WO2022161414A1 - Composé aromatique, composition pharmaceutique le contenant et son application - Google Patents
Composé aromatique, composition pharmaceutique le contenant et son application Download PDFInfo
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- WO2022161414A1 WO2022161414A1 PCT/CN2022/074129 CN2022074129W WO2022161414A1 WO 2022161414 A1 WO2022161414 A1 WO 2022161414A1 CN 2022074129 W CN2022074129 W CN 2022074129W WO 2022161414 A1 WO2022161414 A1 WO 2022161414A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Definitions
- the present invention relates to an aromatic compound, a pharmaceutical composition containing the same and its application.
- UPP ubiquitin-proteasome pathway
- the role of the ubiquitin-proteasome pathway (UPP) in vivo is to selectively identify and remove excess proteins, and to degrade misfolded or abnormal proteins.
- the ubiquitin molecule is covalently linked to the terminal lysine residue by E3 ubiquitin ligase, thereby labeling the protein and then degrading it into a small peptide by the proteasome, and finally digesting it into its constituent amino acids. Used as building blocks for new proteins.
- UPP is central to multiple cellular processes and, if defective or unbalanced, contributes to the pathogenesis of various diseases.
- UPP is central to the regulation of nearly all cellular processes, including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune response and inflammation, neural and muscle degeneration, neural network Morphogenesis, regulation of cell surface receptors, ion channels and secretory pathways, response to stress and extracellular modulators, ribosome biogenesis and viral infection.
- Defective proteasomal degradation is associated with a variety of clinical conditions including Alzheimer's disease, Parkinson's disease, Huntington's disease, muscular dystrophy, cardiovascular disease and cancer, among others.
- Protein degradation targeting chimera is an effective means of degrading pathogenic proteins, combining small molecules that can bind to target proteins with E3 ligases including CRBN, VHL, MDM2, DRAF, etc.
- the molecule forms a heterobifunctional molecule that ubiquitinates the target protein by mimicking the ubiquitin-proteasome pathway (UPP), thereby achieving the degradation of the target protein by the proteasome.
- UPP ubiquitin-proteasome pathway
- a potential advantage of protein degradation-targeted chimeras over small-molecule inhibitors is that they can remove all functions of disease-causing proteins.
- E3 ubiquitin ligases More than 600 E3 ubiquitin ligases have been found to promote in vivo ubiquitination of different proteins, which can be divided into four families: HECT domain E3 family, U-box E3 family, monomeric RINGE3 family and multi-subunit E3 family.
- Cereblon (CRBN) ligase is the most widely used E3 ligase in PROTAC technology. Cereblon belongs to the Cullin RING E3 ubiquitin ligase, a 442 amino acid protein that forms the Cullin-4-RING E3 ubiquitin ligase (CRL4) complex and interacts with the adaptor protein damaged DNA binding protein 1 (DDB1) . In the CRL4 complex, CRBN acts as a substrate-specific receptor.
- CRBN ligands include thalidomide and other derived immunomodulatory imide drugs.
- E3 ubiquitin ligase activity of CRBN is reregulated, leading to increased recruitment of the transcription factors Ikaros and Aiolos, which trigger subsequent ubiquitination and proteasomal degradation.
- CRBN as an E3 ligase in PROTAC, has been successfully used to target more than 30 different proteins, including proteins associated with various cancers (Sun X.
- CRBN-targeted PROTACs employ pomalidomide, 4-hydroxythalidomide, alkyl-linked thalidomide derivatives, or derivatives of lenalidomide. However, it is possible to develop better CRBN ligands. These new CRBN ligands will provide more options for the development of PROTAC technology.
- IRAK4 belongs to the class of serine/threonine kinases that mediate the interleukin-1 (IL-1) receptor family (IL-1, IL-18 and IL-33 receptors) and pathogen recognition Toll-like receptors (TLRs) key protein in signaling.
- IL-1 interleukin-1
- TLRs pathogen recognition Toll-like receptors
- NF- ⁇ B light chain enhancer and activator protein 1 leads to the production of various inflammatory factors in cells, such as tumor necrosis factor alpha (TNF ⁇ ), IL-6, etc., thereby inducing various immune diseases, such as The occurrence of psoriasis, hidradenitis suppurativa, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, etc.
- IRAK4 has been implicated in lymphocytic leukemia and lymphoma, Alzheimer's disease, and fibrotic diseases. Therefore, IRAK4 is an attractive target for drug development.
- IRAK4 small molecule inhibitors into the clinic for hematological tumors, psoriasis, Rheumatoid arthritis, enteritis, systemic lupus erythematosus, etc.
- the IRAK4 inhibitor PF-06650833 researched by Pfizer has entered the phase II clinical research stage.
- Early clinical results show that PF-06650833 has a good safety profile, and its efficacy shows that PF-06650833 can inhibit the inflammatory pathway mediated by IRAK4.
- IRAK4 is a clinically validated drug target that is expected to treat various diseases.
- the IRAK4 protein scaffold can also activate certain inflammatory signaling pathways.
- inhibition of IRAK4 by ATP-competitive small molecules was not able to effectively inhibit IL-1 ⁇ -stimulated IL-6 and TNF- ⁇ release.
- knockdown of IRAK4 effectively abolished the inflammatory response mediated by IL-1, IL-8 and TLR ligands. Therefore, the inflammatory signaling pathway mediated by IRAK4 protein cannot be completely abolished by ATP-competitive small-molecule inhibitors.
- targeting IRAK4 with small-molecule inhibitors has its therapeutic limitations.
- Protein degradation targeting chimera is an effective means of degrading pathogenic proteins, combining small molecules that can bind to the target protein with E3 ligases including CRBN, VHL, MDM2, DRAF, etc.
- the molecule forms a heterobifunctional molecule that ubiquitinates the target protein by mimicking the ubiquitin-proteasome pathway (UPP), thereby achieving the degradation of the target protein by the proteasome.
- UPP ubiquitin-proteasome pathway
- a potential advantage of protein degradation-targeted chimeras over small-molecule inhibitors is that they can remove all functions of disease-causing proteins.
- the degrader consists of CRBN ligands, linking groups and target protein ligands. Such compounds containing E3 ligand fragments can be used to prepare PROTAC compounds capable of recruiting target proteins to CRBN E3 ubiquitin ligase for degradation or otherwise inhibiting the activity of target proteins. Also provided herein are compounds that are degraders of the enzyme IRAK4, pharmaceutical compositions containing such compounds, and uses. The degrader can recruit IRAK4 to E3 ubiquitin ligase and degrade it or otherwise inhibit the activity of IRAK4. The compound has the structure shown in formula I, I', Ia-e, II, III, IV or V, or a pharmaceutically acceptable salt, metabolite, prodrug or derivative thereof.
- the present invention solves the above technical problems through the following technical solutions.
- the present invention provides compounds of formula I and pharmaceutically acceptable compositions thereof that are effective as degraders of IRAK4.
- the present invention solves the above technical problems through the following technical solutions.
- the present invention provides a compound represented by formula (I), its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,
- Q is selected from CR 2a , N;
- V is selected from C, N;
- U is selected from CR 2 , NR 2 (eg N);
- W is selected from CR 3 , N;
- X is selected from C (when attached to L), CR4 , N;
- Y is selected from C (when attached to L), CR5 , N;
- Z is selected from C (when attached to L), CR6, N ;
- R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted Saturated 3-10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen,
- Ring A is independently selected from 5-10 membered aromatic heterocycles substituted with 0-4 R 7 ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
- R 2a , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered Heterocyclic group, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 Ring-membered hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstitute
- L is selected from linking groups that are non-hydrogen.
- the compound shown in formula I its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof.
- Some of the groups are as defined below (unmentioned groups are described in any scheme of this application, hereinafter referred to as "in a certain scheme"), and the compound shown in formula I is such as formula Ia or formula Ib shown,
- U is selected from CR2, N.
- U is selected from NR2.
- R 1 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, 3-10 membered cycloalkyl, wherein said substituted
- the group is independently selected from deuterium, halogen, hydroxyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy; the number of substitutions is 1, 2 or 3;
- R 1 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, Monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl; another example -CF2 .
- V is selected from N
- U is selected from CR 2
- W is selected from CR 3 and N.
- R e , R 2a , R 2 , R 3 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted Substituted C1-C6 straight-chain or branched alkoxy; for example, H-substituted or unsubstituted C1-C6 straight-chain or branched alkyl, another example is H or methyl.
- X is selected from CR4, N; Y is selected from CR5 , N; Z is selected from C, CR6, N ; and at most one of X, Y, and Z is N.
- R 4 , R 5 , R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1 -C6 straight or branched alkoxy; for example H, halogen or substituted or unsubstituted C1-C6 straight or branched alkyl, also for example H, F or methyl.
- R 4 , R 5 , R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1 -C6 linear or branched alkoxy; for example H or substituted or unsubstituted C1-C6 linear or branched alkyl, also for example H or methyl.
- a ring is independently selected from 0-4 R 7 substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;
- ring A is independently selected from the following rings substituted with 0, 1, 2, 3 or 4 R 7 :
- ring A is independently selected from:
- R 7 is selected from substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocycle base, substituted or unsubstituted C1-C6 linear or branched alkylamino;
- R 7 is selected from substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocycle base, substituted or unsubstituted C1-C6 linear or branched alkylamino;
- R 7 is selected from:
- L is in
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring, substituted or unsubstituted Unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain or Branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted uns
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 are independently selected from none, hydrogen, deuterium, halogen, cyano , hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C3-C10 heterospirocyclic group Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-
- L b' , L c' , L a' , L i' are independently selected from N, CR 38 ;
- R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substitute
- the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkane Acyl, 3-10-membered cycloalkanoyl, 4-10-membered heterocyclic group, C5-C12 heterobridged ring group, C3-C10 heterospirocyclic group, 6-10-membered aromatic ring, 5-10-membered
- the aromatic heterocyclic ring; the heterocyclic group, the heterobridged ring group, the heterospirocyclic group, and the aromatic heterocyclic ring contain 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; R 38
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;
- L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L21, L2m, L2n, L2a', L2e ' , L2f ' , L2g', L2h ' are independently selected from In none, O, S, NR 39 , COR 40 , -SO2R 41 ;
- L 2b' , L 2c' , L 2d' , L 21' are selected from N, CR 44 ;
- R 39 , R 40 , R 41 , R 44 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , R L243 , R L244 , R L245 , R L246 are independently selected from hydrogen, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted heterocyclyl C
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamin
- L1 is selected from none
- f, g, h, i, j, k, l, m, n, o, p are independently selected from 0, 1 or 2;
- R 8 is selected from hydrogen, substituted or unsubstituted C1-C6 straight chain or Branched alkyl;
- R 9 is selected from unsubstituted, substituted or unsubstituted C1-C6 straight or branched alkyl;
- L a' , Le' , L f' , L g' , L h' are independently selected from none (connection bond);
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L25 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;
- Ring B is selected from the group consisting of no (representing a connecting bond), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged cyclyl, Substituted or unsubstituted C3-C12 heterospirocyclyl;
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0, 1, 2 or 3;
- R 39 is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;
- R 40 is selected from unsubstituted, substituted or unsubstituted C1-C6 linear or branched alkyl;
- L 2a' , L 2e' , L 2f' , L 2g' , L 2h' are independently selected from None;
- L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ;
- R44 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , R L243 , R L244 , R L245 , R L246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl; or R 44 and R L211 , R L212 , R L213 , R L
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10-membered aromatic heterocycle;
- the substituents are independently selected from deuterium, halogen, C1-C6 linear or branched alkyl;
- L1, B ring, L2 and C ring is not null.
- L is in
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 Heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted Substituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsub
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substitute
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, deuterium, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamin
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;
- L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L21, L2m, L2n, L2a', L2e ' , L2f ' , L2g', L2h ' independently selected from In none, O, S, NR 39 (-N(R 39 )-), COR 40 (-C( O)-R 40 -), -SO2R 41 ; R 39 , R 40 , R 41 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamin
- At least one of L1, B-ring, L2 and C-rings is not null; eg, two, three or four of L1, B-ring, L2 and C-rings are not null.
- L, L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ;
- R 44 is independently selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic Cyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5 -10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or un
- R 39 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, and S;
- the substituents are independently selected from deuterium, halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or Branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain al
- L1 is selected from none
- f, g, h, i, j, k, l, m, n, o, p are independently selected from 0, 1 or 2;
- R 8 is selected from hydrogen, substituted or unsubstituted C1-C6 straight chain or Branched alkyl;
- R 9 is selected from unsubstituted, substituted or unsubstituted C1-C6 straight or branched alkyl;
- L a' , L e' , L f' , L g' , L h' are independently selected from none (connection bond);
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L25 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;
- Ring B is selected from the group consisting of no (representing a connecting bond), substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged cyclyl, Substituted or unsubstituted C3-C12 heterospirocyclyl;
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0, 1, 2 or 3;
- R 39 is selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;
- R 40 is selected from unsubstituted, substituted or unsubstituted C1-C6 linear or branched alkyl;
- L 2a' , L 2e' , L 2f' , L 2g' , L 2h' are independently selected from none;
- R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 , R L241 , R L242 , RL243 , RL244 , RL245 , and RL246 are independently selected from hydrogen, substituted or unsubstituted C1-C6 linear or branched alkyl;
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 5-10-membered aromatic heterocycle;
- the substituents are independently selected from deuterium, halogen, C1-C6 linear or branched alkyl;
- L1, B ring, L2 and C ring is not null.
- ring A is selected from:
- L is selected from: (connected to V on the left) Its single cis, trans isomer or mixtures thereof; for example
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3 -10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 linear or branched alkane Oxy group, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkanoyl, 3- 10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
- Ring A is independently selected from 5-10 membered aromatic heterocycles substituted with 0-4 R 7 ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1
- L is selected from a linking group other than hydrogen
- the compound represented by formula I is the compound of formula (Ia) shown below,
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R 7 substituted:
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted
- L is selected from a linking group that is non-hydrogen; for example, the compound represented by formula I is the compound of formula (Ia) shown below,
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R substituted:
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocyclic group Ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 , COR 9 , -SO2R 10 ;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsub
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;
- R 39 , R 40 , R 41 are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsatur
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, Amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy , C1-C6 linear or branched alkylamino group, 3-10 membered cycloalkylamino group, -
- the compound represented by formula I is the compound of formula (Ia) shown below,
- L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ;
- R 44 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon, substituted or unsubstituted C2 -C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or
- R 39 can be respectively combined with R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L211 , R L212 , R L213 , R L214 , R L223 , R L224 , R L225 , R L226 , R L227 , R L228 , R L229 , R L230 form a substituted or unsubstituted 3-10-membered ring through C, N, O, S; the substituents are independently selected from halogen, Cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cyclo
- V is selected from C, N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R 7 substituted:
- R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 Heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocyclic ring, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight chain Or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy
- R 42 and R 43 are selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted Substituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1 -C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3 -10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano,
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- R 4 , R 5 and R 6 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, and substituted or unsubstituted C5-C12 heterobridged ring base, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1- C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 straight or branched chain unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsub
- R 42 and R 43 are selected from hydrogen, cyano, hydroxyl, amino, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted Substituted unsaturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10 membered cycloalkoxy, substituted or unsubstituted C1 -C6 linear or branched alkylamino, substituted or unsubstituted 3-10 membered cycloalkylamino, substituted or unsubstituted C1-C6 linear or branched alkanoyl, substituted or unsubstituted 3 -10-membered cycloalkanoyl; the substituents are independently selected from halogen, cyano,
- Ring A is independently selected from 0-4 R 7 substituted:
- R 7 is selected from:
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- Another aspect of the present invention also provides a compound represented by formula I', its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl Substituted C2-C6 straight-chain or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 straight-chain or branched alkoxy, C1-C6 cycloalkane Oxy group, C1-C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, C1-C6 linear or branched chain alkanoyl group, C1-C6 cycloalkanoyl group, C3-C10 heterocyclic group cyclic group; the heterocyclic group contains 1-4 heteroatom
- Ring A is independently selected from a 5-10 membered aromatic heterocycle substituted with 0-4 R 7 ; the heteroaryl group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6
- L is selected from linking groups that are non-hydrogen.
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R 7 substituted:
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6
- L is selected from linking groups that are non-hydrogen.
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R 7 substituted:
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclyl group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocyclic ring, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated Hydrocarbyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- L1 is selected from none
- a, b, d are independently selected from 1-6;
- c, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 ;
- R 8 is selected from hydrogen, substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged ring, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aryl ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, Substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branche
- R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched alkyl, substituted or unsubstituted C1
- L b' , L c' , L d' , L i' are independently selected from N, CR 36 , respectively;
- R36 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged ring group, substituted or unsubstituted C3-C10 heterocyclic group Heterospirocyclyl, substituted
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridge, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R 9 COR 10 , -
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;
- L2a, L2b, L2c, L2d, L2e, L2f, L2a', L2e ' , L2f ' , L2g', L2h ' are independently selected from none, O, S, NR37;
- R37 is selected from hydrogen, Substituted or unsubstituted C3-C10 heterocyclyl, substituted or unsubstituted C3-C10 heterobridged, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 Aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl , substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstitute
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle; the substituents are independently selected from halogen, cyano, hydroxyl, amino , C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, C1-C6 cycloalkoxy, C1- C6 linear or branched alkylamino group, C1-C6 cycloalkylamino group, -R 9 COR 10 ,
- the compound of general formula (I') its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof,
- V is selected from C, N;
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- Ring A is independently selected from 0-4 R 7 substituted:
- R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterocyclic group Bridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1- C6 linear or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubsti
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- R 38 and R 39 are as described for R 2 .
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoromethyl base, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl;
- R 4 , R 5 , R 6 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted C3-C10 heterocyclic group, substituted or unsubstituted C3-C10 heterobridged cyclic group , substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C5-10 aromatic ring, substituted or unsubstituted C5-10 aromatic heterocycle, substituted or unsubstituted C1-C6 straight chain Or branched alkyl, substituted or unsubstituted C1-C6 linear or branched cycloalkyl, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1- C6 linear or branched alkoxy, substituted or unsubstituted C1-C6 cycloalkoxy, substituted or unsubstituted
- Ring A is independently selected from 0-4 R 7 substituted:
- R 7 is selected from:
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- R 38 and R 39 are as described for R 2 .
- each of said halogens may independently be fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.
- the C1-C6 alkyl group in each of the substituted or unsubstituted C1-C6 straight or branched chain alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including the various isomers of hexyl); such as methyl, ethyl or propyl.
- the 3-10-membered cycloalkyl group in each of the substituted or unsubstituted 3-10-membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl ,
- C1-C6 cycloalkyl in each of the substituted or unsubstituted C1-C6 linear or branched cycloalkyl, C1-C6 in C1-C6 cycloalkylamino Cycloalkyl, C1-C6 cycloalkyl in substituted or unsubstituted C1-C6 cycloalkoxy, C1-C6 cycloalkyl in C1-C6 cycloalkanoyl may independently be cyclopropyl , cyclobutyl, cyclopentyl, cyclobutyl.
- the 4-10-membered heterocyclic group in each of the substituted or unsubstituted 4-10-membered heterocyclic groups can be independently E.g
- the C3-C10 heterocyclic group in each of the substituted or unsubstituted C3-C10 heterocyclic groups may be independently E.g
- the C3-C10 heterospirocyclyl group in each of the substituted or unsubstituted C3-C10 heterospirocyclyl groups may independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 6-azaspiro[3.4] Octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro Cyclo[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example
- the C5-C12 heterobridged ring group in each of the substituted or unsubstituted C5-C12 heterobridged ring groups is independently octahydrocyclopenta[C]pyrrolyl, octahydro Pyrro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3 - azabicyclo[3.2.1]octyl; for example
- C5 in each of said substituted or unsubstituted substituted 6-10-membered aromatic rings, 6-10-membered aromatic rings, substituted or unsubstituted substituted C5-10 aromatic rings is independently a benzene ring or a naphthalene ring.
- the 5-10-membered aromatic heterocycle in each of the substituted or unsubstituted substituted 5-10-membered aromatic heterocycles can be independently
- the C5-10 aromatic heterocycle in each of the substituted or unsubstituted substituted C5-10 aromatic heterocycles may be independently
- the compound represented by the formula I or formula I' is selected from:
- the pharmaceutically acceptable salt of the present invention is a salt formed by the direct reaction of the compound of general formula (I) or (I') with inorganic acid, organic acid and inorganic base.
- the present invention provides an aromatic compound represented by formula E, its enantiomer, diastereomer, racemate and mixture or a pharmaceutically acceptable salt thereof,
- L is selected from a linking bond or a non-hydrogen linking group
- V, U, W, X, Y, Z, Q, Re are as described above.
- some groups in the compound represented by the formula E are defined as follows (the unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain scheme”), where,
- L is selected from a linking bond or a non-hydrogen linking group
- Q is selected from CR 2a , N;
- V is selected from C, N;
- U is selected from CR 2 , NR 2 (eg N);
- W is selected from CR 3 , N;
- X is selected from C (when attached to L), CR4 , N;
- Y is selected from C (when attached to L), CR5 , N;
- Z is selected from C (when attached to L), CR6, N ;
- R 2 is selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted Saturated 3-10 membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, hydroxyl, substituted or unsubstituted C1-C6 linear or branched alkoxy, substituted or unsubstituted 3-10-membered cycloalkoxy, substituted or unsubstituted amino group; wherein the substituents are independently selected from deuterium, halogen, hydroxyl, cyano, amino, C1-C6 linear or branched alkoxy , 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloal
- R 2a , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5- 10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or unsubstituted unsaturated 3-10-membered cyclic hydrocarbon group , substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group, substituted or unsubstituted C1
- some groups in the compound represented by the formula E are defined as follows (unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain "In the scheme"), the compound shown in the formula I is shown in the formula Ea or the formula Eb,
- R a when R a is halo, it can be bromo or chloro.
- the C1-C6 linear or branched alkyl can be methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
- R 2 is selected from hydrogen, deuterium, halogen, cyano, hydroxyl, substituted or unsubstituted amino, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, wherein the substituents are independently selected from deuterium, halogen, hydroxyl, amino, C1-C6 linear or branched alkoxy, 3-10-membered cycloalkoxy, 3- 10-membered cycloalkyl, 4-10-membered heterocyclyl; the number of the substitution is 1, 2 or 3;
- R 2 is selected from hydrogen, deuterium, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl base, monofluoromethyl, methoxymethyl, ethoxymethyl, cyclopropyloxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetane base, 2-azetidinyl, 3-azetidinyl.
- U is selected from CR 2a , N; X is selected from C, CR 4 , N; Y is selected from C, CR 5 , N; Z is selected from C, CR 6 , N; is N; one or both of U, V, and W are N.
- R 4 , R 5 , R 6 are independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted C1 -C6 straight or branched alkoxy; for example H, halogen or substituted or unsubstituted C1-C6 straight or branched alkyl, also for example H, F or methyl.
- R e , R 2a , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, deuterium, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain Alkyl, substituted or unsubstituted C1-C6 linear or branched alkoxy; for example H or methyl.
- the L when the L is a non-hydrogen linking group, it can be a conventional linking group in PROTAC in the field.
- L when L is a non-hydrogen linking group, L is as defined in any one of the schemes for L in compounds of Formula I or Formula I' as previously described.
- L is selected from a non-hydrogen linking group; the general formula for the linking group is expressed as:
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aryl, substituted or unsubstituted 5-10 membered aromatic heterocycle ( base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10-membered cycloalkyl, substituted or un
- Substituted or unsubstituted 3-10 membered rings are independently selected from deuterium, halogen, cyano, hydroxyl, amino, C1-C6 straight or branched alkyl, C2-C6 straight or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino , -R 11 COR 12 , -R 13 OCOR 14 , -R 15 COOR 16 , -R 17 NR 18 COR 19 , -R 20 CONR 21 R 22 , -R 23 SO2R 24 , -R 25 OSO2R 26 , -R 27 SO2OR 28 , -R 29 NR 30 SO2R 31 , -R 32 SO2 NR 33 R 34 , R 9 , R 10 , R 11 , R 12 , R 11
- L b' , L c' , L d' , L i' are independently selected from N, CR 38 ;
- R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , R L117 , R L118 , R L119 , R L120 , R L121 , R L122 , R L123 , R L124 , R L25 , R L126 , R L127 , R L128 , R L129 , R L130 , R L131 , R L132 , R L133 , R L134 are independently selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, Substituted or unsubstituted C3
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p, 2q, 2r, 2s are independently selected from 0-6;
- L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2j, L2k, L2l, L2m, L2n, L2a', L2e ' , L2f ' , L2g', L2h ' independently selected from in none, O, S, NR 39 (-N(R 39 )-), COR 40 (-C( O)-R 40 -), -SO2R 41 (-SO2-R 41 -); L 2b' , L 2c' , L 2d' , L 2i' are selected from N, CR 44 ; R 39 , R 40 , R 41 , R 44 , R L21 , R L22 , R L23 , R L24 , R L25 , R L26 , R L27 , R L28 , R L29 , R L210 , R L21 , R L22 , R L23 , R L24
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from deuterium , halogen, cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3 -10-membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10-membered cycl
- two, three or four of the L1, B ring, L2 and C rings are not none.
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 , COR 9 , -SO2R 10 ;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 Member cycloalkyl, substituted or unsubstituted unsaturated 3-10
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 , R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118, RL119 , RL120 , RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 are independent Selected from hydrogen, deuterium, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3 -C10 heterospirocyclyl, substituted
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamin
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;
- R 39 , R 40 , R 41 are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsatur
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring, substituted or unsubstituted 5-10-membered aromatic heterocycle; the substituents are independently selected from deuterium, halogen, cyano, Hydroxyl, amine group, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkane Oxygen, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamin
- L is selected from a non-hydrogen linking group; the general formula for the linking group is expressed as:
- the compound of formula E or a pharmaceutically acceptable salt thereof is selected from the following structures:
- the present invention provides a ligand of a ubiquitin ligase connected to a ligand-linker targeting a degraded protein as shown in formula E3,
- the present invention provides a ligand of ubiquitin ligase, which contains the structure shown in formula E3,
- the ligand of the ubiquitin ligase is connected with the linker, and further connected with the target degradation protein ligand.
- its 1-position is linked to a linker
- the present invention provides a linker-ubiquitin ligase ligand that is linked to a ligand targeting degraded proteins as shown in formula E2,
- L, Q, U, V, W, X, Y, Z and Re are as described above.
- the aromatic compounds represented by formula E, their enantiomers, diastereomers, L, Q, U, V, W, X, Y, Z and R e are as defined in the convolved forms and mixtures or pharmaceutically acceptable salts thereof.
- the present invention provides a linker-ubiquitin ligase ligand, which contains the structure shown in formula E2,
- L, Q, U, V, W, X, Y, Z and Re are as described above.
- the aromatic compounds represented by formula E, their enantiomers, diastereomers, L, Q, U, V, W, X, Y, Z and R e are as defined in the convolved forms and mixtures or pharmaceutically acceptable salts thereof.
- the linker-ubiquitin ligase ligand is connected with the target degradation protein ligand through the linker.
- the present invention provides an aromatic compound represented by formula E as described above, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof, as described above
- the ligand of the ubiquitin ligase (as shown in formula E3 linked to a ligand-targeted degradation protein)-linker, or as described above (as shown in formula E2 linked to a ligand targeted to degraded protein) ) use of a ligand of a linker-ubiquitin ligase for the preparation of ligand-drug conjugates; wherein, the E3 fragment shown below can be used as a (recruitment) ligand for E3 ubiquitin ligase,
- Said (recruiting) ligand for E3 ubiquitin ligase can bind to Cereblon (CRBN) ligase.
- the ligand-drug conjugate may be a protein-targeted degradation chimera (PROTAC) or an antibody-drug conjugate (ADC).
- PROTAC protein-targeted degradation chimera
- ADC antibody-drug conjugate
- the present invention provides an aromatic compound (PROTAC compound) represented by formula X, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof,
- T is the ligand group targeting degradation protein
- L, Q, U, V, W, X, Y, Z and Re are as defined by L, Q, U, V, W, X, Y, Z and Re in the aromatic compound represented by formula Y above described.
- some groups in the compound represented by the formula X are defined as follows (unmentioned groups are the same as those described in any scheme of this application, hereinafter referred to as "in a certain "In the scheme"), the compound shown in the formula X is shown in the formula Xa or the formula Xb,
- the T is selected from the group consisting of:
- the MAT2A targeting ligand group can be:
- the SOS1 targeting ligand group can be:
- the DGK ⁇ targeting ligand group can be:
- SIK2 and SIK3 targeting ligand groups can be:
- the KRAS G12D targeting ligand group can be:
- the POL ⁇ targeting ligand group can be:
- the Cbl-b targeting ligand group can be:
- PARG targeting ligand groups can be:
- the DNA-PK targeting ligand group can be:
- the ATR targeting ligand group can be:
- the NMT targeting ligand group can be:
- the STAT3 targeting ligand group can be:
- the ligand group T targeting the degraded protein is Its definition is as described in any one of the preceding formula I or formula I',
- V is selected from C, N;
- R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3 -10-membered cyclic hydrocarbon group, substituted or unsubstituted C2-C6 linear or branched unsaturated hydrocarbon group; wherein the substituents are independently selected from halogen, hydroxyl, cyano, C1-C6 linear or branched alkane Oxy group, 3-10 membered cycloalkoxy, C1-C6 straight or branched chain alkylamino, 3-10 membered cycloalkylamine, C1-C6 straight or branched alkanoyl, 3- 10-membered cycloalkanoyl, 4-10-membered heterocyclic group; the heterocyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen;
- Ring A is independently selected from: 5-10-membered aromatic heterocycle, or 5-6-membered aromatic heterocycle-5-6-membered aromatic heterocycle substituted by 0-4 R 7 ;
- the aromatic heterocycle (base) contains 1- 4 heteroatoms selected from oxygen, sulfur and nitrogen;
- R 7 are independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged ring group, substituted or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10 membered aromatic ring, substituted or unsubstituted 5-10 membered aromatic heterocycle, Substituted or unsubstituted C1-C6 linear or branched alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 member
- the ligand group T targeting the degraded protein is wherein, R 1 is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C6 straight or branched chain alkyl, 3-10 membered cycloalkyl, wherein said substituent is independently selected from halogen, Hydroxyl, C1-C6 linear or branched alkoxy, 3-10 membered cycloalkoxy; the number of substitutions is 1, 2 or 3;
- R1 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, trifluoromethyl, difluoromethyl, monofluoro Methyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl; eg -CF2 .
- the ligand group T targeting the degraded protein is in, for
- the ligand group T targeting the degraded protein is wherein, the A ring is independently selected from 0-4 R 7 substituted: 5-10 membered aromatic heterocycle, or 5-6 membered aromatic heterocycle-5-6 membered aromatic heterocycle;
- ring A is independently selected from 0-4 R 7 substituted:
- ring A is independently selected from:
- R 7 is selected from substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocycle base, substituted or unsubstituted C1-C6 linear or branched alkylamino;
- R 7 is selected from: substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospiro Cyclic, substituted or unsubstituted C1-C6 straight or branched chain alkylamino;
- R 7 is selected from:
- ring A is selected from:
- the ligand group T targeting the degraded protein is , it is the IRAK4 targeting ligand group.
- the targeted degradation protein is selected from the group consisting of SOS1, SIK2, SIK3, IRAK4, MAT2A, HPK1, menin, MLL, Cb1-b, POL ⁇ , DNA-PK, STAT3, PARG, KIT, EPHA2, PDE4D, SRC, BRAF, KYN, ITK, PARP1, EPHB2, BLK, IGF1R, TGFBR1, AKT2, AKT1, PTK2, MAPK1, MAPK14, MCL1, BRD3, BRD4, AKT3, PAK4, MAPKAPK2, TNK2, SIRT2, DAPK1, ABL2, PRKAA2, KAT2A, PBRM1, EIF2AK2, MAP3K7, MAPT, RIPK1, IRAK1, MAP4K1, MARK4, BRD9, RIPK2, LIMK1, STK38, TRIM24, SMARCA4, PRKAA1, TBK1, KRAS, SMARCA2, PCNA, BRD7, SUZ12, IKZF
- each of said halogens may independently be fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.
- the C1-C6 alkyl group in each of the substituted or unsubstituted C1-C6 straight or branched chain alkyl groups can be independently methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including the various isomers of hexyl); such as methyl, ethyl or propyl.
- the 3-10-membered cycloalkyl group in each of the substituted or unsubstituted 3-10-membered cycloalkyl groups can be independently cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl ,
- C1-C6 cycloalkyl in each of the substituted or unsubstituted C1-C6 linear or branched cycloalkyl, C1-C6 in C1-C6 cycloalkylamino Cycloalkyl, C1-C6 cycloalkyl in substituted or unsubstituted C1-C6 cycloalkoxy, C1-C6 cycloalkyl in C1-C6 cycloalkanoyl may independently be cyclopropyl , cyclobutyl, cyclopentyl, cyclobutyl.
- the 4-10-membered heterocyclic group in each of the substituted or unsubstituted 4-10-membered heterocyclic groups can be independently
- the C3-C10 heterocyclic group in each of the substituted or unsubstituted C3-C10 heterocyclic groups may be independently
- the C3-C10 heterospirocyclyl group in each of the substituted or unsubstituted C3-C10 heterospirocyclyl groups may independently be 2-azaspiro[3.3]heptyl, 7-azaspiro[3.5]nonanyl, 2-azaspiro[3.5]nonanyl, 2,7-diazaspiro[3.5]nonanyl, 6-azaspiro[3.4] Octyl, 4-oxa-7-azaspiro[2.5]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro Cyclo[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 4,7-diazaspiro[2.5]octyl; for example
- the C5-C12 heterobridged ring group in each of the substituted or unsubstituted C5-C12 heterobridged ring groups is independently octahydrocyclopenta[C]pyrrolyl, octahydro Pyrro[3,4-c]pyrrolyl, 3-azabicyclo[3.1.0]hexyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-oxa-3 - azabicyclo[3.2.1]octyl; for example
- C5 in each of said substituted or unsubstituted substituted 6-10-membered aromatic rings, 6-10-membered aromatic rings, substituted or unsubstituted substituted C5-10 aromatic rings is independently a benzene ring or a naphthalene ring.
- the 5-10-membered aromatic heterocycle in each of the substituted or unsubstituted substituted 5-10-membered aromatic heterocycles can be independently
- the C5-10 aromatic heterocycle in each of the substituted or unsubstituted substituted C5-10 aromatic heterocycles may be independently
- the aromatic compound represented by formula X its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof.
- the groups are defined as follows (the unmentioned groups are described in any scheme of this application, hereinafter referred to as "in a certain scheme"), and the compound represented by the formula X is as described in any of the previous schemes.
- Said compound represented by formula I, its enantiomers, diastereomers, racemates and mixtures or pharmaceutically acceptable salts thereof or as described in any of the preceding schemes, such as formula I' The represented compounds, their enantiomers, diastereomers, racemates and mixtures or their pharmaceutically acceptable salts are shown.
- Q is selected from CR 2a , N;
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, mono Fluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetanyl, 2 - azetidine, 3-azetidine;
- R 2a , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5-10 membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C
- L is selected from a linking group other than hydrogen
- T is a ligand targeting degraded proteins.
- Q is selected from CR 2a , N;
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N
- X is selected from CR 4 , N;
- Y is selected from CR 5 , N;
- Z is selected from CR 6 , N;
- R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, mono Fluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetanyl, 2 - azetidine, 3-azetidine;
- R 2a , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5-10 membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- L1 is selected from none
- a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p are independently selected from 0-6;
- La, Lb, Lc, Ld, Le, L a' , Le ' , L f' , L g' , L h' are independently selected from none, O, S, NR 8 , COR 9 , -SO2R 10 ;
- R 8 is selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclyl, substituted or unsubstituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl Unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or Unsubstituted 3-10-membered cycloalkyl, substituted or unsubstit
- L b' , L c' , L d' , Li' are independently selected from N, CR 38 ;
- R38 R L11 , R L12 , R L13 , R L14 , R L15 , R L16 , R L17 , R L18 , R L19 , R L110 , R L111 , R L112 , R L113 , R L114 , R L115 , R L116 , RL117 , RL118 , RL119 , RL120, RL121 , RL122 , RL123 , RL124 , RL25 , RL126 , RL127 , RL128 , RL129 , RL130 , RL131 , RL132 From hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted or unsubstituted C3-C10 Heterospirocyclyl, substituted or unsubstituted 6
- Ring B is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino,
- L2 is selected from none
- 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2l, 2m, 2n, 2o, 2p are independently selected from 0-6;
- L2a, L2b, L2c, L2d, L2e, L2f, L2g, L2h, L2i, L2i, L2a', L2e ' , L2f ' , L2g', L2h ' are independently selected from None, O, S, NR 39 , COR 40 , -SO2R 41 ;
- R 39 , R 40 , R 41 are selected from hydrogen, substituted or unsubstituted 4-10-membered heterocyclic group, substituted or unsubstituted C5-C12 heterobridged cyclic group, substituted Or unsubstituted C3-C10 heterospirocyclic group, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3
- Ring C is selected from unsubstituted, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C3-C12 heterocyclyl, substituted or unsubstituted C3-C12 heterobridged, substituted or unsubstituted C3-C12 heterocyclyl C3-C12 heterospirocyclyl, substituted or unsubstituted 6-10-membered aromatic ring (base), substituted or unsubstituted 5-10-membered aromatic heterocycle (base); the substituents are independently selected from halogen , cyano, hydroxyl, amine, C1-C6 linear or branched alkyl, C2-C6 linear or branched unsaturated hydrocarbon group, C1-C6 linear or branched alkoxy, 3-10 Membered cycloalkoxy, C1-C6 linear or branched alkylamino, 3-10 membered cycloalkylamino,
- T is a ligand targeting degraded proteins.
- Q is selected from CR 2a , N;
- V is selected from C, N;
- U is selected from CR 2 , N;
- W is selected from CR 3 , N;
- X is selected from C, CR 4 , N;
- Y is selected from C, CR 5 , N;
- Z is selected from C, CR 6 , N;
- R 2 is selected from hydrogen, halogen, cyano, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, hydroxymethyl, hydroxy, trifluoromethyl, difluoromethyl, mono Fluoromethyl, methoxymethyl, ethoxymethyl, cyclopropoxymethyl, amino, aminomethylcyclobutylamine-1-yl, 2-oxetanyl, 3-oxetanyl, 2 - azetidine, 3-azetidine;
- R 2a , R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, cyano, hydroxyl, amino, substituted or unsubstituted 4-10 membered heterocyclyl, substituted or unsubstituted Substituted C5-C12 heterobridged cyclyl, substituted or unsubstituted C3-C10 heterospirocyclyl, substituted or unsubstituted 6-10 membered aromatic ring (base), substituted or unsubstituted 5-10 membered aromatic heterocycle (base), substituted or unsubstituted C1-C6 straight or branched chain alkyl, substituted or unsubstituted 3-10 membered cycloalkyl, substituted or unsubstituted unsaturated 3-10 membered ring Hydrocarbyl, substituted or unsubstituted C2-C6 straight or branched unsaturated hydrocarbyl, substituted or unsubstituted C
- L is selected from a non-hydrogen linking group; the general formula of the linking group is expressed as:
- T is a ligand targeting degraded proteins.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of Substance B and one or more pharmaceutically acceptable carriers;
- the Substance B is according to any one of claims 1-5 or 8 Described compound shown in formula I, its enantiomer, diastereomer, racemate and its mixture or its pharmaceutically acceptable salt, as described in any one of claim 6-8
- Aromatic compounds, enantiomers, diastereomers, racemates and mixtures as represented by formula E or pharmaceutically acceptable salts thereof, or as claimed in any one of claims 16-18 Aromatic compounds, enantiomers, diastereomers, racemates and mixtures as represented by formula X or pharmaceutically acceptable salts thereof.
- the pharmaceutical composition can be used to treat and prevent diseases related to or mediated by kinase 4 (IRAK4); the kinase 4 (IRAK4) can be related to tumor necrosis factor alpha (TNF ⁇ ) and/or interleukin-1 receptor Kinase 4 (IRAK4);
- TNF ⁇ tumor necrosis factor alpha
- IRAK4 interleukin-1 receptor Kinase 4
- the tumor necrosis factor alpha (TNF ⁇ ) and/or interleukin-1 receptor-associated kinase 4 (IRAK4)-related or mediated disease may be an autoimmune disease or cancer.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of the compound represented by the above general formula (I) or (I'), its enantiomers, diastereomers, external Racemates and mixtures thereof or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutically acceptable excipients such as diluents or excipients).
- the pharmaceutical composition can be used for the treatment and prevention of autoimmune diseases or cancers related to or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4).
- IRAK4 interleukin-1 receptor-associated kinase 4
- the present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), which comprises the general formula (I) or (I) ')
- IRAK4 interleukin-1 receptor-associated kinase 4
- the pharmaceutically acceptable salt thereof accounts for 1-99 wt% of the total weight of the composition.
- the present invention provides the use of a substance B in the preparation of a medicine;
- the substance B is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and mixtures thereof or their pharmaceutically acceptable salts, the compounds represented by the general formula E as described above, their enantiomers, diastereomers, racemates and their mixtures or Its pharmaceutically acceptable salts, or the compounds represented by the general formula X as described above, its enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts.
- the medicament can be used for the treatment and/or prevention of interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and tumor necrosis factor alpha (TNF ⁇ ). of one or more related or mediated diseases.
- IRAK4 interleukin-1 receptor-associated kinase 4
- IL-6 interleukin-6
- TNF ⁇ tumor necrosis factor alpha
- the present invention provides the use of a substance C in the preparation of a medicine;
- the substance C is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and their mixtures or their pharmaceutically acceptable salts, or the compounds represented by the general formula X as described above, their enantiomers, diastereomers, racemates and their mixtures or a pharmaceutically acceptable salt thereof;
- the medicament can be used for the treatment and/or prevention of interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway, interleukin-6 (IL-6) receptor and Drugs for one or more related or mediated diseases in tumor necrosis factor alpha (TNF ⁇ );
- the drugs can be used for the treatment and/or prevention of cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, Inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation, immunodeficiency diseases, bone destructive diseases, pro
- the present invention provides the use of a substance X in the preparation of a medicine; the substance X is the compound represented by the general formula (I) or formula I' as described above, its enantiomer, and diastereomer. isomers, racemates and mixtures thereof or their pharmaceutically acceptable salts.
- the medicament can be a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.
- IRAK4 interleukin-1 receptor-associated kinase 4
- the present invention provides compounds of general formula (I) or (I'), their enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts in the preparation for treatment Use in medicaments for preventing diseases related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.
- IRAK4 interleukin-1 receptor-associated kinase 4
- the present invention provides a pharmaceutical composition containing a therapeutically effective amount of the aromatic compound, enantiomer, diastereomer, racemate and The mixture, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers (or pharmaceutically acceptable excipients such as diluents or excipients).
- the pharmaceutical composition can be used for the treatment and prevention of interleukin-6 (IL-6) receptor-related or mediated diseases, such as autoimmune diseases or cancer.
- IL-6 interleukin-6
- the present invention provides the application of a substance A in the preparation of medicine, wherein the substance A is the aromatic compound, enantiomer, diastereomer, Racemates and mixtures or pharmaceutically acceptable salts thereof.
- the medicament may be a medicament for treating and preventing diseases related to or mediated by interleukin-6 (IL-6) receptors.
- IL-6 interleukin-6
- the present invention provides a pharmaceutical composition for the treatment and prevention of interleukin-6 (IL-6) receptor-related or mediated diseases (such as autoimmune diseases or cancer), comprising the general formula E Or the compound of formula X, its enantiomers, diastereomers, racemates and mixtures thereof or their pharmaceutically acceptable salts, pharmaceutically acceptable carriers, diluents or excipients.
- IL-6 interleukin-6
- the pharmaceutically acceptable salt thereof accounts for 1-99 wt% of the total weight of the composition.
- the present invention provides a pharmaceutical composition for treating and preventing autoimmune diseases or cancers related or mediated by interleukin-1 receptor-associated kinase 4 (IRAK4), comprising the compound of general formula X, its Enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carriers, diluents or excipients.
- IRAK4 interleukin-1 receptor-associated kinase 4
- the pharmaceutically acceptable salt thereof accounts for 1-99 wt% of the total weight of the composition.
- the present invention provides the use of a substance X in the preparation of a medicine; the substance X is the compound represented by the general formula X, its enantiomer, diastereomer and racemate as described above. and mixtures or pharmaceutically acceptable salts thereof.
- the medicament can be a medicament for treating and preventing diseases related to or mediated by the interleukin-1 receptor-associated kinase 4 (IRAK4) signal transduction pathway.
- IRAK4 interleukin-1 receptor-associated kinase 4
- the present invention provides compounds of general formula X, their enantiomers, diastereomers, racemates and their mixtures or their pharmaceutically acceptable salts in preparation for the treatment and prevention of interleukin-1 receptors Use in the medicament of a disease associated or mediated by the body-associated kinase 4 (IRAK4) signaling pathway.
- IRAK4 body-associated kinase 4
- the diseases described in any of the above schemes include cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, diseases related to organ transplantation. Diseases, immunodeficiency diseases, bone destructive diseases, proliferative diseases, infectious diseases, thrombin-induced platelet aggregation, liver diseases, lesions caused by T cell activation, cardiovascular diseases.
- the cancer or proliferative disease is selected from brain cancer, kidney cancer, liver cancer, bladder cancer, breast cancer, stomach cancer, ovarian cancer, colon cancer, rectal cancer, esophageal cancer, lung cancer, prostate cancer, pancreatic cancer, vaginal cancer, cervical cancer Cancer, testicular cancer, genitourinary tract cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, head and neck cancer, epidermoid cancer, large cell cancer , non-small cell lung cancer, lymphoma, Hodgkin or non-Hodgkin lymphoma, seminoma, melanoma, leukemia, diffuse large B-cell lymphoma (DLBCL), ABCDLBCL, chronic lymphocytic leukemia (CLL) , chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lympho
- the MyD88-driven disease is selected from the group consisting of ABC DLBCL, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma and chronic lymphocytic leukemia.
- the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, traumatic neurodegenerative disease, and graft-versus-host disease.
- the inflammatory disease is selected from ocular allergy, conjunctivitis, keratoconjunctivitis sicca, phlebitis conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic Thrombocytopenia, cutaneous acne; or another inflammatory disease resulting from an autoimmune response, selected from systemic lupus erythema, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatophytosis Myositis, chronic active hepatitis, myasthenia gravis, Stephen Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac Disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, en
- the compounds and derivatives described in the present invention may be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.
- the compounds of the present invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomeric, diastereomeric, and other stereoisomeric forms.
- Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
- the present invention is intended to include all possible isomers, as well as their racemates and optically pure forms.
- the compounds of the present invention can be prepared by selecting racemates, diastereomers or enantiomers as starting materials or intermediates.
- Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques such as crystallization and chiral chromatography.
- Stereoisomers of the compounds of the present invention may be (R)- or (S)-isomers.
- salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
- base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
- acids additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
- a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
- the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
- Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
- a "pharmaceutical composition” refers to a formulation of a compound of the present invention with a medium generally accepted in the art for delivering a biologically active compound to a mammal (eg, a human).
- the medium includes a pharmaceutically acceptable carrier.
- the purpose of the pharmaceutical composition is to facilitate the administration of the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- the term "pharmaceutically acceptable” refers to a substance (eg, a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing adverse biological effects React or interact in an undesirable manner with any component contained in the composition.
- pharmaceutically acceptable adjuvant includes, but is not limited to, any adjuvant, carrier, excipient, glidant approved by the relevant governmental administration as acceptable for human or livestock use , sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
- prophylactic As used herein, the terms “prophylactic”, “preventing” and “preventing” include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.
- treatment and other similar synonyms include the following meanings:
- an "effective amount” for treatment is that amount of a composition comprising a compound disclosed herein required to provide clinically significant relief of a condition.
- An effective amount appropriate in any individual case can be determined using techniques such as dose escalation assays.
- administering refers to methods capable of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, the oral route, the duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
- parenteral injection including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
- topical administration and rectal administration.
- Those skilled in the art are familiar with administration techniques useful for the compounds and methods described herein, for example in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Those discussed in Easton, Pa.
- the compounds and compositions discussed herein are administered orally.
- the terms "containing” or “including (including)” can be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of,” or “consisting of.”
- substitution refers to the replacement of a hydrogen atom in a molecule by a different atom or chemical group.
- the substituents can be one or more; when the substitution position is not specified, the substitution can be in any position, but only if a stable or chemically feasible chemical is formed Allowed.
- any variable eg, R
- its definition in each case is independent.
- the group may optionally be substituted with up to two Rs, with independent options for R in each case.
- combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
- moiety refers to a specific fragment or functional group in a molecule.
- a chemical moiety is usually thought of as a chemical entity embedded or attached to a molecule.
- substituents When substituents are described by conventional chemical formulae written from left to right, the substituents also include the chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2- .
- linking substituents are described.
- the Markush variables listed for that group should be understood to be the linking group.
- the structure requires a linking group and "alkyl” is listed for the definition of a Markush group for that variable, it should be understood that the "alkyl” represents the attached alkylene group.
- alkyl group when an alkyl group is clearly represented as a linking group, then the alkyl group represents the alkylene group to which it is attached, eg, the group "halo- C1 - C6alkane” C 1 -C 6 alkyl in "radical” is to be understood as C 1 -C 6 alkylene.
- the description method "...independently” used in the present invention should be understood in a broad sense, meaning that the described individuals are independent of each other, Can be independently the same or different specific groups.
- the description mode "...independently” can either mean that in different groups, the specific options expressed between the same symbols do not affect each other; it can also mean that in the same group, the same The specific options expressed by the symbols do not affect each other.
- Cyano refers to -CN.
- Amino refers to -NH2 .
- Carboxyl refers to -COOH.
- Halogen refers to a halogen group: fluorine, chlorine, bromine or iodine.
- Ca-Cb alkyl indicates any alkyl group containing "a" to "b” carbon atoms.
- C1-C6 alkyl refers to an alkyl group containing 1-6 carbon atoms.
- alkyl refers to a saturated hydrocarbon chain having the specified number of member atoms.
- C1-C6 alkyl refers to an alkyl group having 1 to 6 carbon atoms.
- Alkyl groups can be straight or branched. Representative branched alkyl groups have one, two or three branches. Alkyl groups may be optionally substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and hexyl (including various identities of hexyl).
- Alkyl groups can also be part of other groups such as C1-C6 alkylamino groups.
- "optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes both instances where the event or circumstance occurs and instances where it does not.
- the Ca-Cb unsaturated hydrocarbon group refers to an aliphatic hydrocarbon group containing "a" to "b" carbon atoms and containing one or ethylenic bond and one or more alkyne bonds.
- Unsaturated hydrocarbon groups include branched and straight chain groups. Olefinic bonds include cis double bonds and trans double bonds.
- Ca-Cb alkoxy refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding oxygen atom.
- the Ca-Cb alkylamino group refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding nitrogen atom.
- Ca-Cb alkanoyl refers to a group obtained by linking an alkyl group containing "a" to "b" carbon atoms with a corresponding acyl group.
- the ab-membered cycloalkyl in the present invention refers to a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms.
- 3-10 membered cycloalkyl another example is cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl,
- the cycloalkyl group of Ca-Cb in the present invention refers to a saturated cyclic hydrocarbon containing "a" to "b" carbon atoms.
- C1-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl.
- the a-b membered unsaturated cyclic hydrocarbon group refers to an unsaturated cyclic hydrocarbon containing "a" to "b” carbon atoms and containing one or more olefinic bonds or one or more alkyne bonds.
- a-b membered cycloalkoxy refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to “b” carbon atoms with a corresponding oxygen atom.
- the cycloalkoxy group of Ca-Cb refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b” carbon atoms with a corresponding oxygen atom.
- the a-b membered cycloalkylamino group refers to a group obtained by connecting a saturated cyclic hydrocarbon containing "a" to "b” carbon atoms with a corresponding nitrogen atom.
- the cycloalkylamino group of Ca-Cb refers to a group obtained by connecting a saturated cyclic hydrocarbon containing "a" to "b” carbon atoms to a corresponding nitrogen atom.
- the a-b membered cycloalkanoyl group refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b” carbon atoms with a corresponding acyl group.
- the cycloalkanoyl group of Ca-Cb refers to a group obtained by linking a saturated cyclic hydrocarbon containing "a" to "b” carbon atoms with the corresponding acyl group.
- the ab-membered heterocyclic group in the present invention refers to a group composed of "a” to “b” carbons and heteroatoms in total, and the heterocyclic group contains 1-4 selected from oxygen, sulfur and nitrogen
- the heteroatom of Ca-Cb; the heterocyclic group of Ca-Cb refers to a group composed of a total of "a” to "b” carbons and a ring containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated; such as 4-10 membered heterocycloalkyl, which can be (E.g ), (E.g ), (E.g ) (E.g ), (E.g ), (E.g ), (E.g ), (E.g ).
- the ab-membered aromatic heterocycle in the present invention refers to an aromatic ring composed of "a” to “b” carbons and heteroatoms in total.
- the heterocyclyl group of Ca-Cb refers to an aromatic ring composed of "a” to “b” carbons in total and containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.
- the a-b-membered aromatic ring in the present invention refers to an aromatic ring composed of "a" to "b" carbon atoms in total, such as a benzene ring and a naphthalene ring.
- the heterospirocyclic group of Ca-Cb refers to a group containing "a" to "b" carbon atoms, and one carbon atom is shared by two rings, and the heterospirocyclic group contains 1 -4 heteroatoms selected from oxygen, sulfur and nitrogen; including saturated or partially unsaturated non-aromatic heterospirocyclic groups; such as 4-10 membered heterospirocycloalkyl, which can be 2-azaspiro[ 3.3] Heptyl (e.g. ), 7-azaspiro[3.5]nonanyl (e.g. ), 2-azaspiro[3.5]nonanyl (e.g.
- 2,7-diazaspiro[3.5]nonanyl e.g.
- 6-azaspiro[3.4]octyl e.g.
- 4-oxa-7-azaspiro[2.5]octyl e.g.
- 5-oxa-8-azaspiro[3.5]nonanyl e.g.
- 2-oxa-6-azaspiro[3.3]heptyl e.g.
- 2-oxa-6-azaspiro[3.4]octyl e.g.
- 4,7-diazaspiro[2.5]octyl e.g.
- the heterobridged cyclic group of Ca-Cb in the present invention refers to a group containing "a" to "b" carbon atoms, and two rings share two carbon atoms or heteroatoms, and the heterobridged cyclic group contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen.
- Including saturated or partially unsaturated non-aromatic heterobridged ring groups; such as 4-10 membered heterobridged cycloalkyl; may be octahydrocyclopenta[C]pyrrolyl (eg ), octahydropyrro[3,4-c]pyrrolyl (e.g. ), 3-azabicyclo[3.1.0]hexyl (e.g. ), 2-oxa-5-azabicyclo[2.2.1]heptyl (e.g. ), 8-oxa-3-azabicyclo[3.2.1]octyl (e.g. ).
- the reagents and raw materials used in the present invention are all commercially available.
- the positive improvement effect of the present invention is that the aromatic compounds provided by the present invention can be used as E3 ligands to prepare PROTAC compounds that can effectively degrade IRAK4 or inhibit the activity of IRAK4 in other ways, as well as interleukin-6 (IL-6) receptors Intermediates for inhibitors (CRBN ligand-linker compounds).
- the interleukin-6 (IL-6) receptor inhibitor and PROTAC compound have better activities, and provide a new choice for clinical screening and/or preparation of drugs for related diseases.
- Figure 1 is a comparison of the middle ear thickness effect of Test Example 11.
- Figure 2 is a comparison of the effects of silver flakes in Test Example 11.
- reaction temperature is room temperature, and room temperature refers to 20-25°C. All temperatures are expressed in °C (degrees Celsius).
- High performance liquid chromatography (HPLC) measurement conditions Shimadzu high pressure liquid chromatography (Shimadzu LC-20A).
- Analytical high performance liquid chromatography conditions C18 column (5 ⁇ m, 4.6x 150mm), UV detection bands are 214 and 254nm, elution conditions 0-90% acetonitrile (containing 0.03% V/VTFA) gradient washing for 30 minutes.
- Reversed-phase purification was performed using a Gilson GX-281 Preparative Reversed-Phase Chromatograph or the Biotage Isolera One Rapid Purification System.
- NMR measurements were carried out on a Bruker Avance III 400 nuclear magnetometer, and NMR shifts ( ⁇ ) are given in units of 10-6 (ppm).
- the solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) and deuterated methanol (CD3OD), etc., and the internal standard is tetramethylsilane (TMS).
- the hydrogenation reaction needs to be evacuated to discharge the air, filled with hydrogen, then evacuated to discharge the gas, filled with hydrogen, and the operation is repeated 3 times.
- the known starting materials, reagents and solvents of the present invention can be synthesized using or according to methods known in the art, or can be purchased from Shaoyuan Chemical Technology, Bailingwei Technology, Shanghai Bide Pharmaceutical Technology Co., Ltd. and Shanghai Titan Technology Co., Ltd. etc.
- MPLC medium pressure preparative chromatography
- TLC thin layer chromatography
- MeOH is methanol
- EtOH is ethanol
- DMAP 4-dimethylaminopyridine
- DMF is N,N-dimethylformamide
- Methylacetamide is ethyl acetate
- THF is tetrahydrofuran
- DMSO is dimethyl sulfoxide
- DCM is dichloromethane
- DCE dichloroethane
- MTBE methyl tert-butyl ether
- tert-butyl ester Boc is tert-butyloxycarbonyl
- SEMCl is 2-(trisilyl)ethoxymethyl chloride
- SEM is 2-(trisilyl)ethoxymethyl
- CbzCl is benzyloxycarbonyl chloride
- Cbz is Benzyloxycarbonyl chloride
- Cbz is Benzyloxycarbonyl chloride
- Cbz is
- Methyl cis-4-hydroxycyclohexyl-1-carboxylate (10 g, 63.2 mmol) was dissolved in 100 mL of dichloromethane, then triethylamine (12.5 g, 123 mmol) and methanesulfonyl chloride (10.9 g) were added under ice bath , 94.8 mmol), gradually warmed to room temperature and stirred for 2 hours. After the completion of the reaction, the reaction was extracted with dichloromethane and water, the aqueous phase was washed twice with dichloromethane, the organic phase was collected, dried over anhydrous sodium sulfate and the solvent was removed. cis-4-methanesulfonyloxycyclohexyl-1-carboxylic acid methyl ester (12.45 g, 83% yield) was obtained.
- Methyl cis-4-methanesulfonyloxycyclohexyl-1-carboxylate (6.22 g, 26.3 mmol) and 3-aldehyde-1H-pyrazole (1.68 g, 17.5 mmol) were dissolved in 50 mL of DMF, then Cesium carbonate (10.26 g, 31.6 mmol) was added, followed by stirring at 80°C overnight. After the reaction was completed, the reaction was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate.
- N-Boc-4-hydroxypiperidine (4.02 g, 20 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, then sodium hydride (1.20 g, 30 mmol) was added at 0 °C, and after stirring for 30 minutes, propargyl bromide (3.56 g) was added. g, 30 mmol) and stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate.
- Step 1 to Step 3 Synthesis of 4-(3-(difluoromethyl)-1H-pyrazol-1yl)piperidine-1-carboxylic acid tert-butyl ester
- Step 1 to Step 4 5-((1R,4R)-2-oxa--5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl) - Synthesis of 1-((1R,4R)-4-aldocyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
- 3-Methyl-4-bromoindazole (210 mg, 1 mmol) was dissolved in 5 mL of anhydrous THF/DMSO (1/1) mixed solvent, then sodium hydride (120 mg, 3 mmol, 60% purity) was added at 0°C, After stirring for 30 minutes, 3-bromopiperidine-2,6-dione (288 mg, 1.5 mmol) and potassium iodide (133 mg, 0.8 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, 10 mL of saturated aqueous ammonium chloride solution was added to quench, and then extracted with ethyl acetate.
- Step 2 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indazol-4-yl)prop-2-ynyl-1- Synthesis of tert-butyl)oxy)piperidine-1-carboxylate.
- Step 1 (3-(difluoromethyl)-1-((1r,4r)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)- 3-Methyl-1-1H-indazol-4-yl)-prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4- Synthesis of tert-butyl carbamate
- Step 2 3-(4-(3-((1-(((1r,4r)-4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl) ring Hexyl)methyl)-piperidin-4-yl)oxy)prop-1-yn-1-yl)-3-methyl-1H-indazol-1-yl)piperidine-2,6-dione synthesis
- step 1 The product of step 1 (1 g, 1.4 mmol) was dissolved in 5 mL of dioxane, a dioxane hydrochloric acid solution (4 M) was added, and the reaction solution was stirred at room temperature for 5 h. After the reaction was completed, the reaction solution was concentrated to obtain the target product, which was directly used in the next reaction without purification.
- Step 2 4-((3-(1-(2,6-dicarbonylpiperidin-3-yl)-3-methyl-1H-indol-4-yl)prop-2-ynyl-1- base)oxy)piperidine
- Step 1 to Step 3 3-(3-methyl-4-(3-(piperidin-1-yloxy)prop-1-yn-1-yl)-1H-pyrrole[2,3-b] Synthesis of Pyridin-1-yl)piperidine-2,6-dione trifluoroacetate
- Trans-4-(tert-butyldimethylsiloxymethyl)cyclohexanol (1.41 g, 5.80 mmol) was dissolved in ultra-dry DMF, then sodium hydride (580 mg, 14.5 mmol) was added at 0°C and stirred for 0.5 Hour. Finally, propyne bromide (1.38 g, 11.6 mmol) was added and the mixture was returned to room temperature and stirred overnight. After the reaction was completed, it was extracted with ethyl acetate and water, and the aqueous phase was washed twice with ethyl acetate.
- Trans-4-(tert-butyldimethylsiloxymethyl)cyclohexyl propargyl ether 716 mg, 2.53 mmol was dissolved in 5 mL of tetrahydrofuran, followed by the addition of a 2M solution of TBAF in tetrahydrofuran (5 mL, 10 mmol). It was stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by a rotary evaporator, and the residue was purified by column chromatography to obtain 317 mg (1.89 mmol) of trans-trans-(4-hydroxymethyl)cyclohexyl propargyl ether. , the yield is 75%).
- tert-butyl 4-(2-(hydroxyethyl)piperidine-1-carboxylate (4.59 g, 20 mmol) in 50 mL of dichloromethane then add triethylamine (4.04 g, 40 mmol) and methyl benzene under an ice bath Sulfonyl chloride (2.52 g, 22 mmol) was gradually raised to room temperature and stirred for 2 hours. After the reaction was completed, the reaction was extracted with dichloromethane and water, and the aqueous phase was washed twice with dichloromethane. The organic phase was collected and dried over anhydrous sodium sulfate. And the solvent was removed to give tert-butyl 4-(2-(methanesulfonyloxyethyl)piperidine-1-carboxylate (5.92 g, 19.3 mmol, 96% yield).
- N-Boc-4-piperidinemethanol (5.0 g, 23.3 mmol) was dissolved in 30 mL of dichloromethane, Et 3 N (7.1 g, 69.9 mmol) was added, and p-toluenesulfonyl chloride (6.7 g, 35.9 mmol) was added at 0° C. mmol), the reaction solution was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction solution was extracted with dichloromethane, washed twice with water, the organic layers were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain the target product, which was directly used in the one-step reaction with a yield of 97%.
- step 3 500 mg, 1.0 mmol was dissolved in 4 mL of dioxane, 5 mL of 4M hydrochloric acid dioxane solution was added, and the mixture was stirred at room temperature for 5 h. After the completion of the reaction, the reaction solution was concentrated to obtain the target product, which was directly used in the next step without purification.
- LCMS (ESI) m/z: (M+H)+ 407.2.
- N-Boc-4-hydroxypiperidine (4.02 g, 20 mmol) was dissolved in 30 mL of anhydrous tetrahydrofuran, then sodium hydride (880 mg, 22 mmol) was added at 0°C, and after stirring for 30 minutes, ethyl bromoacetate (5.01 g) was added. , 30 mmol), and stirred at room temperature overnight. After the reaction was completed, 20 ml of saturated aqueous ammonium chloride solution was added to quench, and then the organic solvent was removed by a rotary evaporator, and then extracted with ethyl acetate.
- Step 3 to Step 5 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)- Synthesis of 1-(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
- Step 1 to Step 2 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1 Synthesis of -(2-azaspiro[3.5]nonan-7-yl)-1H-pyrazol-4-yl)pyrazol[1,5-a]pyrimidine-3-carboxamide
- Methyl 6-oxospiro[3.3]heptane-2-carboxylate (20 mmol, 3.36 g) was dissolved in 40 mL of methanol, then sodium borohydride (30 mmol, 1.14 g) was added at 0°C, stirred for 2 hours, and then Return to room temperature and stir for 16 hours.
- Step 6 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5 Synthesis of ]nonane-2-carboxylic acid
- Step 8 6-(4-(5-((4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)pyrazolo[1,5-a]pyrimidine-3 -formamide)-3-(difluoromethyl)-1H-pyrazol-1-yl)spiro[3.3]heptane-2-carboxylate methyl-methanesulfonyloxy-2-azaspiro[3.5 Synthesis of ]nonane-2-carbaldehyde
- tert-butyl (4-bromopyridin-2-yl)(cyclopropylmethyl)carbamate (1.77 g, 5.4 mmol) and ethyl oxazole-4-carboxylate (761 mg, 5.4 mmol), tri-o-tolylphosphine ( 329 mg, 1.08 mmol), Pd(OAc) 2 (121 mg, 0.54 mmol) and Cs 2 CO 3 (3.51 g, 108 mmol) were dissolved in DMF (20 mL) and stirred at 80° C. overnight under nitrogen protection.
- Step 3 to Step 5 (Cyclopropylmethyl)(4-(4-((3-(difluoromethyl)-1-((1R,4R)-4-formylcyclohexyl)-1H-pyrazole- Synthesis of tert-butyl 4-yl)carbamoyl)oxazol-2-yl)pyridin-2-yl)carbamate
- Step 1 to Step 2 3-(3-methyl-4-(3-(piperazin-1-yl)prop-1-yn-1-yl)-1H-indazol-1-yl)piperidine- Synthesis of 2,6-diketone trifluoroacetate
- Step 1 to Step 2 3-(3-methyl-4-(4-(piperazin-1-yloxy)but-1-yn-1-yl)-1H-pyrrole[2,3-b] Synthesis of Pyridin-1-yl)piperidine-2,6-dione trifluoroacetate
- Step 1 to Step 2 3-(4-(3-(hexahydropyrrolo[3,4-c]pyrrolidinyl-2(1H)-yl)prop-1-yn-1-yl)-3- Methyl-1H-indazol-1-yl)piperidine-2,6-dione.
- Step poly-1 (3-(difluoromethyl)-1-((1S,4r)-4-(((3S)-3-((3-(1-(2,6-dioxopiperidine- 3-yl)-3-methyl-1H-indazol-4-yl)prop-2-yn-1-yl)oxy)pyrrolidin-1-yl)methyl)cyclohexyl)-1H-pyrazole- Synthesis of tert-butyl 4-yl)carbamate
- step 3 The intermediate obtained in step 3 was dissolved in dichloromethane, cooled to 0° C., TFA was added, and the temperature was returned to room temperature. After the reaction was completed, the reaction solution was concentrated to dryness, and the obtained residue was directly used in the next reaction.
- LCMS (ESI) m/z: [M+1] 405.2.
- Methyl cis-4-hydroxy-cyclohexylcarboxylate (90 g) was dissolved in THF, cooled to 0°C, and LiAlH4 (23 g) was added portionwise. After the addition was completed, react for half an hour, add aqueous sodium hydroxide solution, stir at 0 °C for 15 minutes, suction filtration, extract the filtrate with ethyl acetate, wash with water, dry over sodium sulfate, and concentrate to obtain a colorless oil, 60.88 g, which was produced rate 82%.
Abstract
La divulgation concerne un composé aromatique contenant un fragment de ligand E3, une composition pharmaceutique le contenant, et son application. La divulgation concerne un composé aromatique tel que représenté par la formule générale E, un énantiomère, un diastéréomère, un racémate et un mélange, ou un sel pharmaceutiquement acceptable de celui-ci. Un tel composé contenant le fragment de ligand E3 peut être utilisé pour préparer un composé PROTAC, qui peut recruter des protéines cibles sur une ubiquitine ligase de CRBN E3 pour la dégradation, ou inhiber l'activité des protéines cibles d'autres manières. Un agent de dégradation d'une enzyme IRAK4 contenant celui-ci peut dégrader efficacement l'IRAK4 ou inhiber l'activité d'IRAK4 d'autres manières. Le composé présente une bonne perspective d'application dans des maladies médiées par IRAK4 telles que des maladies immunitaires, des tumeurs, la maladie d'Alzheimer et des maladies fibrotiques, et fournit un nouveau choix en clinique pour le criblage et/ou la préparation de médicaments pour les maladies liées à l'activité d'IRAK4.
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Cited By (2)
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| CN115772180A (zh) * | 2021-09-08 | 2023-03-10 | 南京明德新药研发有限公司 | 戊二酰亚胺类化合物与其应用 |
| WO2023131167A1 (fr) * | 2022-01-04 | 2023-07-13 | 海思科医药集团股份有限公司 | Composé pour inhiber et dégrader irak4, composition pharmaceutique et application pharmaceutique associées |
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| CN117362286B (zh) * | 2023-12-08 | 2024-03-12 | 清华大学 | 具有sirt6激动活性的化合物及其用途 |
| CN117720515B (zh) * | 2024-02-05 | 2024-04-26 | 中国药科大学 | 一种Gasdermins蛋白PROTAC降解剂及其制备方法和应用 |
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