermediate 8.

[0361] LC-MS: (ESI, m / z): [M+H] + = 438.2.

[0362] Intermediate 20: 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)acetaldehyde

[0363] Step 1: Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)isoindoline-1,3-dione

[0364]

[0365] To a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (500 mg, 0.0018 mol) and 2-(2-chloroethoxy)ethyl-1-ol (227 mg, 0.0018 mol) in dimethyl sulfoxide (20 mL) solution was added dropwise DIEA (706.2 mg, 0.0055 mol) and potassium iodide (30 mg, 0.0002 mol). The reaction mixture was stirred at 100 °C for 10 h. Water (30 ml) and ethyl acetate (100 ml) were added, the aqueous layer was separated, and the aqueous layer was extracted with ethyl acetate (100 ml × 2). The organic phases were combined, washed with brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 612 mg of the white solid target product.

[0366] LC-MS: (ES, m / z): [M+H] + = 363.0

[0367] Step 2: Preparation of 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)acetaldehyde

[0368]

[0369] At 0 °C, Dess-Martin (393 mg, 0.88 mmol) was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)isoindoline-1,3-dione (162 mg, 0.44 mmol) in THF (10 mL) solution. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 ml) and dichloromethane (50 ml). The aqueous layer was separated, and the aqueous layer was extracted with dichloromethane (50 ml × 2). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 32 mg of the white solid target product.

[0370] LC-MS: (ES, m / z): [M+H] + = 361.0

[0371] Intermediate 21: tert-Butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0372] Step 1: tert-Butyl 9-(2-ethoxy-2-oxoethylidene)-3-azaspiro[5.5]undecane-3-carboxylate

[0373]

[0374] At 0 °C, sodium hydride (60% mineral oil mixture, 224 mg, 5.6 mmol) was added to a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.26 g, 5.63 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was stirred at 0 °C for 0.5 h. Then tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (1.0 g, 3.75 mmol) was added. The reaction mixture was stirred at 0 °C for an additional 3 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was collected, washed with water (2 × 20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. 0.7 g of the target crude product was obtained. The crude product was directly used in the next step.

[0375] Step 2: tert-Butyl 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0376]

[0377] Under a hydrogen atmosphere, a reaction mixture of tert-butyl 9-(2-ethoxy-2-oxoethylidene)-3-azaspiro[5.5]undecane-3-carboxylate (0.7 g, 2.08 mmol) and palladium hydroxide (0.2 g, 1.43 mmol) in ethanol (10 mL) was stirred at room temperature for 16 h. The reaction mixture was filtered and concentrated under reduced pressure. 0.5 g of the target crude product was obtained. The crude product was directly used in the next step.

[0378] 1 H NMR (400 MHz, CDCl3) δ 4.12 (q, J = 7.1 Hz, 2H), 3.35 (ddd, J = 7.6, 6.8, 5.0 Hz, 4H), 2.20 (d, J = 7.1 Hz, 2H), 1.70 - 1.63 (m, 2H), 1.58 (dd, J = 12.7, 7.1 Hz, 2H), 1.45 (s, 9H), 1.27 (dt, J = 14.3, 6.5 Hz, 6H), 1.18 - 1.10 (m, 4H), 0.86 (dd, J = 13.4, 6.3 Hz, 2H).

[0379] Step 3: tert-Butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecane-3-carboxylate

[0380]

[0381] The reaction mixture of tert-butyl 9-(2-ethoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.5 g, 1.47 mmol) and lithium borohydride (0.13 g, 5.9 mmol) in tetrahydrofuran (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was collected and washed with water (2 × 20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. 0.4 g of the target crude product was obtained.

[0382] LC-MS: (ESI, m / z): [M+H]+ = 298.2

[0383] 1 1H NMR (400 MHz, MeOD) δ 3.58 (t, J = 6.6 Hz, 2H), 3.43 - 3.28 (m, 5H), 1.77 - 1.66 (m, 2H), 1.62 - 1.52 (m, 2H), 1.52 - 1.41 (m, 13H), 1.29 (t, J = 5.6 Hz, 3H), 1.12 (dd, J = 19.2, 11.5 Hz, 4H).

[0384] Example 1: N-(2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0385]

[0386] A mixture of N-(6-methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (200 mg, 0.377 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline-1,3-dione (104 mg, 0.377 mmol) and DIEA (243 mg, 1.887 mmol) in NMP (100 mL) was reacted in a microwave reactor at 140 °C for 5 h. The resulting mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by preparative HPLC to give the desired product (14.52 mg).

[0387] LC-MS: (ESI, m / z): [M+H] + = 787.2.

[0388] 1H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 10.50 (s, 1H), 8.69 (s, 1H), 8.54 - 8.31 (m, 3H), 8.22 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 7.24 (m, J = 8.7, 2.1 Hz, 1H), 7.16 (s, 1H), 5.06 (m, 1H), 4.41 - 4.38 (m, 1H), 4.05 (d, J = 13.2 Hz, 2H), 3.98 (s, 3H), 3.04 - 2.85 (m, 5H), 2.71 - 2.53 (m, 2H), 2.42 - 2.36 (m, 2H), 2.11 - 2.05 (m, 6H), 2.03 - 1.95 (m, 1H), 1.79 (d, J = 11.5 Hz, 2H), 1.65 - 1.61 (m, 1H), 1.48 - 1.39 (m, 2H), 1.25 - 1.20 (m, 2H).

[0389] Example 2: N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0390]

[0391] Referring to the preparation method of Example 1, the target compound (27 mg) was obtained.

[0392] LC-MS: (ESI, m / z): [M + H] + = 773.4.

[0393] 11H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.49 - 8.36 (m, 3H), 8.33 (s, 0.3H), 8.25 - 8.17 (m, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.24 (dd, J = 8.7, 2.1 Hz, 1H), 7.17 (s, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.41 - 4.37 (m, 1H), 4.06 (d, J = 13.0 Hz, 2H), 3.99 (s, 3H), 3.03 - 2.83 (m, 5H), 2.65 - 2.53 (m, 2H), 2.22 (d, J = 6.7 Hz, 2H), 2.17 - 1.98 (m, 7H), 1.85 - 1.80 (m, 3H), 1.24 - 1.11 (m, 2H).

[0394] Example 3: N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamine

[0395]

[0396] A mixture of N-(6-methoxy-2-(1-(2-oxoethyl)piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamine (80 mg, 0.174 mmol), 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione (59 mg, 0.174 mmol) and STAB (110 mg, 0.521 mmol) in a solution of tetrahydrofuran (5 mL) was stirred at room temperature for 3 hours. The resulting reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by preparative HPLC to give the product (4.5 mg).

[0397] LC-MS: (ESI, m / z): [M + H] + = 788.2.

[0398] 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 10.51 (s, 1H), 8.69 (s, 1H), 8.53 - 8.33 (m, 3H), 8.22 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.39 - 7.22 (m, 2H), 7.17 (s, 1H), 5.12 - 5.04 (m, 1H), 4.46 - 4.32 (m, 1H), 3.98 (s, 3H), 3.52 - 3.44 (m, 6H), 3.10 - 3.02 (m, 3H), 2.94 - 2.84 (m, 1H), 2.62 - 2.53 (m, 6H), 2.15 - 1.95 (m, 8H).

[0399] Example 4: N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0400]

[0401] A mixture of N-(6-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (285 mg, 0.64 mmol), 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetaldehyde (350 mg, 0.91 mmol) and STAB (407 mg, 1.92 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the concentrate was purified by preparative HPLC to give the product (144.27 mg).

[0402] LC-MS: (ESI, m / z): [M + H] + = 816.2.

[0403] 1H NMR (400 MHz, DMSO) δ 12.37 (s, 1H), 11.08 (s, 1H), 8.72 (s, 1H), 8.46 - 8.28 (m, 3H), 8.16 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.28 - 7.25 (m, 1H), 5.95 (s, 1H), 5.10 - 5.05 (m, 1H), 4.51 - 4.40 (m, 1H), 3.48 - 3.40 (m, 4H), 3.05 (d, J = 10.5 Hz, 2H), 2.92 - 2.84 (m, 1H), 2.66 - 2.51 (m, 10H), 2.22 - 1.97 (m, 7H), 1.62 (s, 6H).

[0404] Example 5: N-(2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0405]

[0406] A mixture of N-(6-(2-hydroxypropan-2-yl)-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (120 mg, 0.27 mmol), 2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)acetaldehyde (165 mg, 0.43 mmol) and STAB (172 mg, 0.81 mmol) in tetrahydrofuran (10 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to give the target product.

[0407] LC-MS: (ESI, m / z): [M + H] + = 815.3.

[0408] 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.08 (s, 1H), 8.72 (s, 1H), 8.46 - 8.35 (m, 3H), 8.16 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.31 (d, J = 1.8 Hz, 1H), 7.25 - 7.22 (m, 1H), 5.97 - 5.93 (m, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 4.47 - 4.43 (m, 1H), 4.05 (d, J = 13.0 Hz, 2H), 3.06 - 2.82 (m, 5H), 2.63 - 2.53 (m, 2H), 2.40 (t, J = 7.1 Hz, 2H), 2.15 - 2.08 (m, 6H), 2.05 - 1.97 (m, 1H), 1.79 (d, J = 10.9 Hz, 2H), 1.64 (d, J = 13.1 Hz, 7H), 1.47 - 1.40 (m, 2H), 1.25 - 1.17 (m, 2H).

[0409] Example 6: N-(2-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)propyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0410]

[0411] Synthesized by referring to the method of Example 5.

[0412] LC-MS: (ESI, m / z): [M + H] + = 829.4.

[0413] 11H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.07 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 7.8 Hz, 1H), 8.16 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.31 (s, 1H), 7.24 (d, J = 8.5 Hz, 1H), 5.95 (s, 1H), 5.06 (dd, J = 12.8, 5.2 Hz, 1H), 4.49 - 4.37 (m, 1H), 4.06 (d, J = 13.0 Hz, 2H), 3.08 - 2.81 (m, 5H), 2.64 - 2.52 (m, 2H), 2.37 - 2.27 (m, 2H), 2.19 - 1.95 (m, 7H), 1.77 (d, J = 11.5 Hz, 2H), 1.67 - 1.45 (m, 9H), 1.30 - 1.10 (m, 4H).

[0414] Example 7: N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0415]

[0416] Synthesized according to the method of Reference Example 5.

[0417] LC-MS: (ESI, m / z): [M + H] + = 801.3.

[0418] 11H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.07 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 8.41 (s, 1H), 8.37 (t, J = 7.8 Hz, 1H), 8.20 - 8.11 (m, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.58 (s, 1H), 7.32 (s, 1H), 7.24 (dd, J = 8.7, 2.0 Hz, 1H), 5.95 (s, 1H), 5.07 (dd, J = 12.8, 5.4 Hz, 1H), 4.51 - 4.40 (m, 1H), 4.06 (d, J = 13.2 Hz, 2H), 3.09 - 2.78 (m, 5H), 2.63 - 2.51 (m, 2H), 2.28 - 1.95 (m, 9H), 1.90 - 1.78 (m, 3H), 1.62 (s, 6H), 1.25 - 1.10 (m, 2H).

[0419] Example 8: N-(2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-2-methylpropyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0420]

[0421] Synthesized according to the method of Reference Example 5.

[0422] LC-MS: (ESI, m / z): [M + H] + = 843.1.

[0423] Example 9: N-(2-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-1-yl)-2-methylpropyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0424]

[0425] Synthesized according to the method of Reference Example 4.

[0426] LC-MS: (ESI, m / z): [M + H] + = 844.1.

[0427] 11H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 11.07 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 7.6 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 7.9 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.33 (s, 1H), 7.25 (d, J = 8.6 Hz, 1H), 5.94 (s, 1H), 5.07 (dd, J = 12.9, 5.3 Hz, 1H), 4.50 - 4.35 (m, 1H), 3.45 - 3.35 (m, 4H), 3.15 - 3.02 (m, 2H), 2.95 - 2.85 (m, 1H), 2.77 - 2.70 (m, 4H), 2.68 - 2.53 (m, 2H), 2.45 - 2.30 (m, 4H), 2.20 - 2.07 (m, 2H), 2.05 - 1.97 (m, 3H), 1.62 (s, 6H), 1.06 (s, 6H).

[0428] Example 10: N-(2-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperidin-4-yl)-3-methylbutyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0429]

[0430] Synthesized according to the method of Reference Example 5.

[0431] LC-MS: (ESI, m / z): [M + H] + = 857.4.

[0432] Example 11: N-(2-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)-3-methylbutyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0433]

[0434] Synthesized according to the method of Reference Example 4.

[0435] LC-MS: (ESI, m / z): [M + H] + = 858.4.

[0436] Example 12: N-(2-(1-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undecan-9-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0437]

[0438] Synthesized according to the method of Reference Example 5.

[0439] LC-MS: (ESI, m / z): [M+H] + = 883.4.

[0440] 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 11.03 (s, 1H), 8.72 (s, 1H), 8.45 (d, J = 7.7 Hz, 1H), 8.40 (s, 1H), 8.37 (t, J = 7.9 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.58 (s, 1H), 7.29 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 5.95 (s, 1H), 5.06 (dd, J = 12.9, 5.3 Hz, 1H), 4.46 - 4.37 (m, 1H), 3.50 - 3.40 (m, 4H), 3.05 - 2.95 (m, 2H), 2.94 - 2.80 (m, 1H), 2.63 - 2.51 (m, 2H), 2.36 (t, J = 7.3 Hz, 2H), 2.16 - 1.93 (m, 7H), 1.73 - 1.49 (m, 12H), 1.45 - 1.35 (m, 4H), 1.34 - 1.25 (m, 1H), 1.19 - 1.05 (m, 4H).

[0441] Example 13: N-(2-(1-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolylamide

[0442]

[0443] Synthesized according to the method of Reference Example 4.

[0444] LC-MS: (ESI, m / z): [M+H] += 884.4.

[0445] Example 14: N-(2-(1-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undec-9-yl)-2-methylpropyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0446]

[0447] Synthesized according to the method of Reference Example 5.

[0448] LC-MS: (ESI, m / z): [M+H] + = 911.4.

[0449] Example 15: N-(2-(1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-3-azaspiro[5.5]undec-9-yl)methyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0450]

[0451] Synthesized according to the method of Reference Example 5.

[0452] LC-MS: (ESI, m / z): [M+H] + = 869.4.

[0453] Example 16:

[0454]

[0455] Synthesized according to the method of Reference Example 4.

[0456] LC-MS: (ESI, m / z): [M+H] + = 912.4.

[0457] Control Group 1: N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0458]

[0459] To a mixture of N-(6-methoxy-2-(piperidin-4-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide (24 mg, 0.05 mmol) and 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)ethoxy)acetaldehyde (40 mg, 0.11 mmol) in a solution of 1,2-dichloroethane (5 ml) was added STAB (36 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure, and the concentrate was purified by HPLC to obtain 3.25 mg of the target product as a white solid.

[0460] LC-MS: (ES, m / z): [M+H] + = 764.3.

[0461] 1 H-NMR-LT-002-007: 1 H NMR (400 MHz, CD3OD_SPE) δ 8.77 (s, 1H), 8.47 (d, J = 8.0 Hz, 3H), 8.31 (t, J = 7.8 Hz, 1H), 8.18 (s, 1H), 8.05 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.07 (s, 1H), 5.12 - 5.07 (m, 1H), 4.51 (s, 1H), 4.37 (s, 2H), 4.05 (s, 3H), 3.91 (s, 2H), 3.82 (t, J = 5.0 Hz, 2H), 3.37 (s, 2H), 2.96 (s, 2H), 2.90 - 2.77 (m, 1H), 2.77 - 2.60 (m, 4H), 2.26 (s, 4H), 2.08 (d, J = 5.2 Hz, 1H).

[0462] Control Group 2: N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0463] Step 1: Preparation of 5-(allyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0464]

[0465] Under nitrogen protection, 3-bromoprop-1-en-1-yl (470 mg, 3.89 mmol) was added to a mixture of 2-(2,6-dioxopiperidin-3-yl)-5-hydroxyisoindoline-1,3-dione (1 g, 3.65 mmol) and potassium carbonate (1.01 g, 7.29 mmol) in N,N-dimethylformamide (10 mL) solution. The reaction mixture was stirred at 50 °C overnight. At 0 °C, the reaction was quenched with water (60 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography to obtain 0.85 g of the target product.

[0466] LC-MS: (ES, m / z): [M+H] + = 315.1

[0467] Step 2: 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetaldehyde

[0468]

[0469] At -78 °C, ozone was passed through a solution of 5-(allyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (0.7 g, 2.23 mmol) in dichloromethane (200 ml) until the reaction solution turned blue. Then nitrogen was passed through until the reaction solution turned colorless. Dimethyl sulfide (7.61 g, 123 mmol) was added at -78 °C under nitrogen protection, and the reaction mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the concentrate was purified by silica gel column chromatography to obtain the target product.

[0470] LC-MS: (ES, m / z): [M+H] + = 317.1

[0471] Step 3: Preparation of N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0472]

[0473] Synthesized by referring to the method of Step 3 of Control Group 1.

[0474] LC-MS: (ESI, m / z): [M+H] + = 817.1.

[0475] 11H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.50 (s, 1H), 8.69 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 8.41 (t, J = 7.8 Hz, 1H), 8.37 (s, 1H), 8.22 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.3 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.3, 2.3 Hz, 1H), 7.16 (s, 1H), 5.12 (dd, J = 12.8, 5.3 Hz, 1H), 4.43 - 4.34 (m, 1H), 4.29 (t, J = 5.5 Hz, 2H), 3.00 - 2.91 (m, 5H), 2.78 - 2.70 (m, 2H), 2.64 - 2.54 (m, 2H), 2.22 - 2.16 (m, 3H), 2.13 - 2.02 (m, 9H), 1.74 - 1.66 (m, 2H), 1.58 - 1.44 (m, 1H), 1.18 - 1.08 (m, 2H).

[0476] Control Group 3: N-(2-((1r,4r)-4-((((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidin-4-yl)methyl)(methyl)amino)methyl)cyclohexyl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide

[0477]

[0478] Prepared according to the method of Compound I-317 in WO2020113233.

[0479] LC-MS: (ESI, m / z): [M + H] + = 843.3

[0480] 11H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 11.08 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 7.8 Hz, 1H), 8.41 - 8.32 (m, 2H), 8.16 (d, J = 7.8 Hz, 1H), 7.74 - 7.62 (m, 1H), 7.57 (s, 1H), 7.42 - 7.17 (m, 2H), 5.94 (s, 1H), 5.09 (dd, J = 12.8, 5.3 Hz, 1H), 4.47 - 4.36 (m, 1H), 3.70 (d, J = 10.0 Hz, 2H), 2.90 (d, J = 12.7 Hz, 3H), 2.65 - 2.52 (m, 2H), 2.25 - 2.10 (m, 9H), 2.05 - 1.81 (m, 7H), 1.74 - 1.55 (m, 8H), 1.32 (d, J = 11.6 Hz, 2H), 1.11 (d, J = 11.9 Hz, 2H)

[0481] II Examples of Biological Activity Tests

[0482] Test Example 1: IRAK4 Kinase Activity Test

[0483] The inhibitory effect of the compound on IRAK4 kinase activity was detected using the KinEASE-STK S1 serine / threonine kinase kit (Cisbio). The specific method was as follows: The compound was dissolved in dimethyl sulfoxide and then serially diluted with the buffer of the kit so that the final concentration range of the test compound in the reaction system was 10000 nM - 0.038 nM. Then, 2.5 nM kinase, 1 μM biotinylated polypeptide substrate, and 7 μM adenosine triphosphate (ATP) were added successively and incubated at 37 °C for 120 min. Subsequently, an anti-phosphorylated serine / threonine antibody conjugated with an europium-based element compound and modified XL665 streptavidin were added to the reaction system to terminate the reaction. After incubating at room temperature for 1 h, the fluorescence intensities of each well at an excitation wavelength of 337 nm were measured in the HTRF mode on an enzyme-linked immunosorbent assay (ELISA) reader EnVision (PerkinElmer), and the fluorescence intensities of each well at emission wavelengths of 620 nm and 665 nm were read. The formula Ratio = (665 nm / 620 nm) × 10 4 was used to calculate the Ratio value. By comparing with the fluorescence intensity ratio of the control group, the inhibition rate of the compound at each concentration was calculated, and then non-linear curve fitting was performed with logarithmic concentration - inhibition rate using GraphPad Prism 7 to obtain the IC 50 value of the compound.

[0484] Test Example 2: Degradation of IRAK4 in THP-1 Cells by the Compound

[0485] Inoculate 0.95 mL of THP-1 cells (from the Stem Cell Bank of the Chinese Academy of Sciences) into each well of a 24-well cell culture plate, with a cell density of 5×10 5 cells / well; place the cell plate in a 5% carbon dioxide incubator and culture at 37°C overnight. Then add 50 μL of the compound dimethyl sulfoxide solution, with the final concentration of the compound ranging from 1 to 3000 nM, and continue to culture for 24 hours. After that, collect the cells into a 1.5 mL centrifuge tube and centrifuge at 1000 rpm and 4°C for 5 minutes. Wash the cell pellet twice with 1×DPBS, and lyse the resuspended cells with 200 μL of lysis buffer (the cell lysis buffer is Western and IP cell lysis buffer (Beyotime), supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Beyotime)). After standing on ice for 30 minutes, centrifuge at 14000g and 4°C for 10 minutes, and take the supernatant to detect the protein level of IRAK4 by Western Blot respectively.

[0486] The total protein concentration in the above cell lysate supernatant was determined using a BCA protein quantification kit (Tiangen). According to the concentration of total protein detected by BCA, adjust it to 0.2 μg / μL with PBS and 5×SDS-PAGE protein loading buffer (Beyotime), incubate in a 100°C water bath for 10 minutes, then place on ice for 5 minutes, centrifuge at 14000g and 4°C for 5 minutes, and collect the supernatant as the loading sample for WB. Use a precast gel (Kaiji) for protein electrophoresis, with a loading volume of 10 μL (2 μg of total protein), and perform electrophoresis at a constant voltage of 120V with Tris-MOPS-SDS electrophoresis buffer (Adamas). After electrophoresis, transfer the protein on the gel strip to a PVDF membrane and transfer at a constant current of 250V for 50 minutes. After the transfer is completed, place the membrane in 1×QuickBlock blocking solution (Beyotime) and incubate at room temperature for 30 minutes. After blocking, incubate the PVDF membrane with the IRAK4 primary antibody (Abcam) at 4°C overnight, wash the membrane with TBST buffer (2.4 g Tris, 8.8 g NaCl, 1.5 mL Tween 20, adjust the pH to 7.4, make up to 1 L) for 30 minutes, incubate with the secondary antibody (Abcam) at room temperature for 2 hours, and finally incubate with Clarity Western ECL Substrate (BIO-RAD) for 5 minutes to develop and visualize the chemiluminescence. Use a chemiluminescence imaging system (Qinxiang, ChemiScope 6200 Touch) to develop and take pictures of the protein map. The protein map was analyzed for gray value using Qinxiang chemiluminescence analysis software. Use the formula: Gray correction value = (gray value of the target protein / gray value of the corresponding internal reference) × 10 3 , calculate the gray correction value of each sample. Then compare it with the gray correction value of the control group to calculate the degradation rate. Furthermore, perform non-linear curve fitting with logarithmic concentration-inhibition rate using GraphPad Prism 7 to obtain the DC 50 and Dmax Value

[0487] Table 1:

[0488]

[0489] Note: WB refers to the Western Blot method, D(%) refers to the percentage of degradation of IRAK4 kinase protein in THP-1 cells detected by the Western Blot method for the compounds of the present invention, D(%) (1000 nM) is the degradation percentage of IRAK4 when the compound concentration is 1000 nM, and D(%) (300 nM) is the degradation percentage of IRAK4 when the compound concentration is 300 nM.

[0490] Experimental results: The compounds of the present invention can effectively bind to the IRAK4 target protein; the compounds of the present invention can significantly degrade the IRAK4 kinase protein in cells.

[0491] Test Example 3: Pharmacokinetic Property Study

[0492] The following experimental protocol was used to study the pharmacokinetic behavior of the compounds of the present invention in mice and evaluate their pharmacokinetic characteristics.

[0493] Experimental protocol: Three healthy male SD mice, weighing 18 - 25 mg, were given the compound by gavage at a dose of 100 mg / kg, and the administration volume was 10 mL / kg, prepared with 5% DMSO / 15% solutol / 80% PBS (w / v). They were fasted for 12 h before the test and allowed free access to water. They were fed uniformly 4 h after administration.

[0494] Three healthy male SD mice, weighing 18 - 25 mg, were given the compound by intravenous injection at a dose of 1 mg / kg, and the administration volume was 5 mL / kg, prepared with 5% DMSO / 15% solutol / 80% PBS (w / v). They were fasted for 12 h before the test and allowed free access to water. They were fed uniformly 4 h after administration.

[0495] At 0.08 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after gavage administration and at 0.08 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, 24 h after intravenous administration, 0.1 mL of venous blood was collected from the submandibular venous plexus of the mice, placed in a heparinized test tube, centrifuged at 11000 rpm for 5 min to separate the plasma, and the concentration of the compound in the plasma was determined by liquid chromatography - tandem mass spectrometry.

[0496] Table 2:

[0497]

[0498] The experimental results show that the compound of the present invention has a low clearance rate, a high plasma exposure, a good oral bioavailability, good pharmacokinetic properties, and is conducive to drug development.

[0499] Test Example 4: Degradation of IKZF1 and IKZF3 in L363 cells by the compound

[0500] Each well of a 24-well cell culture plate was inoculated with 0.95 mL of L363 cells (Nanjing Kebai), and the cell density was 6×10 5 cells / well; the cell plate was placed in a 5% carbon dioxide incubator and cultured at 37°C for 8 hours, then 50 μL of the compound solution was added, and the final concentration of the compound was 1000 nM. After continued culture for 16 hours, the cells were collected into a 1.5 mL centrifuge tube and centrifuged at 3000 rpm and 4°C for 5 minutes. The cell pellet was washed twice with 1×DPBS, and the resuspended cells were lysed with 100 μL of lysis buffer (the cell lysis buffer was Western and IP cell lysis buffer (Beyotime), supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Beyotime)). After standing on ice for 30 minutes, it was centrifuged at 14000 g and 4°C for 10 minutes, and the supernatant was used to detect the protein levels of IKZF1 and IKZF3 by Western Blot.

[0501] The total protein concentration in the above cell lysis supernatant was measured using a BCA Protein Quantification Kit (Tiangen). According to the BCA assay for total protein concentration, it was adjusted to 0.2 μg / μL with PBS and 5× SDS-PAGE Protein Loading Buffer (Beyotime), incubated in a 100°C water bath for 10 minutes, then placed on ice for 5 minutes. After centrifugation at 14,000 g for 5 minutes at 4°C, the supernatant was collected as the loading sample for WB. Protein electrophoresis was performed using a precast gel (Kaiji), with a loading volume of 10 μL (2 μg of total protein). After using Tris-MOPS-SDS electrophoresis buffer (Adamas), electrophoresis was carried out at a constant voltage of 120 V. After electrophoresis, the proteins on the gel strip were transferred to a PVDF membrane, and transferred at a constant current of 250 mA for 50 minutes. After the transfer, the membrane was placed in a 5% bovine serum albumin solution and incubated at room temperature for 2 hours. After blocking, the PVDF membrane was incubated with the IKZF1 primary antibody (CST) and the IKZF3 primary antibody (Abcam) overnight at 4°C. The membrane was washed with TBST buffer (2.4 g Tris, 8.8 g NaCl, 1.5 mL Tween 20, adjusted to pH 7.4, made up to 1 L) for 30 minutes, incubated with the secondary antibody (Abcam) at room temperature for 2 hours, and finally incubated with Clarity Western ECL Substrate (BIO-RAD) for 5 minutes for chemiluminescent color development. A chemiluminescent imaging system (Qinxiang, ChemiScope 6200 Touch) was used for color development and protein map photography. The protein map was analyzed for gray value using Qinxiang chemiluminescent analysis software. Using the formula: Gray correction value = (gray value of the target protein / gray value of the corresponding internal reference) × 10 3 , the gray correction values of each sample were calculated. Then, the degradation rate was calculated by comparing with the gray correction value of the control group.

[0502] Table 4:

[0503]

[0504]

[0505] Note: In Table 4, "-" indicates no degradation of IKZF1 and IKZF3.

[0506] The experimental results show that the compound of the present invention has good selectivity, has no or little degradation of IKZF1 and IKZF3, has low toxicity and side effects, and is conducive to drug development.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, wherein: the compound of formula I is a compound of formula II R a is hydrogen; ring A is pyridyl; R d each independently is a halogen, a C1-C6 alkyl group, and the alkyl group is optionally substituted with one or more halogens; n is 1; R e is hydrogen; R c is -O-(C1-C6 alkyl), C1-C6 alkyl, and the alkyl is optionally substituted by one or more hydroxyl groups; R b is hydrogen; Ring B is The ring C is X is a bond; W is -C(O); L is -(CH2) j -, and one or more methylenes in the said -(CH2) j - are optionally replaced by -CR 1’ R 2’ -; R 1’ 、R 2’ each independently represents a C1-C4 alkyl group; j is 1, 2, 3, 4, 5 or 6.

2. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The ring C is 3. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R d is a C1-C6 alkyl group substituted by one or more F.

4. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 3, characterized in that, R d is trifluoromethyl.

5. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R c is a C1-C6 alkyl group substituted by one hydroxyl group, or -O(C1-C6 alkyl).

6. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 5, characterized in that, R c is 2-hydroxypropyl or methoxy.

7. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein, L is -(CH2) j -, and one or more of the -(CH2) j - are optionally replaced by -CR 1’ R 2’ -; the R 1’ , R 2’ are each independently a C1-C4 alkyl group; j is 1, 2, or 3.

8. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 7, characterized in that, L is 9. The compound of formula I or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that is the following specific compound 10. A pharmaceutical composition comprising the compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

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