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WO2023186069A1 - Composé hétérocyclique chimérique bifonctionnel de la kinase 4 associée au récepteur de l'interleukine-1, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée - Google Patents

Composé hétérocyclique chimérique bifonctionnel de la kinase 4 associée au récepteur de l'interleukine-1, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée Download PDF

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Publication number
WO2023186069A1
WO2023186069A1 PCT/CN2023/085387 CN2023085387W WO2023186069A1 WO 2023186069 A1 WO2023186069 A1 WO 2023186069A1 CN 2023085387 W CN2023085387 W CN 2023085387W WO 2023186069 A1 WO2023186069 A1 WO 2023186069A1
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Prior art keywords
alkyl
compound
cycloalkyl
hydrogen
pharmaceutically acceptable
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English (en)
Chinese (zh)
Inventor
张朝再
赵传武
范丽雪
李子真
张雪明
杨银平
张红芬
辛岭岭
王琛
米国瑞
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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CSPC Zhongqi Pharmaceutical Technology Shijiazhuang Co Ltd
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Priority to CN202380008533.1A priority Critical patent/CN117157298A/zh
Publication of WO2023186069A1 publication Critical patent/WO2023186069A1/fr
Anticipated expiration legal-status Critical
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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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention requires an invention patent application submitted in China on March 31, 2022, titled “A class of bifunctional chimeric heterocyclic compounds of interleukin-1 receptor-related kinases and their preparation methods and uses” and the application number is 202210334860.3 And priority is given to the invention patent application submitted in China on September 28, 2022, titled “A class of bifunctional chimeric heterocyclic compounds of interleukin-1 receptor-related kinases and their preparation methods and uses” with application number 202211214397.5 The entire contents of the above patent application are incorporated herein by reference.
  • the invention belongs to the field of medical technology. Specifically, the invention relates to a bifunctional chimeric heterocyclic compound of interleukin-1 receptor-associated kinase 4 (IRAK4) and its preparation method, pharmaceutical composition and use.
  • IRAK4 interleukin-1 receptor-associated kinase 4
  • Interleukin-1 receptor-associated kinase 4 belongs to the IRAK family (including IRAK1, IRAK2, IRAK3 and IRAK4). It is encoded by the IRAK4 gene and is located on chromosome 12. As a threonine/serine protein kinase, IRAK4 consists of 460 amino acids, contains a kinase domain and a death domain, and has high homology with IRAK1, IRAK2, IRAK3 (IRAKM) and Pelle kinase. IRAK4 is the most unique member of the family in that it lacks a C-terminal domain and functions upstream of other members. IRAK4 is expressed in multiple tissues of the human body, but is mainly distributed in liver and lung tissues.
  • IRAK4 is a key regulator downstream of the interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) signaling pathways. It causes the transcription and expression of pro-inflammatory cytokine genes through the IL-1R/TLRs signaling pathway, triggering the innate immune response. Abnormal IL-1R/TLRs conduction is involved in a variety of autoimmune diseases, so IRAK4 has become a target of autoimmune diseases. An effective target; and MyD88 serves as a key regulator of the IL-1R/TLRs signaling pathway, making IRAK4 play an important role in tumors with MyD88 mutations.
  • IL-1R interleukin-1 receptor
  • TLRs toll-like receptors
  • IL-1R/TLRs receptors In the innate immune response, both IL-1R/TLRs receptors rely on MyD88 as a regulator to activate downstream inflammatory signaling pathways.
  • MyD88 factor When IL-1R/TLRs and ligands recruit MyD88 factor, MyD88 factor forms a dimer and further recruits IRAK4 through its N-terminal death domain.
  • IRAK4 exerts kinase activity through autophosphorylation and activates the substrate IRAK1, and IRAK1 then It undergoes a conformational change and forms a complex with TNF receptor-associated factor 6 (TRAF6).
  • TNF receptor-associated factor 6 TNF receptor-associated factor 6
  • TRAF6 activates NF- ⁇ B through the adapter protein TAK1, etc., causing the activated NF- ⁇ B to enter the nucleus and cause the transcription and expression of pro-inflammatory cytokine genes.
  • TRAF6 can also activate p38 and JNK, thereby activating the AP1 pathway.
  • IRAK4 overexpression can enhance the activity of LPS-induced NADPH oxidase, thereby affecting downstream MAPK signaling. Therefore, IRAK4 can trigger inflammatory responses through multiple pathways such as IRAK1/TRAF6/NF- ⁇ B/AP1 and NADPH/MAPK/AP1.
  • IRAK4 as a degradation target can provide new treatment options for the treatment of autoimmune diseases, inflammation and tumor-related diseases.
  • IRAK4 protein degradation targeting chimeras
  • TPD target protein degradation
  • thalidomide derivatives, lenalidomide and pomalidomide can recruit protein substrates to a ubiquitin ligase complex called cereblon (CRBN) to degrade the protein substrates.
  • CRBN cereblon
  • KT-474 SAR444656
  • KT-413 PROTAC bifunctional small molecules developed by Kymera Therapeutics are in clinical phase I as oral and intravenous IRAK4 degraders respectively.
  • Some of the company's other PROTAC bifunctional small molecules see WO2020264499A1, WO2020113233A1 and WO2022027058A1 also showed good PK and PD in animal experiments.
  • IRAK4 inhibitor PF-06650833 (see WO2015150995A1) developed by Pfizer has a therapeutic effect on autoimmune diseases such as rheumatoid arthritis and lupus erythematosus, and is currently in clinical phase II.
  • the object of the present invention is to provide a bifunctional chimeric heterocyclic compound that acts as a degradation product of IRAK4 through the ubiquitin proteasome pathway, as well as its pharmaceutical composition, preparation method and use.
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, amino or -OC 1 -6 alkyl; wherein, the C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, -OC 1-6 alkyl can be substituted by one or more F atoms;
  • L represents -L 1 -L 2 -L 3 -L 4 -L 5 -, wherein L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from the group consisting of bonds, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heterocyclyl, 5-12 membered heteroaryl, C 1-12 alkylene, C 2-12 alkenylene, C 2-12 alkynylene, -OC 2 -12 alkenylene, -OC 2-12 Alkynylene, -C(O)-, -C(O)-(CH 2 ) n -, -C(O)O-, -O-, -N(R b )-, -N(R b ) -(CH 2 ) n -, -S-, -C(S)-, -C(S)-O-, -S(O) 2 -, -S(O)(R b )
  • Each R c2 is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl or -OC 1-6 alkyl; wherein, the C 1-6 Alkyl, -OC 1-6 alkyl can be substituted by 1-3 F atoms;
  • Each R d is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl or -OC 1-6 alkyl; wherein, the C 1-6 Alkyl, -OC 1-6 alkyl can be substituted by 1-3 F atoms;
  • R g is selected from C 1-6 alkyl or C 4-12 cycloalkyl
  • R h is selected from hydrogen, C 1-6 alkyl, C 4-6 cycloalkyl, C 6-8 aryl, 4-11 membered heterocyclyl or 5-8 membered heteroaryl;
  • n and p are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • LBM is the ligase binding moiety.
  • X and Z 1 are each independently selected from CH or N;
  • Z 2 is selected from O or S
  • Ring A and Ring B are each independently selected from 3-12-membered heterocyclyl, C 6-14 aryl or 5-12-membered heteroaryl, and the heterocyclyl and heteroaryl have 1-4 independent choices.
  • Each R 1 is independently selected from hydrogen, cyano, C 1-6 alkyl, halogen, -NO 2 , -OR a1 , -SR a1 , -N(R a1 ) 2 , -S(O) 2 R a1 , -S(O) 2 N(R a1 ) 2 , -S(O)R a1 , -S(O)(NR a1 )R a1 , -P(O)(OR a1 ) 2 , -P(O )(N(R a1 ) 2 ) 2 , -CF 2 (R a1 ), -CF 3 , -CR 2 (OR a1 ), -CR 2 (N(R a1 ) 2 ), -C(O)R a1 , -C(O)OR a1 , -C(O)N(R a1 ) 2 , -C(O)N(R
  • n is selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • Each R a1 is independently selected from hydrogen, C 1-6 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, phenyl, C 4-7 cycloalkyl, C 3-6 cycloalkenyl , 4-7-membered heterocycloalkyl or 5-6-membered heteroaryl; wherein, the heterocycloalkyl or heteroaryl has 1-4 heteroatoms selected from N, O, and S;
  • R 2 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, amino or -O C 1 -6 alkyl; wherein, the C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6-12 aryl, 5-12 membered heteroaryl, -OC 1-6 alkyl groups may be substituted by one or more fluorine atoms;
  • R b is selected from hydrogen or C 1-6 alkyl
  • Each R c1 is independently selected from H or C 1-6 alkyl
  • R g is selected from C 1-6 alkyl or C 4-12 cycloalkyl
  • n and p are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • the ring A and ring B are each independently selected from partially saturated 4-6-membered heterocyclyl, 5-6-membered heteroaryl or C 6-8 aryl.
  • ring A is selected from partially saturated 5-membered heterocyclyl or 5-membered heteroaryl
  • ring B is selected from phenyl or 6-membered heteroaryl
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are:
  • the ring A and ring B formed together are selected from:
  • the ring A and ring B formed together are selected from:
  • each R 1 is independently selected from hydrogen, cyano, C 1-6 alkyl, halogen, hydroxyl, amino, -C(O)C 1-6 alkyl , -COOH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)N(C 1-6 alkyl) 2 or 7-9 membered heterocycloalkyl; m Choose from 0, 1 or 2.
  • each R 1 is independently selected from hydrogen, cyano, methyl, ethyl, n-propyl, isopropyl, F, Cl, Br, hydroxyl, amino, -C(O)CH 3 , -C(O)CH 2 CH 3 , -COOH, -C(O)OCH 2 CH 3 , -C(O)OCH 3 , -C(O)NH 2 , -C( O)N(CH 3 ) 2- or 7-membered heterocycloalkyl; m is selected from 0 or 1.
  • each R 1 is independently selected from hydrogen, cyano, methyl, F, hydroxyl, amino, -C(O)NH 2 or 7-membered heterocycloalkyl; m is chosen from 0 or 1.
  • each R 1 is independently selected from hydrogen, cyano, C 1-6 alkyl, halogen, hydroxyl, amino, -C(O)C 1-6 alkyl , -COOH, -C(O)OC 1-6 alkyl, -C(O)NH 2 , -C(O)N(C 1-6 alkyl) 2 ; m is selected from 0, 1 or 2.
  • each R 1 is independently selected from hydrogen, cyano, methyl, ethyl, n-propyl, isopropyl, F, Cl, Br, hydroxyl, amino, -C(O)CH 3 , -C(O)CH 2 CH 3 , -COOH, -C(O)OCH 2 CH 3 , -C(O)OCH 3 , -C(O)NH 2 , -C( O)N(CH 3 ) 2 ; m is selected from 0 or 1.
  • each R 1 is independently selected from hydrogen, cyano, methyl, F, hydroxyl, amino, -C(O)NH 2 , -C(O)N( CH 3 ) 2 ; m is selected from 0 or 1.
  • said R 1 is selected from 7-9 membered heterocycloalkyl.
  • said R 1 is selected from 7-membered heterocycloalkyl.
  • said R 1 is selected from
  • the R 2 is selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocycloalkyl, C 6-12 aryl, 5 -12-membered heteroaryl, amino or -OC 1-6 alkyl.
  • the R 2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, amino or methoxy.
  • Each R d is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl or -OC 1-6 alkyl; wherein, the C 1-6 alkyl Base, -OC 1-6 alkyl group can be substituted by 1-3 fluorine atoms;
  • L represents -L 1 -L 2 -L 3 -L 4 -L 5 -, wherein L 1 , L 2 , L 3 , L 4 and L 5 are each independently selected from bond, C 4-6 cycloalkyl, C 6-8 aryl, 4-11 membered heterocyclyl, 5-8 membered heteroaryl, C 1-3 alkylene, C 2-4 alkenylene, C 2-4Alkynylene , -C(O)-, -C(O)O-, -O-, -N(R b )-, -N(R b )-(CH 2 ) 2 - or -C (O)-N(R b )-; R b is selected from hydrogen or C 1-6 alkyl.
  • L represents -L 1 -L 2 -L 3 -L 4 -L 5 -, where L 5 is connected to LBM, and L 1 , L 2 , L 3 , L 4 and L 5 is each independently selected from bond, C 3-11 cycloalkyl, 3-12 membered heterocyclyl, C 1-6 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, - OC 2-8 alkenylene, -OC 2-8 alkynylene, -C(O)-, -C(O)-(CH 2 ) n -, -O-, -N(R b )-, - N(R b )-(CH 2 ) n -, -C(O)-N(R b )-, -(CH 2 ) n -C(O)-N(R b )-, -(CH 2 ) n -C(O)-N(R b )-, -
  • L 4 is selected from bond, C 1-3 alkylene, -C(O)- or -C(O)-(CH 2 ) n -;
  • L 3 is selected from a bond or a 5-10 membered heterocyclic group
  • L 5 is selected from bond, 5-6 membered heterocyclyl, C 1-3 alkylene, C 2-4 alkynylene, -N(R b )-(CH 2 ) n -, -OC 2-4 Alkynyl or -C(O)-(CH 2 ) n -;
  • n is selected from 0, 1, 2 or 3.
  • L 2 is selected from C 1-3 alkylene, -C(O)-NH-, -C(O)-, -C(O)-(CH 2 ) n -, -(CH 2 ) n -C( O)-N(R b )-, -N(R b )-(CH 2 ) n -or 5-6 membered heterocyclyl;
  • L 5 is selected from bond, 5-6 membered heterocyclyl, methylene, ethylene, n-propylene, ethynylene, propynylene, butynylene, -N(R b )-(CH 2 ) n -, -O-ethynylene, -O-propynylene or -C(O)-(CH 2 ) n -;
  • R b is selected from hydrogen, methyl or ethyl
  • said L is selected from the structure shown below and its stereoisomers:
  • said L is selected from the structure shown below and its stereoisomers:
  • the LBM is a compound of formula (II):
  • R h is selected from hydrogen, C 1-6 alkyl, C 4-6 cycloalkyl, C 6-8 aryl, 4-11 membered heterocyclyl or 5-8 membered heteroaryl.
  • the LBM is a compound of formula (II), wherein,
  • Each R f2 is independently selected from halogen, oxo, cyano, hydroxyl, C 1-6 alkyl, C 3-8 cycloalkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl Base, -OC 1-6 alkyl group can be substituted by 1-3 fluorine atoms;
  • Rg is selected from C 1-6 alkyl, C 4-12 cycloalkyl
  • R h is selected from hydrogen, C 1-6 alkyl, C 4-6 cycloalkyl, C 6-8 aryl, 4-11 membered heterocyclyl or 5-8 membered heteroaryl;
  • the LBM is a compound of formula (IIa):
  • R e is selected from hydrogen or C 1-6 alkyl
  • Each R f is independently selected from halogen, nitro, cyano, hydroxyl, C 1-6 alkyl, C 1-6 haloalkyl or -OC 1-4 alkyl;
  • q is selected from 0, 1, 2 or 3.
  • the LBM is a compound of formula (IIa'):
  • Each R f is independently selected from halogen, nitro, cyano, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or -OC 1-4 alkyl; preferably, R f is selected from halogen, Nitro, cyano, hydroxyl, C 1-3 alkyl, C 1-3 haloalkyl or -OC 1-4 alkyl;
  • q is selected from 0, 1, 2 or 3.
  • the LBM is a compound of formula (IIa'), wherein,
  • q is chosen from 0 or 1.
  • the LBM is selected from:
  • the LBM is a compound of formula (IIb):
  • W is selected from C( Re ) or N;
  • R e is selected from hydrogen or C 1-6 alkyl
  • Each R f is independently selected from F, Cl, Br, nitro, cyano, hydroxyl, methyl or methoxy;
  • the LBM is a compound of formula (IIb') or a compound of formula (IIb"),
  • R f is F.
  • the LBM is a compound of formula (IIb'):
  • the LBM is selected from:
  • the LBM is selected from:
  • the LBM is a compound of formula (IIc):
  • W is selected from C( Re ) or N;
  • R e is selected from hydrogen or C 1-6 alkyl
  • Each R i1 is independently selected from hydrogen or C 1-6 alkyl
  • Each R i2 is independently selected from halogen, oxo, cyano, hydroxy, C 1-6 alkyl, C 3-8 cycloalkyl or -OC 1-6 alkyl, wherein said C 1-6 alkyl Base, -OC 1-6 alkyl group can be substituted by 1-3 fluorine atoms;
  • Rg is selected from C 1-6 alkyl, C 4-12 cycloalkyl
  • the LBM is a compound of formula (IIc-1):
  • W, Y 1 and Y 2 are each independently selected from CH or N.
  • the LBM is:
  • the LBM is a compound of formula (IIc-2):
  • W and Y 2 are each independently selected from CH or N;
  • the LBM is:
  • the LBM is a compound of formula (IIc-3):
  • W, M 2 and M 3 are independently selected from CH or N; M 1 is selected from O or S;
  • Ri can be selected from methyl, ethyl, n-propyl, isopropyl, F, Cl, nitro, cyano, hydroxyl or methoxy.
  • the LBM is a compound of formula (IIc-3'):
  • W is selected from CH or N; Ri can be selected from methyl, ethyl, n-propyl, isopropyl, F, Cl, hydroxyl or methoxy.
  • W is selected from CH or N; Ri can be selected from methyl, ethyl, n-propyl, isopropyl, F, Cl, hydroxyl or methoxy.
  • the LBM is selected from:
  • the LBM is a compound of formula (IIc-4):
  • W, M 2 and M 3 are independently selected from CH or N;
  • M 1 is selected from O or S.
  • W, M 2 and M 3 are independently selected from CH or N.
  • the LBM is:
  • the LBM is a compound of formula (IIc-5):
  • W and M 4 are independently selected from CH or N;
  • X 1 is selected from O or S
  • X 2 is selected from CH or N
  • X 3 is selected from C
  • Rf is selected from hydrogen, halogen, cyano, hydroxyl, methyl, ethyl, n-propyl or isopropyl.
  • the LBM is a compound of formula (IIc-5'):
  • the LBM is a compound of formula (IIc-5′′):
  • Rf is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the LBM is a compound of formula (IIc-6):
  • the LBM is a compound of formula (IId):
  • W is selected from CH or N;
  • W 1 Represents a single bond or a double bond, when When representing a single bond, W 1 is selected from CH 2 or NH, when When representing a double bond, W 1 is selected from CH or N;
  • the LBM is a compound of formula (IId), wherein,
  • W is selected from CH or N;
  • the LBM is a compound of formula (IId'):
  • the LBM is a compound of formula (II), wherein,
  • W, W 1 is selected from CH or N;
  • Each R f is independently selected from halogen, nitro, cyano, hydroxy, methyl, ethyl, n-propyl, or isopropyl.
  • Cy2 is selected from phenyl, pyridine, pyrazole, imidazole, thiazole or pyrrole, wherein the phenyl, pyridine, pyrazole, imidazole, thiazole or pyrrole can be substituted by 1-2 R f ;
  • Each R f is independently selected from F, Cl, bromine, nitro, cyano, hydroxy or methyl.
  • the LBM is:
  • the LBM is a compound of formula (IIIa) or a compound of formula (IIIb):
  • ring A, ring B, R 1 , m, R 2 , X, Z 1 , L and LBM are as described for the compound of formula (I) above.
  • ring A is selected from 5-membered heterocyclyl or 5-membered heteroaryl
  • ring B is selected from phenyl or 6-membered heteroaryl
  • R 2 is selected from hydrogen, C 1-3 alkyl, amino or methoxy.
  • R 1 , m, R 2 , L and LBM are as defined in the compound of formula (I) above.
  • R 1 is selected from hydrogen, cyano, methyl, F, Cl, hydroxyl, amino, -C(O)CH 3 , - C(O)NH 2 , -C(O)N(CH 3 ) 2 or 7-9 membered heterocycloalkyl;
  • n is selected from 0, 1 or 2;
  • the invention provides compounds having the following structures, and stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic labels thereof:
  • the present invention also provides a pharmaceutical composition, which contains the compound of the present invention or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope label.
  • the present invention also provides a pharmaceutical composition, which contains the compound of the present invention or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope label, and a pharmaceutically acceptable of excipients.
  • the object of the present invention also includes providing the compound of the present invention or its stereoisomer, optical isomer, pharmaceutical salt, prodrug, solvate or isotope label or the pharmaceutical combination of the present invention.
  • the compounds of the present invention or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope labels or the pharmaceutical compositions of the present invention are used in the preparation of prevention and/or treatment of It can be used alone or in combination with other pharmaceutical active ingredients when treating IRAK4-mediated diseases, disorders or conditions.
  • the object of the present invention also includes providing a method for degrading and/or inhibiting IRAK protein kinase (preferably IRAK4) in a patient or biological sample, which includes administering to the patient a compound of the present invention or a stereoisomer thereof , optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope labels or the pharmaceutical compositions of the present invention, or the biological sample and the compounds of the present invention or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic labels or pharmaceutical compositions of the invention.
  • IRAK protein kinase preferably IRAK4
  • the compounds of the present invention or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope labels or the pharmaceutical compositions of the present invention degrade and/or inhibit patients or biological samples.
  • IRAK protein kinase preferably IRAK4
  • it can be used alone or in combination with other drugs.
  • the object of the present invention also includes providing a method for preventing and/or treating diseases, disorders or conditions mediated by IRAK4, which includes administering to the patient a preventive and/or therapeutically effective dose of a compound of the present invention or Its stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope labels or the pharmaceutical composition of the present invention.
  • the compounds of the present invention or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotope labels or the pharmaceutical compositions of the present invention are used in the prevention and/or treatment of IRAK4-mediated It may be used alone or in combination with other medicines to treat a disease, disorder or condition.
  • the object of the present invention also includes providing the compound of the present invention or its stereoisomer, optical isomer, pharmaceutically acceptable salt, prodrug, solvate or isotope label or the pharmaceutical composition of the present invention. , for the prevention and/or treatment of diseases, disorders or conditions mediated by IRAK4.
  • the disease, disorder or condition mediated by IRAK4 is cancer, neurodegenerative disease, viral disease, autoimmune disease, inflammatory disorder, genetic disorder, hormone-related disease, metabolic disease Disorders, conditions related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immunity involving T cell activation medical condition, cardiovascular disease, or central nervous system (CNS) disease disease.
  • cancer neurodegenerative disease, viral disease, autoimmune disease, inflammatory disorder, genetic disorder, hormone-related disease, metabolic disease Disorders, conditions related to organ transplantation, immunodeficiency disorders, destructive bone diseases, proliferative disorders, infectious diseases, conditions related to cell death, thrombin-induced platelet aggregation, liver disease, pathological immunity involving T cell activation medical condition, cardiovascular disease, or central nervous system (CNS) disease disease.
  • CNS central nervous system
  • the cancer includes: benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, gastric tumors, ovarian cancer, colon cancer, rectum Cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma Neoplasms, multiple myeloma, gastrointestinal cancer, colorectal adenomas, tumors of the neck and head, epidermal hyperplasia, prostatic hyperplasia, neoplasia, neoplasia with epithelial features, adenoma, adenocarcinoma, keratoacanthoma , epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lympho
  • the hematological malignancies include: leukemia, diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion Lymphoma, Burkitt's lymphoma/leukemia, acute lymphoblastic leukemia, B-cell prelymphoblastic leukemia, lymphoplasmacytic lymphoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma neoplasia, multiple myeloma, plasmacytoma or intravascular large B-cell lymphoma, Waldenström's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and indolent multiple Myeloma.
  • LLBCL diffuse large B-cell lymphoma
  • CLL chronic lymphocytic leukemia
  • chronic lymphocytic lymphoma primary effusion Lymphoma
  • the neurodegenerative diseases include: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia and those caused by traumatic injury, trough Neurodegenerative diseases caused by amino acid neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease;
  • the inflammatory disorders include: ocular allergies, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis; hemolytic anemia, aplastic anemia, pure red blood cell anemia, special Idiopathic thrombocytopenia or other diseases in which an autoimmune reaction is involved or has an autoimmune component or cause: systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's disease, dermatitis Myositis, chronic active hepatitis, myasthenia gravis, Steven Johnson syndrome, idiopathic steatorrhea, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome , Celiac disease, periodontitis, hyaline membrane disease, nephropathy, glomerular disease, alcoholic liver disease, endoc
  • the present invention also provides the following two general preparation methods of the compounds of the present invention:
  • compound I-a2 can be obtained;
  • compound I-a3 can be obtained;
  • compound I-a3 and carboxylic acid are used as basic raw materials, and compound I-a4 is obtained by reaction;
  • compound I-a4 reacts with Lawson's reagent to obtain compound I-a5;
  • compound I of the general formula can be obtained through reactions such as condensation and reductive amination.
  • compound I-b2 can be obtained;
  • compound I-b3 can be obtained;
  • compound I-b3 and pinacol borate are used as basic raw materials, and compound I-b4 is obtained by reaction;
  • compound I-b4 and I-b5 undergo a coupling reaction to obtain compound I-b6;
  • compound I of the general formula can be obtained through reactions such as condensation and reductive amination.
  • the present invention also provides compounds of formula (III) or their stereoisomers, optical isomers, pharmaceutically acceptable salts, prodrugs, solvates or isotopic labels that can be used as E3 ligands:
  • W, M 2 and M 3 are each independently selected from CH or N;
  • R 12 is selected from hydrogen, halogen (preferably F, Cl or Br), tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, -CH 2 -tert-butoxycarbonyl, -CH 2 COOH, - COC 1-3 alkyl or C 1-3 alkyl;
  • R 12 is selected from hydrogen, tert-butoxycarbonyl, benzyl, benzyloxycarbonyl, -CH 2 -tert-butoxycarbonyl, -CH 2 COOH, -COC 1-3 alkyl or C 1- 3 alkyl;
  • M 1 is selected from O or S
  • Ri is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, nitro, cyano, hydroxyl or methoxy.
  • the compound of formula (III) is a compound of formula (III'):
  • R 12 is selected from hydrogen, tert-butoxycarbonyl, -CH 2 -tert-butoxycarbonyl, -CH 2 COOH or -COCH 3 ;
  • W is selected from CH or N;
  • Ri is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, hydroxyl or methoxy.
  • the compound of formula (III) is a compound of formula (III") or a compound of formula (III"'):
  • W is selected from CH or N;
  • Ri is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, F, Cl, hydroxyl or methoxy.
  • R 12 is selected from hydrogen, tert-butoxycarbonyl, -CH 2 -tert-butoxycarbonyl, -CH 2 COOH or -COCH 3 .
  • R 13 is selected from hydrogen, halogen, amino, hydroxyl, tert-butoxycarbonyl, -CH 2 -tert-butoxycarbonyl, -NH-tert-butoxycarbonyl, -NH-benzyl, -NH-benzyloxycarbonyl, -CH 2 COOH, -COC 1-3 alkyl, C 1-3 alkyl, C 1-3 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 aryl, 5 -14-membered heteroaryl or 3-14-membered heterocyclyl;
  • W and M 4 are each independently selected from CH or N;
  • Rf is selected from hydrogen, methyl, ethyl, n-propyl or isopropyl.
  • the compound of formula (IV) is a compound of formula (IV'):
  • the compound of formula (IV) is selected from:
  • Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing 3 heteroatoms include, but are not limited to, triazacyclohexyl, oxadiazinyl, thiadiazinyl, oxothiazinyl, and dioxa Dioxazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azepanyl, oxpanyl, and thiepanyl.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, but are not limited to, tetrahydroquinolyl, tetrahydroisoquinolyl wait.
  • Exemplary structures of ring systems in which the heterocyclyl ring is fused with one or more carbocyclyl or heteroaryl groups include, but are not limited to, the following structures:
  • It preferably contains 3 to 14 ring atoms ("3-14 membered heterocycloalkyl”), more preferably contains 3 to 12 ring atoms (“3-12 membered heterocycloalkyl”), and further preferably contains 3 to 10 ring atoms.
  • Ring atoms ("3-10 membered heterocycloalkyl"), more preferably contain 3 to 8 ring atoms ("3-8 membered heterocycloalkyl"), or even more preferably contain 3 to 7 ring atoms ( "3-7 membered heterocycloalkyl"), or more preferably contains 4-8 ring atoms ("4-8 membered heterocycloalkyl"), or even more preferably contains 4-7 ring atoms ("4 -7-membered heterocycloalkyl”), or more preferably contains 5 to 10 ring atoms ("5-10 membered heterocycloalkyl"), or even more preferably contains 5 to 6 ring atoms ("5- 6-membered heterocycloalkyl”).
  • Heterocycloalkyl also includes bridged (“heterobridged cycloalkyl” or “bridged cycloheterocycloalkyl”) or spiro-fused (“heterospirocycloalkyl” or “spirocycloheterocycloalkyl”). ”) ring system, and may be saturated or partially unsaturated. Based on the above heterocycloalkyl, 7-9 membered heterocycloalkyl is preferred, and 7-membered heterocycloalkyl is further preferred. Examples Structures include but are not limited to the following structures:
  • aryl or "aromatic ring group” means a group containing 6 to 16 carbon atoms (C 6-16 aryl), or 6 to 14 carbon atoms (C 6-14 aryl), Or a monocyclic ring of 6-12 carbon atoms (C 6-12 aryl), or 6-10 carbon atoms (C 6-10 aryl), or 6-8 carbon atoms (C 6-8 aryl),
  • aryl may be used interchangeably with the term "aromatic ring”. Examples of aryl groups may include phenyl, naphthyl, anthracenyl, phenanthrenyl or pyrenyl, and the like.
  • alkenyl refers to a linear or branched monovalent unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond.
  • the alkenyl group may contain 2-20 carbon atoms, preferably 2-12 carbon atoms (i.e. C 2-12 alkenyl), more preferably 2-10 carbon atoms (i.e. C 2-10 alkenyl), further preferably Contains 2-8 carbon atoms (C 2-8 alkenyl), more preferably 2-6 carbon atoms (ie C 2-6 alkenyl), 2-5 carbon atoms (ie C 2-5 alkenyl ), 2-4 carbon atoms (i.e.
  • alkenyl means that the group is an alkenyl group and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6).
  • alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkylene (which is used interchangeably with “alkylene chain”) alone or in combination refers to a straight or branched divalent saturated hydrocarbon radical composed of carbon and hydrogen atoms. group.
  • Cx-y alkylene (x and y are each an integer) refers to a linear or branched alkylene group containing x to y carbon atoms, including C 1 - 30 alkylene, preferably C 1 -15 alkylene, C 1-12 alkylene, C 1-8 alkylene, C 1-6 alkylene, C 1-5 alkylene, C 1-4 alkylene, C 1-3 alkylene.
  • Representative examples include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, tert-butylene, pentylene, isopentylene , neopentylene, tepentylene, hexylene, heptylene, octylene, nonylene, decylene, undecylene, dodecylene, tridecylene, tenylene Tetraalkyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, hexadecyl, eicosyl Dialkyl, tritricoylene, tetradecylethylene, pentadecylethylene, hexadecylethylene, heptadecylethylene, octadecy
  • alkylene group is optionally substituted, and the substituent is preferably one or more selected from hydroxyl, amino, mercapto, halogen, cyano, C 1-3 alkyl, C 1- 3 Substituents of alkoxy, trifluoromethyl, heterocyclyl or combinations thereof.
  • alkynylene used alone or in combination refers to a group having one or more carbon-carbon triple bonds containing 2 to 12 (C 2-12 alkynylene), preferably 2 to 8 ( C 2-8 alkynylene), more preferably 2 to 6 (C 2-6 alkynylene), even more preferably 2 to 4 (C 2-4 alkynylene) carbon atoms in a straight or branched chain.
  • Valent hydrocarbon group examples include, but are not limited to, ethynylene, 1-propynylene, 1-butynylene, and 1,3-butadinylene.
  • alkenylene used alone or in combination refers to a group having one or more carbon-carbon double bonds containing 2 to 12 (C 2-12 alkenylene), preferably 2 to 8 ( C 2-8 alkenylene), more preferably 2 to 6 (C 2-6 alkenylene), even more preferably 2 to 4 (C 2-4 alkenylene) carbon atoms, straight or branched. Valent hydrocarbon group.
  • cycloalkenyl means composed of the subgroups monocyclic hydrocarbon ring, bicyclic hydrocarbon ring or spiro-hydrocarbon ring, however, the system is unsaturated, that is, there is at least one carbon-carbon double bond but no aromatic sex.
  • oxo or "oxo group” means that two H's at the same substitution position are replaced by the same O to form a double bond.
  • pharmaceutically acceptable salts and “pharmaceutically acceptable salts” refer to salts that are suitable for contact with mammalian (especially human) tissue without excessive toxicity, irritation, or allergy within the scope of reasonable medical judgment. Reactions, etc., and are commensurate with a reasonable benefit/risk ratio, such as pharmaceutically acceptable salts of amines, carboxylic acids, and other types of compounds are well known in the art.
  • solvate means the physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain circumstances, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, solvates will be able to be separated.
  • the solvent molecules in a solvate may exist in regular and/or disordered arrangements. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. "Solvate” encompasses both solution phase and isolable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methoxides, and isopropoxides. Solvation methods are well known in the art.
  • isotopically labeled analogue refers to a molecule in a compound that is isotopically labeled, thereby providing an isotopically labeled analogue that may have improved pharmacological activity.
  • Isotopes commonly used as isotope labels include: hydrogen isotopes: deuterium ( 2H ) and tritium ( 3H ); carbon isotopes: 11C , 13C and 14C ; chlorine isotopes: 35Cl and 37Cl ; fluorine isotopes: 18F ; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; Oxygen isotopes: 15 O, 17 O and 18 O; and, sulfur isotope 35 S.
  • isotopically labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues.
  • deuterium and carbon 13 C are more widely used because they are easy to label and detect.
  • Isotopically labeled compounds generally start from labeled starting materials and are synthesized using known synthetic techniques as for non-isotopically labeled compounds.
  • the compounds of the present invention include isotopic labels, such as deuterated compounds. In some embodiments of the invention, the isotopic label of the compound is its deuterated form.
  • optical isomers refers to substances with identical molecular structures and similar physical and chemical properties, but different optical rotations.
  • stereoisomer refers to compounds that have the same chemical structure but different arrangements of atoms or groups in space.
  • Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans) isomers, atropisomers, etc. Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography. method and/or fractional crystallization method.
  • the structural formulas described in the present invention include all isomeric forms (such as enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, those containing asymmetric centers R, S configuration, double bond (Z), (E) isomers, and (Z), (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the compounds of the present invention are within the scope of the present invention.
  • prodrug refers to a drug that is converted in the body to the parent drug.
  • Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. For example, they are bioavailable via oral administration, whereas the parent body is not.
  • Prodrugs also have increased solubility in pharmaceutical compositions compared to the parent drug.
  • An example of a prodrug, but not limited thereto, may be any compound of formula (I) administered as an ester ("prodrug") to facilitate delivery across cell membranes, where water solubility is detrimental to mobility, but Once the water-soluble substance is beneficial within the cell, it is subsequently metabolized and hydrolyzed into carboxylic acids, the active entities.
  • Another example of a prodrug may be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to reveal the active moiety.
  • the term "optionally substituted” means that the hydrogen at the substitutable position of the group is unsubstituted or substituted by one or more substituents, which substituents are preferably selected from the group consisting of: Group: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1- 6 alkoxy group, C 3-10 cycloalkyl group, C 3-10 cycloalkylsulfonyl group, 3-10 membered heterocycloalkyl group, C 6-14 aryl group or 5-10 membered heteroaryl ring group, wherein, The C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cycloalkylsulfonyl, 3 -10-membered
  • the starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.
  • Step 1 Synthesis of methyl 6-chloro-4-(methylamino)nicotinate
  • Step 2 Synthesis of 6-chloro-4-(methylamino)nicotinic acid hydrazide
  • Step 3 Synthesis of tert-butyl ((1r,4r)-4-(2-(6-chloro-4-(methylamino)nicotinoyl)hydrazinecarbonyl)cyclohexyl)carbamate
  • Step 4 tert-Butyl((1r,4r)-4-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl) )Synthesis of cyclohexyl)carbamate
  • reaction system was poured into water (500 mL), extracted with DCM (400 mL ⁇ 4), and the combined organic phases were washed with saturated sodium chloride water (500 mL), dried over anhydrous sodium sulfate, and spun to dryness to obtain crude product. Beat with EA to obtain tert-butyl ((1r,4r)-4-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazole-2) -(yl)cyclohexyl)carbamate (7.00g).
  • Step 1 Synthesis of tert-butyl 4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(piperazin-1-yl)isoindoline-1,3-dione
  • Step 3 tert-Butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazine-1 -Synthesis of acetate
  • Step 4 Synthesis of 2-(4-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetic acid
  • Step 1 Synthesis of tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate
  • reaction solution was filtered through Celite, the filter cake was rinsed with ethyl acetate (100 mL), and the filtrate was concentrated under reduced pressure to obtain tert-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate. (9.20g).
  • Step 2 Synthesis of 3-((6-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyridin-3-yl)amino)propionic acid
  • Step 3 Synthesis of 1-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 1 Synthesis of tert-butyl (1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidin-4-yl)carbamate
  • Step 4 tert-Butyl(1-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-4-yl )Synthesis of urethane
  • Step 2 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)piperidine-4-carboxylic acid
  • Step 2 tert-Butyl 1-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yne-1 Synthesis of -yl)piperidine-4-carboxylate
  • 1-Boc-4-piperidinecarboxylic acid (0.69g, 3.0mmol) and N,N-dimethylformamide (10mL) were added to a 50mL reaction bottle.
  • 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.48g, 3.9mmol)
  • N,N-di Isopropylethylamine (1.16g, 9.0mmol).
  • 6-chloro-4-(methylamino)nicotinic acid hydrazide (0.60g, 3.0mmol) was added.
  • the reaction system was raised to room temperature and reacted for 3 hours.
  • Step 3 tert-Butyl 4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridin-3-yl Synthesis of )-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate
  • ESI-MS(m/z):517.11[M+H] + .
  • Step 3 Synthesis of 1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indole-6-carbaldehyde
  • Step 4 tert-Butyl 1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl )Methyl)piperidine-4-carboxylate synthesis
  • Step 5 1-((1-(2,6-dioxopiperidin-3-yl)-2-oxo-1,2-dihydrobenzo[cd]indol-6-yl)methyl )Synthesis of piperidine-4-carboxylic acid
  • Step 1 Synthesis of tert-butyl 2-(5-bromo-1,3,4-thiadiazol-2-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate
  • Step 1 tert-Butyl((1r,4r)-4-(5-(6-(4-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamine) Synthesis of (yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)carbamate
  • Step 2 1-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine-2 Synthesis of -yl)-1H-pyrrolo[2,3-b]pyridine-4-nitrile
  • Step 1 tert-Butyl(S)-10-bromo-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -3(4H)-carboxylic acid ester
  • Step 2 tert-Butyl(S)-10-methyl-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxane Synthesis of oxazine-3(4H)-carboxylate
  • Step 3 tert-Butyl(S)-8-amino-10-methyl-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -3(4H)-carboxylic acid ester
  • Step 4 (S)-3-((3-(tert-butoxycarbonyl)-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2 -Synthesis of [1,4]oxazin-8-yl)amino)propionic acid
  • Step 5 (S)-1-(3-acetyl-10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1 ,Synthesis of 4]oxazin-8-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 6 (S)-1-(10-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -8-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 7 tert-Butyl(S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydro Synthesis of benzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetate
  • Step 8 (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-10-methyl-1,2,4a,5-tetrahydrobenzo[ Synthesis of b]pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetic acid
  • Step 1 Synthesis of tert-butyl (S)-4-(2-fluoro-4-nitrophenyl)-3-(hydroxymethyl)piperazine-1-carboxylate
  • Step 2 tert-Butyl(S)-8-nitro-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H )-Synthesis of carboxylic acid esters
  • Step 3 tert-Butyl(S)-8-amino-1,2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H) -Synthesis of carboxylic acid esters
  • Step 4 (S)-3-((3-(tert-butoxycarbonyl)-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][ Synthesis of 1,4]oxazin-8-yl)amino)propionic acid
  • Step 5 (S)-1-(3-acetyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -8-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 6 (S)-1-(1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazin-8-yl) Synthesis of dihydropyrimidine-2,4(1H,3H)-dione
  • Step 7 tert-Butyl(S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b] Synthesis of pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetate
  • Step 8 (S)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1,2,4a,5-tetrahydrobenzo[b]pyrazine[ Synthesis of 1,2-d][1,4]oxazin-3(4H)-yl)acetic acid
  • step 2 to step 4 The operations from step 2 to step 4 are the same as steps 2 to step 4 in Intermediate Preparation Example 2 to obtain 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-di Oxoisoindoline-5-carbonyl)piperazin-1-yl)acetic acid (0.68 g).
  • Step 1 Synthesis of di-tert-butyl 2-(4-(methoxycarbonyl)-3-methylphenyl)malonate
  • Step 3 Synthesis of methyl 4-(2-(benzyloxy)-2-oxyethyl)-2-methyl benzoate
  • Step 4 Synthesis of methyl 4-(2-(benzyloxy)-2-oxyethyl)-2-(bromomethyl)benzoate
  • Step 5 Synthesis of benzyl 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetate
  • Step 6 Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)acetic acid:
  • Step 3 tert-Butyl 3-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridin-3-yl) Synthesis of -1,3,4-thiadiazol-2-yl)pyrrolidine-1-carboxylate
  • the reaction solution was lowered to room temperature, poured into water (100 mL), and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • Step 4 1-(4-(methylamino)-5-(5-(pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)-1H- Synthesis of pyrrolo[2,3-b]pyridine-5-nitrile
  • reaction solution was directly concentrated under reduced pressure to obtain crude product -(4-(methylamino)-5-(5-(pyrrolidin-3-yl)-1,3,4-thiadiazol-2-yl)pyridine-2- methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (0.80 g).
  • Step 1 Synthesis of tert-butyl 3-(2-(6-chloro-4-(methylamino)nicotinoyl)hydrazinecarbonyl)azetidine-1-carboxylate
  • Step 2 tert-Butyl 3-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)azetidine-1 -Synthesis of carboxylic acid esters
  • Step 1 Synthesis of 6-chloro-4-((methyl-d 3 )amino)nicotinic acid methyl ester
  • Step 2 Synthesis of 6-chloro-4-((methyl-d 3 )amino)nicotinic acid hydrazide
  • N,N-dimethylformamide 100 mL
  • 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate 11.93g, 31.38mmol
  • N,N-diisopropylethylamine 11.06g, 85.59mmol
  • Step 5 Methyl(1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-((methyl- d 3 ) Synthesis of amino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexane-1-carboxylate
  • the reaction system was heated to 130°C under nitrogen protection for microwave reaction for 1.5 h.
  • LCMS confirmed the end of the reaction.
  • the reaction solution was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (100mL). The organic phase was collected and poured into water (200mL). The organic phase was separated. The water phase was continued to be washed with ethyl acetate (50mL). ⁇ 4) Extraction, combine the organic phases, wash twice with saturated sodium chloride aqueous solution (100 mL), dry, and concentrate to dryness under reduced pressure.
  • Step 6 1-(5-(5-((1r,4r)-4-(hydroxymethyl)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-((methyl -d 3 ) Synthesis of amino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile
  • Step 7 1-(5-(5-((1r,4r)-4-formylcyclohexyl)-1,3,4-thiadiazol-2-yl)-4-((methyl-d3) Synthesis of amino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile
  • Step 1 Synthesis of 1-(5-nitropyrimidin-2-yl)piperidine-4-carboxylic acid tert-butyl ester
  • Step 2 Synthesis of tert-butyl 1-(5-aminopyrimidin-2-yl)piperidine-4-carboxylate
  • Step 3 Synthesis of 3-((2-(4-(tert-butoxycarbonyl)piperidin-1-yl)pyrimidin-5-yl)amino)propionic acid
  • Step 4 Synthesis of tert-butyl 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrimidin-2-yl)piperidine-4-carboxylate
  • Step 5 Synthesis of 1-(5-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid
  • Step 2 Synthesis of: (1r,4r)-4-((tert-butoxycarbonyl)(methyl-d 3 )amino)cyclohexane-1-carboxylic acid methyl ester
  • Step 1 Synthesis of tert-butyl 4-(3-bromo-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate
  • Tetrahydrofuran 75 mL was added to 2-bromo-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (5.00 g, 12.98 mmol) under nitrogen. After the reaction solution is cooled to -78°C, methyllithium (1.6M) (8.1mL, 12.98mmol) is slowly added dropwise. After the dropwise addition is completed, stir at -78°C for 30 minutes, and then n-butyllithium (2.5M) is added dropwise. (6.2 ml, 15.50 mmol) and continued stirring for 30 minutes.
  • N,N-dimethylformamide (2.85g, 38.94mmol) was added dropwise at -78°C, and the reaction was stirred at -78°C for 1 hour.
  • the reaction solution was slowly raised to room temperature, and stirring was continued for 1 hour.
  • LCMS detects that the reaction is complete. Slowly pour the reaction solution into saturated ammonium chloride solution (30mL) to quench, adjust the pH of the reaction solution to 4-5 with 2N dilute hydrochloric acid, and then extract with ethyl acetate (100mL x 3).
  • the organic phase is added with water (100mL) and Wash once with brine (100 mL), dry the organic phase over anhydrous sodium sulfate and concentrate to dryness under reduced pressure to obtain crude 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-formylbenzoic acid. .
  • Step 4 Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(((2,6-dioxopiperidin-3-yl)amino)methyl)benzoic acid
  • Step 5 Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazine-1-carboxylate
  • Step 2 Synthesis of methyl 2-(bromoethyl)-4,5-difluoromethyl benzoate
  • Step 2 tert-Butyl 4-(3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H- Synthesis of benzo[d]imidazol-4-yl)piperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl 4-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperazine-1-carboxylate
  • the filtrate is concentrated to dryness under reduced pressure.
  • Step 5 (R)-3-((3-(tert-butoxycarbonyl)-7-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2 -Synthesis of [1,4]oxazin-9-yl)amino)propionic acid
  • Step 6 (R)-1-(3-acetyl-7-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1 ,Synthesis of 4]oxazin-9-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 7 (R)-1-(7-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -9-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 8 tert-butyl(R)-2-(9-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-7-methyl-1,2,4a,5-tetrahydrobenzene Synthesis of pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetate
  • Step 9 (R)-1-(7-methyl-1,2,3,4,4a,5-hexahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine Synthesis of -9-yl)dihydropyrimidine-2,4(1H,3H)-dione
  • Step 2 Synthesis of tert-butyl 2-(hydroxymethyl)-7-azaspiro[3.5]nonane-7-carboxylate
  • Example 1 N-((1r,4r)-4-(5-(6-(5-cyano-1H-indol-1-yl)-4-(methylamino)pyridin-3-yl)- 1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoiso Synthesis of indolin-5-yl)piperazin-1-yl)acetamide (compound 1)
  • reaction system was reacted at 105°C for 16 hours under nitrogen protection. After the reaction was detected by LCMS, the reaction solution was cooled to room temperature, then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate. The filtrate was collected, and the solvent was concentrated under reduced pressure to dryness.
  • Step 2 1-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine-2- Synthesis of -1H-indole-5-nitrile
  • Step 3 N-((1r,4r)-4-(5-(6-(5-cyano-1H-indol-1-yl)-4-(methylamino)pyridin-3-yl)-1 ,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindole Synthesis of Dolin-5-yl)piperazin-1-yl)acetamide
  • Example 4 Referring to the preparation method of Example 4, only 5-cyanoindole in Example 4 was replaced by 7H-pyrrolo[2,3-d]pyrimidine to obtain 2-(4-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoindolin-5-yl)piperazin-1-yl)-N-((1r,3r)-3-(5-(4- (Methylamino)-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclobutyl) Acetamide (80 mg). ESI-MS(m/z):761.19[M+H] + .
  • Example 7 N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine -3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1 ,Synthesis of 2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetamide (compound 7)
  • Step 1 7-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine-2- Synthesis of pyrrolo[1,2-b]pyridazine-3-nitrile:
  • Step 2 N-((1r,4r)-4-(5-(6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-4-(methylamino)pyridine- 3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(8-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1, Synthesis of 2,4a,5-tetrahydrobenzo[b]pyrazine[1,2-d][1,4]oxazine-3(4H)-yl)acetamide:
  • Example 8 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-(4-(2,4-dioxotetrahydropyrimidine-1(2H)) Synthesis of -yl)phenyl)piperazin-1-yl)acetamide (compound 8)
  • Example 10 N-((1r,4r)-4-(5-(6-(5-cyano-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl )-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-(2-(2,6-dioxopiperyl) Synthesis of (din-3-yl)-1,3-dioxoisoindolin)-5-yl)piperazin-1-yl)acetamide (compound 10)
  • Example 12 1-(5-(5-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindole Phin-5-yl)piperazin-1-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)-1,3,4-thiadiazol-2-yl)-4 Synthesis of -(methylamino)pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (compound 12)
  • Example 13 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-(2-(2,6-dioxopiperidin-3-yl)- Synthesis of 6-fluoro-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetamide (compound 13)
  • Example 14 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-6-(2-((2-(2,6-dioxopiperidin-3-yl) Synthesis of -1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-azaspiro[3.3]heptane-2-carboxamide (compound 14)
  • Step 1 1-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine-2- Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • Step 2 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) Pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-6-(2-((2-(2,6-dioxopiperidin-3-yl)- Synthesis of 1,3-dioxoisoindolin-4-yl)amino)ethyl)-2-azaspiro[3.3]heptane-2-carboxamide
  • Example 16 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Synthesis of dioxoisoindolin-4-yl)piperidine-4-carboxamide (compound 16)
  • Example 17 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-1-(2-(2,6-dioxopiperidin-3-yl)-1,3 -Synthesis of dioxoisoindolin-5-yl)piperidine-4-carboxamide (compound 17)
  • Step 1 tert-Butyl 4-(4-(5-(6-(6-cyanopyrazolo[1,5-a]pyrimidin-3-yl)-4-(isopropylamine)pyridine-3- Synthesis of (yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carbonyl)piperidine-1-carboxylate
  • Step 2 3-(4-(isopropylamino)-5-(5-(4-(piperidin-4-carbonyl)piperazin-1-yl)-1,3,4-thiadiazole-2 Synthesis of -yl)pyridin-2-yl)pyrazole[1,5-a]pyrimidine-6-nitrile
  • Step 3 3-(5-(5-(4-(1-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4- (yl)piperidin-4-carbonyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(isopropylamino)pyridin-2-ylpyrazolo[1 ,Synthesis of 5-a]pyrimidine-6-nitrile
  • reaction solution was reacted at 90°C for 3 hours.
  • LCMS monitors that the reaction is completed.
  • the reaction solution is cooled to 0°C, H 2 O (15 mL) is added to quench the reaction, ethyl acetate is added to extract three times, and washed three times with water and saturated sodium chloride aqueous solution.
  • the organic phase is added to anhydrous sodium sulfate.
  • Step 1 3-(3-methyl-2-oxo-4-(3-(piperidin-4-yloxy)prop-1-yn-1-yl)-2,3-dihydro-1H -Synthesis of benzo[d]imidazol-1-yl)piperidine-2,6-dione
  • Step 2 tert-Butyl 2-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro) Synthesis of -1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)acetate
  • Step 3 2-(4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H- Synthesis of benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)acetic acid
  • Step 4 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) Pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(4-((3-(1-(2,6-dioxopiperidine-3- yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidine-1 -Acetamide synthesis
  • Example 20 1-(5-(5-(2-(2-(4-(2-(2,6-dioxopiperidin-3-yl))-6-fluoro-1,3-dioxo Isoindolin-5-yl)piperazin-1-yl)acetyl)-2-azaspiro[3.3]heptan-6-yl)-1,3,4-thiadiazol-2-yl) Synthesis of -4-(methylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile (compound 50)
  • the 5-cyanoindole in step 1 of Example 1 is replaced with 5-cyano-7-azaindole, and the 2-(4-(2,6-dioxanol) in step 3 Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetic acid crude product was replaced with 2-(4-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindoline-5-carbonyl)piperazin-1-yl)acetic acid crude product to obtain N-((1r,4r)-4-(5 -(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazole -2-yl)cyclohexyl)-2-(2-(2,6-dioxopiperidin
  • Example 22 N-((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(7-(2-(2,6-dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl) Synthesis of Acetamide (Compound 52)
  • the 5-cyanoindole in step 1 of Example 1 is replaced with 5-cyano-7-azaindole, and the 2-(4-(2,6-dioxanol) in step 3 Piperidin-3-yl)-1,3-dioxoisoindolin-5-yl)piperazin-1-yl)acetic acid crude product was replaced with 2-(7-(2-(2,6-di Oxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2,7-diazaspiro[3.5]nonan-2-yl)acetic acid crude product, N -((1r,4r)-4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridine-3- yl)-1,3,4-thiadiazol-2-yl)cyclohexyl)-2-(7-(2-
  • Example 23 1-(5-(5-(1-(2-(4-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindoline-5 -yl)piperazin-1-yl)acetyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)- Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-nitrile (compound 53)
  • Step 1 1-(4-(methylamino)-5-(5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl)pyridin-2-yl)-1H -Synthesis of pyrrolo[2,3-b]pyridine-5-nitrile
  • Step 2 tert-Butyl 4-(2-(4-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino) Synthesis of )pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidin-1-yl)-2-oxoethyl)piperazine-1-carboxylate
  • Step 3 1-(4-(methylamino)-5-(5-(1-(2-(piperazin-1-yl)acetyl)piperidin-4-yl)-1,3,4- Synthesis of thiadiazol-2-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • Step 4 1-(5-(5-(1-(2-(4-((1-(2,6-dioxopiperidin-3-yl))-2-oxo-1,2-di Hydrobenzo[cd]indol-6-yl)methyl)piperazin-1-yl)acetyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-4 Synthesis of -(methylamino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • Example 26 1-(5-(5-((1r,4r)-4-(((1-(2-(2,6-dioxopiperidin-3-yl))-1,3-di Oxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine Synthesis of -2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile (compound 61)
  • Step 1 1-(5-(5-((1r,4r)-4-aminocyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine-2- Synthesis of 1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • Step 2 1-(5-(5-((1r,4r)-4-(((1-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxo Isoindolin-5-yl)piperidin-4-yl)methyl)amino)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine- Synthesis of 2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • Example 27 1-(5-(5-((1r,4r)-4-(((1-(2-(2,6-dioxopiperidin-3-yl))-6-fluoro-1 ,3-Dioxoisoindolin-5-yl)piperidin-4-yl)methyl)amino)cyclohexyl)-1,3,4-thiadiazol-2-yl)-4-(methyl Synthesis of amino)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile (compound 65)
  • Example 28 1-(5-(5-(1-(2-(4-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindole Phin-5-yl)piperazin-1-yl)acetyl)azetidin-3-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridine- Synthesis of 2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile (compound 68)
  • Step 1 Synthesis of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
  • the reaction solution was concentrated to dryness under reduced pressure, water (20mL) was added to the concentrate, and extracted with ethyl acetate (20mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • Step 2 Synthesis of tert-butyl 4-(1-(5-bromo-1,3,4-thiadiazol-2-yl)piperidin-4-yl)piperazine-1-carboxylate
  • the concentrate was purified by preparative thin layer plate (ethyl acetate) to obtain tert-butyl 4-(1-(5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazole- 2-yl)piperidin-4-yl)piperazine-1-carboxylate (70.0 mg, 31.5%).
  • Step 4 tert-Butyl 4-(1-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)piperidine-4 Synthesis of -yl)piperazine-1-carboxylate
  • the reaction solution was poured into water (20 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • the concentrate was purified using thin layer preparative plate (ethyl acetate) to give tert-butyl 4-(1-(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thi Diazol-2-yl)piperidin-4-yl)piperazine-1-carboxylate (100.0 mg, 47.0%).
  • Step 5 tert-Butyl 4-(1-(5-(6-(5-cyano-1H-pyrrolo[2,3-b]pyridin-1-yl)-4-(methylamino)pyridine-3) Synthesis of -1,3,4-thiadiazol-2-yl)piperidin-4-yl)piperazine-1-carboxylate
  • reaction system was raised to 100°C and reacted under nitrogen protection for 16 hours. LCMS showed the reaction was complete. After the reaction solution cooled to room temperature, it was poured into water (30mL) and extracted with ethyl acetate (15mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure.
  • Step 6 1-(4-(methylamino)-5-(5-(4-(piperazin-1-yl)piperidin-1-yl)-1,3,4-thiadiazol-2-yl) Synthesis of )pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-nitrile
  • reaction solution was concentrated to dryness under reduced pressure to obtain 1-(4-(methylamino)-5-(5-(4-(piperazin-1-yl)piperidin-1-yl)-1,3,4-thi Diazol-2-yl)pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (80.0 mg, crude product) and used directly in the next reaction.
  • Step 7 1-(5-(5-(4-(4-(2-(2,6-dioxopiperidin-3-yl))-1,3-dioxoisoindoline-5- Carbonyl)piperazin-1-yl)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)-4-(methylamino)pyridin-2-yl)-1H-pyrrolo[ Synthesis of 2,3-b]pyridine-5-nitrile

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Abstract

L'invention concerne un composé hétérocyclique chimérique bifonctionnel de la kinase 4 associée au récepteur de l'interleukine-1 (IRAK4) représenté par la formule (I), son procédé de préparation, une composition pharmaceutique de celui-ci et une utilisation associée. Le composé recrute IRAK4 en ubiquitine ligases, favorisant ainsi l'ubiquitination d'IRAK4 et la dégradation d'IRAK4 par des protéasomes. Des résultats de recherche montrent que le composé a une activité de dégradation d'IRAK4 relativement bonne et peut ainsi être utilisé pour traiter des maladies médiées par IRAK4.
PCT/CN2023/085387 2022-03-31 2023-03-31 Composé hétérocyclique chimérique bifonctionnel de la kinase 4 associée au récepteur de l'interleukine-1, son procédé de préparation, composition pharmaceutique de celui-ci et utilisation associée Ceased WO2023186069A1 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
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WO2024015340A1 (fr) * 2022-07-12 2024-01-18 Regents Of The University Of Michigan Ligands de céréblon et leurs utilisations
WO2024056005A1 (fr) * 2022-09-14 2024-03-21 先声再明医药有限公司 Composé polycyclique et utilisation correspondante
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2024240268A1 (fr) * 2023-05-25 2024-11-28 甘李药业股份有限公司 Inhibiteur de l'ubiquitine ligase e3 de la protéine cérébelleuse et composé chimérique ciblant la dégradation des protéines
WO2024245331A1 (fr) * 2023-05-30 2024-12-05 上海汇伦医药股份有限公司 Composé tricyclique, son procédé de préparation et son utilisation
CN119684303A (zh) * 2023-12-28 2025-03-25 上海超阳药业有限公司 一种双功能可降解雄激素受体的杂环化合物及其应用
WO2025098503A1 (fr) * 2023-11-08 2025-05-15 甘李药业股份有限公司 Inhibiteur de l'ubiquitine ligase e3 céréblon
WO2025149070A1 (fr) * 2024-01-10 2025-07-17 甘李药业股份有限公司 Synthèse et utilisation d'un nouveau composé chimère de protéolyse ciblant la kinase 4 associée au récepteur de l'interleukine-1 (irak4)

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CN112566915A (zh) * 2018-08-13 2021-03-26 吉利德科学公司 噻二唑irak4抑制剂
WO2021168197A1 (fr) * 2020-02-19 2021-08-26 Nurix Therapeutics, Inc. Agents de dégradation bifonctionnels de kinases associées au récepteur de l'interleukine-1 et leur utilisation thérapeutique
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12097261B2 (en) 2021-05-07 2024-09-24 Kymera Therapeutics, Inc. CDK2 degraders and uses thereof
WO2024015340A1 (fr) * 2022-07-12 2024-01-18 Regents Of The University Of Michigan Ligands de céréblon et leurs utilisations
WO2024056005A1 (fr) * 2022-09-14 2024-03-21 先声再明医药有限公司 Composé polycyclique et utilisation correspondante
WO2024240268A1 (fr) * 2023-05-25 2024-11-28 甘李药业股份有限公司 Inhibiteur de l'ubiquitine ligase e3 de la protéine cérébelleuse et composé chimérique ciblant la dégradation des protéines
WO2024245331A1 (fr) * 2023-05-30 2024-12-05 上海汇伦医药股份有限公司 Composé tricyclique, son procédé de préparation et son utilisation
WO2025098503A1 (fr) * 2023-11-08 2025-05-15 甘李药业股份有限公司 Inhibiteur de l'ubiquitine ligase e3 céréblon
CN119684303A (zh) * 2023-12-28 2025-03-25 上海超阳药业有限公司 一种双功能可降解雄激素受体的杂环化合物及其应用
WO2025149070A1 (fr) * 2024-01-10 2025-07-17 甘李药业股份有限公司 Synthèse et utilisation d'un nouveau composé chimère de protéolyse ciblant la kinase 4 associée au récepteur de l'interleukine-1 (irak4)

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