WO2022088551A1 - 吲唑类衍生物及其制备方法和应用 - Google Patents

吲唑类衍生物及其制备方法和应用 Download PDF

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WO2022088551A1
WO2022088551A1 PCT/CN2021/075341 CN2021075341W WO2022088551A1 WO 2022088551 A1 WO2022088551 A1 WO 2022088551A1 CN 2021075341 W CN2021075341 W CN 2021075341W WO 2022088551 A1 WO2022088551 A1 WO 2022088551A1
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alkyl
membered
cycloalkyl
compound
disease
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PCT/CN2021/075341
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French (fr)
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冯焱
李世强
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上海领泰生物医药科技有限公司
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Priority to JP2022573683A priority Critical patent/JP7474527B2/ja
Priority to CN202180018079.9A priority patent/CN115244042A/zh
Priority to US18/000,205 priority patent/US20230192655A1/en
Priority to EP21884295.3A priority patent/EP4238968A1/en
Publication of WO2022088551A1 publication Critical patent/WO2022088551A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and the specific present invention relates to the indazole derivatives of targeting IRAK4 protein degradation, and preparation method thereof and medicines for treating and/or preventing related diseases or diseases mediated by IRAK4 in preparation applications in cancer, immune and inflammatory diseases.
  • Interleukin-1 receptor kinase 4 is a serine/threonine specific protein kinase with biologically important kinase activity and plays an important role in activating the immune system.
  • IRAK4 is a key factor downstream of interleukin (IL)-1 ⁇ family receptors (including IL-1R, IL-18R, IL-33R, IL-36R) and Toll-like receptor (TLR) signaling pathways
  • IL-1 ⁇ family receptors including IL-1R, IL-18R, IL-33R, IL-36R
  • TLR Toll-like receptor
  • TLR/IL-1 ⁇ -mediated signaling pathways can be divided into MyD88-dependent signaling pathways and MyD88-independent signaling pathways, among which IL-1R and TLR2, TLR4, TLR7/8, TLR9 Signal transduction pathways all rely on MyD88 as a regulator to activate downstream inflammatory signaling pathways.
  • TLR/IL-1 ⁇ binds to the ligand, it recruits MyD88 molecule, MyD88 further recruits IRAK4 to the TLR/IL-1 ⁇ complex through its N-terminal death domain, and interacts with and activates IRAK1 or IRAK2 (Kollewe, 2007).
  • IRAK4-dependent TLR/IL-1 ⁇ signaling pathway has been shown to be associated with various diseases: such as multiple sclerosis, atherosclerosis, myocardial infarction, myocarditis (Valaperti, Nishii et al., Circulation, 2013) Vogt-Koyanagi - Harada syndrome (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, Alope
  • Velayudham et al. Am J Physiol Gastrointest Liver Physio l, 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 and neurological disorders such as myocardial reperfusion injury, myocardial infarction, high Blood pressure (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; Bo
  • neoplastic diseases such as certain lymphomas: ABC-DLBCL (activated B-cell diffuse large cell B-cell lymphoma), mantle cell lymphoma, and Waldanstrom disease, and 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
  • IRAK4-mediated signaling pathways The regulation of IRAK4-mediated signaling pathways is primarily related to its kinase function, however, there are also some reports that in some cell types, IRAK4's signaling regulation of downstream processes is related to IRAK4's non-kinase functions. Cushing et al. showed that pharmacological inhibition of IRAK4 did not result in inhibition of IL-6 and TNF- ⁇ , although IRAK4 phosphorylation was reduced in IL-1 ⁇ -stimulated human skin fibroblasts. Supporting these results, the scaffolding function of IRAK4 is important for IL1 signaling but its kinase function is redundant in IRAK4-deficient fibroblasts compared to wild-type cells.
  • IRAK4 kinase activity is dispensable in human B and T cells, dendritic cells, and monocytes, and siRNA gene ablation also showed that IRAK4 has a scaffolding role in these cells.
  • a variety of potent and 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, mainly For the prevention and treatment of autoimmune diseases, inflammatory diseases and neoplastic diseases.
  • IRAK4 functions as a scaffold protein and active kinase
  • traditional small-molecule inhibitors are prone to drug resistance. Therefore, inhibition of IRAK4 kinase activity alone may not be sufficient to produce therapeutic effects.
  • Protein degradation targeting chimera 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 A heterogeneous bifunctional molecule, one end of which is a small molecule inhibitor that can recognize the target protein, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase.
  • This bifunctional molecule is in vivo It recognizes the target protein and E3 ubiquitin ligase, and draws the target protein and E3 ubiquitin ligase closer to form a ternary complex.
  • the target protein After ubiquitinating the target protein, the target protein is degraded in vivo through the ubiquitin-proteasome pathway. Compared with traditional small molecule inhibitors, PROTAC only needs to bring the target protein closer to E3 ubiquitin ligase to degrade the substrate.
  • PROTAC technology has also been applied to the transformation of various target drugs, such as androgen receptor, estrogen protein receptor, BTK and so on.
  • target drugs such as androgen receptor, estrogen protein receptor, BTK and so on.
  • Several classes of compounds targeting IRAK4 degradation are disclosed in US2019/0151295, US2019/0192688, WO2019/160915 and WO2020/113233, and more compounds targeting IRAK4 degradation are yet to be developed.
  • PK of PROTAC Due to its large molecular weight, PK of PROTAC has become one of the main obstacles to its drug formulation. Therefore, compounds with good PK properties are preferred for drug formulation.
  • the present invention provides a class of compounds with good degradation properties as well as PK properties.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or pharmaceutically acceptable compounds thereof the salt
  • R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl) optionally substituted with halogen or hydroxy;
  • Ring A is a 6-10-membered aryl group or a 5-10-membered heteroaryl group
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 membered cycloalkyl), C3-C6 membered cycloalkyl Or 5-10 membered heteroaryl, the alkyl, cycloalkyl and heteroaryl are optionally substituted by 1 or more groups selected from halogen, hydroxyl, amino;
  • n 1, 2, 3 or 4;
  • Re is hydrogen or C1-C6 alkyl
  • R c is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • Ring B is 6-10-membered aryl, 5-10-membered heteroaryl, C3-C12-membered cycloalkyl or 3-12-membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S,
  • the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy Substituent substitution of alkyl or -O-(C1-C6 alkyl);
  • Ring C is 6-10-membered aryl, 5-10-membered heteroaryl, C3-C12-membered cycloalkyl or 3-12-membered heterocycloalkyl containing 1-2 heteroatoms selected from N, O or S,
  • the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxy Substituent substitution of alkyl or -O-(C1-C6 alkyl);
  • W is -CR g Rh or -C(O);
  • R g and R h are independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 membered cycloalkyl;
  • L is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' -, -O-, -S-, - S(O)-, -S(O)NR 3' -, -NR 3' S(O)-, -S(O) 2 -, -S(O) 2 NR 3' -, -NR 3' S (O) 2 -, -NR 4' S(O) 2 NR 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 3' -, -NR 3' C(O)NR 3' -, -NR 3' C(O
  • R 1' and R 2' are each independently halogen, -OH, -NH 2 , C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 membered cycloalkyl, -O(C3-C6 membered cycloalkyl), -NH(C3-C6 membered cycloalkyl) ), 3-6 membered heterocycloalkyl, -O(3-6 membered heterocycloalkyl), -NH(C3-C6 membered cycloalkyl);
  • R 3' , R 4' are each independently hydrogen or C1-C6 alkyl
  • j is 1, 2, 3, 4, 5 or 6;
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and / or its pharmaceutically acceptable salt is the compound of formula II
  • Ra , Rb , Rc , Rd , Re , n, Ring A, Ring B, L, Ring C, X, W are as defined above.
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and /or a pharmaceutically acceptable salt thereof, X is a bond.
  • ring B is 3-8 membered monocyclic cycloalkyl, 7-12 membered spirocyclic cycloalkyl, 7-12 membered fused ring cycloalkyl, containing 1-2 N heterocyclic 3-8 membered monocyclic heterocycloalkyl of atoms, 7-12 membered fused ring heterocycloalkyl containing 1-2 N heteroatoms, or 7-12 membered spiroheterocycle containing 1-2 N heteroatoms alkyl.
  • ring B is cyclohexane, piperidinyl or piperazinyl.
  • Ring B is piperidinyl.
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and /or a pharmaceutically acceptable salt thereof, ring B is
  • ring C is 3-8 membered monocyclic cycloalkyl, 7-12 membered spirocyclic cycloalkyl, 7-12 membered fused ring cycloalkyl, containing 1-2 N heterocyclic 3-8 membered monocyclic heterocycloalkyl of atoms, 7-12 membered fused ring heterocycloalkyl containing 1-2 N heteroatoms, or 7-12 membered spiroheterocycle containing 1-2 N heteroatoms alkyl.
  • ring C is cyclohexane, piperidinyl, piperazinyl,
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or a pharmaceutically acceptable salt thereof, ring C is
  • R a is hydrogen
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and /or a pharmaceutically acceptable salt thereof, W is C(O).
  • ring A is phenyl or pyridyl.
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, C3-C6 membered cycloalkyl, and the alkyl and cycloalkyl are optionally replaced by 1 One or more groups selected from halogen, hydroxy, amino are substituted.
  • each R d is independently hydrogen, halogen or C1-C6 alkyl optionally substituted with one or more groups selected from F or hydroxy.
  • R d is hydrogen, F, methyl, difluoromethyl, trifluoromethyl or 2-hydroxypropyl.
  • n 1 or 2.
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and /or a pharmaceutically acceptable salt thereof, Re is hydrogen.
  • R c is hydrogen, -O(C1-C6 alkyl), -N(C1-C6 alkyl) 1-2 , C1-C6 alkyl, -O(C3-C6 membered cycloalkyl), -N(C3-C6 membered cycloalkyl), -O(3-6 membered heterocycloalkyl), -N(3-6 membered heterocycloalkyl), the alkyl, ring Alkyl and heterocycloalkyl are optionally substituted with one or more groups independently selected from hydroxy, amino, halogen, cyano.
  • R c is C1-C6 alkyl optionally substituted by 1 or more independent groups selected from hydroxyl or halogen, containing 1 or 2 N heteroatoms C3-C6 membered cycloalkyl or -O(C1-C6 alkyl) optionally substituted with one or more independent groups selected from hydroxy or halogen.
  • R c is difluoromethyl, hydroxy-substituted pyrrolidinyl, 2-hydroxypropyl, methoxy, ethoxy or isopropoxy.
  • R b is hydrogen or C1-C6 alkyl optionally substituted by one or more groups independently selected from hydroxyl, amino, halogen, cyano.
  • R b is hydrogen or methyl.
  • the compound of formula I is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' - , -O-, -CR 1' R 2' -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR 3' -, -NR 3' Group substitution of C(O)-;
  • the compound of formula I and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and /or a pharmaceutically acceptable salt thereof, L is -(CH 2 ) j -, and j is 1, 2 or 3.
  • the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, prodrugs and/or a pharmaceutically acceptable salt thereof, L is
  • R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;
  • Ring A is a 6-10-membered aryl group or a 5-10-membered heteroaryl group
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 membered cycloalkyl), C3-C6 membered cycloalkyl or 5-10 membered heteroaryl, the alkyl, cycloalkyl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxyl, amino;
  • n 1, 2, 3 or 4;
  • Re is hydrogen or C1-C6 alkyl
  • 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 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, -NH Heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered Heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups optionally substituted with one or more groups independently selected from
  • R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • Ring B is 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, so Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkane Substituent substitution of -O-(C1-C6 alkyl);
  • Ring C is 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, so Said aryl, heteroaryl, cycloalkyl and heterocycloalkyl are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkane Substituent substitution of -O-(C1-C6 alkyl);
  • X is the key
  • W is -CR g Rh or -C(O);
  • R g and R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;
  • L is -(CH 2 ) j -;
  • j is 1, 2, 3, 4, 5 or 6.
  • R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;
  • Ring A is a 6-10-membered aryl group or a 5-10-membered heteroaryl group
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 membered cycloalkyl), C3-C6 membered cycloalkyl or 5-10 membered heteroaryl, the alkyl, cycloalkyl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxyl, amino;
  • n 1, 2, 3 or 4;
  • Re is hydrogen or C1-C6 alkyl
  • 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 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, -NH Heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered Heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups optionally substituted with one or more groups independently selected from
  • R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • Ring B is a 6-10-membered aryl group, a 5-10-membered heteroaryl group, or a 3-12-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, the aryl, heteroaryl radical, and heterocycloalkyl are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 Substituent substitution of alkyl);
  • Ring C is 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, so
  • the aryl, heteroaryl, and heterocycloalkyl groups are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or - Substituent substitution of O-(C1-C6 alkyl);
  • X is the key
  • W is -CR g Rh or -C(O);
  • R g and R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;
  • L is -(CH 2 ) j -, and one or more methylene groups in the -(CH 2 ) j - are optionally selected from -NR 3' -, -O-, -S-, - S(O)-, -S(O)NR 3' -, -NR 3' S(O)-, -S(O) 2 -, -S(O) 2 NR 3' -, -NR 3' S (O) 2 -, -NR 4' S(O) 2 NR 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 3' -, -NR 3' C(O)NR 3' -, -NR 3' C(O
  • R 1' and R 2' are each independently halogen, -OH, -NH 2 , C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl, -O(C1-C4 alkyl), -NH(C1-C4 alkyl), -NH(C1-C4 alkyl), C3-C6 membered cycloalkyl, -O(C3-C6 membered cycloalkyl), -NH(C3-C6 membered cycloalkyl) ), 3-6 membered heterocycloalkyl, -O(3-6 membered heterocycloalkyl), -NH(C3-C6 membered cycloalkyl);
  • R 3' , R 4' are each independently hydrogen or C1-C6 alkyl
  • j is 1, 2, 3, 4, 5 or 6.
  • R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;
  • Ring A is a 6-10-membered aryl group or a 5-10-membered heteroaryl group
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 membered cycloalkyl), C3-C6 membered cycloalkyl or 5-10 membered heteroaryl, the alkyl, cycloalkyl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxyl, amino;
  • n 1, 2, 3 or 4;
  • Re is hydrogen or C1-C6 alkyl
  • 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 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, -NH Heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered Heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups optionally substituted with one or more groups independently selected from
  • R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • Ring B is a 6-10-membered aryl group, a 5-10-membered heteroaryl group, or a 3-12-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, the aryl, heteroaryl radical, and heterocycloalkyl are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 Substituent substitution of alkyl);
  • Ring C is a 6-10-membered aryl group, a 5-10-membered heteroaryl group, or a 3-12-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, the aryl, heteroaryl radical, and heterocycloalkyl are optionally selected from halogen, oxo, cyano, amino, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, or -O-(C1-C6 Substituent substitution of alkyl);
  • X is the key
  • W is -CR g Rh or -C(O);
  • R g and R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;
  • L is -(CH 2 ) j -;
  • j is 1, 2, 3, 4, 5 or 6.
  • R a is hydrogen, halogen, C1-C6 alkyl or -O-(C1-C6 alkyl), and the alkyl is optionally substituted by halogen or hydroxyl;
  • Ring A is a 6-10-membered aryl group or a 5-10-membered heteroaryl group
  • R d is each independently hydrogen, halogen, cyano, C1-C6 alkyl, -O-(C1-C6 alkyl), -O-(C3-C6 membered cycloalkyl), C3-C6 membered cycloalkyl or 5-10 membered heteroaryl, the alkyl, cycloalkyl and heteroaryl are optionally substituted with 1 or more groups selected from halogen, hydroxyl, amino;
  • n 1, 2, 3 or 4;
  • Re is hydrogen or C1-C6 alkyl
  • 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 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, -NH Heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered Heteroaryl, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups optionally substituted with one or more groups independently selected from
  • R b is hydrogen, -O-(C1-C6 alkyl), -O-(C3-C8 membered cycloalkyl), -O-(3-8 membered heterocycloalkyl), -O-aryl, - O-heteroaryl, -N(C1-C6 alkyl) 1-2 , -NH(C3-C8 membered cycloalkyl), -NH(3-8 membered heterocycloalkyl), -NHaryl, - NH heteroaryl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-10 membered A membered heteroaryl group, the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are optionally substituted with one or
  • Ring B is a 3-12 membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, optionally selected from halogen, oxo, cyano, amino, hydroxyl, Substituent substitution of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);
  • Ring C is a 3- to 12-membered heterocycloalkyl group containing 1-2 heteroatoms selected from N, O or S, optionally selected from halogen, oxo, cyano, amino, hydroxyl, Substituent substitution of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl or -O-(C1-C6 alkyl);
  • X is the key
  • W is -CR g Rh or -C(O);
  • R g and R h are each independently hydrogen, halogen, C1-C4 alkyl, C1-C4 chloroalkyl, C1-C4 hydroxyalkyl or C3-C6 cycloalkyl;
  • L is -(CH 2 ) j -;
  • j is 1, 2, 3, 4, 5 or 6.
  • the compound of formula I is selected from
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Methods for the preparation of acceptable salts.
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites thereof , a prodrug and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides a method for degrading IRAK4 protein, comprising making the compound of formula I, and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites
  • the drug, prodrug and/or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted with the IRAK4 protein.
  • the compound of formula I of the present invention and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof
  • the acceptable salts, or pharmaceutical compositions thereof are used as medicaments for the treatment or prevention of IRAK4-mediated diseases or disorders.
  • the compound of formula I of the present invention and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Acceptable salts, or pharmaceutical compositions thereof for use in the treatment or prevention of TLR (other than TLR3R) or IL-1 ⁇ receptor family (including IL-1R, IL-18R, IL-33R, IL-36R) mediated diseases or medical use of the disorder.
  • TLR other than TLR3R
  • IL-1 ⁇ receptor family including IL-1R, IL-18R, IL-33R, IL-36R
  • the compound of formula I of the present invention and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof
  • An acceptable salt, or a pharmaceutical composition thereof is for use as a medicament for the treatment or prevention of an IRAK4-mediated disease or disorder that is a MyD88-driven disease or disorder.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Use of an acceptable salt, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of IRAK4-mediated diseases or disorders.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Use of an acceptable salt, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition mediated by IRAK4, wherein the disease or condition mediated by IRAK4 is a disease or condition driven by MyD88.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Acceptable salts, or pharmaceutical compositions thereof, are prepared for the treatment or prevention of cancer, neurodegenerative disorders, viral diseases, autoimmune diseases, inflammatory diseases, genetic disorders, hormone-related diseases, metabolic disorders, related to organ transplantation Disease, immunodeficiency disorder, destructive bone disease, proliferative disorder, infectious disease, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immune conditions involving T cell activation, cardiovascular disorders, or CNS Use in medicines for disorders and diseases.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Use of acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicaments for the treatment or prevention of cancer or proliferative diseases, the cancer or proliferative diseases being 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, genitourinary tract cancer, esophagus cancer, throat cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, nerve Glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, neck or head tumor, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, adenoma
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Use of acceptable salts, or pharmaceutical compositions thereof, in the preparation of medicines for treating or preventing neurodegenerative diseases, the 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, organ transplantation or graft-versus-host disease of neurodegenerative diseases.
  • the 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, organ transplantation or graft-versus-host disease of neurodegenerative diseases.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof
  • an acceptable salt, or a pharmaceutical composition thereof in the preparation of a medicament for the treatment or prevention of an inflammatory disease
  • the inflammatory disease being an eye disease, such as eye allergy, conjunctivitis, dry eye or vernal conjunctivitis, Diseases, 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, Stephen-Johnson syndrome, idiopathic sprue, font immune inflammatory bowel disease, easy
  • the present invention provides a method of treating or preventing a disease or disorder mediated by IRAK4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and/or stereoisomers, enantiomers, non-pair Enantiomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof.
  • the present invention provides a method of treating or preventing a disease or disorder mediated by IRAK4, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I, and/or stereoisomers, enantiomers, non-pair Enantiomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, the IRAK4-mediated disease or disorder being driven by MyD88 disease or condition.
  • the present invention provides a method of treating or preventing a disease or condition mediated by TLRs (other than 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 a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
  • the present invention provides compounds of formula I, and/or stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Methods for the preparation of acceptable salts:
  • the intermediate Int-a and the 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, and sodium bicarbonate.
  • X 1 is halogen; preferably F.
  • Said Ra , Rb , Rc , Rd , Re , n, Ring A, Ring B, L, Ring C, X, W are as defined above.
  • the intermediate Int-c and the intermediate Int-d undergo reductive amination reaction to obtain the compound of formula I.
  • the reducing reagents for the reductive amination include, but are not limited to, Pd/C, sodium borohydride, sodium cyanoborohydride, borane, and sodium triacetoxyborohydride.
  • the L 1 is -(CH 2 ) j-1
  • the methylene group in the -(CH 2 ) j-1 is as defined in L above, optionally substituted by one or more groups.
  • Said Ra , Rb , Rc , Rd , Re , n, Ring A, Ring B, Ring C, X, W are as defined above.
  • Reductive amination of intermediate Int-e and intermediate Int-f yields the compound of formula I.
  • the reducing reagents for the reductive amination include, but are not limited to, Pd/C, sodium borohydride, sodium cyanoborohydride, borane, and sodium triacetoxyborohydride.
  • L 1 is -(CH 2 ) j-1
  • the methylene group in the -(CH 2 ) j-1 is as defined in L above, optionally substituted by one or more groups.
  • Said Ra , Rb , Rc , Rd , Re , n, Ring A, Ring B, Ring C, X, W are as defined above.
  • Alkyl refers to saturated aliphatic hydrocarbon groups, including straight or branched chain alkyl groups; C1-C8 refers to alkyl groups containing 1-8 carbon atoms, such as methyl, ethyl, n-propyl, iso- Propyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethyl propyl, 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-methylpenty
  • Cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent; "C3-11 cycloalkyl” refers to a cycloalkyl group comprising 3 to 11 carbon atoms; “C3-C8 membered ring” "Alkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atoms; “C5-C10 membered cycloalkyl” refers to a cycloalkyl group comprising 5 to 10 carbon atoms;
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptyl Alkenyl, cyclooctyl, etc., preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably C3-C8 membered cycloalkyl; more preferably C3-C6 membered cycloalkyl.
  • 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 the single rings. They may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably 7-12 membered double-spirocycloalkyl groups.
  • Non-limiting examples of spirocycloalkyl include:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but None of the rings have a fully conjugated pi electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic fused cycloalkyl.
  • fused cycloalkyl groups include:
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms, they may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system , according to the number of rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl.
  • Non-limiting examples of bridged cycloalkyl groups include:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydro Naphthyl, benzocycloheptyl, etc.
  • the cycloalkyl group may be optionally substituted or unsubstituted.
  • Heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r is the integer 0, 1 or 2), but excluding ring moieties of -O-O-, -O-S- or -S-S-, the remaining ring atoms being 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
  • “Cycloalkyl” refers to a ring group containing 3 to 8 ring atoms, preferably "3-11 membered heterocycloalkyl” containing 1-2 heteroatoms selected from N, O or S, more preferably containing 1 or 2 3- to 11-membered heterocycloalkyl with N atoms.
  • Monocyclic heterocycloalkyl is preferably a 3-8 membered monocyclic heterocyclyl containing 1-2 N heteroatoms; non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, piperidinyl, piperazine group, morpholinyl group, thiomorpholinyl group, homopiperazinyl group, etc., preferably piperidinyl group and piperazinyl group.
  • Polycyclic heterocycloalkyl groups include spiro, fused and bridged ring heterocycloalkyl groups.
  • “Spiroheterocycloalkyl” refers to a polycyclic heterocycloalkyl group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O)r (where r are integers 0, 1, 2) and the remaining ring atoms are carbon. They can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
  • the spirocycloalkyl group is divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl, preferably containing 1-2 atoms selected from N, O or a saturated "3-11-membered bis-spiroheterocycloalkyl" of an S heteroatom; more preferably a saturated "7-12-membered bis-spiroheterocycloalkyl" containing 1 or 2 N atoms.
  • spiroheterocycloalkyl include:
  • “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 None of the rings has a fully conjugated pi-electron system, wherein 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.
  • the number of rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkanes, preferably "3-11-membered bicyclic fused heterocycloalkanes containing 1-3 heteroatoms selected from N, O or S" group"; more preferably a saturated "3-11 membered bicyclic fused heterocycloalkyl" containing 1 or 2 N atoms.
  • fused heterocycloalkyl include:
  • Bridged heterocycloalkyl refers to polycyclic heterocycloalkyl groups in which any two rings share two atoms that are not directly connected, they may contain one or more double bonds, but none of the rings have fully conjugated pi electrons System wherein 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.
  • Bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic or polycyclic according to the number of constituent rings, non-limiting examples of bridged heterocycloalkyl include:
  • heterocycloalkyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring linked to the parent structure is a heterocycloalkyl, non-limiting examples include:
  • the heterocycloalkyl group can be optionally substituted or unsubstituted.
  • Aryl refers to an all-carbon monocyclic or fused polycyclic group (that is, rings that share adjacent pairs of carbon atoms) and a polycyclic group with a conjugated pi-electron system
  • 6-10 membered aryl refers to a group containing 6 to 10 members.
  • -10 carbon percarbon aryl groups such as phenyl and naphthyl; preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples include:
  • the aryl group can be optionally substituted or unsubstituted.
  • Heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms including nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2), 5-6 membered heteroatoms
  • Aryl 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 a 5-6 membered heteroaryl; more preferably contains 1 5-6 membered heteroaryl with 1 or 2 N atoms; non-limiting examples include furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyrazole, imidazole pyridyl, triazolyl, tetrazolyl, etc.; preferably pyridyl.
  • the heteroaryl ring can be fused to an aryl, heterocyclo
  • the heteroaryl group can be optionally substituted or unsubstituted.
  • alkenyl refers to an alkyl group 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 or branched chain alkene containing 2 to 8 carbons group, 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 group may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group 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 or branched chain alkynyl group 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 group may be substituted or unsubstituted.
  • Subgroup 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, and Heterocycloalkyl refers to divalent heterocycloalkyl, arylene refers to divalent aryl, heteroarylene refers to divalent heteroaryl, the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkane Radyl, aryl, heteroaryl are as defined above, and the subunits may be optionally substituted or unsubstituted.
  • Haloalkyl refers to an alkyl group optionally substituted with one or more fluorine, chlorine, bromine or iodine atoms, wherein the alkyl group is as defined above, non-limiting examples include difluoromethyl, dichloromethyl , dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Hydroxyalkyl refers to an alkyl group optionally substituted with one or more -OH, wherein the alkyl group is as defined above, non-limiting examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl base.
  • Cyano refers to -CN.
  • Amino refers to -NH2 .
  • Carboxyl or “carboxylic acid” refers to -COOH.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • NMP refers to N-methylpyrrolidone
  • IBX refers to 2-iodoylbenzoic acid.
  • DIEA refers to N,N-diisopropylethylamine.
  • STAB sodium triacetoxyborohydride
  • T3P refers to 2,4,6-tripropyl-1,3,5,2,4,6 - trioxytriphosphoric acid-2,4,6-trioxide.
  • DPBS Dulbecco's Phosphate Buffered Saline.
  • Dess-Martin refers to Dess-Martin reagents.
  • PBS refers to phosphate buffered saline.
  • SDS-PAGE refers to sodium dodecyl sulfate-polyacrylamide gel electrophoresis.
  • PVDF polyvinylidene fluoride
  • Multiple refers to 2, 3, 4, 5, 6, etc., preferably fully substituted.
  • multiple halogens (eg, F) substituted may refer to trifluoromethyl F3C .
  • Optional means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or instances where it does not occur.
  • a heterocycloalkyl group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the specification includes the case where the heterocycloalkyl group is substituted with an alkyl group and the case where the heterocycloalkyl group is not substituted with an alkyl group replaced situation.
  • Substituted means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are independently of one another substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art can determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated (e.g., olefinic) bonds.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the present invention also provides pharmaceutically acceptable salts of the compounds of formula (I).
  • pharmaceutically acceptable salts refers to relatively nontoxic acid or base addition salts of compounds of the present invention.
  • the acid addition salts are salts of the compounds of formula (I) of the present invention with suitable inorganic or organic acids. These salts can be prepared during the final isolation and purification of the compounds, or the purified compounds of formula (I) can be used as It is prepared by reacting its free base form with a suitable organic or inorganic acid.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, bisulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearic acid salt, laurosilicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, rich Maleate, succinate, tartrate, benzoate, mesylate, p-toluenesulfonate, gluconate, lactobionate, lauryl sulfonate, and the like.
  • the base addition salts are salts of compounds of formula (I) with suitable inorganic or organic bases, including, for example, salts with alkali metals, alkaline earth metals, quaternary ammonium cations, such as sodium salts, lithium salts, potassium salts, Calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.; amine salts include salts with ammonia (NH 3 ), primary, secondary or tertiary amines, such as methylamine salts, dimethylamine Amine salt, trimethylamine salt, triethylamine salt, ethylamine salt, etc.
  • quaternary ammonium cations such as sodium salts, lithium salts, potassium salts, Calcium salts, magnesium salts, tetramethyl quaternary ammonium salts, tetraethyl quaternary ammonium salts, etc.
  • the compounds of the present invention can be administered to mammals, including humans, orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically (in powders, ointments or drops) , or intratumoral administration.
  • the compounds of the present invention may be administered at a dose of 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.
  • the compounds of the present invention or pharmaceutically acceptable salts thereof can be formulated into solid dosage forms for oral administration, including but not limited to capsules, tablets, pills, powders, granules, and the like.
  • the compounds of formula (I) of the present invention are mixed as active ingredient with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (1 ) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol and silicic acid, etc.; (2) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabino glue, etc.; (3) humectants, such as glycerin, etc.; (4) disintegrating agents, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, some complex silicates and sodium carbonate, etc.; (5) slow Sol
  • the solid dosage forms such as tablets, dragees, capsules, pills and granules can be coated or microencapsulated with coatings 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 may be in a certain part of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric substances and waxes. If desired, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • liquid dosage forms for oral administration, including, but not limited to, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, tinctures, and the like.
  • liquid dosage forms may contain inert diluents conventionally employed in the art such as water and other solvents, solubilizers and emulsifiers 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 and sesame oil or the like mixture, etc.
  • the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening
  • Such suspending agents include, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan only, microcrystalline cellulose, aluminum methoxide and agar, and the like or mixtures of these substances.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof can be formulated in dosage forms for parenteral injection including, but not limited to, physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and for reconstitution Sterile powder for sterile injectable solution or dispersion.
  • Suitable carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof may also be formulated for topical administration in dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
  • dosage forms including, for example, ointments, powders, suppositories, drops, propellants, inhalants, and the like.
  • the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, as the active ingredient is under sterile conditions together with a physiologically acceptable carrier and optionally a preservative, buffer, or propellant which may be required if necessary mix.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the compound of formula (I) of the present invention, or a pharmaceutically acceptable salt thereof is usually admixed with a pharmaceutically acceptable carrier, excipient or diluent.
  • compositions 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, propellants, and the like.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof, can be administered alone, or (if desired) in combination with other pharmaceutically acceptable therapeutic agents, such as other antineoplastic, anti-inflammatory or autoimmune agents sexual drug combination.
  • the ingredients to be combined may be administered simultaneously or sequentially, in a single formulation or in separate formulations.
  • the combination may include not only a combination of a compound of the present invention and one other active agent, but also a combination of a compound of the present invention and two or more other active agents.
  • the IRAK4 kinase activity test experiment proves that the compound of formula I of the present invention can effectively bind to IRAK4 target protein or produce an inhibitory effect;
  • Western-Blot proves that the compound of formula I of the present invention can effectively and specifically degrade THP- 1 IRAK4 protein in cells;
  • studies on the pharmacokinetic properties of mice prove that the compound of the present invention has low clearance rate, high plasma exposure, good oral bioavailability, and good pharmacokinetic properties;
  • IKZF3 degradation experiments proved that the compounds of the present invention have good selectivity.
  • the compound of formula I described in the present invention and/or its stereoisomers, enantiomers, diastereomers, deuterated compounds, hydrates, solvates, metabolites, prodrugs and/or pharmaceutically acceptable compounds thereof Acceptable salts can effectively degrade IRAK4 protein, thereby achieving the effect of preventing or treating diseases or conditions related to IRAK4.
  • the present invention will be further described in detail and completely below in conjunction with the embodiments, but the present invention is by no means limited, and the present invention is not limited to the contents of the embodiments.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the experimental methods that do not specify specific conditions in the examples of the present invention are usually in accordance with conventional conditions, or in accordance with conditions suggested by raw material or commodity manufacturers.
  • Step 3 Preparation of tert-butyl 4-(6-methoxy-5-nitro-2H-indazol-2-yl)piperidine-1-carboxylate
  • Step 4 Preparation of tert-butyl 4-(5-amino-6-methoxy-2H-indazol-2-yl)piperidine-1-carboxylate
  • Step 5 tert-butyl 4-(6-methoxy-5-(6-(trifluoromethyl)pyridine-2-amide)-2H-indazol-2-yl)piperidine-1-carboxylate preparation
  • Step 7 4-(2-(4-(6-Methoxy-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidin-1-yl ) ethyl) piperidine-1-carboxylate tert-butyl ester preparation
  • the reaction solution was diluted with ethyl acetate (50 mL), 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 to obtain 700 mg of the target product as a yellow solid.
  • Step 8 N-(6-Methoxy-2-(1-(2-(piperidin-4-yl)ethyl)piperidin-4-yl)-2H-indazol-5-yl)-6 Preparation of -(trifluoromethyl)picolinamide
  • Step 1 N-(2-(1-(2,2-Dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-( Preparation of trifluoromethyl)picolinamide
  • N-(2-(1-(2,2-dimethoxyethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoro A mixture of methyl)picolinamide (500 mg, 0.99 mmol) in a solution of hydrochloric acid (4 mL)/dioxane (5 mL) was stirred at 50°C overnight. Concentrate under reduced pressure to remove the solvent, add water (20 mL), extract with ethyl acetate (20 mL ⁇ 3), combine the organic layers, wash with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure. The concentrate was purified by column to obtain 300 mg of the target product as an oil.
  • Step 2 Preparation of methyl 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-nitro-2H-indazole-6-carboxylate
  • the organic layers were combined, washed with brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the concentrate was purified by silica gel column to obtain 2.01 g of the target product as a yellow solid.
  • Step 3 Preparation of methyl 5-amino-2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-2H-indazole-6-carboxylate
  • Step 4 2-(1-(tert-Butoxycarbonyl)piperidin-4-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazole-6-carboxylic acid methyl ester
  • the organic layers were combined, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the concentrate was purified by silica gel column to obtain 150 mg of the target product as a yellow solid.
  • Step 5 4-(6-(2-Hydroxypropan-2-yl)-5-(6-(trifluoromethyl)picolinamido)-2H-indazol-2-yl)piperidine-1- Preparation of tert-butyl carboxylate
  • the aqueous layer was separated and extracted with ethyl acetate (50 mL ⁇ 2), the organic layers were combined, washed with brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the concentrate was purified by silica gel column to obtain White solid target product 435 mg.
  • Step 1 Preparation of tert-butyl 4-(2,2-dimethoxyethyl)piperazine-1-carboxylate
  • Step 3 5-(4-(2,2-Dimethoxyethyl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline Preparation of -1,3-dione
  • Step 4 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1- Preparation of acetaldehyde
  • Step 1 2-(2,6-Dioxopiperidin-3-yl)-5-(4-(2-hydroxyethyl)piperidin-1-yl)isoindoline-1,3- Preparation of diketones
  • Step 1 4-(2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylic acid tert.
  • Step 2 Preparation of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione
  • Step 1 Reduction of 2-(2,6-dioxopiperidin-3-yl)-5-(2-(2-hydroxyethoxy)ethoxy)isoindoline-1,3-dione preparation
  • 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 to obtain 32 mg of the target product as a white solid.
  • Step 1 9-(2-Ethoxy-2-oxoethylidene)-3-azaspiro[5.5]undecane-3-carboxylate tert-butyl ester
  • Step 2 9-(2-Ethoxy-2-oxoethyl)-3-azaspiro[5.5]undecan-3-carboxylate tert-butyl ester
  • Step 3 tert-Butyl 9-(2-hydroxyethyl)-3-azaspiro[5.5]undecan-3-carboxylate
  • Example 1 N-(2-(1-(2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)piperidin-4-yl)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide
  • Example 6 N-(2-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)piperidin-4-yl)propyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(tris Fluoromethyl)picolinamide
  • Example 7 N-(2-(1-((1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5 -yl)piperidin-4-yl)methyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)-6-(trifluoromethyl) base) picolinamide
  • Example 8 N-(2-(1-(2-(1-(2-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)piperidin-4-yl)2-methylpropyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl)- 6-(Trifluoromethyl)picolinamide
  • Example 10 N-(2-(1-(3-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline -5-yl)piperidin-4-yl)-3-methylbutyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl) -6-(Trifluoromethyl)picolinamide
  • Example 11 N-(2-(1-(3-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)piperazin-1-yl)-3-methylbutyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5-yl) -6-(Trifluoromethyl)picolinamide
  • Example 12 N-(2-(1-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)-3-azaspiro[5.5]undecan-9-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazole -5-yl)-6-(trifluoromethyl)picolinamide
  • Example 13 N-(2-(1-(9-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- yl)-3,9-diazaspiro[5.5]undecan-3-yl)ethyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazole -5-yl)-6-(trifluoromethyl)picolinamide
  • Example 14 N-(2-(1-(2-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) -5-yl)-3-azaspiro[5.5]undecan-9-yl)-2-methylpropyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl) -2H-Indazol-5-yl)-6-(trifluoromethyl)picolinamide
  • Example 15 N-(2-(1-(3-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5- yl)-3-azaspiro[5.5]undecan-9-yl)methyl)piperidin-4-yl)-6-(2-hydroxypropan-2-yl)-2H-indazol-5- yl)-6-(trifluoromethyl)picolinamide
  • Control 1 N-(2-(1-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline- 5-yl)oxy)ethoxy)ethyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoromethyl)picolinamide
  • Control 2 N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline) dol-5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(tris Fluoromethyl)picolinamide
  • Step 1 Preparation of 5-(allyloxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione
  • Step 2 2-((2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)oxy)acetaldehyde
  • Step 3 N-(2-(1-((1-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole -5-yl)oxy)ethyl)piperidin-4-yl)methyl)piperidin-4-yl)-6-methoxy-2H-indazol-5-yl)-6-(trifluoro Preparation of methyl)picolinamide
  • KinEASE-STK S1 serine/threonine kinase kit (Cisbio) was used to detect the inhibitory effect of compounds on IRAK4 kinase activity.
  • the specific method was as follows: the compounds were dissolved in dimethyl sulfoxide, and then the kit's buffer was used for equal gradient dilution. , so that the final concentration of the test compound in the reaction system ranges from 10000nM to 0.038nM, and then 2.5nM kinase, 1 ⁇ M biotinylated polypeptide substrate and 7 ⁇ M adenosine triphosphate (ATP) were added in sequence and incubated at 37°C for 120min.
  • ATP adenosine triphosphate
  • the inhibition rate of the compound at each concentration was calculated, and then the nonlinear curve fitting was performed by GraphPad Prism 7 with logarithmic concentration-inhibition rate, and the IC 50 value of the compound was obtained.
  • the cell pellet was washed twice with 1 ⁇ DPBS, and the resuspended cells were washed with 200 ⁇ L of lysis buffer (the cell lysis buffer was Western and IP cell lysis buffer (Biyuntian), supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Biyuntian). )) was lysed, and after standing on ice for 30 minutes, centrifuged at 14000g and 4°C for 10 minutes, and the supernatant was collected to detect the protein level of IRAK4 by Western Blot.
  • the cell lysis buffer was Western and IP cell lysis buffer (Biyuntian), supplemented with 1 mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Biyuntian).
  • the total protein concentration in the above cell lysis supernatant was determined with BCA protein quantification kit (Tiangen).
  • the concentration of total protein detected by BCA was adjusted to 0.2 ⁇ g/ ⁇ L with PBS and 5 ⁇ SDS-PAGE protein loading buffer (Biyuntian), water bathed at 100°C for 10 minutes, and then placed on ice for 5 minutes, 14000g , After centrifugation at 4°C for 5 minutes, the supernatant was collected as the loading sample for WB.
  • Use precast gel (Keygen) for protein electrophoresis the loading volume is 10 ⁇ L (total protein 2 ⁇ g), and then electrophoresis at 120V constant voltage after Tris-MOPS-SDS electrophoresis solution (Adamas).
  • the membrane was transferred at a constant current of 250V for 50 minutes. After transfer, the membrane was placed in 1 ⁇ QuickBlock blocking solution (Biyuntian) and incubated at room temperature for 30 minutes. After blocking, the PVDF membranes were incubated with IRAK4 primary antibody (Abcam) at 4° overnight, and the membranes were washed with TBST buffer (2.4g Tris, 8.8g NaCl, 1.5mL Tween 20, adjusted to pH 7.4, and the volume was adjusted to 1L) for 30 minutes.
  • TBST buffer 2.4g Tris, 8.8g NaCl, 1.5mL Tween 20, adjusted to pH 7.4, and the volume was adjusted to 1L
  • the secondary antibody (Abcam) was incubated at room temperature for 2 hours, and finally incubated with Clarity Western ECL Substrate (BIO-RAD) for 5 minutes for luminescence and color development.
  • WB refers to Western Blot method
  • D (%) refers to the percentage of degradation of IRAK4 kinase protein in THP-1 cells detected by Western Blot method
  • D (%) (1000nM) refers to the degradation of IRAK4 when the compound concentration is 1000nM
  • the percentage, D(%) (300 nM) is the percent degradation of IRAK4 at a compound concentration of 300 nM.
  • mice mice were treated with the following experimental protocol to study the pharmacokinetic behavior of the compounds of the present invention in mice, and to evaluate their pharmacokinetic characteristics.
  • mice Male, weighing 18-25 mg, were given 1 mg/kg of compound by intravenous injection in a volume of 5 mL/kg, formulated in 5% DMSO/15% solutol% 80% PBS (w/v). The rats were fasted for 12 h before the test and had free access to water. 4h after the administration of unified food.
  • 0.1 mL of venous blood was collected from the submandibular venous plexus of the rat, placed in a heparinized test tube, centrifuged at 11,000 rpm for 5 min, the plasma was separated, and the concentration of the compounds in the plasma was determined by liquid chromatography-tandem mass spectrometry.
  • the experimental results show that the compound of the present invention has low clearance rate, high plasma exposure, good oral bioavailability and good pharmacokinetic properties, which is beneficial to finished medicine.
  • Test Example 4 Degradation of IKZF1, IKZF3 in L363 Cells by Compounds
  • the cell pellet was washed twice with 1 ⁇ DPBS, and the resuspended cells were washed with 100 ⁇ L of lysis buffer (the cell lysis buffer was Western and IP cell lysis buffer (Biyuntian), supplemented with 1mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Biyuntian). )) was lysed, and after standing on ice for 30 minutes, centrifuged at 14000g and 4°C for 10 minutes, and the supernatant was collected to detect the protein levels of IKZF1 and IKZF3 by Western Blot respectively.
  • the cell lysis buffer was Western and IP cell lysis buffer (Biyuntian), supplemented with 1mM phenylmethylsulfonyl fluoride and protease inhibitor mixture (Biyuntian).
  • the total protein concentration in the above cell lysis supernatant was determined with BCA protein quantification kit (Tiangen).
  • the concentration of total protein detected by BCA was adjusted to 0.2 ⁇ g/ ⁇ L with PBS and 5 ⁇ SDS-PAGE protein loading buffer (Biyuntian), water bathed at 100°C for 10 minutes, and then placed on ice for 5 minutes, 14000g , After centrifugation at 4°C for 5 minutes, the supernatant was collected as the loading sample for WB.
  • Use precast gel (Keygen) for protein electrophoresis the loading volume is 10 ⁇ L (total protein 2 ⁇ g), and then electrophoresis at 120V constant voltage after Tris-MOPS-SDS electrophoresis solution (Adamas).
  • the membrane was transferred at a constant current of 250V for 50 minutes. After transfer, the membrane was placed in 5% bovine serum albumin solution and incubated at room temperature for 2 hours. After blocking, the PVDF membrane was incubated with IKZF1 primary antibody (CST) and IKZF3 primary antibody (Abcam) at 4° overnight, respectively, in TBST buffer (2.4g Tris, 8.8g NaCl, 1.5mL Tween 20, pH was adjusted to 7.4, and the volume was adjusted to 7.4).
  • CST IKZF1 primary antibody
  • IKZF3 primary antibody Abcam
  • the compound of the present invention has good selectivity, no or a small amount of degradation of IKZF1 and IKZF3, and less toxic and side effects, which is beneficial to finished medicine.

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Abstract

提供了一类靶向IRAK4激酶蛋白降解的吲唑类衍生物、及其制备方法和应用。具体涉及式Ⅰ化合物、其制备方法、及其药物组合物和应用，其中所述Ra、Rb、Rc、Rd、Re、n、环A、环B、L、环C、X、W如说明书中所定义。所述化合物能够显著的降解细胞中的IRAK4激酶蛋白，可用作制备治疗和/或预防由IRAK4介导的相关疾病或病症的药物，如癌症、免疫性疾病和炎性疾病。

Description

吲唑类衍生物及其制备方法和应用
技术领域:本发明属于药物领域，具体的本发明涉及靶向IRAK4蛋白降解的吲唑类衍生物、及其制备方法和其在制备治疗和/或预防由IRAK4介导的相关疾病或病症的药物中的应用，如癌症、免疫性疾病和炎性疾病。
背景技术：白介素-1受体激酶4(IRAK4)是一种丝氨酸/苏氨酸特异性蛋白激酶，具有生物学上重要的激酶活性，在激活免疫系统中起重要作用。研究表明，IRAK4是白细胞介素(IL)-1β家族受体(包括IL-1R、IL-18R、IL-33R、IL-36R)和Toll样受体(TLR)信号传导通路下游的关键因子,IRAK4缺失的小鼠和IRAK4缺失的患者均对TLR(TLR3除外)和IL-1β家族的刺激不起反应(Suzuki,Suzuki等人，Nature,2002；Davidson,Currie等人，The Journal ofImmunology,2006；Ku,von Bernuth等人，JEM,2007；Kim,Staschke等人，JEM,2007)。
根据有无MyD88的参与，TLR/IL-1β介导的信号通路可分为MyD88依赖型信号通路和MyD88非依赖性通路，其中IL-1R和TLR2、TLR4、TLR7/8、TLR9所介导的信号转导通路都依赖MyD88作为调节因子激活下游的炎症信号通路。TLR/IL-1β与配体结合后，募集MyD88分子，MyD88通过其N末端死亡结构域进一步募集IRAK4到TLR/IL-1β复合物中，并与IRAK1或IRAK2相互作用且将其激活(Kollewe,Mackensen等人，Journal ofBiological Chemistry,2004；Precious等人，J.Biol.Chem.,2009)，从而向下游传递信号至E3泛素连接酶TNF受体相关因子(TRAF6)，活化丝氨酸/苏氨酸激酶TAK1，进而激活NF－κB及MAPK信号通路(Wang,Deng等人，Nature,2001)，引起多种炎症细胞因子和抗凋亡分子的释放。IRAK4依赖性的TLR/IL-1β信号通路已经被证明与多种疾病相关：如多发性硬化、动脉粥样硬化、心肌梗死、心肌炎(Valaperti,Nishii等人，Circulation,2013)伏格特-小柳-原田综合征(Vogt-Koyanagi-Harada syndrome)、系统性红斑狼疮(SLE)、肥胖(Ahmad,R.,P.Shihab等人，Diabetology&Metabolic Syndrome,2015)、1型糖尿病、类风湿性关节炎、脊椎关节炎(特别是牛皮癣性脊椎关节炎和别克捷列夫氏病(Bekhterev's disease))、红斑狼疮、银屑病、白癜风、巨细胞动脉炎、慢性炎性肠道疾病和病毒性疾病，例如HIV(人免疫缺陷病毒)、肝炎病毒(Staschke等人，The Journal ofImmunology,2009；Marquez等人，Ann Rheum Dis,2014；Zambrano-Zaragoza等人，International Journal of Inflammation,2014；Wang等人，Experimental andTherapeutic Medicine,2015；Ciccia等人，Rheumatology,2015)；皮肤病如银屑病、特应性皮炎、金德勒综合征(Kindler's syndrome)、大疱性类天疱疮、变应性接触性皮炎、斑秃、反常性痤疮(acneinversa)和寻常痤疮；其他炎症性疾病如过敏症、贝切特氏病、痛风、成人斯蒂尔氏病(adult-onset Still's disease)、心包炎和慢性炎性肠道疾病例如溃疡性结肠炎和克罗恩氏病(Crohn's disease)、移植排斥反应和移植物抗宿主反应；妇科疾病例如子宫内膜异位症(adenomyosis)、痛经、交媾困难和子宫内膜组织异位症(endometriosis)，特别是与子宫内膜异位症相关的疼痛和其他与子宫内膜异位症相关的症状例如痛经、交媾困难、排尿困难和大便困难(Akoum,Lawson等人，Human Reproduction,2007；Allhorn,Boing等人，Reproductive Biology and Endocrinology,2008；Lawson,Bourcier等人，Journal of Reproductive  Immunology,2008；Sikora,Mielczarek-Palacz等人，American Journal of Reproductive Immunology,2012；Khan,Kitajima等人，Journal of Obstetrics and Gynaecology Research,2013；Santulli,Borghese等人，Human Reproduction,2013)；眼部疾病如视网膜缺血、角膜炎、过敏性结膜炎、干燥性角结膜炎、黄斑变性和眼色素层炎(Kaarniranta和Salminen,J Mol Med(Berl),2009；Sun和Pearlman,InvestigativeOphthalmology&Visual Science,2009；Redfern和McDermott,Experimental EyeResearch,2010；Kezic,Taylor等人，J Leukoc Biol,2011；Chang,McCluskey等人，Clinical&Experimental Ophthalmology,2012；Guo,Gao等人，Immunol Cell Biol,2012；Lee,Hattori等人，Investigative Ophthalmology&Visual Science,2012；Qi,Zhao等人，Investigative Ophthalmology&Visual Science,2014)；纤维化疾病如肝纤维化、心肌炎、原发性胆汁性肝硬化、囊性纤维化(Zhao,Zhao等人，Scand J Gastroenterol,2011；Benias,Gopal等人，Clin Res Hepatol Gastroenterol,2012；Yang,L.和E.Seki,FrontPhysiol,2012；Liu,Hu等人，Biochim Biophys Acta.,2015)；慢性肝脏疾病，例如脂肪肝肝炎，特别是非酒精性脂肪性肝病(NAFLD)和/或非酒精性脂肪性肝炎(NASH)、酒精性脂肪性肝炎(ASH)(Nozaki,Saibara等人，Alcohol Clin Exp Res,2004；Csak,T.,A.Velayudham等人，Am J PhysiolGastrointest Liver Physiol,2011；Miura,Kodama等人，Gastroenterology,2010；Kamari,Shaish等人，J Hepatol,2011；Ye,Li等人，Gut,2012；Roh,Seki,J GastroenterolHepatol,2013；Ceccarelli,S.,V.Nobili等人，World J Gastroenterol,2014；Miura,Ohnishi,World J Gastroenterol,2014；Stojsavljevic,Palcic等人，World JGastroenterol,2014)；心血管疾病和神经障碍，例如心肌再灌注损伤、心肌梗死、高血压(Oyama,Blais等人，Circulation,2004；Timmers,Sluijter等人，Circulation Research,2008；Fang和Hu,MedSci Monit,2011；Bijani,International Reviews of Immunology,2012；Bomfim,DosSantos等人，Clin Sci(Lond),2012；Christia和Frangogiannis,European Journal ofClinical Investigation,2013；Thompson和Webb,Clin Sci(Lond),2013；Hernanz,Martínez-Revelles等人，British Journal of Pharmacology,2015；Frangogiannis,Curr OpinCardiol,2015；Bomfim,Echem等人，LifeSciences,2015),以及阿尔茨海默氏病、中风、颅脑创伤、肌萎缩性侧索硬化(ALS)和帕金森氏症(Brough,Tyrrell等人，Trends inPharmacological Sciences,2011；Carty和Bowie,Biochemical Pharmacology,2011；Denes,Kitazawa,Cheng等人，The Journal of Immunology,2011；Lim,Kou等人，TheAmerican Journal of Pathology,2011；Béraud和Maguire-Zeiss,Parkinsonism&RelatedDisorders,2012；Denes,Wilkinson等人，Disease Models&Mechanisms,2013；Noelker,Morel等人，Sci.Rep.,2013；Wang,Wang等人，Stroke,2013；Xiang,Chao等人，RevNeurosci,2015；Lee,Lee等人，J Neuroinflammation,2015)；瘙痒和疼痛(包括急性、慢性、炎性和神经性疼痛)如痛觉过敏、异常性疼痛、经前痛、与子宫内膜异位症相关的疼痛、手术后疼痛、间质性膀胱炎、CRPS(复杂性局部疼痛综合征)、三叉神经痛、前列腺炎、脊髓损伤引起的疼痛、炎症引发的疼痛、下腰痛、癌痛、化疗相关的疼痛、HIV治疗诱发的神经病、烧伤引起的疼痛和慢性疼痛(Wolf,Livshits等人，Brain,Behavior,and Immunity,2008；Kim,Lee等人，Toll-like Receptors:Roles in Infection and Neuropathology,2009；del Rey,Apkarian等人，Annals of the New York Academy of Sciences,2012；Guerrero,Cunha等人，European Journal of Pharmacology,2012； Kwok,Hutchinson等人，PLoS ONE,2012；Nicotra,Loram等人，Experimental Neurology,2012；Chopra和Cooper,J NeuroimmunePharmacol,2013；David,Ratnayake等人，Neurobiology of Disease,2013；Han,Zhao等人，Neuroscience,2013；Liu和Ji,Pflugers Arch.,2013；Stokes,Cheung等人，Journal ofNeuroinflammation,2013；Zhao,Zhang等人，Neuroscience,2013；Liu,Zhang等人，CellResearch,2014；Park,Stokes等人，Cancer Chemother Pharmacol,2014；Van der Watt,Wilkinson等人，BMC Infect Dis,2014；Won,K.A.,M.J.Kim等人，J Pain,2014；Min,Ahmad等人，Photochem Photobiol.,2015；Schrepf,Bradley等人，Brain Behav Immun,2015；Wong,L.,J.D.Done等人，Prostate,2015)；肿瘤疾病如某些淋巴瘤：ABC-DLBCL(活化B细胞弥漫性大细胞B细胞淋巴瘤)、套细胞淋巴瘤和沃尔丹斯特伦疾病(disease)，以及慢性淋巴细胞性白血病、黑色素瘤、胰腺肿瘤和肝细胞癌(Ngo,Young等人，Nature,2011；Puente,Pinyol等人，Nature,2011；Ochi,Nguyen等人，J Exp Med,2012；Srivastava,Geng等人，CancerResearch,2012；Treon,Xu等人，New England Journal of Medicine,2012；Choi,Kim等人，Human Pathology,2013；Liang,Chen等人，Clinical Cancer Research,2013)、ras-依赖性肿瘤、乳腺癌、卵巢癌、结肠直肠癌、头颈部癌、肺癌、前列腺癌。
IRAK4介导的信号传导途径的调节主要与其激酶功能有关，但是，也有一些报道表明在某些细胞类型中，IRAK4对下游过程的信号调节与IRAK4的非激酶功能有关。Cushing等人就表示，尽管在IL-1β刺激的人皮肤成纤维细胞中IRAK4磷酸化水平降低，但IRAK4的药理抑制作用并不会导致IL-6和TNF-α的抑制。支持这些结果的是，IRAK4缺乏的成纤维细胞与野生型细胞相比，IRAK4的支架功能对于IL1信号传导很重要，但是它的激酶作用却是多余的。同时，Chiang和他的同事也表示，IRAK4激酶活性在人类B细胞和T细胞、树突状细胞和单核细胞中不是必要的，且siRNA基因切除也显示IRAK4在这些细胞中具有支架功能作用。现已报道了多种针对IRAK4的强效的选择性抑制剂，如CA-4948、BAY-1834845、BMS-986126以及PF-06650833等，这些抑制剂都能选择性的抑制IRAK4的激酶活性，主要用于自身免疫性疾病，炎性疾病和肿瘤性疾病的预防和治疗。然而，一方面由于IRAK4具有支架蛋白和活性激酶的作用，且另一方面传统的小分子抑制剂易产生耐药性，因此，仅抑制IRAK4激酶活性可能不足以产生治疗效果。
蛋白降解靶向嵌合体(Proteolysis Targeting Chimeria，PROTAC)是一种不同于传统小分子抑制剂的技术，传统小分子抑制剂通常需要作用于靶蛋白的活性位点才能抑制其活性，而PROTAC为一种异质双功能分子，其一端为可识别靶蛋白的小分子抑制剂，通过连接链，另一端为可识别E3泛素连接酶的E3泛素连接酶配体，这种双功能分子在体内识别靶蛋白和E3泛素连接酶，将靶蛋白和E3泛素连接酶拉近，形成三元复合物，将靶蛋白泛素化后，在体内通过泛素－蛋白酶体途径将靶蛋白降解。相较于传统小分子抑制剂，一方面PROTAC只需要将靶蛋白与E 3泛素连接酶拉近，使底物降解，这种作用模式使得这种技术可以应用于一些不可成药靶点；另一方面，由于靶蛋白在被降解后，PROTAC分子还可释放出来继续参与下一蛋白的降解过程，因此这种具有催化效果的降解作用，使得较少的PROTAC药物剂量就可以实现高效的降解；再一方面，传统的小分子抑制剂易产生耐药性常常是因为发生了点突变，使得小分子抑制剂失去了对靶点的抑制 作用，而PROTAC可以直接将靶蛋白降解，在一定程度上能过避免点突变产生的耐药性。因此，相较于传统小分子抑制剂，运用PROTAC技术进行新药小分子研发具有很高的优势和可行性，有望成为下一代极具前途的新型药物。PROTAC技术也已被应用于多种靶点药物的改造，如雄性激素受体、雌性激素蛋白受体、BTK等等。US2019/0151295、US2019/0192688、WO2019/160915和WO2020/113233中公开了几类靶向IRAK4降解的化合物，更多的靶向IRAK4降解的化合物丞待开发。
发明内容
PROTAC由于其分子量大，PK成为其成药的主要障碍之一，因此具有好的PK性质的化合物是成药所优先考虑的。本发明提供了一类具有好的降解性质以及PK性质的化合物。
本发明提供了式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐
Figure PCTCN2021075341-appb-000001
其中：
R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
环A为6-10元芳基或5-10元杂芳基；
R d各自独立的为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6元环烷基)、C3-C6元环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选的被1个或多个选自卤素、羟基、氨基的基团取代；
n为1、2、3或者4；
R e为氢或者C1-C6烷基；
R c为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
R b为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
环B为6-10元芳基、5-10元杂芳基、C3-C12元环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
环C为6-10元芳基、5-10元杂芳基、C3-C12元环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
X为键、-O-、-NH-、-N(C1-C6烷基)-、-S-、-C＝C-、-C≡C-、-C(O)-、-OC(O)-、-C(O)O-、-NHC(O)-或-C(O)NH-；
W为-CR gR h或-C(O)；
R g、R h各自独立的为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6元环烷基；
L为-(CH 2) j-，所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-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-、亚乙烯基或亚乙炔基的基团替代；
R 1’、R 2’各自独立为卤素、-OH、-NH 2、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基、-O(C1-C4烷基)、-NH(C1-C4烷基)、-NH(C1-C4烷基)、C3-C6元环烷基、-O(C3-C6元环烷基)、-NH(C3-C6元环烷基)、3-6元杂环烷基、-O(3-6元杂环烷基)、-NH(C3-C6元环烷基)；
R 3’、R 4’各自独立的为氢或C1-C6烷基；
j为1、2、3、4、5或6；
条件是式Ⅰ化合物不包括以下化合物
Figure PCTCN2021075341-appb-000002
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐为式Ⅱ化合物
Figure PCTCN2021075341-appb-000003
其中所述R a、R b、R c、R d、R e、n、环A、环B、L、环C、X、W如上所定义。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，X为键。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环B为3-8元单环环烷基、7-12元螺环环烷基、7-12元稠环环烷基、含有1-2个N杂原子的3-8元单环杂环烷基、含有1-2个N杂原子的7-12元稠环杂环烷基或含有1-2个N杂原子的7-12元螺环杂环烷基。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环B为环己烷、哌啶基或哌嗪基。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环B为哌啶基。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环B为
Figure PCTCN2021075341-appb-000004
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环C为3-8元单环环烷基、7-12元螺环环烷基、7-12元稠环环烷基、含有1-2个N杂原子的3-8元单环杂环烷基、含有1-2个N杂原子的7-12元稠环杂环烷基或含有1-2个N杂原子的7-12元螺环杂环烷基。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环C为环己烷、哌啶基、哌嗪基、
Figure PCTCN2021075341-appb-000005
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环C为
Figure PCTCN2021075341-appb-000006
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R a为氢。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，W为C(O)。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，环A为苯基或吡啶基。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R d各自独立的为氢、卤素、氰基、C1-C6烷基、C3-C6元环烷基，所述烷基、环烷基任选的被1个或多个选自卤素、羟基、氨基的基团取代。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R d各自独立的为氢、卤素或任选的被1个或多个选自F或羟基的基团取代的C1-C6烷基。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R d为氢、F、甲基、二氟甲基、三氟甲基或2-羟基丙基。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，n为1或2。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R e为氢。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R c为氢、-O(C1-C6烷基)、-N(C1-C6烷基) 1-2、C1-C6烷基、-O(C3-C6元环烷基)、-N(C3-C6元环烷基)、-O(3-6元杂环烷基)、-N(3-6元杂环烷基)，所述烷基、环烷基、杂环烷基任选被1个或多个独立的选自羟基、氨基、卤素、氰基的基团取代。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R c为任选被1个或多个独立的选自羟基或卤素的基团取代的C1-C6烷基、含有1个或2个N杂原子的C3-C6元环烷基或任选被1个或多个独立的选自羟基或卤素的基团取代的-O(C1-C6烷基)。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R c为二氟甲基、羟基取代的吡咯烷基、2-羟基丙基、甲氧基、乙氧基或异丙氧基。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R b为氢或C1-C6烷基，所述烷基任选被1个或多个独立的选自羟基、氨基、卤素、氰基的基团取代。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，R b为氢或甲基。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受 的盐，L为-(CH 2) j-，所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-NR 3’-、-O-、-CR 1’R 2’-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NR 3’-、-NR 3’C(O)-的基团替代；所述R 1’、R 2’各自独立为卤素、-OH、-NH 2、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或-O(C1-C4烷基)；所述R 3’、R 4’各自独立的为氢或甲基；j为1、2或3。
优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，L为-(CH 2) j-，j为1、2或3。
更优选的，本发明某些实施方式中，式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，L为
Figure PCTCN2021075341-appb-000007
在另一优选例中，R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
环A为6-10元芳基或5-10元杂芳基；
R d各自独立地为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6元环烷基)、C3-C6元环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选地被1个或多个选自卤素、羟基、氨基的基团取代；
n为1、2、3或者4；
R e为氢或者C1-C6烷基；
R c为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
R b为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
环B为6-10元芳基、5-10元杂芳基、C3-C12环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
环C为6-10元芳基、5-10元杂芳基、C3-C12环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
X为键；
W为-CR gR h或-C(O)；
R g、R h各自独立地为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6环烷基；
L为-(CH 2) j-；
j为1、2、3、4、5或6。
在另一优选例中，R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
环A为6-10元芳基或5-10元杂芳基；
R d各自独立地为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6元环烷基)、C3-C6元环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选地被1个或多个选自卤素、羟基、氨基的基团取代；
n为1、2、3或者4；
R e为氢或者C1-C6烷基；
R c为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
R b为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
环B为6-10元芳基、5-10元杂芳基、或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
环C为6-10元芳基、5-10元杂芳基、C3-C12环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
X为键；
W为-CR gR h或-C(O)；
R g、R h各自独立地为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6环烷基；
L为-(CH 2) j-，所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-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-、 亚乙烯基或亚乙炔基的基团替代；
R 1’、R 2’各自独立为卤素、-OH、-NH 2、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基、-O(C1-C4烷基)、-NH(C1-C4烷基)、-NH(C1-C4烷基)、C3-C6元环烷基、-O(C3-C6元环烷基)、-NH(C3-C6元环烷基)、3-6元杂环烷基、-O(3-6元杂环烷基)、-NH(C3-C6元环烷基)；
R 3’、R 4’各自独立的为氢或C1-C6烷基；
j为1、2、3、4、5或6。
在另一优选例中，R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
环A为6-10元芳基或5-10元杂芳基；
R d各自独立地为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6元环烷基)、C3-C6元环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选地被1个或多个选自卤素、羟基、氨基的基团取代；
n为1、2、3或者4；
R e为氢或者C1-C6烷基；
R c为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
R b为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
环B为6-10元芳基、5-10元杂芳基、或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
环C为6-10元芳基、5-10元杂芳基、或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
X为键；
W为-CR gR h或-C(O)；
R g、R h各自独立地为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6环烷基；
L为-(CH 2) j-；
j为1、2、3、4、5或6。
在另一优选例中，R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
环A为6-10元芳基或5-10元杂芳基；
R d各自独立地为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6元环烷基)、C3-C6元环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选地被1个或多个选自卤素、羟基、氨基的基团取代；
n为1、2、3或者4；
R e为氢或者C1-C6烷基；
R c为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
R b为氢、-O-(C1-C6烷基)、-O-(C3-C8元环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8元环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8元环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立的选自羟基、氨基、卤素或氰基的基团取代；
环B为含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
环C为含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
X为键；
W为-CR gR h或-C(O)；
R g、R h各自独立地为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6环烷基；
L为-(CH 2) j-；
j为1、2、3、4、5或6。
更优选的，本发明某些实施方式中，式Ⅰ化合物选自
Figure PCTCN2021075341-appb-000008
Figure PCTCN2021075341-appb-000009
Figure PCTCN2021075341-appb-000010
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐的制备方法。
本发明提供了药物组合物，包括治疗有效量的式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，以及药学上可接受的载体、稀释剂或赋形剂。
本发明提供了一种降解IRAK4蛋白的方法，包括使式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物与IRAK4蛋白接触。
本发明所述式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物用作治疗或预防IRAK4介导的疾病或病症的药物使用。
本发明所述式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物用作治疗或预防TLR(除TLR3R以外)或IL-1β受体家族(包括IL-1R、IL-18R、IL-33R、IL-36R)介导的疾病或病症的药物使用。
本发明所述式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物用作治疗或预防IRAK4介导的疾病或病症的药物使用，所述IRAK4介导的疾病或病症为MyD88所驱动的疾病或病症。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防IRAK4介导的疾病或病症的药物中的应用。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防TLR(除TLR3R以外)或IL-1β受体家族(包括IL-1R、IL-18R、IL-33R、IL-36R)介导的疾病或病症的药物中的应用。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防IRAK4调控的疾病或病症的药物中的应用，所述IRAK4介导的疾病或病症为MyD88所驱动的疾病或病症。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防癌症、神经退化性病症、病毒性疾病、自身免疫性疾病、炎性疾病、遗传性病症、激素相关疾病、代谢病症、与器官移植相关疾病、免疫缺陷病症、破坏性骨病、增生性病症、感染性疾病、与细胞死亡相关的病况、凝血酶诱发的血小板凝集、肝病、涉及T细胞活化的病理性免疫病况、心血管病症或CNS病症疾病的药物中的应用。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防癌症或增生性疾病中药物的应用，所述癌症或增生性疾病为脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳癌、胃癌、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、宫颈癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、皮肤癌、骨癌、甲状腺癌、肉瘤、神经胶母细胞瘤、神经母细胞瘤、多发性骨髓瘤、胃肠癌、颈部或头部肿瘤、表皮过度增生、牛皮藓、前列腺增生、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、淋巴瘤、霍奇金氏和非霍奇金氏、乳腺癌、滤泡癌、未分化性瘤、乳头装瘤、精原细胞瘤、 黑素瘤、ABC DLBCL、霍奇金氏淋巴瘤、原发性皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、冒烟型惰性多发性骨髓瘤、白血病、弥漫性大B细胞淋巴瘤DLBCL、慢性淋巴细胞性白血病CLL、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstroms′s macroglobulinemia WM)脾边缘区淋巴瘤、多发性骨髓瘤、或浆细胞瘤或血管内大B细胞淋巴瘤。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防神经退化性疾病的药物中的应用，所述神经退化性疾病为阿尔茨海默症、帕金森氏病、肌肉萎缩性侧索硬化、亨廷顿氏病(Huntington′s disease)、大脑缺血或有创伤性损伤、谷氨酸神经毒性、低氧症、癫痫症、糖尿病治疗、代谢综合症、肥胖、器官移植或移植物抗宿主疾病造成的神经退化性疾病。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物在制备治疗或预防炎性疾病药物中的应用，所述炎性疾病为眼病，如眼过敏、结膜炎、干眼症或春季结膜炎、影响鼻部的疾病，包括过敏性鼻炎；自身免疫性血液病症，如溶血性贫血、再生不全性贫血、纯红细胞贫血和特发性血小板减少、全身性红斑性狼疮症、类风湿性关节炎、多软骨炎、硬皮病、皮肌炎、慢性活性肝炎、重症肌无力、史蒂芬－约翰逊综合症、特发性口炎性腹泻、字体免疫性发炎性肠病、肠易综合症、乳糜泻、齿根骨膜炎、肺透明膜病、肾病、肾小球疾病、酒精性肝病、多发性硬化症、内分泌性眼病、格雷弗氏病(Grave′s disease)、肉瘤病、干眼症、春季结膜角膜炎、间质性肺纤维化、牛皮藓性关节炎、全身性幼年型特发性关节炎、肾炎、血管炎、间质性膀胱炎、憩室炎、肾小球肾炎、慢性肉芽肿性疾病、子宫内膜异位、钩端螺旋体病肾病、青光眼、视网膜疾病、老化、头痛、疼痛、复杂区域疼痛综合症、心肥大、肌肉萎缩、分解代谢症、肥胖、胎儿生长缓慢、高胆固醇血症、心脏病、慢性心脏衰竭、间皮瘤、无汗性外胚层发育不良、白塞氏病、色素失禁症、佩吉特氏病(Paget′s disease)、胰脏炎、遗传性周期性发热综合症、哮喘、急性肺损伤、急性呼吸窘迫综合症、嗜伊红血球增多、过敏反应、全身性过敏反应、鼻窦炎、眼过敏、二氧化硅诱发的疾病、COPD、肺病、囊肿性纤维化、肝纤维化、肾纤维化、酒精性脂肪肝、非酒精性脂肪肝、心脏纤维化、银屑病、克罗恩病、炎症性肠病、酸诱发的肺损伤、肺动脉高压、多发性神经病、白内障、与全身性硬化症结合的肌肉炎症、包涵体肌炎、重症肌无力、甲状腺炎、阿狄森氏病(Addison′s disease)、扁平苔藓、1型糖尿病、2型糖尿病、阑尾炎、异位性皮炎、哮喘、过敏、细支气管炎、支气管炎、滑囊炎、子宫颈炎、胆管炎、胆囊炎、慢性移植排斥反应、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上踝炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、亨诺－许兰紫斑病(Henoch-Schonlein purpura)、肝炎、化脓性汗腺炎、免疫球蛋白A肾病、间质性肺病、喉炎、乳腺炎、脑膜炎、脊髓炎、心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰脏炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉 炎、局部肺炎、肺炎、多发性肌炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、窦炎、口腔炎、关节膜炎、肌腱炎、扁桃腺炎、溃疡性结肠炎、葡萄膜炎、阴道炎、血管炎、外阴炎、斑秃、多形性红斑、疱疹样皮炎、硬化病、白斑病、超敏性血管炎、荨麻疹、大疱性类天疱疮、寻常天疱疮、落叶型天疱疮、副肿瘤性天疱疮、获得性大疱性表皮松懈、急性和慢性痛风、慢性痛风性关节炎、牛皮藓、牛皮藓性关节炎、类风湿性关节炎、幼年型类风湿性关节炎、隐热蛋白相关周其综合症或骨关节炎。
本发明提供一种治疗或预防由IRAK4介导的疾病或病症的方法，包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物。
本发明提供一种治疗或预防由IRAK4介导的疾病或病症的方法，包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物，所述IRAK4介导的疾病或病症为MyD88所驱动的疾病或病症。
本发明提供一种治疗或预防由TLR(除TLR3R以外)或IL-1受体家族(包括IL-1R、IL-18R、IL-33R、IL-36R)介导的疾病或病症的方法，包括向有需要的患者施用治疗有效量的式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐，或其药物组合物。
本发明提供了式Ⅰ化合物、和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐的制备方法：
方法1：
Figure PCTCN2021075341-appb-000011
中间体Int-a和中间体Int-b在碱性条件下发生取代反应得到式Ⅰ化合物。其中所述碱为无机碱或有机碱，包括但不限于三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸氢钠。X 1为卤素；优选为F。所述R a、R b、R c、R d、R e、n、环A、环B、L、环C、X、W如上所定义。
方法2：
Figure PCTCN2021075341-appb-000012
中间体Int-c和中间体Int-d发生还原胺化反应得到式Ⅰ化合物。所述还原胺化的还原试剂包括但不限于Pd/C、硼氢化钠、氰基硼氢化钠、硼烷、三乙酰氧基硼氢化钠。其中所述L 1为-(CH 2) j-1，所述-(CH 2) j-1中的亚甲基如上述L中所定义，任选被1个或多个基团替代。所述R a、R b、R c、R d、R e、n、环A、环B、环C、X、W如上所定义。
方法3：
Figure PCTCN2021075341-appb-000013
中间体Int-e和中间体Int-f发生还原胺化反应得到式Ⅰ化合物。所述还原胺化的还原试剂包括但不限于Pd/C、硼氢化钠、氰基硼氢化钠、硼烷、三乙酰氧基硼氢化钠。其中所述L 1为-(CH 2) j-1，所述-(CH 2) j-1中的亚甲基如上述L中所定义，任选被1个或多个基团替代。所述R a、R b、R c、R d、R e、n、环A、环B、环C、X、W如上所定义。
详细说明：除非有相反陈述、下列用在说明书和权利要求书中的术语具有下述含义。
“烷基”是指饱和的脂肪族烃基团，包括直链或支链烷基；C1-C8是指含有1-8个碳原子的烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1、1-二甲基丙基、1、2-二甲基丙基、2、2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1、1、2-三甲基丙基、1、1-二甲基丁基、1、2-二甲基丁基、2、2-二甲基丁基、1、3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2、3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2、3-二甲基戊基、2、4-二甲基戊基、2、2-二甲基戊基、3、3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2、3-二甲基己基、2、4-二甲基己基、2、5-二甲基己基、2、2-二甲 基己基、3、3-二甲基己基、4、4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基或其各种支链异构体；优选C1-C6烷基；更优选C1-C4烷基。所述烷基可以是取代的或未取代的。
“环烷基”指饱和或部分不饱和的单环或多环环状烃取代基；“C3-11环烷基”指包括3至11个碳原子的环烷基；“C3-C8元环烷基”指包括3至8个碳原子的环烷基；“C5-C10元环烷基”指包括5至10个碳原子的环烷基；
单环环烷基的非限制性实施例包含环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等，优选环丙基、环丁基、环戊基、环己基；优选C3-C8元环烷基；更优选C3-C6元环烷基。
多环环烷基包括螺环、稠环和桥环的环烷基。“螺环烷基”指单环之间共用一个碳原子(称螺原子)的多环基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基基或多螺环烷基，优选7-12元双螺环烷基。螺环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000014
“稠环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选双环稠环烷基。稠环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000015
“桥环烷基”指任意两个环共用两个不直接连接的碳原子的全碳多环基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，根据组成环的数目可以分为双环、三环、四环或多环桥环烷基。桥环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000016
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实施例包括茚满基、四氢萘基、苯并环庚烷基等。所述环烷基可以是任选取代的或未取代的。
“杂环烷基”指饱和的或部分不饱和的单环或多环环状烃取代基，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1或2)，但不包含-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“3-11元杂环烷基”指包含3至11个环原子的环基，“5-10元杂环烷基”指包含5至10个环原子的环基，“3-8元杂环烷基”指包含3至8个环原子的环基，优选含有1-2个选自N、O或S杂原子的“3-11元杂环烷基”，更优选含有1个或2个N原子的3-11元杂环烷基。
单环杂环烷基优选为含有1-2个N杂原子的3-8元单环杂环基；单环杂环烷基的非限制性实施例包含吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等，优选哌啶基和哌嗪基。
多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“螺杂环烷基”指单环之间共用一个原子(称螺原子)的多环杂环烷基团，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。根据环与环之间共用螺原子的数目将螺环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基，优选含有1-2个选自N、O或S杂原子的饱和的“3-11元双螺杂环烷基”；更优选含有1个或2个N原子的饱和的“7-12元双螺杂环烷基”。螺杂环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000017
“稠杂环烷基”指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选含有1-3个选自N、O或S杂原子的“3-11元双环稠杂环烷基”；更优选含有1个或2个N原子的饱和的“3-11元双环稠杂环烷基”。稠杂环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000018
“桥杂环烷基”指任意两个环共用两个不直接连接的原子的多环杂环烷基团，他们可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子选自氮、氧或S(O)r(其中r是整数0、1、2)，其余环原子为碳。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，桥杂环烷基的非限制性实施例包含：
Figure PCTCN2021075341-appb-000019
Figure PCTCN2021075341-appb-000020
所述杂环烷基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环烷基，非限制性实施例包含：
Figure PCTCN2021075341-appb-000021
所述杂环烷基可以是任选取代的或未取代的。
“芳基”指全碳单环或稠合多环(也就是共享毗邻碳原子对的环)且具有共轭的π电子体系的多环基团，“6-10元芳基”指含有6-10个碳的全碳芳基，例如苯基和萘基；优选苯基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含：
Figure PCTCN2021075341-appb-000022
Figure PCTCN2021075341-appb-000023
所述芳基可以是任选取代的或未取代的。
“杂芳基”指包含1至4个杂原子的杂芳族体系，所述杂原子包括氮、氧或S(O) r(其中r是整数0、1、2)，5-6元杂芳基指含有5-6个环原子的杂芳族体系，5-10元杂芳基指含有5-10个环原子的杂芳族体系，优选5-6元杂芳基；更优选含有1个或2个N原子的5-6元杂芳基；非限制实施例包括呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、吡唑、咪唑基、三唑基、四唑基等；优选吡啶基。所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含：
Figure PCTCN2021075341-appb-000024
Figure PCTCN2021075341-appb-000025
所述杂芳基可以是任选取代的或未取代的。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述所定义的烷基，“C2-8烯基”指含有2-8个碳的直链或支链烯基，包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3丁烯基等，优选“C2-6烯基”，更优选“C2-4烯基”。 所述烯基可以是取代的或未取代的。
“炔基”指至少两个碳原子和至少一个碳-碳三键组成的如上所定义的烷基，“C2-8炔基”指含有2-8个碳的直链或支链炔基，包括但不限于乙炔基、1-丙炔基、2-丙炔基、1-、2-或3-丁炔基，优选“C2-6炔基”，更优选“C2-4炔基”。所述炔基可以是取代的或未取代的。
“亚基”指二价基团，如亚烷基指二价烷基，亚烯基指二价烯基，亚炔基指二价炔基，亚环烷基指二价环烷基，亚杂环烷基指二价杂环烷基，亚芳基指二价芳基，亚杂芳基指二价杂芳基，所述烷基、烯基、炔基、环烷基、杂环烷基、芳基、杂芳基如上所定义，所述亚基可以是任选取代的或未取代的。
“卤代烷基”指任选的被一个或多个氟、氯、溴或碘原子取代的烷基，其中所述烷基如上所定义，非限制性实施例包括二氟甲基、二氯甲基、二溴甲基、三氟甲基、三氯甲基、三溴甲基等。
“羟基烷基”指任选被一个或多个-OH取代的烷基，其中所述烷基如上所定义，非限制性实施例包括羟甲基、羟乙基、羟基丙基、羟基异丙基。
“氰基”指-CN。
“氨基”指-NH 2。
“羟基”指-OH。
“羧基”或“羧酸”指-COOH。
“氧代”指＝O基团。
“卤素”指氟、氯、溴或碘。
“NMP”指N-甲基吡咯烷酮。
“IBX”指2-碘酰基苯甲酸。
“DIEA”指N,N-二异丙基乙胺。
“STAB”指三乙酰氧基硼氢化钠。
“T 3P”指2,4,6-三丙基-1,3,5,2,4,6-三氧三磷酸-2,4,6-三氧化物。
“DPBS”指杜氏磷酸缓冲液。
“Dess-Martin”指戴斯-马丁试剂。
“PBS”指磷酸缓冲盐溶液。
“SDS-PAGE”指十二烷基硫酸钠-聚丙烯酰胺凝胶电泳。
“PVDF”指聚偏二氟乙烯。
“多个”指2、3、4、5、6个等，优选全取代的。示例，如对于甲基，多个卤素(如F)取代时可指三氟甲基F 3C。
“任选”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在，该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子、优选为最多5个、更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻、取代基仅处在它们的可能的化学位置、本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如、具有游离氢的氨基或羟基与具有不饱和(如烯 属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物、以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药、利于活性成分的吸收进而发挥生物活性。
本发明还提供式(I)化合物药学上可接受的盐。术语“药学上可接受的盐”是指相对无毒的本发明化合物的酸加成盐或碱加成盐。所述酸加成盐为本发明式(I)化合物与合适的无机酸或者有机酸形成的盐，这些盐可在化合物最后的分离和提纯过程中制备，或者可用纯化的式(I)化合物以其游离碱形式与适宜的有机酸或无机酸进行反应来制备。代表性酸加成盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月硅酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、磷酸氢盐、碳酸盐、碳酸氢盐、甲苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐等。所述碱加成盐为式(I)化合物与合适的无机碱或者有机碱形成的盐，包括例如与碱金属、碱土金属、季铵阳离子形成的盐，例如钠盐、锂盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐等；胺盐包括与氨(NH 3)、伯胺、仲胺或叔胺形成的盐，如甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐等。
本发明的化合物或其药学上可接受的盐可给药于哺乳动物包括人，可口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药(粉剂、软膏剂或滴剂)、或瘤内给药。
本发明化合物的给药剂量可以大约为0.05-300mg/kg体重/天，优选10-300mg/kg体重/天，更优选10-200mg/kg体重/天。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的固体剂型，包括但不限于胶囊剂、片剂、丸剂、散剂和颗粒剂等。在这些固体剂型中，本发明式(I)化合物作为活性成分与至少一种常规惰性赋形剂(或载体)混合，例如与柠檬酸钠或磷酸二钙，或与下述成分混合：(1)填料或增容剂，如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸等；(2)粘合剂，如羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶等；(3)保湿剂，如甘油等；(4)崩解剂，如琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐和碳酸钠等；(5)缓溶剂，如石蜡等；(6)吸收加速剂，如季铵化合物等；(7)润湿剂如鲸蜡醇和单硬脂酸甘油酯等；(8)吸附剂，如高岭土等；和(9)润滑剂，如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠等，或其混合物。胶囊剂、片剂和丸剂中也可包含缓冲剂。
所述固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材料例如肠溶衣和其他本领域公知的材料进行包衣或微囊化。它们可包含不透明剂，并且这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时、活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
本发明化合物或其药学上可接受的盐可以配制为用于口服给药的液体剂型，包括但不限于药学上可接受的乳液、溶液、悬浮液、糖浆和酊剂等。除了作为活 性成分的式(I)化合物或其药学上可接受的盐外，液体剂型可包含本领域中常规采用的惰性稀释剂如水和其他溶剂、增溶剂和乳化剂，如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1、3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包含常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。
所述悬浮剂包括如乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇只、微晶纤维素、甲醇铝和琼脂等或这些物质的混合物。
本发明化合物或其药学上可接受的盐可以配制为用于肠胃外注射的剂型包括但不限于生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物或其药学上可接受的盐也可以配制为用于局部给药的剂型包括如软膏剂、散剂、栓剂、滴剂、喷射剂和吸入剂等。作为活性成分的本发明式(I)化合物或其药学上可接受的盐在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明还提供药物组合物，它含有本发明式(I)化合物或其药学上可接受的盐作为活性成分，以及药学上可接受载体、赋形剂或稀释剂。在制备药物组合物时，通常是将本发明式(I)化合物或其药学上可接受的盐与药学上可接受载体、赋形剂或稀释剂混合。
可以按常规制备方法将所述本发明组合物配制为常规药物制剂。例如片剂、丸剂、胶囊剂、散剂、颗粒剂、乳液剂、混浮剂、分散液、溶液剂、糖浆剂、酏剂、软膏剂、滴剂、栓剂、吸入剂、喷射剂等。
本发明所述的化合物或其药学上可接受的盐可以单独给药，或者(如果需要)与其他药学上可接受的治疗剂联合给药，如与其他抗肿瘤药物、抗炎症药物或自身免疫性药物组合。待组合的各成分可同时或顺序的给予，以单一制剂形式或以不同制剂的形式给予。所述组合不仅可包括本发明化合物和一种其他活性剂的组合，也可包括本发明化合物和两种或更多种其他活性剂的组合。
本发明通过IRAK4激酶活性测试实验证明本发明所述式Ⅰ化合物能够有效的与IRAK4靶蛋白结合或产生抑制效果；通过Western-Blot证明本发明所述式Ⅰ化合物能够有效的特异性的降解THP-1细胞中的IRAK4蛋白；通过小鼠药代动力学性质研究证明本发明化合物清除率低，血浆暴露量高，口服生物利用度好，具有良好的药代动力学性质；通过对L363细胞中IKZF1、IKZF3的降解实验证明本发明化合物有很好的选择性。本发明所述式Ⅰ化合物，和/其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、代谢物、前药和/或其药学上可接受的盐可有效的降解IRAK4蛋白，从而达到预防或治疗与IRAK4相关的疾病或病症的效果。
具体实施例
下面将结合实施例对本发明做进一步详细、完整地说明，但决非限制本发明，本发明也并非仅局限于实施例的内容。本发明实施例中的起始原料是已知的并且可以在市场上买到、或者可以采用或按照本领域已知的方法来合成。在无特殊说 明的情况下，本发明实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。
Ⅰ化合物制备实施例
中间体1：2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮
Figure PCTCN2021075341-appb-000026
向4-氟邻苯二甲酸(5.52g，0.03mol)的乙酸(50mL)溶液中加入3-氨基哌啶-2,6-二酮盐酸盐(5.0g，0.03mol)和乙酸钾(8.8g，0.09)，反应混合物于120℃搅拌反应过夜，将反应混合物减压浓缩，浓缩物用水(100mL)稀释，在室温下搅拌30分钟，过滤，固体用水(50mL×2)洗涤。减压干燥得到产物(6.0g)。
LC-MS:(ESI,m/z):[M-H] +＝277.1
1H NMR(400MHz,DMSO)δ11.14(s,1H),8.01(dd,J＝8.2,4.5Hz,1H),7.85(dd,J＝7.4,2.1Hz,1H),7.79–7.66(m,1H),5.17(dd,J＝12.8,5.4Hz,1H),2.90(ddd,J＝17.0,13.8,5.4Hz,1H),2.58(dd,J＝24.5,11.8Hz,2H),2.20–2.01(m,1H).
中间体2:N-(6-甲氧基-2-(1-(2-(哌啶-4-基)乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
步骤1：2-氟-4-甲氧基-5-硝基苯甲醛的制备
Figure PCTCN2021075341-appb-000027
向2-氟-4-羟基-5-硝基苯甲醛(2g，10.8mmol)的N,N-二甲基甲酰胺溶液中(20ml)加入碳酸铯(3.5g，10.8mmol)和碘化钾(1.85g，13.0mmol)。反应液室温下搅拌反应10小时，加入水(30ml)，乙酸乙酯萃取三次，收集有机相，用饱和食盐水洗涤，无水硫酸钠干燥后过滤，减压浓缩，浓缩物柱纯化得到目标产物2-氟-4甲氧基-5-硝基苯甲醛1.6g。
LC-MS:(ES,m/z):[M+H] +＝200.1
步骤2：2-叠氮基-4-甲氧基-5-硝基苯甲醛的制备
Figure PCTCN2021075341-appb-000028
往2-氟-4甲氧基-5-硝基苯甲醛(1.6g，8.04mmol)的二甲亚砜(20ml)溶液中加入叠氮化钠(1.06g，16.1mmol)，室温下搅拌反应2小时，随后将反应液倒入冰水中，乙酸乙酯萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩得到1.7g粗产品，无需纯化，直接用于下一步反应。
步骤3：4-(6-甲氧基-5-硝基-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000029
2-叠氮基-4-甲氧基-5-硝基苯甲醛(1.7g，7.65mmol)和4-氨基哌啶-1-羧酸叔丁酯(1.53g，7.65mmol)的甲苯(20ml)溶液在100℃下搅拌反应2小时，冷却至室温，浓缩反应液，加入水50ml，乙酸乙酯萃取，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩有机相，将浓缩物柱纯化得到4-(6-甲氧基-5-硝基-2H-吲唑-2-基)哌啶-1-羧酸叔丁基1.72g。
LC-MS:(ES,m/z):[M+H] +＝377.2
步骤4：4-(5-氨基-6-甲氧基-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000030
向4-(6-甲氧基-5-硝基-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(1.7g，4.5mmol)的乙醇(20ml)溶液中加入铁粉(2.85g，50.9mmol)和氯化铵(0.13g，2.3mmol)，反应液90℃反应2小时。将反应液冷却至室温后，过滤，浓缩，得到2.01g目标粗产物，并直接用于下一步反应。
LC-MS:(ES,m/z):[M+H] +＝347.3
步骤5：4-(6-甲氧基-5-(6-(三氟甲基)吡啶-2-酰胺)-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000031
往4-(5-氨基-6-甲氧基-2H-吲唑-2-基)哌啶-1-羧酸叔丁基酯(1.7g，4.9mmol)的四氢呋喃溶液中加入6-(三氟甲基)吡啶-2-甲酸(940mg，4.9mmol)和N,N-二异丙基乙胺(1.9g，14.7mmol)，随后加入T 3P(1.5g)，反应液室温下搅拌反应2小时。浓缩反应液后，加入水，乙酸乙酯萃取三次，收集有机相，饱和食盐水洗涤，无水硫酸钠干燥，浓缩。浓缩物柱纯化得到目标产物4-(6-甲氧基-5-(6-(三氟甲基)吡啶-2-酰胺)-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯1.78g。
LC-MS:(ES,m/z):[M+H] +＝520.2
步骤6：N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000032
向4-(6-甲氧基-5-(6-(三氟甲基)吡啶-2-酰胺)-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(435mg，0.795mmol)的二氯甲烷溶液中加入三氟乙酸(1ml)。将反应液在室温下搅拌反应1h。减压浓缩除去溶剂，得到粗产物(500mg)。粗产物直接用于下一步。
LC-MS:(ES,m/z):[M+H] +＝420.2
步骤7：4-(2-(4-(6-甲氧基-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-2-基)哌啶-1-基)乙基)哌啶-1-甲酸叔丁酯的制备
Figure PCTCN2021075341-appb-000033
向N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(1.0g，2.386mmol)和4-(2-氧代乙基)哌啶-1-羧酸叔丁酯(0.813g，3.581mmol)在四氢呋喃(20mL)溶液中的混合物中添加入STAB(1.518g，7.160mmol)。将该反应液在室温下搅拌反应过夜。将反应液用乙酸乙酯(50mL)稀释，并用水(2×50mL)和饱和食盐水(50mL)洗涤，收集有机相，并用无水硫酸钠干燥，减压浓缩。浓缩物通过硅胶柱纯化，得到黄色固体目标产物700mg。
LC-MS:(ESI,m/z):[M+H] +＝631.3
步骤8：N-(6-甲氧基-2-(1-(2-(哌啶-4-基)乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000034
将4-(2-(4-(6-甲氧基-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-2-基)哌啶-1-基)乙基)哌啶-1-甲酸叔丁酯(700mg，1.11mmol)在盐酸/乙酸乙酯(1M，20mL)溶液中的混合物在室温下搅拌反应过夜。减压浓缩反应物，得到黄色油状目标粗产物650mg。粗产物直接用于下一步。
LC-MS:(ESI,m/z):[M+H] +＝531.3
中间体3：N-(6-甲氧基-2-(1-(哌啶-4-基甲基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000035
参照中间体2的方法合成中间体3。
LC-MS:(ESI,m/z):[M+H] +＝517.2.
中间体4：N-(6-甲氧基-2-(1-(2-氧代乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
步骤1：N-(2-(1-(2,2-二甲氧基乙基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000036
向N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(750mg，1.79mmol)和2-溴-1，1-二甲氧基乙烷(46mg，0.3mmol)在乙腈(20mL)溶液中的混合物中加入碳酸钾(1.235g，8.95mmol)和碘化钾(149mg， 0.89mmol)。将该反应液在80℃下搅拌反应过夜。减压浓缩除去溶剂，加入水(20mL)，并用乙酸乙酯(20mL×3)萃取，合并有机层，用饱和食盐水(50mL)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。浓缩物通过柱纯化，得到油状物目标产物500mg。
LC-MS:(ESI,m/z):[M+H] +＝508.1
步骤2：N-(6-甲氧基-2-(1-(2-氧代乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000037
将N-(2-(1-(2,2-二甲氧基乙基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(500mg，0.99mmol)在盐酸(4mL)/二氧六环(5mL)溶液中的混合物50℃搅拌反应过夜。减压浓缩除去溶剂，加入水(20mL)，并用乙酸乙酯(20mL×3)萃取，合并有机层，用饱和食盐水(50mL)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。浓缩物通过柱纯化，得到油状物目标产物300mg。
LC-MS:(ESI,m/z):[M+H] +＝462.1
中间体5：N-(6-(2-羟基丙-2-基)-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
步骤1：5-硝基-1H-吲唑-6-羧酸甲酯的制备
Figure PCTCN2021075341-appb-000038
在-10℃下，向1H-吲唑-6-羧酸甲酯(9.2g.0.052mol)在浓硫酸(20mL)中的溶液中缓慢加入浓硝酸(15mL)。将该反应液在-10℃下搅拌反应2h。将反应液倒入冰水中，过滤固体得到白色固体的目标粗产物10.8g。粗产物直接用于下一步。
LC-MS:(ES,m/z):[M+H] +＝222.1
步骤2：2-(1-(叔丁氧基羰基)哌啶-4-基)-5-硝基-2H-吲唑-6-羧酸甲酯的制备
Figure PCTCN2021075341-appb-000039
向5-硝基-1H-吲唑-6-羧酸甲酯(6g，27.12mmol)和4-(对甲苯磺酰氧基)哌啶-1-羧酸叔丁酯(15.3g，43.5mmol)的N，N-二甲基甲酰胺(100mL)溶液中加入碳酸钾(11.1g，81.3mmol)。将该反应液在100℃下搅拌反应10h。将反应液冷却至室温，加入水(50ml)和乙酸乙酯(100ml)，分离水层，并用乙酸乙酯(100ml×2)萃取。合并有机层，用盐水(100mL×2)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。将浓缩物通过硅胶柱纯化得到黄色固体目标产物2.01g。
LC-MS:(ES,m/z):[M+H] +＝405.2
步骤3：5-氨基-2-(1-(叔丁氧基羰基)哌啶-4-基)-2H-吲唑-6-羧酸甲酯的制备
Figure PCTCN2021075341-appb-000040
向2-(1-(叔丁氧基羰基)哌啶-4-基)-5-硝基-2H-吲唑-6-羧酸甲酯(1.7g，4.5mmol)的乙醇(20ml)溶液中加入铁粉(2.85g，50.9mmol)和氯化铵(0.13g，2.3mmol)。将该反应液在90℃下搅拌反应2h。将反应液冷却至室温，过滤，将滤液减压浓缩，得到油状物目标粗产物2.01g。粗产物直接用于下一步。
LC-MS:(ES,m/z):[M+H] +＝375.3
步骤4：2-(1-(叔丁氧基羰基)哌啶-4-基)-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-6-羧酸甲酯
Figure PCTCN2021075341-appb-000041
向5-氨基-2-(1-(叔丁氧基羰基)哌啶-4-基)-2H-吲唑-6-羧酸甲酯(170mg，0.45mmol)，6-(三氟甲基)吡啶-2-甲酸(86.8mg，0.45mmol)和DIEA(88mg，0.68mmol)在THF溶液中的混合物中加入T 3P(650mg)。将反应液在室温搅拌反应2h。减压浓缩除去溶剂。加入水(20mL)和乙酸乙酯(20mL)。分离水层，并用乙酸乙酯(20ml×2)萃取。合并有机层，用盐水(20mL×2)洗涤，用无水硫酸钠干燥，过滤并减压浓缩。将浓缩物通过硅胶柱纯化，得到黄色固体目标产物150mg。
LC-MS:(ES,m/z):[M+H] +＝548.3
步骤5：4-(6-(2-羟基丙-2-基)-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000042
向2-(1-(叔丁氧基羰基)哌啶-4-基)-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-6-羧酸甲酯(500mg，0.91mmol)的四氢呋喃溶液中加入氯化锂(192mg，4.57mmol)。将该反应液冷却至0℃，然后加入四氢呋喃甲基溴化镁(3.04ml，1M)。将反应液在室温搅拌反应12h，用氯化铵水溶液淬灭，加入水(30mL)和乙酸乙酯(50mL)。分离水层，并用乙酸乙酯(50ml×2)萃取，合并有机层，用盐水(50mL×2)洗涤，经无水硫酸钠干燥，过滤并减压浓缩，将浓缩物通过硅胶柱纯化，得到白色固体目标产物435mg。
LC-MS:(ES,m/z):[M+H] +＝548.3
步骤6：N-(6-(2-羟基丙-2-基)-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000043
将4-(6-(2-羟基丙-2-基)-5-(6-(三氟甲基)吡啶甲酰胺基)-2H-吲唑-2-基)哌啶-1-羧酸叔丁酯(435mg.0.79)在二氯甲烷(3mL)和三氟乙酸(1mL)溶液中的混合物在室温下搅拌反应1h，减压浓缩除去溶剂，得到黄色油状目标粗产物500mg。粗产物直接用于下一步。
LC-MS:(ES,m/z):[M+H] +＝448.2
中间体6：2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙醛
步骤1：4-(2,2-二甲氧基乙基)哌嗪-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000044
向哌嗪-1-羧酸叔丁酯(2.0g，10.75mmol)，碳酸钾(4.45g，32.26mmol)和碘化钾(892mg，5.38mmol)的丙酮(20mL)混合物中加入2-溴-1，1-二甲氧基乙烷(3.63g，21.51mmol)。并于80℃下搅拌反应过夜。反应液混合物减压下浓缩。将浓缩物溶解在乙酸乙酯(50mL)中，并用水(50mL*2)和饱和食盐水(50mL)洗涤。收集有机相，有机相经无水硫酸钠干燥，过滤并浓缩。浓缩物经硅胶柱纯化，得到所需产物(2.2g)。
LC-MS:(ES,m/z):[M+H] +＝275.0.
步骤2：1-(2,2-二甲氧基乙基)哌嗪的制备
Figure PCTCN2021075341-appb-000045
4-(2,2-二甲氧基乙基)哌嗪-1-羧酸叔丁酯(2.2g，8.03mmol)在盐酸/二氧六烷(4M，10mL)溶液中的混合物室温下搅拌过夜。减压浓缩得到浅黄色油状产物(1.5g，粗品)。粗产物直接用于下一步。
步骤3：5-(4-(2,2-二甲氧基乙基)哌嗪-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮的制备
Figure PCTCN2021075341-appb-000046
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(1.48g，5.36mmol)，1-(2,2-二甲氧基乙基)哌嗪(1.4g，8.05mmol)和DIEA(4.15g，36.16mmol)的NMP(10mL)溶液的混合物在微波反应器中140℃反应5h。用水(50mL)稀释混合物，并用乙酸乙酯(50mL*2)萃取。收集有机相并用水(100mL*2)和饱和食盐水(50mL)洗涤，经无水硫酸钠干燥，过滤并浓缩。浓缩物经硅胶柱纯化，得到所需产物(1.8g)。
LC-MS:(ESI,m/z):[M+H] +＝431.1.
步骤4：2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙醛的制备
Figure PCTCN2021075341-appb-000047
5-(4-(2,2-二甲氧基乙基)哌嗪-1-基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮(1.8g，4.19mmol)在三氟乙酸/二氯甲烷(5mL/5mL)溶液中的混合物于室温下搅拌反应60h。减压浓缩混合物，加入水，并用碳酸氢钠(水溶液)将pH调节至8。混合物用乙酸乙酯(100mL*2)萃取。收集有机相，并用水(100mL*2)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤并浓缩。浓缩物经硅胶柱上纯化，得到所需产物(700mg)。
LC-MS:(ESI,m/z):[M+H] +＝285.0.
中间体7：2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)-2-甲基丙醛
Figure PCTCN2021075341-appb-000048
参照中间体6的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝413.2.
中间体8：2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛
步骤1：2-(2,6-二氧代基哌啶-3-基)-5-(4-(2-羟乙基)哌啶-1-基)异吲哚啉-1,3-二酮的制备
Figure PCTCN2021075341-appb-000049
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(500mg，1.81mmol)， 2-(哌啶-4-基)乙基-1-醇(280，2.17mmol))和DIEA(701mg，5.43mmol)在NMP(5mL)中的混合物于140℃的微波反应器中反应5小时。用水(50mL)稀释反应混合物，并用乙酸乙酯(50mL*2)萃取。收集有机相并用水(100mL*2)和饱和食盐水(50mL)洗涤，经无水硫酸钠干燥后，过滤并浓缩。浓缩物经硅胶柱上纯化，得到产物(650mg)。
LC-MS:(ES,m/z):[M+H] +＝386.1.
步骤2：2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛的制备
Figure PCTCN2021075341-appb-000050
2-(2,6-二氧代基哌啶-3-基)-5-(4-(2-羟乙基)哌啶-1-基)异吲哚啉-1,3-二酮(300mg，0.78mmol)和IBX(436mg，1.56mmol)在乙腈(6mL)中的混合物于80℃下搅拌反应2h。用水(30mL)稀释反应混合物，并用乙酸乙酯(30mL*2)萃取。收集有机相并用水(50mL×2)和饱和食盐水(30mL)洗涤，经无水硫酸钠干燥后，过滤并浓缩。浓缩物经通过硅胶柱纯化得到产物(22mg)。
LC-MS:(ES,m/z):[M+H] +＝384.1.
1H NMR(400MHz,DMSO-d 6)δ11.07(s,1H),9.69(t,J＝1.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.31(d,J＝2.0Hz,1H),7.23(dd,J＝8.6,2.2Hz,1H),5.06(dd,J＝12.9,5.4Hz,1H),4.03(dd,J＝10.3,2.9Hz,2H),3.04–2.82(m,3H),2.65–2.52(m,2H),2.41(dd,J＝6.7,1.6Hz,2H),2.17–1.97(m,2H),1.73(d,J＝11.1Hz,2H),1.2-1.18(m,2H).
中间体9：3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)丙醛
Figure PCTCN2021075341-appb-000051
参照中间体8的方法合成。
LC-MS:(ES,m/z):[M+H] +＝398.2.
中间体10：1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-甲醛
Figure PCTCN2021075341-appb-000052
参照中间体8的方法合成。
LC-MS:(ES,m/z):[M+H] +＝370.1.
中间体11：2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)-2-甲基丙醛
Figure PCTCN2021075341-appb-000053
参照中间体8的方法合成。
LC-MS:(ES,m/z):[M+H] +＝412.2.
中间体12：2-(2,6-二氧代基哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮
步骤1：4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-羧酸叔丁酯的制备
Figure PCTCN2021075341-appb-000054
2-(2,6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1,3-二酮(300mg，1.09mmol)，哌嗪-1-羧酸叔丁酯(203mg，1.09mmol)和DIEA(422mg，3.27mmol)在NMP(1mL)溶液中的混合物在微波反应器上140℃反应5h。将混合物冷却至室温，用水(20mL)稀释，并用二氯甲烷(10mL×3)萃取。合并有机相，减压浓缩，浓缩物经硅胶柱纯化得到产物(90mg)。
LC-MS:(ESI,m/z):[M+H] +＝788.2.
步骤2：2-(2,6-二氧代基哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮的制备
Figure PCTCN2021075341-appb-000055
向4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-羧酸叔丁酯(65mg，0.147mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(1mL)，混合物在室温下搅拌反应2h。减压浓缩，浓缩物用饱和碳酸氢钠水溶液(5mL)稀释，并用二氯甲烷(5mL x 3)萃取。合并有机相，减压浓缩得到粗产物(59mg)。粗产物无需进一步纯化即可直接用于下一步。
LC-MS:(ESI,m/z):[M+H] +＝343.3.
中间体13：3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)-3-甲基丁醛
Figure PCTCN2021075341-appb-000056
参照中间体8的方法合成。
LC-MS:(ES,m/z):[M+H] +＝426.2.
中间体14：3-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)-3-甲基丁醛
Figure PCTCN2021075341-appb-000057
参照中间体6的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝427.2.
中间体15：2-(9-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3,9-二氮杂螺[5.5]十一烷-3-基)乙醛
Figure PCTCN2021075341-appb-000058
参照中间体6的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝453.2.
中间体16：2-(9-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3,9-二氮杂螺[5.5]十一烷-3-基)-2-甲基丙醛
Figure PCTCN2021075341-appb-000059
参照中间体6的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝481.2.
中间体17：2-(3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-基)-2-甲基丙醛
Figure PCTCN2021075341-appb-000060
参照中间体8的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝480.2.
中间体18：2-(3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-基)乙醛
Figure PCTCN2021075341-appb-000061
参照中间体8的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝452.2.
中间体19：3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-甲醛
Figure PCTCN2021075341-appb-000062
参照中间体8的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝438.2.
中间体20：2-(2-((2-(2，6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氧基)乙氧基)乙醛
步骤1：2-(2，6-二氧代哌啶-3-基)-5-(2-(2-羟基乙氧基)乙氧基)异吲哚啉-1，3-二酮的制备
Figure PCTCN2021075341-appb-000063
向2-(2，6-二氧代哌啶-3-基)-5-羟基异吲哚啉-1，3-二酮(500mg，0.0018mol)和2-(2-氯乙氧基)乙基-1-醇(227mg，0.0018mol)在二甲亚砜(20mL)溶液中的混合物中逐滴加入DIEA(706.2mg，0.0055mol)和碘化钾(30mg，0.0002mol)。反应液在100℃下搅拌反应10h。加入水(30ml)和乙酸乙酯(100ml)，分离水层，并用乙酸乙酯(100ml×2)萃取。合并有机相，并用盐水(100mL×2)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。将浓缩物通过硅胶柱纯化，得到白色固体目标产物612mg。
LC-MS:(ES,m/z):[M+H] +＝363.0
步骤2：2-(2-((2-(2，6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-5-基)氧基)乙氧基)乙醛的制备
Figure PCTCN2021075341-appb-000064
在0℃下，向2-(2，6-二氧代哌啶-3-基)-5-(2-(2-羟基乙氧基)乙氧基)异吲哚啉-1，3-二酮(162mg，0.44mmol)在THF(10mL)溶液中的混合物中 加入Dess-Martin(393mg，0.88mmol)，所得反应液室温下搅拌反应16小时。反应液用水(30ml)和二氯甲烷(50ml)淬灭。分离水层，并用二氯甲烷(50ml×2)萃取。合并有机相，用饱和食盐水(50mL×2)洗涤，经无水硫酸钠干燥，过滤并减压浓缩。将浓缩物通过硅胶柱纯化，得到白色固体状目标产物32mg。
LC-MS:(ES,m/z):[M+H] +＝361.0
中间体21：9-(2-羟乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯
步骤1：9-(2-乙氧基-2-氧代基亚乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯
Figure PCTCN2021075341-appb-000065
在0℃下，向2-(二乙氧基磷酰基)乙酸乙酯(1.26g，5.63mmol)在N，N-二甲基甲酰胺(15mL)中的溶液中加入氢化钠(60％矿物油混合物，224mg，5.6mmol)，并于0℃下搅拌反应0.5小时，然后加入9-氧代基-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(1.0g，3.75mmol)。反应混合物在0℃下继续搅拌反应3h。用水(100mL)稀释反应混合物，并用乙酸乙酯(3×30mL)萃取。收集有机层，并用水(2×20mL)和饱和食盐水(20mL)洗涤，用无水硫酸钠干燥，过滤并浓缩。得到目标粗产物0.7g。粗产物直接用于下一步。
步骤2：9-(2-乙氧基-2-氧代基乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯
Figure PCTCN2021075341-appb-000066
在氢气氛围下，将9-(2-乙氧基-2-氧代基亚乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.7g，2.08mmol)和氢氧化钯(0.2g，1.43mmol)在乙醇(10mL)中的反应混合物于室温下搅拌反应16h。将反应混合物过滤，并减压浓缩。得到目标粗产物0.5g。粗产物直接用于下一步。
1H NMR(400MHz,CDCl 3)δ4.12(q,J＝7.1Hz,2H),3.35(ddd,J＝7.6,6.8,5.0Hz,4H),2.20(d,J＝7.1Hz,2H),1.70–1.63(m,2H),1.58(dd,J＝12.7,7.1Hz,2H),1.45(s,9H),1.27(dt,J＝14.3,6.5Hz,6H),1.18–1.10(m,4H),0.86(dd,J＝13.4,6.3Hz,2H).
步骤3：9-(2-羟乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯
Figure PCTCN2021075341-appb-000067
将9-(2-乙氧基-2-氧代基乙基)-3-氮杂螺[5.5]十一烷-3-羧酸叔丁酯(0.5g，1.47mmol)和硼氢化锂(0.13g，5.9mmol)在四氢呋喃(5mL)中的反应混合物回流过夜。用水(50mL)稀释反应混合物，并用乙酸乙酯(3×30mL)萃取。收集有机层并用水(2×20mL)和饱和食盐水(20mL)洗涤，用无水硫酸钠干燥，过滤并浓缩。得到目标粗产物0.4g。
LC-MS:(ESI,m/z):[M+H]+＝298.2
1H NMR(400MHz,MeOD)δ3.58(t,J＝6.6Hz,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＝5.6Hz,3H),1.12(dd,J＝19.2,11.5Hz,4H).
实施例1：N-(2-(1-(2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000068
N-(6-甲氧基-2-(1-(2-(哌啶-4-基)乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(200mg，0.377mmol)，2-(2，6-二氧代基哌啶-3-基)-5-氟异吲哚啉-1，3-二酮(104mg，0.377mmol)和DIEA(243mg，1.887mmol)在NMP(100mL)溶液中的混合物在微波反应器中140℃下反应5h。所得混合物用乙酸乙酯稀释，并用水和盐水洗涤。收集有机相，有机相经无水硫酸钠干燥，减压浓缩，浓缩物经制备型HPLC纯化，得到所需产物(14.52mg)。
LC-MS:(ESI,m/z):[M+H] +＝787.2.
1H NMR(400MHz,DMSO-d 6)δ11.07(s,1H),10.50(s,1H),8.69(s,1H),8.54–8.31(m,3H),8.22(d,J＝7.7Hz,1H),7.65(d,J＝8.6Hz,1H),7.31(s,1H),7.24(m,J＝8.7,2.1Hz,1H),7.16(s,1H),5.06(m,1H),4.41-4.38(m,1H),4.05(d,J＝13.2Hz,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＝11.5Hz,2H),1.65-1.61(m,1H),1.48–1.39(m,2H),1.25-1.20(m,2H).
实施例2：N-(2-(1-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000069
参照实施例1的制备方法，得到目标化合物(27mg)。
LC-MS:(ESI,m/z):[M+H] +＝773.4.
1H NMR(400MHz,DMSO-d 6)δ11.08(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＝8.6Hz,1H),7.32(d,J＝1.9Hz,1H),7.24(dd,J＝8.7,2.1Hz,1H),7.17(s,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.41-4.37(m,1H),4.06(d,J＝13.0Hz,2H),3.99(s,3H),3.03–2.83(m,5H),2.65–2.53(m,2H),2.22(d,J＝6.7Hz,2H),2.17–1.98(m,7H),1.85-1.80(m,3H),1.24–1.11(m,2H).
实施例3：N-(2-(1-(2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000070
N-(6-甲氧基-2-(1-(2-氧代乙基)哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(80mg，0.174mmol)，2-(2,6-二氧代基哌啶-3-基)-5-(哌嗪-1-基)异吲哚啉-1,3-二酮(59mg，0.174mmol)和STAB(110mg，0.521mmol)在四氢呋喃(5mL)溶液中的混合物在室温下搅拌反应3小时。所得反应液混合物用乙酸乙酯稀释，并用水和盐水洗涤。收集有机相，有机相经无水硫酸钠干燥并减压浓缩。浓缩物经制备型HPLC纯化，得到产物(4.5mg)。
LC-MS:(ESI,m/z):[M+H] +＝788.2.
1H NMR(400MHz,DMSO-d 6)δ11.08(s,1H),10.51(s,1H),8.69(s,1H),8.53–8.33(m,3H),8.22(d,J＝7.6Hz,1H),7.68(d,J＝8.5Hz,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).
实施例4：N-(2-(1-(2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000071
N-(6-(2-羟基丙-2-基)-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(285mg，0.64mmol)，2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)乙醛(350mg，0.91mmol)和STAB(407mg，1.92mmol)在四氢呋喃(10mL)溶液中的混合物室温下搅拌过夜。将反应液混合物减压浓缩，浓缩物经制备型HPLC纯化，得到产物(144.27mg)。
LC-MS:(ESI,m/z):[M+H] +＝816.2.
1H NMR(400MHz,DMSO)δ12.37(s,1H),11.08(s,1H),8.72(s,1H),8.46-8.28(m,3H),8.16(d,J＝7.8Hz,1H),7.68(d,J＝8.5Hz,1H),7.58(s,1H),7.35(d,J＝1.9Hz,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＝10.5Hz,2H),2.92-2.84(m,1H),2.66–2.51(m,10H),2.22–1.97(m,7H),1.62(s,6H).
实施例5：N-(2-(1-(2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000072
N-(6-(2-羟基丙-2-基)-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(120mg，0.27mmol)，2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)乙醛(165mg，0.43mmol)和STAB(172mg，0.81mmol)在四氢呋喃(10mL)中混合物于室温下搅拌过夜。减压浓缩反应混合物，得到粗产物。粗产物经制备型HPLC纯化，得到目标产物。
LC-MS:(ESI,m/z):[M+H] +＝815.3.
1H NMR(400MHz,DMSO-d 6)δ12.37(s,1H),11.08(s,1H),8.72(s,1H),8.46–8.35(m,3H),8.16(d,J＝7.8Hz,1H),7.65(d,J＝8.5Hz,1H),7.58(s,1H),7.31(d,J＝1.8Hz,1H),7.25–7.22(m,1H),5.97-5.93(m,1H),5.07(dd,J＝12.9,5.4Hz,1H),4.47–4.43(m,1H),4.05(d,J＝13.0Hz,2H),3.06–2.82(m,5H),2.63–2.53(m,2H),2.40(t,J＝7.1Hz,2H),2.15–2.08(m,6H),2.05–1.97(m,1H),1.79(d,J＝10.9Hz,2H),1.64(d,J＝13.1Hz,7H),1.47–1.40(m,2H),1.25–1.17(m,2H).
实施例6：N-(2-(1-(3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)丙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000073
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝829.4.
1H NMR(400MHz,DMSO-d 6)δ12.37(s,1H),11.07(s,1H),8.72(s,1H),8.45(d,J＝7.7Hz,1H),8.40(s,1H),8.37(t,J＝7.8Hz,1H),8.16(d,J＝7.7Hz,1H),7.65(d,J＝8.5Hz,1H),7.58(s,1H),7.31(s,1H),7.24(d,J＝8.5Hz,1H),5.95(s,1H),5.06(dd,J＝12.8,5.2Hz,1H),4.49–4.37(m,1H),4.06(d,J＝13.0Hz,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＝11.5Hz,2H),1.67–1.45(m,9H),1.30–1.10(m,4H).
实施例7：N-(2-(1-((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)甲基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000074
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝801.3.
1H NMR(400MHz,DMSO-d 6)δ12.37(s,1H),11.07(s,1H),8.72(s,1H),8.45(d,J＝7.7Hz,1H),8.41(s,1H),8.37(t,J＝7.8Hz,1H),8.20–8.11(m,1H),7.66(d,J＝8.6Hz,1H),7.58(s,1H),7.32(s,1H),7.24(dd,J＝8.7,2.0Hz,1H),5.95(s,1H),5.07(dd,J＝12.8,5.4Hz,1H),4.51–4.40(m,1H),4.06(d,J＝13.2Hz,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).
实施例8：N-(2-(1-(2-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)2-甲基丙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000075
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝843.1.
实施例9：N-(2-(1-(2-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-1-基)2-甲基丙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000076
参照实施例4的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝844.1.
1H NMR(400MHz,DMSO-d 6)δ12.36(s,1H),11.07(s,1H),8.71(s,1H),8.45(d,J＝7.6Hz,1H),8.40(s,1H),8.37(t,J＝7.9Hz,1H),8.16(d,J＝8.3Hz,1H),7.68(d,J＝8.4Hz,1H),7.58(s,1H),7.33(s,1H),7.25(d,J＝8.6Hz,1H),5.94(s,1H),5.07(dd,J＝12.9,5.3Hz,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).
实施例10：N-(2-(1-(3-(1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌啶-4-基)-3-甲基丁基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000077
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝857.4.
实施例11：N-(2-(1-(3-(4-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)哌嗪-1-基)-3-甲基丁基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000078
参照实施例4的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝858.4.
实施例12：N-(2-(1-(2-(3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-基)乙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000079
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝883.4.
1H NMR(400MHz,DMSO-d 6)δ12.37(s,1H),11.03(s,1H),8.72(s,1H),8.45(d,J＝7.7Hz,1H),8.40(s,1H),8.37(t,J＝7.9Hz,1H),8.16(d,J＝7.8Hz,1H),7.65(d,J＝8.5Hz,1H),7.58(s,1H),7.29(s,1H),7.21(d,J＝8.7Hz,1H),5.95(s,1H),5.06(dd,J＝12.9,5.3Hz,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＝7.3Hz,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).
实施例13：N-(2-(1-(9-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3，9-二氮杂螺[5.5]十一烷-3-基)乙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000080
参照实施例4的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝884.4.
实施例14：N-(2-(1-(2-(3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-基)-2-甲基丙基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000081
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝911.4.
实施例15：N-(2-(1-(3-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)-3-氮杂螺[5.5]十一烷-9-基)甲基)哌啶-4-基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000082
参照实施例5的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝869.4.
实施例16：
Figure PCTCN2021075341-appb-000083
参照实施例4的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝912.4.
对照组1：N-(2-(1-(2-(2-((2-(2，6-二氧代哌啶-3-基)-1，3-二氧代异吲哚啉-5-基)氧基)乙氧基)乙基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000084
向N-(6-甲氧基-2-(哌啶-4-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺(24mg，0.05mmol)和2-(2-((2-(2，6-二氧代哌啶-3-基)-1,3-二氧异吲哚啉基-5-基)氧基)乙氧基)乙醛(40mg，0.11mmol)，在1,2-二氯乙烷(5ml)溶液中的混合物中加入STAB(36mg，0.17mmol)。将反应液在室温下搅拌反应2h。减压浓缩除去溶剂，将浓缩物通过HPLC纯化，得到白色固体目标产物3.25mg。
LC-MS:(ES,m/z):[M+H] +＝764.3.
1H-NMR-LT-002-007: 1H NMR(400MHz,CD 3OD_SPE)δ8.77(s,1H),8.47(d,J＝8.0Hz,3H),8.31(t,J＝7.8Hz,1H),8.18(s,1H),8.05(d,J＝7.4Hz,1H),7.81(d,J＝8.3Hz,1H),7.47(d,J＝1.9Hz,1H),7.35(d,J＝8.3Hz,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＝5.0Hz, 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＝5.2Hz,1H).
对照组2：N-(2-(1-((1-(2-((2-(2,6-二氧代基哌啶-3-基)-1，3-二氧代基异吲哚-5-基)氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
步骤1：5-(烯丙氧基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮的制备
Figure PCTCN2021075341-appb-000085
在氮气保护下，向2-(2，6-二氧代哌啶-3-基)-5-羟基异吲哚啉-1，3-二酮(1g，3.65mmol)和碳酸钾(1.01g，7.29mmol)在N，N-二甲基甲酰胺(10mL)溶液中的混合物中加入3-溴丙烯-1-基(470mg,3.89mmol)。反应混合物50℃下搅拌反应过夜。0℃下，用水(60mL)萃灭反应，并用乙酸乙酯萃取(30mL×3),收集有机相并经饱和食盐水洗涤，无水硫酸钠干燥，过滤并减压浓缩。浓缩物经硅胶柱纯化得到目标产物0.85g。
LC-MS:(ES,m/z):[M+H] +＝315.1
步骤2：2-((2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-5-基)氧基)乙醛
Figure PCTCN2021075341-appb-000086
-78℃，向5-(烯丙氧基)-2-(2,6-二氧代基哌啶-3-基)异吲哚啉-1,3-二酮(0.7g，2.23mmol)的二氯甲烷(200ml)溶液中通入臭氧，直到反应液变为蓝色。而后通入氮气直到反应液变为无色。-78℃并在氮气保护下加入二甲硫醚(7.61g，123mmol),反应混合物在室温下搅拌反应过夜。浓缩反应液，浓缩物经硅胶柱纯化得到目标产物。
LC-MS:(ES,m/z):[M+H] +＝317.1
步骤3：N-(2-(1-((1-(2-((2-(2,6-二氧代基哌啶-3-基)-1，3-二氧代基异吲哚-5-基)氧基)乙基)哌啶-4-基)甲基)哌啶-4-基)-6-甲氧基-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺的制备
Figure PCTCN2021075341-appb-000087
参照对照组1步骤3的方法合成。
LC-MS:(ESI,m/z):[M+H] +＝817.1.
1H NMR(400MHz,DMSO-d 6)δ11.11(s,1H),10.50(s,1H),8.69(s,1H),8.46(d,J＝7.6Hz,1H),8.41(t,J＝7.8Hz,1H),8.37(s,1H),8.22(d,J＝8.6Hz,1H),7.83(d,J＝8.3Hz,1H),7.47(d,J＝2.2Hz,1H),7.37(dd,J＝8.3,2.3Hz,1H),7.16(s,1H),5.12(dd,J＝12.8,5.3Hz,1H),4.43–4.34(m,1H),4.29(t,J＝5.5Hz,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).
对照组3：N-(2-((1r，4r)-4-((((1-(2-(2,6-二氧代基哌啶-3-基)-1,3-二氧代基异吲哚啉-4-基)哌啶-4-基)甲基)(甲基)氨基)甲基)环己基)-6-(2-羟基丙-2-基)-2H-吲唑-5-基)-6-(三氟甲基)吡啶甲酰胺
Figure PCTCN2021075341-appb-000088
参照WO2020113233中化合物I-317的方法制备。
LC-MS:(ESI,m/z):[M+H] +＝843.3
1H NMR(400MHz,DMSO-d 6)δ12.36(s,1H),11.08(s,1H),8.71(s,1H),8.45(d,J＝7.8Hz,1H),8.41–8.32(m,2H),8.16(d,J＝7.8Hz,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＝12.8,5.3Hz,1H),4.47–4.36(m,1H),3.70(d,J＝10.0Hz,2H),2.90(d,J＝12.7Hz,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＝11.6Hz,2H),1.11(d,J＝11.9Hz,2H)
Ⅱ生物活性测试实施例
测试实施例1：IRAK4激酶活性测试
用KinEASE-STK S1丝/苏氨酸激酶试剂盒(Cisbio)检测化合物对IRAK4激酶活性的抑制作用，具体方法为：化合物溶解于二甲亚砜中，再用试剂盒的缓冲液进行等梯度稀释，使受试化合物在反应体系中的终浓度范围为10000nM～0.038nM，再依次加入2.5nM激酶、1μM生物素化的多肽底物和7μM三磷酸腺苷(ATP)在37℃下孵育120min。随后向反应体系中加入偶联有铕系元素化合物的抗磷酸化丝/苏氨酸抗体和偶联有修饰化的XL665链霉亲和素以终止反应，在室温下孵育1h后，在酶标仪EnVision(PerkinElmer)上以HTRF模式测定各孔在激发波长为337nm，读取各孔在发射波长为620nm和665nm的荧光强度，使用公式Ratio＝(665nm/620nm)×10 4算出Ratio值。通过与对照组荧光强度比值进行对比，计算化合物在各浓度下的抑制率，进而通过GraphPad Prism 7以对数浓度-抑制率进行非线性曲线拟合，得出化合物的IC 50值。
测试实施例2：化合物对THP-1细胞中IRAK4的降解
24孔细胞培养板每孔接种0.95mL THP-1细胞(中国科学院干细胞库)，细胞密度为5×10 5个/孔；细胞板置于5％二氧化碳培养箱中37℃培养过夜，然后再加入50μL化合物二甲亚砜溶液，化合物终浓度在1～3000nM范围内，继续培养24小时后，收集细胞至1.5mL的离心管中，1000rpm、4℃离心5分钟。细胞沉淀用1×DPBS清洗2次，重悬的细胞用200μL裂解液(细胞裂解液为Western及IP细胞裂解液(碧云天)，补充1mM苯甲基磺酰氟和蛋白酶抑制剂混合物(碧云天))裂解，冰上静置30分钟后14000g、4℃离心10分钟，取上清液分别用蛋白免疫印迹法(Western Blot)检测IRAK4蛋白水平。
上述细胞裂解上清液中总蛋白浓度用BCA蛋白质定量试剂盒(天根)测定。根据BCA检测总蛋白的浓度，用PBS和5×SDS-PAGE蛋白上样缓冲液(碧云天)调整至0.2μg/μL，100℃水浴10分钟，然后置于冰上冰浴5分钟后，14000g、4℃ 离心5分钟后收集上清作为WB的上样样品。用预制胶(凯基)做蛋白电泳，上样量为10μL(总蛋白2μg)，Tris-MOPS-SDS电泳液(Adamas)后120V恒压电泳，电泳结束后，把胶条上的蛋白转至PVDF膜上，恒流250V转膜50分钟。转膜结束后将膜放入1×QuickBlock封闭液(碧云天)中室温孵育30分钟。封闭结束后，PVDF膜分别进行IRAK4一抗(Abcam)孵育4°过夜，TBST缓冲液(2.4g Tris，8.8g NaCl，1.5mL Tween 20，调pH至7.4，定容至1L)洗涤膜30分钟，二抗(Abcam)室温孵育2小时，最后用Clarity Western ECL Substrate(BIO-RAD)孵育5分钟发光显色，化学发光成像系统(勤翔，ChemiScope 6200Touch)进行显色和蛋白图谱拍照。蛋白图谱通过勤翔化学发光分析软件进行灰度值分析。使用公式：灰度校正值＝(目的蛋白灰度值/对应内参灰度值)×10 3，计算出各样品的灰度校正值。再与对照组灰度校正值对比计算降解率。进而通过GraphPad Prism 7以对数浓度-抑制率进行非线性曲线拟合，得出化合物的DC 50和D max值。
表1：
Figure PCTCN2021075341-appb-000089
注：WB指Western Blot方法，D(％)指Western Blot方法检测的本发明化合物对THP-1细胞中IRAK4激酶蛋白的降解百分比，D(％)(1000nM)为化合物浓度为1000nM时IRAK4的降解百分比，D(％)(300nM)为化合物浓度为300nM时IRAK4的降解百分比。
实验结果：本发明所述化合物能够有效的与IRAK4靶蛋白相结合；本发明所述化合物能够显著的降解细胞中的IRAK4激酶蛋白。
测试实施例3：药代动力学性质研究
如下实验方案用于研究本发明化合物在小鼠体内的药代动力学行为，评价其药动学特征。
实验方案：健康SD小鼠3只，雄性，体重18-25mg，灌胃给予100mg/kg的化合物，给药体积为10mL/kg，以5％DMSO/15％solutol％80％PBS(w/v)配制。试验前禁食12h，自由饮水。给药后4h统一进食。
健康SD小鼠3只，雄性，体重18-25mg，静脉注射给予1mg/kg的化合物，给药体积为5mL/kg，5％DMSO/15％solutol％80％PBS(w/v)配制。试验前禁食12h，自由饮水。给药后4h统一进食。
分别于灌胃给药后0.08h、0.25h、0.5h、1h、2h、4h、8h、24h以及静脉给药后0.08h、0.25h、0.5h、1h、2h、4h、8h、24h经小鼠颌下静脉丛取静脉血0.1mL，置肝素化试管中，11000rpm离心5min，分离血浆，以液相色谱-串联质谱法测定血浆中化合物的浓度。
表2：
Figure PCTCN2021075341-appb-000090
实验结果表明：本发明化合物清除率低，血浆暴露量高，口服生物利用度好，具有良好的药代动力学性质，利于成药。
测试实施例4：化合物对L363细胞中IKZF1、IKZF3的降解
24孔细胞培养板每孔接种0.95mL L363细胞(南京科佰)，细胞密度为6×10 5个/孔；细胞板置于5％二氧化碳培养箱中37℃培养8小时，然后再加入50μL化合物溶液，化合物终浓度在1000nM，继续培养16小时后，收集细胞至1.5mL的离心管中，3000rpm、4℃离心5分钟。细胞沉淀用1×DPBS清洗2次，重悬的细胞用100μL裂解液(细胞裂解液为Western及IP细胞裂解液(碧云天)，补充1mM苯甲基磺酰氟、蛋白酶抑制剂混合物(碧云天))裂解，冰上静置30分钟后14000g、4℃离心10分钟，取上清液分别用蛋白免疫印迹法(Western Blot)检测IKZF1与IKZF3蛋白水平。
上述细胞裂解上清液中总蛋白浓度用BCA蛋白质定量试剂盒(天根)测定。根据BCA检测总蛋白的浓度，用PBS和5×SDS-PAGE蛋白上样缓冲液(碧云天)调整至0.2μg/μL，100℃水浴10分钟，然后置于冰上冰浴5分钟后，14000g、4℃离心5分钟后收集上清作为WB的上样样品。用预制胶(凯基)做蛋白电泳，上样量为10μL(总蛋白2μg)，Tris-MOPS-SDS电泳液(Adamas)后120V恒压电泳，电泳结束后，把胶条上的蛋白转至PVDF膜上，恒流250V转膜50分钟。转膜结束后将膜放入5％牛血清白蛋白溶液中室温孵育2小时。封闭结束后，PVDF膜分别进行IKZF1一抗(CST)与IKZF3一抗(Abcam)孵育4°过夜，TBST缓冲液(2.4g Tris，8.8g NaCl，1.5mL Tween 20，调pH至7.4，定容至1L)洗涤膜30分钟，二抗(Abcam)室温孵育2小时，最后用Clarity Western ECL Substrate(BIO-RAD)孵育5分钟发光显色，化学发光成像系统(勤翔，ChemiScope 6200 Touch)进行显色和蛋白图谱拍照。蛋白图谱通过勤翔化学发光分析软件进行灰度值分析。使用公式：灰度校正值＝(目的蛋白灰度值/对应内参灰度值)×10 3，计算出各样品的灰度校正值。再与对照组灰度校正值对比计算降解率。
表4：
Figure PCTCN2021075341-appb-000091
Figure PCTCN2021075341-appb-000092
注：表4中，“-”指IKZF1、IKZF3无降解。
实验结果表明：本发明化合物选择性好，对IKZF1、IKZF3没有或少量降解，毒副作用小，利于成药。

Claims (19)

  1. 式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，
    Figure PCTCN2021075341-appb-100001
    其中：
    R a为氢、卤素、C1-C6烷基或-O-(C1-C6烷基)，所述烷基任选被卤素或羟基取代；
    环A为6-10元芳基或5-10元杂芳基；
    R d各自独立地为氢、卤素、氰基、C1-C6烷基、-O-(C1-C6烷基)、-O-(C3-C6环烷基)、C3-C6环烷基或5-10元杂芳基，所述烷基、环烷基和杂芳基任选地被1个或多个选自卤素、羟基、氨基的基团取代；
    n为1、2、3或者4；
    R e为氢或者C1-C6烷基；
    R c为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
    R b为氢、-O-(C1-C6烷基)、-O-(C3-C8环烷基)、-O-(3-8元杂环烷基)、-O-芳基、-O-杂芳基、-N(C1-C6烷基) 1-2、-NH(C3-C8环烷基)、-NH(3-8元杂环烷基)、-NH芳基、-NH杂芳基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-8元杂环烷基、6-10元芳基或5-10元杂芳基，所述烷基、环烷基、杂环烷基、芳基和杂芳基任选被1个或多个独立地选自羟基、氨基、卤素或氰基的基团取代；
    环B为6-10元芳基、5-10元杂芳基、C3-C12环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
    环C为6-10元芳基、5-10元杂芳基、C3-C12环烷基或含有1-2个选自N、O或S杂原子的3-12元杂环烷基，所述芳基、杂芳基、环烷基和杂环烷基任选被选自卤素、氧代、氰基、氨基、羟基、C1-C6烷基、C1-C6卤代烷基、C1-C6羟基烷基或-O-(C1-C6烷基)的取代基取代；
    X为键、-O-、-NH-、-N(C1-C6烷基)-、-S-、-C＝C-、-C≡C-、-C(O)-、-OC(O)-、-C(O)O-、-NHC(O)-或-C(O)NH-；
    W为-CR gR h或-C(O)；
    R g、R h各自独立地为氢、卤素、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或C3-C6环烷基；
    L为-(CH 2) j-，所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-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-、亚乙烯基或亚乙炔基的基团替代；
    R 1’、R 2’各自独立地为卤素、-OH、-NH 2、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基、-O(C1-C4烷基)、-NH(C1-C4烷基)、-NH(C1-C4烷基)、C3-C6环烷基、-O(C3-C6环烷基)、-NH(C3-C6环烷基)、3-6元杂环烷基、-O(3-6元杂环烷基)、-NH(C3-C6环烷基)；
    R 3’、R 4’各自独立地为氢或C1-C6烷基；
    j为1、2、3、4、5或6；
    条件是式Ⅰ化合物不包括以下化合物
    Figure PCTCN2021075341-appb-100002
  2. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，所述式Ⅰ化合物为式Ⅱ化合物
    Figure PCTCN2021075341-appb-100003
    其中所述R a、R b、R c、R d、R e、n、环A、环B、L、环C、X、W如权利要求1中所定义。
  3. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，环B为3-8元单环环烷基、7-12元螺环环烷基、7-12元稠环环烷基、含有1-2个N杂原子的3-8元单环杂环烷基、含有1-2个N杂原子的7-12元稠环杂环烷基或含有1-2个N杂原子的7-12元螺环杂环烷基。
  4. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，环B为环己烷、哌啶基或哌嗪基。
  5. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对 映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，环C为3-8元单环环烷基、7-12元螺环环烷基、7-12元稠环环烷基、含有1-2个N杂原子的3-8元单环杂环烷基、含有1-2个N杂原子的7-12元稠环杂环烷基或含有1-2个N杂原子的7-12元螺环杂环烷基。
  6. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，环C为环己烷、哌啶基、哌嗪基、
    Figure PCTCN2021075341-appb-100004
  7. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，环A为苯基或吡啶基。
  8. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，R d各自独立地为氢、卤素或任选的被1个或多个选自F或羟基的基团取代的C1-C6烷基。
  9. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，R d为氢、F、甲基、二氟甲基、三氟甲基或2-羟基丙基。
  10. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，R c为任选被1个或多个独立地选自羟基或卤素的基团取代的C1-C6烷基、任选被1个或多个独立地选自羟基或卤素的基团取代的-O(C1-C6烷基)或含有1个或2个N杂原子的C3-C6环烷基。
  11. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，R c为二氟甲基、羟基取代的吡咯烷基、2-羟基丙基、甲氧基、乙氧基或异丙氧基。
  12. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，R b为氢或甲基。
  13. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，L为-(CH 2) j-，所述-(CH 2) j-中的1个或多个亚甲基任选的被选自-NR 3’-、-O-、-CR 1’R 2’-、-C(O)-、-C(O)O-、-OC(O)-、-C(O)NR 3’-、-NR 3’C(O)-的基团替代；所述R 1’、R 2’各自独立为卤素、-OH、-NH 2、C1-C4烷基、C1-C4氯代烷基、C1-C4羟基烷基或-O(C1-C4烷基)；所述R 3’、R 4’各自独立地为氢或甲基；j为1、2或3。
  14. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于，L为
    Figure PCTCN2021075341-appb-100005
  15. 如权利要求1所述的式Ⅰ化合物、和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，其特征在于为以下具体化合物
    Figure PCTCN2021075341-appb-100006
    Figure PCTCN2021075341-appb-100007
  16. 一种药物组合物，其包含权利要求1-15任一项所述化合物，和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐，以及药学上可接受的载体、稀释剂或赋形剂。
  17. 权利要求1-15任一项所述化合物，和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐在制备治疗和/预防IRAK4介导的疾病或病症的药物使用，或者TLR(除TLR3R以外)或IL-1β受体家族介导的疾病或病症的药物使用。
  18. 权利要求1-15任一项所述化合物，和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐在制备治疗和/预防癌症、神经退化性病症、病毒性疾病、自身免疫性疾病、炎性疾病、遗传性病症、激素相关疾病、代谢病症、与器官移植相关疾病、免疫缺陷病症、破坏性骨病、增生性病症、感染性疾病、与细胞死亡相关的病况、凝血酶诱发的血小板凝集、肝病、涉及T细胞活化的病理性免疫病况、心血管病症或CNS病症疾病的药物中的应用。
  19. 权利要求1-15任一项所述化合物，和/或其立体异构体、对映异构体、非对映异构体、氘代化物、水合物、溶剂化物、前药和/或其药学上可接受的盐在制备治疗和/预防脑癌、肾癌、肝癌、肾上腺癌、膀胱癌、乳癌、胃癌、卵巢癌、结肠癌、直肠癌、前列腺癌、胰腺癌、肺癌、阴道癌、宫颈癌、睾丸癌、泌尿生殖道癌、食道癌、喉癌、皮肤癌、骨癌、甲状腺癌、肉瘤、神经胶母细胞瘤、神经母细胞瘤、多发性骨髓瘤、胃肠癌、颈部或头部肿瘤、表皮过度增生、牛皮藓、前列腺增生、腺瘤、腺癌、角化棘皮瘤、表皮样癌、大细胞癌、非小细胞肺癌、淋巴瘤、霍奇金氏和非霍奇金氏、乳腺癌、滤泡癌、未分化性瘤、乳头装瘤、精原细胞瘤、黑素瘤、ABC DLBCL、霍奇金氏淋巴瘤、原发性皮肤T细胞淋巴瘤、慢性淋巴细胞性白血病、冒烟型惰性多发性骨髓瘤、白血病、弥漫性大B细胞淋巴瘤DLBCL、慢性淋巴细胞性白血病CLL、慢性淋巴细胞性淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)/白血病、急性淋巴细胞性白血病、B细胞前淋巴细胞白血病、淋巴浆细胞淋巴瘤、瓦尔登斯特伦氏巨球蛋白血症(Waldenstroms′s macroglobulinemia WM)脾边缘区淋巴瘤、多发性骨髓瘤、或浆细胞瘤或血管内大B细胞淋巴瘤、阿尔茨海默症、帕金森氏病、肌肉萎缩性侧索硬化、亨廷顿氏病(Huntington′s disease)、大脑缺血或有创伤性损伤、谷氨酸神经毒性、低氧症、癫痫症、糖尿病治疗、代谢综合症、肥胖、器官移植或移植物抗宿主疾病造成的神经退化性疾病、眼病，如眼过敏、结膜炎、干眼症或春季结膜炎、影响鼻部的疾病，包括过敏性鼻炎；自身免疫性血液病症，如溶血性贫血、再生不全性贫血、纯红细胞贫血和特发性血小板减少、全身性红斑性狼疮症、类风湿性关节炎、多软骨炎、硬皮病、皮肌炎、慢性活性肝炎、重症肌无力、史蒂芬－约翰逊综合症、特发性口炎性腹泻、字体免疫性发炎性肠病、肠易综合症、乳糜泻、齿根骨膜炎、肺透明膜病、肾病、肾小球疾病、酒精性肝病、多发性硬化症、内分泌性眼病、格雷弗氏病(Grave′s disease)、肉瘤病、干眼症、春季结膜角膜炎、间质性肺纤维化、牛皮藓性关节炎、全身性幼年型特发性关节炎、肾炎、血管炎、间质性膀胱炎、憩室炎、肾小球肾炎、慢性肉芽肿性疾病、子宫内膜异位、钩端螺旋体病肾病、青光眼、视网膜疾病、老化、头痛、疼痛、复杂区域疼痛综合症、心肥大、肌肉萎缩、分解代谢症、肥胖、胎儿生长缓慢、高胆 固醇血症、心脏病、慢性心脏衰竭、间皮瘤、无汗性外胚层发育不良、白塞氏病、色素失禁症、佩吉特氏病(Paget′s disease)、胰脏炎、遗传性周期性发热综合症、哮喘、急性肺损伤、急性呼吸窘迫综合症、嗜伊红血球增多、过敏反应、全身性过敏反应、鼻窦炎、眼过敏、二氧化硅诱发的疾病、COPD、肺病、囊肿性纤维化、酸诱发的肺损伤、肺动脉高压、多发性神经病、白内障、与全身性硬化症结合的肌肉炎症、包涵体肌炎、重症肌无力、甲状腺炎、阿狄森氏病(Addison′s disease)、扁平苔藓、1型糖尿病、2型糖尿病、阑尾炎、异位性皮炎、哮喘、过敏、细支气管炎、支气管炎、滑囊炎、子宫颈炎、胆管炎、胆囊炎、慢性移植排斥反应、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上踝炎、附睾炎、筋膜炎、纤维组织炎、胃炎、胃肠炎、亨诺－许兰紫斑病(Henoch-Schonlein purpura)、肝炎、化脓性汗腺炎、免疫球蛋白A肾病、间质性肺病、喉炎、乳腺炎、脑膜炎、脊髓炎、心肌炎、肌炎、肾炎、肝纤维化、肾纤维化、酒精性脂肪肝、非酒精性脂肪肝、心脏纤维化、银屑病、克罗恩病、炎症性肠病、卵巢炎、睾丸炎、骨炎、耳炎、胰脏炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、局部肺炎、肺炎、多发性肌炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、窦炎、口腔炎、关节膜炎、肌腱炎、扁桃腺炎、溃疡性结肠炎、葡萄膜炎、阴道炎、血管炎、外阴炎、斑秃、多形性红斑、疱疹样皮炎、硬化病、白斑病、超敏性血管炎、荨麻疹、大疱性类天疱疮、寻常天疱疮、落叶型天疱疮、副肿瘤性天疱疮、获得性大疱性表皮松懈、急性和慢性痛风、慢性痛风性关节炎、牛皮藓、牛皮藓性关节炎、类风湿性关节炎、幼年型类风湿性关节炎、隐热蛋白相关周其综合症或骨关节炎病症疾病的药物中的应用。
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