Aza polycyclic degradation agent as well as preparation method and application thereof

Abstract

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

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to an azapolycyclic degradation agent and a preparation method and application thereof. Background Art

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

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

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

[0005] The object of the present invention is to provide a compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has the following structure:

[0006]

[0007] in:

[0008] Ring A is selected from heteroarylene;

[0009] Ring B is selected from aryl or heteroaryl;

[0010] Ring C is selected from heterocyclylene or heteroarylene;

[0011] M 1 Select from N or CR 1 ;

[0012] M 2 Select from N, C or CR 2 ;

[0013] M 3 Select from N or CR 3 ;

[0014] ------ indicates that the key may not exist;

[0015] R a , R b , R c , R d and R e Each independently selected from hydrogen, deuterium, halogen, cyano, oxo, -P(=O)R 4 R 5 , alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclic group, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclic group are optionally further substituted by deuterium, halogen, cyano, hydroxyl, -NR 6 R 7 , oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl;

[0016] Or, any two R b Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0017] Or, R e Linked to the carbon atom or nitrogen atom on the ring C to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0018] Or, R 2 Linked to the carbon atom or nitrogen atom on the ring C to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0019] Or, any two R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0020] R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7Each is independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, alkyl, alkoxy, aminoalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0021] L 1 , L 3 and L 4 Each independently selected from a bond, -NH-, -S-, -O-, -CH 2 -、CH 2 CH 2 -, -C(O)NH-, -NHC(O)-, or -C(O)-;

[0022] L 2 Selected from -(CH 2 ) j -, the -(CH 2 ) j -1, 2 or 3 methylene groups in the group are optionally replaced by -NH-, -NCH 3 -、-NCH 2 CH 3 -、-O-、-C(CH 3 ) 2 -、-CHF-、-CHCF 3 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH 3 -、-NHC(O)-、-NCH 3 C(O)-, cycloalkylene, heterocyclylene, heteroarylene, and the substituted group is optionally substituted by one or more substituents selected from halogen, oxo, hydroxy, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl;

[0023] Or, L 2 With R a Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted;

[0024] x, y, z, p and q are each independently selected from 0, 1, 2, 3 or 4;

[0025] n1 and n2 are each independently selected from 0, 1, 2 or 3; and

[0026] j is selected from 2, 3, 4, 5 or 6.

[0027] In a preferred embodiment of the present invention, the above ring C is selected from pyridinone, pyrimidinone, pyridazinone, pyridinyl or pyridinoxyl. Selected from

[0028] In a preferred embodiment of the present invention, the ring B mentioned above is selected from phenyl, pyridyl, pyrimidinyl, benzimidazolyl, pyrazolopyrimidinyl, pyridone or pyridazinone; preferably, the Selected from

[0029] Where: R b1 and R b2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group, the amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-4 The cycloalkyl group and the 3-4-membered heterocyclic group may be further substituted.

[0030] In a preferred embodiment of the present invention, R b1 and R b2 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxy, cyano, amino, methyl, ethyl, methoxy, ethoxy, trifluoromethyl, trifluoroethyl, hydroxymethyl, cyclopropyl, cyclobutyl, aziridine, azetidinyl, oxirane or oxetanyl.

[0031] In a preferred embodiment of the present invention, the ring A mentioned above is selected from benzopyrazolylene, pyridoimidazolylene, pyridotriazolylene, benzoimidazolylene or pyridopyrazolylene; preferably, the Selected from

[0032]

[0033] In a preferred embodiment of the present invention, the above L 2 Selected from -(CH 2 ) j -, the -(CH 2 ) j -1, 2 or 3 methylene groups in the group are optionally replaced by -NH-, -NCH 3 -、-NCH 2 CH 3 -、-O-、-C(CH 3 )2 -、-CHF-、-CHCF 3 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH 3 -、-NHC(O)-、-NCH 3 C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxetane, oxolylene, oxhexylene, aziridine, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, and the substituted groups are optionally substituted by one or more halogen, oxo, hydroxy, cyano, C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxolyl, oxolyl, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, and the substituted groups are optionally substituted by one or more halogen, oxo, hydroxy, cyano, C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxolyl, aziridine, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, and the substituted groups are optionally substituted by one or more halogen, oxo, hydroxy, cyano, C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, aziridine ... 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 The cycloalkyl group or the 3- to 6-membered heterocyclic group is substituted.

[0034] Preferably, the L 2 for Among them, M 4 Select from N or CR 8 ;M 5 Select from N or CR 9 ; R 8 and R 9 Each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; n3 and n4 are each independently selected from 0, 1, 2, 3 or 4; or, the methylene group is optionally replaced by NH-, -NCH 3 -、-NCH 2 CH 3 -、-O-、-C(CH 3 ) 2 -、-CHF-、-CHCF 3 -, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH 3 -、-NHC(O)-、-NCH 3 C(O)-, cycloalkylene, heterocyclylene, heteroarylene group, and the replacement group is optionally substituted by one or more selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Substituted by a cycloalkyl group or a 3-4-membered heterocyclic group;

[0035] More preferably, the L 2 Selected from:

[0036] In a preferred embodiment of the present invention, R a , R b , R c , R d and R e Each independently selected from hydrogen, deuterium, halogen, cyano, oxo, -P(=O)R 4 R 5 , C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, halogen, cyano, hydroxyl, -NR 6 R 7 , oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-6 is substituted by one or more substituents in a cycloalkyl group or a 3-6-membered heterocyclic group;

[0037] Preferably, the R a , R b , R c , R d and R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, methyl, ethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, methoxy, ethoxy, -CH 2 CH 2 OH, -CH 2 CH 2 N(CH 3 ) 2 , -P(=O)(CH 3 ) 2 or

[0038] In a preferred embodiment of the present invention, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Halogenated alkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; preferably, the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxy, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, aziridine, oxirane, hydroxymethyl or difluoromethyl.

[0039] In a preferred embodiment of the present invention, the above-mentioned compound is selected from the following compounds:

[0040]

[0041]

[0042]

[0043]

[0044]

[0045] The present invention also relates to a compound of formula (Aa), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, the specific structure of which is as follows:

[0046]

[0047] Where: M 3 , L 1 , R c , z and As defined above.

[0048] The present invention also relates to the use of the structural unit of formula (Aa-1) as an E3 ubiquitin structural unit of a protein degradation agent:

[0049]

[0050] Where: M 3 , L 1 , R c , z and As defined above.

[0051] The present invention also relates to a protein degradation agent containing a structural unit of formula (Aa-1):

[0052]

[0053] Where: M 3 , L 1 , R c , z and As defined above.

[0054] The present invention also relates to a compound of general formula (B), its stereoisomers or pharmaceutically acceptable salts thereof, the structure of which is as follows:

[0055]

[0056] in:

[0057] The PTM is selected from a drug or a derivative thereof that binds to a target protein;

[0058] L 2 , L 4 , L 1 、M 1 、M 2 、M 3 、n1、n2、R e , R c , q, z, and As defined above.

[0059] In a preferred embodiment of the present invention, the PTM mentioned above is selected from drugs or derivatives thereof that act on AR, ER, kinase, phosphatase, MDM2, proteins of human BET bromodomain, Hsp90, HDAC, human lysine methyltransferase, RAF receptor, FKBP, vascular growth factor, receptors or proteins related to immunosuppression, aryl hydrocarbon receptor, thyroid hormone receptor, HIV protease, HIV integrase, HCV protease, HBV protease or acyl protein thioesterase 1 and / or acyl protein thioesterase 2; preferably, the PTM mentioned above is selected from drugs or derivatives thereof that act on ALK, BET, CDK, PARP, EGFR, γ-secretase, CBFβ-SMMHC, WEEI, MEK, BCR-ABL, MET, RAS, BTK, VEGFR, JAK, HER2, HDAC, Akt, PI3K, Mtor, AR, ER, PDE, SRC, MDM2, RAF, IRAK4, STAT3 and c-Myc.

[0060] The present invention also provides a pharmaceutical composition, which comprises a therapeutically effective dose of the compound represented by the general formula described above, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0061] The present invention also provides a preferred embodiment, involving the use of the compounds described in the general formulae and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of drugs for treating or preventing IRAK4-mediated diseases.

[0062] The present invention also provides a preferred embodiment, involving the use of the compounds of the general formulae and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions described above in the preparation of drugs for treating or preventing autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death or cardiovascular diseases.

[0063] The present invention also relates to a method for treating or preventing an IRAK4-mediated disease, which comprises administering to a mammal an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate or hydrate thereof; the IRAK4-mediated disease is selected from autoimmune diseases, inflammatory diseases, cancer, viral diseases, neurodegenerative diseases, genetic disorders, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions associated with cell death or cardiovascular diseases.

[0064] Detailed description of the invention

[0065] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0066] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc., and various branched isomers thereof, etc. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl, and hydroxy-substituted alkyl are preferred in the present invention.

[0067] The term "alkylene" refers to an alkyl group with one hydrogen atom further substituted, for example, "methylene" refers to -CH 2 -, "ethylene" means -(CH 2 ) 2 -, "propylene" refers to -(CH 2 ) 3 -, "butylene" refers to -(CH 2 ) 4 -wait.

[0068] The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio.

[0069] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls, non-limiting examples of which include

[0070] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0071] The term "cycloalkylene" refers to a cycloalkyl group in which one of the hydrogen atoms is further substituted. Non-limiting examples include: cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, The cycloalkylene group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0072] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring part of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 12 ring atoms; most preferably, it contains 3 to 6 ring atoms. Non-limiting examples of monocyclic heterocyclic radicals include oxetane, thietanyl, azetidine, tetrahydropyranyl, azepanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably oxetane, thietanyl, azetidine, tetrahydrofuranyl, tetrahydropyranyl, 1-aminosubyl-1-oxothiopyran, azepanyl, piperidinyl and piperazinyl. Polycyclic heterocyclic radicals include spirocyclic, condensed ring and bridged ring heterocyclic radicals, non-limiting examples include The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0073] The term "heterocyclylene" refers to a heterocyclyl group in which one of its hydrogen atoms is further substituted, and non-limiting examples thereof include: oxirane, oxetane, oxolanyl, oxhexane, aziridine, aziridinyl, aziridinyl, morpholinyl, homomorpholinyl, piperidinyl, piperazinyl, pyrrolopyrrolyl, diazaspiro[5.5]undecyl, diazaspiro[5.5]undecyl, benzopiperidinyl, azetidinyl, diazetidinyl, pyrrolidinyl, diazaspiro[3.5]nonanyl, diazaspiro[3.5]nonanyl, azabicyclo[3.1.1]heptanyl, azaspiro[2.5]octanyl, The heterocyclylene group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0074] The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6 to 10 members, more preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring. The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0075] The term "arylene" refers to an aryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include: The arylene group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, haloalkyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0076] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably a 5-8-membered monoheteroaryl or an 8-14-membered diheteroaryl, more preferably a 5-membered monoheteroaryl, a 6-membered monoheteroaryl or a 9-membered diheteroaryl, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, pyridoimidazolyl, pyrimidoimidazolyl, etc., preferably pyridoimidazolyl and pyrimidoimidazolyl.

[0077] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0078] The term "heteroarylene" refers to a heteroaryl group in which one hydrogen atom is further substituted, and non-limiting examples thereof include pyridylene, pyrimidylene, pyrazolylene, pyridazinylene, and pyrazinylene.

[0079] The term "alkoxy" refers to-O-(alkyl) and-O-(non-substituted cycloalkyl), wherein the definition of alkyl is as described above. The non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or non-substituted, and when substituted, substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate. Non-limiting examples include trifluoromethoxy, trifluoroethoxy, difluoromethoxy.

[0080] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0081] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0082] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above. Non-limiting examples include: -C(CH 3 ) 2 (OH).

[0083] "Hydroxyl" refers to the -OH group. "Halogen" refers to fluorine, chlorine, bromine or iodine. "Amino" refers to -NH 2"Cyano" refers to -CN. "Nitro" refers to -NO 2 "Carboxyl" refers to -C(O)OH. "THF" refers to tetrahydrofuran. "EtOAc" refers to ethyl acetate. "MeOH" refers to methanol. "DMF" refers to N,N-dimethylformamide. "TFA" refers to trifluoroacetic acid. "MeCN" refers to acetonitrile. "DMA" refers to N,N-dimethylacetamide. "Et 2 "O" refers to diethyl ether. "DCE" refers to 1,2-dichloroethane. "DIPEA" refers to N,N-diisopropylethylamine. "NBS" refers to N-bromosuccinimide. "NIS" refers to N-iodosuccinimide. "Cbz-Cl" refers to benzyl chloroformate. "Pd 2 (dba) 3 " refers to tris(dibenzylideneacetone)dipalladium. "Dppf" refers to 1,1'-bisdiphenylphosphinoferrocene. "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate. "KHMDS" refers to potassium hexamethyldisilazide. "LiHMDS" refers to lithium bistrimethylsilylamide. "MeLi" refers to methyllithium. "n-BuLi" refers to n-butyllithium. "NMP" refers to N-methylpyrrolidone. "EDCI" refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. "TEA" refers to triethylamine. "EA" refers to ethyl acetate. "DCM" refers to dichloromethane. "DMAP" refers to 4-dimethylaminopyridine. "NMO" refers to N-methylmorpholine oxide. "DIBAL-H" refers to diisobutylaluminum hydride. "T 3 "P" refers to 1-propylphosphonic anhydride. "DMP" refers to dimethyl phthalate. "Dess-Martin" refers to Dess-Martin periodinane. "Ruphos" refers to 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl. "Ruphos Pd G3" refers to palladium(II) methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl). "LDA" refers to lithium diisopropylamide. "SEMCl" refers to 2-(trimethylsilyl)ethoxymethyl chloride. "STAB" refers to sodium triacetoxyborohydride. "P-TSA" refers to p-toluenesulfonic acid. "PCC" refers to pyridinium chlorochromate. "Pd-PEPPSI" refers to 1,3-bis[2,6-bis(pentyl-3-yl)phenyl]-4,5-dichloro-2,3-dihydro-1H-imidazol-2-yldichloro(2-methyl-1λ4-pyridin-1-yl)palladium. "LiBH 4 ” refers to lithium borohydride. “DCE” refers to 1,2-dichloroethane. “TEBAC” refers to benzyltriethylammonium chloride. “wt %” refers to mass percentage.

[0084] Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, C.

[0085] In the present invention, "------" means a bond or does not exist;

[0086] Unless otherwise specified, the chiral carbon in the compounds of the present invention is in R configuration or S configuration.

[0087] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atoms in the example compounds of the present invention may also be replaced by deuterium atoms.

[0088] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0089] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0090] The substituent in the "optionally further substituted" of the present invention is selected from deuterium, halogen, cyano, hydroxyl, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein halogen, cyano, hydroxyl, amino, nitro, oxo, alkyl, alkoxy, haloalkyl, haloalkoxy, deuterated alkyl, deuterated alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl and heteroaryl are as defined above.

[0091] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0092] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0093] The present invention is further described below in conjunction with examples, but these examples are not intended to limit the scope of the present invention.

[0094] The starting materials and reagents used in the examples of the present invention are known and can be purchased on the market, or can be synthesized by or according to methods known in the art. For example, intermediate 1 in the present invention can be prepared by referring to the method disclosed in WO2022028547 A1.

[0095] Example 1 Preparation of Compound 1

[0096] N-(6-methoxy-2-[(1r,4r)-4-(2-(4-[4-(2,6-dioxopyridin-3-yl)-2-oxopyridin-1-yl]piperidin-1-ylethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide (1)

[0097]

[0098] Step 1: Synthesis of Compound 1-2

[0099] To a solution of 4-bromopyridin-2-ol (1 g, 5.747 mmol, 1 equiv) in 1,4-dioxane (29 mL) were added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3554.2 mg, 11.494 mmol, 2 equiv), anhydrous copper acetate (1252.67 mg, 6.896 mmol, 1.2 equiv), sodium carbonate (1827.41 mg, 17.241 mmol, 3 equiv), and 2'-2-bipyridine (987.39 mg, 6.322 mmol, 1.1 equiv) at room temperature. The mixture was stirred at 70°C under oxygen for 4 hours. The reaction mixture was poured into water (500 mL) and then extracted with dichloromethane (200 mL x 3). The combined organic layer was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20:1-1:1) to obtain 4-bromo-2-oxo-3',6'-dihydro-2'H-[1,4'-bipyridine]-1'-carboxylic acid tert-butyl ester (1.6 g).

[0100] LCMS: (ESI, m / z): 356 [M+H] + .

[0101] Step 2: Synthesis of Compound 1-3

[0102] Under nitrogen protection, tert-butyl 4-bromo-2-oxo-3',6'-dihydro-2'H-[1,4'-bipyridine]-1'-carboxylate 1-2 (1.35 g, 3.800 mmol, 1 equiv) was dissolved in tetrahydrofuran (30 mL) / water (15 mL), and 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1903.1 mg, 4.560 mmol, 1.2 equiv), tetrakis(triphenylphosphine)palladium (439.16 mg, 0.380 mmol, 0.1 equiv), potassium carbonate (1050.45 mg, 7.600 mmol, 2 equiv) were added respectively. The temperature was raised to 65°C and the reaction was carried out for 3 hours. The desired product was found in the liquid. The reaction was quenched with ice water (100 mL), and the tetrahydrofuran was removed by concentration under reduced pressure. The reaction solution was extracted with dichloromethane (300 mL), and washed three times with water (100 mL). The organic layer was separated and dried over anhydrous sodium sulfate. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate / petroleum ether (20%) to give tert-butyl 4-[2,6-bis(phenoxy)pyridin-3-yl]-2-oxo-3',6'-dihydro-2'H-[1,4'-bipyridine]-1'-carboxylate 1-3 (500 mg).

[0103] LCMS: (ESI, m / z): 566 [M+H] + .

[0104] Step 3: Synthesis of Compound 1-4

[0105] Under nitrogen protection, a methanol (10 mL) solution of tert-butyl 4-[2,6-bis(phenoxy)pyridin-3-yl]-2-oxo-3',6'-dihydro-2'H-[1,4'-bipyridine]-1'-carboxylate 1-3 (420 mg, 0.742 mmol, 1 equiv) was added to a 50 mL single-mouth bottle, and palladium carbon (40 mg, 10%, 0.376 mmol, 0.51 equiv) was added. The nitrogen was replaced, and hydrogen (balloon) was introduced, and the reaction was carried out at room temperature for 3 hours. Then diatomaceous earth was added for suction filtration, and the filtrate was concentrated under reduced pressure. 4-[4-(2,6-dioxopiperidin-3-yl)-2-oxopyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester 1-4 (45 mg) was obtained.

[0106] LCMS: (ESI, m / z): 390 [M+H] + .

[0107] Step 4: Synthesis of Compound 1-5

[0108] At 0°C, 4-[4-(2,6-dioxopiperidin-3-yl)-2-oxopyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester 1-4 (40 mg, 0.103 mmol, 1 equiv) in dichloromethane (1 mL) was added dropwise with 4 mol / L hydrogen chloride in 1,4-dioxane solution (0.1 mL), and the mixture was reacted at room temperature for 2 hours. The desired product was found in the liquid. The system was directly concentrated to dryness to obtain 3-[2-oxo-1-(piperidin-4-yl)pyridin-4-yl]piperidine-2,6-dione 1-5 (30 mg).

[0109] LCMS: (ESI, m / z): 290 [M+H] +

[0110] Step 5: Synthesis of Compound 1

[0111] 3-[2-oxo-1-(piperidin-4-yl)pyridin-4-yl]piperidine-2,6-dione 1-5 (30 mg, 0.104 mmol, 1 equiv) and tetrahydrofuran (1 mL) were added to a 40 mL sample bottle. After dissolution and clarification, N-(6-methoxy-2-[(1r, 4r)-4-(2-oxoethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide intermediate 1 (47.74 mg, 0.104 mmol, 1 equiv) was added. Sodium triacetoxyborohydride (65.93 mg, 0.312 mmol, 3 equiv) was added at 0°C, and then reacted at room temperature for 2 hours. After the reaction was completed by liquid mass monitoring, the obtained residue was concentrated under reduced pressure. The crude product was purified by high performance liquid chromatography. Purification conditions: (chromatographic column specifications: XBridge BEH Shield RP18 5um, 30mm*150mm; mobile phase A: water (10 mmol per liter of ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml per minute; elution gradient: 35% B to 55% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 8.6), to obtain N-(6-methoxy-2-[(1r,4r)-4-(2-(4-[4-(2,6-dioxopyridin-3-yl)-2-oxopyridin-1-yl]piperidin-1-ylethyl)cyclohexyl]indazole-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide 1 (10.6 mg).

[0112] LCMS: (ESI, m / z): 734 [M+H] + .

[0113] 1H NMR: (400MHz, Chloroform-d, ppm) δ10.73–10.61(m,1H),8.93–8.72(m,1H),8.54–8.40(m,1H),8.41–8.3 0(m,1H),8.15–8.04(m,1H),7.90–7.75(m,2H),7.44–7.32(m,1H),6.52–6.38(m,1H),6.15–5.99(m,1H), 5.02–4.82(m,1H),4.39–4.21(m,1H),4.08–3.94(m,3H),3.65–3.48(m,1H),3.21–2.99(m,2H),2.85–2.5 8(m,2H),2.55–2.38(m,2H),2.37–2.09(m,6H),2.08–1.83(m,8H),1.57–1.37(m,3H),1.31–1.05(m,2H).

[0114] 19 F NMR:(376MHz,CDCl 3 )δppm-68.0698.

[0115] Example 2 Preparation of Compound 36

[0116] N-(6-methoxy-2-[(1R,4R)-4-(2-(4-[4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxopyridin-1-yl]piperidin-1-ylethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide (36)

[0117]

[0118] Using 36-1 to replace 1-1, referring to the synthesis method of compound 1, N-(6-methoxy-2-[(1R,4R)-4-(2-(4-[4-(2,6-dioxopiperidin-3-yl)-5-fluoro-2-oxopyridin-1-yl]piperidin-1-ylethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide (1.5 mg, 3.00%) was obtained. LCMS: (ESI, m / z): 752.3 [M+H] + .

[0119] 1H NMR: (400MHz, DMSO-d6, ppm) δ10.95(s,1H),10.50(s,1H),8.69(s,1H),8.46(d,J=7.4Hz,1H),8.41(t,J= 7.8Hz,1H),8.33(s,1H),8.22(d,J=7.6Hz,1H),7.95(d,J=6.9Hz,1H),7.16(s,1H),6.37(d,J=7.1Hz,1H) ,4.64-4.57(m,1H),4.39-4.33(m,1H),3.98(s,3H),3.95-3.91(m,1H),3.02(d,J=11.8Hz,2H),2.41-2.3 7(m,4H),2.17-2.10(m,3H),2.09-1.99(m,4H),1.96-1.82(m,7H),1.72-1.66(m,2H),1.46-1.39(m,3H).

[0120] Example 3 Preparation of Compound 37

[0121] 5-(2,6-dioxopiperidin-3-yl)-2-(1-(2-[(1r,4r)-4-(6-methoxy-5-[6-(trifluoromethyl)pyridin-2-amino]indazol-2-ylcyclohexyl]ethylpiperidin-4-yl)pyridin-1-ium-1-ol ester (37)

[0122]

[0123] Step 1: Synthesis of compound 37-2

[0124] Under nitrogen protection, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.19 g, 0.286 mmol, 0.05 eq) was added to a mixed solution of 5-bromo-2-chloropyridine (1.1 g, 5.716 mmol, 1 eq), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.39 g, 5.716 mmol, 1 eq), cesium fluoride (1.74 g, 11.432 mmol, 2 eq) in N,N-dimethylformamide (10 mL) and water (2 mL), and the reaction solution was stirred at 50°C for 2 hours. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined and dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 column, mobile phase: water and acetonitrile, 10% to 100% gradient in 30 minutes, detection wavelength: UV 254nm to obtain 2,6-bis(benzyloxy)-6'-chloro-3,3'-bipyridine (37-2, 1.4 g, 60.79%) as a yellow solid.

[0125] LCMS: (ESI, m / z): 403.1 [M+H] + .

[0126] Step 2: Synthesis of compound 37-3

[0127] Under nitrogen protection, [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.11 g, 0.174 mmol, 0.05 eq) was added to a mixed solution of compound 37-2 (1.4 g, 3.475 mmol, 1 eq), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.07 g, 3.475 mmol, 1 eq), cesium fluoride (1.06 g, 6.950 mmol, 2 eq) in N,N-dimethylformamide (15 mL) and water (3 mL). The reaction solution was stirred at 50°C for 2 hours, then heated to 80°C and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate. After the obtained mixture was filtered, the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 chromatography column, mobile phase: water and acetonitrile, 10% to 100% gradient in 30 minutes, detection wavelength: UV 254nm. Compound 37-3 (1.1 g, 57.59%) was obtained as a yellow solid.

[0128] LCMS: (ESI, m / z): 550.2 [M+H] + .

[0129] Step 3: Synthesis of compound 37-4

[0130] Under nitrogen protection, compound 37-3 (400 mg, 0.728 mmol, 1 eq) was dissolved in tetrahydrofuran (8 mL) solution, and palladium / carbon (100 mg) was added. The nitrogen was replaced, hydrogen was introduced, and the reaction was stirred at room temperature for 24 hours. Then diatomaceous earth was added for suction filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse phase column chromatography under the following conditions: C18 chromatography column, mobile phase: water and acetonitrile, 0% to 100% gradient for 30 minutes, detection wavelength: UV 254 nm. Compound 37-4 (160 mg, 58.87%) was obtained as a purple solid. LCMS: (ESI, m / z): 374.2 [M+H] + .

[0131] Step 4: Synthesis of compound 37-5

[0132] At room temperature, compound 37-4 (140 mg, 0.375 mmol, 1 eq) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (3 mL, 4 M). The reaction solution was stirred for 2 hours. Liquid quality monitoring showed that the starting material disappeared, and the residue was concentrated under reduced pressure to obtain compound 37-5 (100 mg, 97.59%) as a light yellow solid.

[0133] LCMS: (ESI, m / z): 274.2 [M+H] + .

[0134] Step 5: Synthesis of compound 37-6

[0135] At room temperature, m-chloroperbenzoic acid (126.26 mg, 0.732 mmol, 2 eq) was added to a solution of compound 37-5 (100 mg, 0.366 mmol, 1 eq) in dichloromethane (4 mL). The reaction was continued until the starting material disappeared, and the reaction solution was quenched with a saturated sodium bicarbonate solution, extracted with dichloromethane three times, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the residue was concentrated in vacuo to obtain compound 37-6 (90 mg, 85.02%).

[0136] LCMS: (ESI, m / z): 290.1 ​​[M+H] + .

[0137] Step 6: Synthesis of compound 37

[0138] At room temperature, compound 37-6 (90 mg, 0.311 mmol, 1 eq) and N-(6-methoxy-2-[(1r, 4r)-4-(2-oxoethyl)cyclohexyl]indazol-5-yl-6-(trifluoromethyl)pyridine-2-carboxamide (143.23 mg, 0.311 mmol, 1 eq) were dissolved in tetrahydrofuran (6 mL), and the reaction solution was stirred at room temperature for 30 minutes, and then sodium triacetoxyborohydride (131.85 mg, 0.622 mmol, 2 eq) was added to the reaction solution. The reaction solution was stirred at room temperature for 2 hours. The desired product was found in the liquid. The crude product was purified by high performance liquid chromatography to obtain compound 37 (25.6 mg, 10.98%) under the following conditions (chromatographic column specifications: XBridge BEHShield RP18 5um, 30mm*150mm; mobile phase A: water (10 mmol / L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 ml / min; elution gradient: 39% B to 53% B in 10 minutes; detection wavelength: UV 254nm / 220nm; retention time (minutes): 5.4). LCMS: (ESI, m / z): 734.3 [M+H] + .

[0139] 1 H NMR: (400MHz, DMSO-d6, ppm) δ10.92(s,1H),10.50(s,1H),8.68(s,1H),8.46(d,J=7.5Hz,1H),8.41(t,J=7.8Hz,1H),8.34(s, 1H),8.26-8.18(m,2H),7.39(d,J=8.2Hz,1H),7.22(dd,J=1.5,8.2Hz,1H),7.16(s,1H),4.43-4.31(m,1H),3.98(s,3H),3.91( dd,J=4.8,12.7Hz,1H),3.26-3.19(m,1H),3.01(d,J=11.0Hz,2H),2.73-2.60(m,2H),2.37(t,J=6.7Hz,2H),2.32-2.23(m,J=4 .1Hz,1H),2.18-2.10(m,2H),2.08-1.96(m,3H),1.95-1.84(t,6H),1.64-1.50(m,2H),1.50-1.373(m,3H),1.25-1.11(m,2H).

[0140] Other compounds described in the present invention can be prepared by referring to the preparation methods of Examples 1, 36 and 37 above, as follows:

[0141]

[0142]

[0143]

[0144]

[0145] Biological test evaluation

[0146] The present invention is further described and explained in conjunction with the test examples below, but these examples are not intended to limit the scope of the present invention. Test Example 1 Detection of the degradation level of HiBiT-IRAK4 protein in K562 IRAK4-HiBiT cells after co-incubation with the compound of the present invention

[0147] Experimental reagents, equipment and consumables:

[0148] Nano-Glo Lytic Detection Assay, purchased from Promega;

[0149] EnVision, purchased from PerkinElmer;

[0150] Cell line name: K562 IRAK4-HiBiT stable cell line (can stably express IRAK4-HiBiT fusion protein) was constructed by Shanghai Runnuo Biotechnology Co., Ltd., where the K562 cell line was purchased from ATCC and the culture medium was IMDM + 10% FBS + 1% P / S (volume percentage, where FBS is fetal bovine serum, P / S is Penicillin-Streptomycin, an antibiotic solution of 1:1 mixed penicillin and streptomycin (10,000 units / mL)).

[0151] Experimental steps:

[0152] Cell culture: K562 IRAK4-HiBiT cells were cultured at 37°C and passaged every 2-3 days at a seeding density of 200,000 cells / mL.

[0153] IRAK4-HiBiT protein degradation assay:

[0154] Step 1: Cell seeding and compound treatment

[0155] 1. Use DMSO to prepare a 10 mM compound stock solution, and use the Bravo automated liquid handling platform to prepare a 1000-fold working concentration compound solution (the highest working concentration is 10 μM, 3.162-fold dilution, and a total of 10 concentration gradients).

[0156] 2. Transfer 40 nL of compound working solution to a 384-well plate and add an equal volume of DMSO to the positive control wells.

[0157] 3. Add 20 μL of culture medium to each well and shake for 10 minutes.

[0158] 4. Add 20 μL K562 IRAK4-HiBiT cell suspension (6000 cells / well) to each well and add an equal volume of culture medium to the negative control well.

[0159] 5. Spin the plate at 1000 rpm for 1 minute.

[0160] 6. Incubate at 37°C, 5% CO 2 Incubate in incubator for 6 hours or 24 hours.

[0161] Step 2: HiBiT Lytic Experiment

[0162] 1 Allow the plate to equilibrate at room temperature for 30 minutes.

[0163] 2. Add 20 μL Nano-Glo HiBiT Lytic reagent (trade name: HiBiT LyticDetection Reagent) and protect from light.

[0164] 3. Place the plate on an orbital shaker at 300 rpm for 5 minutes.

[0165] 4. Incubate at room temperature for 10 minutes.

[0166] 5. Envision reads the luminescence value.

[0167] 6. Calculate and process data. Degradation degree % = (negative control - experimental well) / (negative control - positive control) * 100%; Use XL-fit software to fit the degradation curve using 4Parameter Logistic Model to obtain Relative DC 50 (nM) and Absolute DC 50 (nM) value.

[0168] The experimental results are as follows:

[0169]

[0170] The other compounds of the present invention were tested by referring to the experimental method to obtain the Relative DC of the compounds of the present invention. 50 The value of (nM) is between 0.01 and 100. The Relative DC 50The value of (nM) is less than 100; the Absolute DC 50 The value of (nM) is between 0.01 and 100. The Absolute DC 50 The value of (nM) is less than 100.

[0171] Experimental conclusion:

[0172] The compound of the present invention has good degradation activity on IRAK4 protein.

[0173] Test Example 2 Study on the pharmacokinetic behavior of the compound of the present invention in mice

[0174] Experimental drugs: Compounds of the present invention, homemade.

[0175] Experimental protocol:

[0176] Three healthy ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), male, weighing 18-25g, were intravenously injected with 1 mg / kg of the compound, with a dosing volume of 5 ml / kg. The compound was prepared with 5% DMSO+10% Solutol+85% Saline (w / v), and the animals were not fasted before the experiment.

[0177] Three healthy ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), male, weighing 18-25g, were given 5mg / kg of the compound by gavage, with a dosing volume of 10ml / kg. The compound was prepared with 5% DMSO+10% Solutol+85% Saline (w / v), and the animals were not fasted before the experiment.

[0178] Blood was collected from the cheek at 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after intravenous administration and 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 24h after oral administration. About 0.05mL of each sample was collected. Heparin sodium was used for anticoagulation. The blood samples were placed on ice after collection and centrifuged to separate plasma within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8℃). The concentration of the compound in plasma was determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored in a -80℃ refrigerator before analysis. Phoenix WinNonlin8.2.0 was used to calculate the pharmacokinetic parameters based on the blood drug concentration data at different time points.

[0179] The experimental results show that the compound of the present invention has a low clearance rate, a high plasma exposure, a good oral availability, and has good pharmacokinetic properties.

Claims

1. A compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: The compound is selected from the compounds represented by general formula (I): in: Ring A is selected from heteroarylene; Ring B is selected from aryl or heteroaryl; Ring C is selected from heterocyclylene or heteroarylene; M1 is selected from N or CR1; M2 is selected from N, C or CR2; M3 is selected from N or CR3; Indicates that a key may not exist; R a , R b , R c , R d and R e Each is independently selected from hydrogen, deuterium, halogen, cyano, oxo, -P(=O)R4R5, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl, wherein the alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl and heterocyclyl are optionally further substituted with one or more substituents selected from deuterium, halogen, cyano, hydroxyl, -NR6R7, oxo, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; Or, any two R b Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; Or, R e Linked to the carbon atom or nitrogen atom on the ring C to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted; Alternatively, R2 is linked to a carbon atom or a nitrogen atom on ring C to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl group may be further substituted; Or, any two R d Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; R1, R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxy, alkyl, alkoxy, aminoalkyl, hydroxyalkyl, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; L1, L3 and L4 are each independently selected from a bond, -NH-, -S-, -O-, -CH2-, CH2CH2-, -C(O)NH-, -NHC(O)- or -C(O)-; L2 is selected from -(CH2) j -, the -(CH2) j -, 1, 2 or 3 methylene groups are optionally replaced by -NH-, -NCH3-, -NCH2CH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cycloalkylene, heterocyclylene, heteroarylene, and the replacement groups are optionally substituted by 1 or more substituents selected from halogen, oxo, hydroxyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl or heterocyclyl; Or, L2 and R a Linked to form a cycloalkyl, heterocyclic, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclic, aryl and heteroaryl groups may be further substituted; x, y, z, p and q are each independently selected from 0, 1, 2, 3 or 4; n1 and n2 are each independently selected from 0, 1, 2 or 3; and j is selected from 2, 3, 4, 5 or 6.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring C is selected from pyridinone, pyrimidinone, pyridazinone, pyridinyl or pyridinoxyl groups; preferably, Selected from 3. The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The ring B is selected from phenyl, pyridyl, pyrimidinyl, benzimidazolyl, pyrazolopyrimidinyl, pyridone or pyridazinone; preferably, Selected from Where: R b1 and R b2 Each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-4 Cycloalkyl or 3-4 membered heterocyclic group; the amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-4 The cycloalkyl group and the 3-4-membered heterocyclic group may be further substituted.

4. The compound according to any one of claims 1 to 3, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is selected from benzopyrazolylene, pyridoimidazolylene, pyridotriazolylene, benzoimidazolylene or pyridopyrazolylene; preferably, Selected from 5. The compound according to any one of claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The L2 is selected from -(CH2) j -, the -(CH2) j -, one, two or three methylene groups in the group are optionally replaced by -NH-, -NCH3-, -NCH2CH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, oxirane, oxetane, oxolyl, oxhexylene, aziridine, aziridine, aziridine, piperidinyl, piperazinyl, morpholinyl, homomorpholinyl groups, and the replacing groups are optionally replaced by one or more groups selected from halogen, oxo, hydroxy, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Substituted by a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, L2 is wherein M4 is selected from N or CR8; M5 is selected from N or CR9; R8 and R9 are each independently selected from hydrogen, deuterium, fluorine, chlorine, hydroxyl, cyano, amino, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Hydroxyalkyl, C 3-4 cycloalkyl or 3-4 membered heterocyclyl; n3 and n4 are each independently selected from 0, 1, 2, 3 or 4; or, the methylene group is optionally replaced by NH-, -NCH3-, -NCH2CH3-, -O-, -C(CH3)2-, -CHF-, -CHCF3-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NH-, -C(O)NCH3-, -NHC(O)-, -NCH3C(O)-, cycloalkylene, heterocyclylene, heteroarylene, and the replacement group is optionally replaced by one or more selected from halogen, oxo, hydroxyl, cyano, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-4 Substituted by a cycloalkyl group or a 3-4-membered heterocyclic group; More preferably, said L2 is selected from:

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R a , R b , R c , R d and R e Each independently selected from hydrogen, deuterium, halogen, cyano, oxo, -P(=O)R4R5, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic group, the C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl and 3-6 membered heterocyclic groups, optionally further substituted with deuterium, halogen, cyano, hydroxyl, -NR6R7, oxo, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-6 is substituted by one or more substituents in a cycloalkyl group or a 3-6-membered heterocyclic group; Preferably, the R a , R b , R c , R d and R e Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, methyl, ethyl, trifluoromethyl, trifluoroethyl, hydroxypropyl, methoxy, ethoxy, -CH2CH2OH, -CH2CH2N(CH3)2, -P(=O)(CH3)2 or 7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The R1, R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Hydroxyalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 3-4 Cycloalkyl or 3-4 membered heterocyclyl; preferably, R1, R2, R3, R4, R5, R6 and R7 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, hydroxyl, methyl, ethyl, methoxy, trifluoromethyl, cyclopropyl, aziridine, oxirane, hydroxymethyl or difluoromethyl.

8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

9. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

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

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