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WO2025077891A1 - Composé d'agent de dégradation ciblant irak4, et son utilisation - Google Patents

Composé d'agent de dégradation ciblant irak4, et son utilisation Download PDF

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Publication number
WO2025077891A1
WO2025077891A1 PCT/CN2024/124493 CN2024124493W WO2025077891A1 WO 2025077891 A1 WO2025077891 A1 WO 2025077891A1 CN 2024124493 W CN2024124493 W CN 2024124493W WO 2025077891 A1 WO2025077891 A1 WO 2025077891A1
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alkyl
cycloalkyl
membered
compound
optionally substituted
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Chinese (zh)
Inventor
古鹏
梁倩倩
王梦妤
赵晓峰
王鑫
刘乐
周旻昀
唐锋
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Jiangsu Simcere Pharmaceutical Co Ltd
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Jiangsu Simcere Pharmaceutical Co Ltd
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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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

  • Patent application No. 202311332090.X filed with the State Intellectual Property Office on October 13, 2023, and
  • Patent application No. 202410038862.7 submitted to the State Intellectual Property Office on January 10, 2024.
  • the present disclosure relates to a compound or a pharmaceutically acceptable salt thereof as an IRAK4 degrader, a method for preparing the same, a pharmaceutical composition containing the same, and use of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preventing or treating a disease or condition mediated by IRAK4.
  • Interleukin-1 receptor kinase 4 is a serine/threonine protein kinase, a core regulator of innate immune response, and plays an important role in activating the immune system. IL-1 receptors and Toll-like receptors are activated after binding to their ligands, and then recruit intracellular myeloid differentiation factor MyD88. MyD88 further recruits IRAK4 through its N-terminal death domain.
  • IRAK4 recruits and activates IRAK1 and IRAK2 to form a MyD88-IRAK4-IRAK1/2 complex, which transmits signals downstream to the E3 ubiquitin ligase TNF receptor-associated factor (TRAF6), activates the serine/threonine kinase TAK1, and further activates the NF- ⁇ B and MAPK signaling pathways, causing the release of a variety of inflammatory cytokines and proliferation-related factors.
  • TNF receptor-associated factor ubiquitin ligase TNF receptor-associated factor
  • TAK1 serine/threonine kinase TAK1
  • NF- ⁇ B and MAPK signaling pathways causing the release of a variety of inflammatory cytokines and proliferation-related factors.
  • overactivation of IRAK4 is associated with a variety of autoimmune diseases, such as atopic dermatitis, suppurative hidradenitis, and rheumatoid arthritis.
  • the scaffold function of IRAK4 can also regulate downstream signaling pathways, and is independent of its kinase function.
  • Proteolysis Targeting Chimeria is a bifunctional molecule, one end of which is a small molecule inhibitor that recognizes the target protein through a linker, and the other end is an E3 ubiquitin ligase ligand that can recognize E3 ubiquitin ligase, thereby forming a ternary complex. After the target protein is ubiquitinated, it is degraded in vivo through the ubiquitin-proteasome pathway.
  • IRAK4 small molecule inhibitors can only block the kinase activity of IRAK4, while IRAK4 PROTAC can degrade intracellular IRAK4, thereby simultaneously blocking the biological activity of IRAK4 kinase activity and scaffold function, and more effectively inhibiting the release of downstream inflammatory factors mediated by IRAK4. Therefore, it is necessary to develop new IRAK4 PROTAC drugs for the treatment of diseases or conditions related to IRAK4.
  • the present disclosure relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • the DIM is a ligand compound capable of binding to E3 ubiquitin ligase
  • the Linker is a linking group that covalently binds at least one TL and at least one DIM;
  • the TL is a group as shown below:
  • a 1 , A 2 , A 3 are independently selected from CR 3 or N;
  • B 1 is selected from S, O or CR 4 ;
  • B 2 is selected from N or C
  • B3 is selected from N or NH
  • R 1 is selected from C 3 -C 6 cycloalkyl, C 5 -C 10 cycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl, C 5 -C 10 cycloalkenyl, C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-14 membered heterocyclyl is optionally substituted with one or more Ra;
  • R 2 is selected from H, C 3 -C 10 cycloalkyl, 4-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6 -C 10 aryl, wherein the C 3 -C 10 cycloalkyl, 4-14 membered heterocyclyl, 5-10 membered heteroaryl or C 6 -C 10 aryl is optionally substituted with one or more R b ;
  • R 3 and R 4 are independently selected from H, deuterium, halogen, CN, NO 2 , OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, wherein the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl are optionally substituted by one or more R c ;
  • R 1a , R 2a , R b , R c are independently selected from deuterium, halogen, OH, CN, NH 2 , ⁇ O, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl, wherein the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more R d ;
  • R d is selected from deuterium, halogen, OH, NH 2 , ⁇ O, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, CN, COOH, C(O)(C 1 -C 3 alkyl), CONH 2 , C(O)O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl or 4-6 membered heterocyclyl.
  • a 1 , A 2 , A 3 are independently selected from CR 3 or N, and R 3 is selected from H, deuterium, halogen, CN, OH or C 1 -C 4 alkyl, and the OH or C 1 -C 4 alkyl is optionally substituted with one or more R c .
  • a 1 , A 2 , A 3 are independently selected from CH or N.
  • a 1 , A 2 , and A 3 are all CR 3 , and R 3 is independently selected from H, deuterium, halogen, CN, OH, or C 1 -C 4 alkyl, and the OH or C 1 -C 4 alkyl is optionally substituted with one or more R c .
  • a 1 , A 2 , and A 3 are all CR 3 , and R 3 is selected from H or OH optionally substituted with one R c .
  • R c is selected from deuterium, halogen, OH, CN, NH 2 , ⁇ O, or C 1 -C 6 alkyl, wherein the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted with one or more R d .
  • R c is selected from C 1 -C 6 alkyl optionally substituted with one or more R d . In some embodiments, R c is selected from C 1 -C 6 alkyl optionally substituted with one or more OH.
  • R c is selected from isopropyl or isobutyl optionally substituted with one or more R d .
  • R c is selected from isopropyl or In some embodiments, R c is selected from isopropyl.
  • a 1 and A 3 are both CH, and A 2 is C—OCH(CH 3 ) 2 or C—OCH 2 C(CH 3 ) 2 OH.
  • a 1 and A 3 are both CH, and A 2 is C—OCH(CH 3 ) 2 .
  • B 1 is selected from S, O or CR 4 , said R 4 is selected from H, deuterium, halogen, CN, OH or C 1 -C 4 alkyl, said OH or C 1 -C 4 alkyl is optionally substituted with one or more R c .
  • B 1 is selected from S, O or CH.
  • B 1 is selected from S or O.
  • B 1 is S.
  • B2 is C.
  • B3 is N.
  • B2 is C and B3 is N.
  • B 1 is selected from S or O, B 2 is C, and B 3 is N. In some embodiments, B 1 is S, B 2 is C, and B 3 is N.
  • R 1 is selected from C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with one or more Ra .
  • R 1 is selected from C 6 -C 10 aryl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the C 6 -C 10 aryl, 5-10 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with one or more Ra .
  • R 1 is selected from the following groups optionally substituted with one or more Ra : pyridyl, pyridonyl,
  • R 1 is selected from the following groups optionally substituted with one or more Ra : pyridyl, pyridonyl or
  • R 1 is selected from the following groups optionally substituted with one or more Ra : pyridone or
  • R 1 is selected from pyridonyl optionally substituted with one or more Ra .
  • R 1a is selected from deuterium, halogen, OH, CN, NH 2 , ⁇ O or C 1 -C 6 alkyl, wherein the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted with one or more R d .
  • R 1a is selected from deuterium or halogen.
  • R 1a is selected from halogen, such as fluorine.
  • R is selected from
  • R is selected from In some embodiments, R is selected from
  • R 1 is In some embodiments, R 1 is
  • R 2 is selected from H, C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or C 6 -C 10 aryl, and the C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or C 6 -C 10 aryl is optionally substituted with one or more R b .
  • R 2 is selected from H, C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl, wherein the C 3 -C 6 cycloalkyl, 4-8 membered heterocyclyl, 5-6 membered heteroaryl or phenyl is optionally substituted with one or more R b .
  • R 2 is selected from H, C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl, wherein the C 3 -C 6 cycloalkyl or 4-8 membered heterocyclyl is optionally substituted by one or more R b .
  • R 2 is selected from H, C 6 cycloalkyl or 6-8 membered heterocyclyl containing 1-3 nitrogen atoms, wherein the C 6 cycloalkyl or 6-8 membered heterocyclyl containing 1-3 nitrogen atoms is optionally substituted by one or more R b .
  • R 2 is selected from H, C 6 cycloalkyl or 6-8 membered heterocycloalkyl containing 1-3 nitrogen atoms, and the C 6 cycloalkyl or 6-8 membered heterocycloalkyl containing 1-3 nitrogen atoms is optionally substituted by one or more R b .
  • R 2 is selected from H, cyclohexyl, piperidinyl, piperazinyl or The cyclohexyl, piperidinyl, piperazinyl or Optionally substituted with one or more R b .
  • R 2 is selected from H, cyclohexyl, piperidinyl, or piperazinyl, which is optionally substituted with one or more R b .
  • R b is selected from halogen, OH, CN, NH 2 , ⁇ O, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl, wherein the OH, NH 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl is optionally substituted with one or more R d .
  • R b is selected from halogen, OH, NH 2 , or C 1 -C 6 alkyl, which OH, NH 2 , or C 1 -C 6 alkyl is optionally substituted with one or more R d .
  • R b is selected from C 1 -C 4 alkyl optionally substituted with one or more R d . In some embodiments, R b is methyl.
  • R 1a , R 2a are independently selected from deuterium, halogen, OH, CN, NH 2 , ⁇ O, or C 1 -C 6 alkyl, wherein the OH, NH 2 or C 1 -C 6 alkyl is optionally substituted with one or more R d .
  • R 1a , R 2a are independently selected from deuterium, halogen, OH, ⁇ O, or C 1 -C 6 alkyl, wherein the OH, C 1 -C 6 alkyl is optionally substituted with one or more R d .
  • R d is selected from halogen, OH, NH 2 , ⁇ O, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C(O)(C 1 -C 3 alkyl), CONH 2 , C(O)O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl.
  • R d is selected from halogen, OH, NH 2 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C(O)(C 1 -C 3 alkyl), CONH 2 , C(O)O(C 1 -C 3 alkyl), C 3 -C 6 cycloalkyl, or 4-6 membered heterocyclyl.
  • R d is selected from halogen, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C(O)(C 1 -C 3 alkyl), CONH 2 or C(O)O(C 1 -C 3 alkyl).
  • Rd is OH
  • the TL is selected from the structure shown below (TL-1):
  • B 1 is selected from S or O, and A 1 , A 2 , A 3 , R 1 and R 2 are as defined above.
  • the TL is selected from the structure shown below (TL-2):
  • R 1 , R 2 , and R 3 are as defined above.
  • the TL is connected to a Linker via R 2 ; when R 2 is H, it is directly linked, that is, as follows Connections shown:
  • the TL is further selected from the group shown below:
  • the TL is further selected from the group shown below:
  • the TL is selected from the following structures:
  • the TL is
  • the TL is
  • the Linker is a linking group that covalently binds a TL and a DIM.
  • the linker is selected from: -L A -, -L B -, -R 1L -, -R 2L -, -Q 1 -, -Q 2 -,
  • -LA- , -LB- are independently selected from a chemical bond, -O-, -S-, -NR 3'-, -CR 4'R5'- , -CR 4'R5' - NR 3'- , -CR 4'R5' - O-, -C(O)-, -CR 4'R5' - C (O)-, -S(O)-, -S(O) 2- , -C(S ) -, -C(O)O- or -C(O)NR 6'- ;
  • R 3′ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 4′ and R 5′ are each independently selected from H, halogen, alkyl, alkoxy, haloalkyl, OH, hydroxyalkyl, CN, NH 2 , ⁇ O, cycloalkyl, heterocyclyl, aryl or heteroaryl;
  • R 6′ is selected from H, alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
  • the Linker is selected from: -L A -, In some embodiments, the Linker is selected from:
  • -LA- , -LB- are each independently selected from a bond or -CR4'R5'- , wherein R4' and R5 ' are each independently selected from H or C1 - C3 alkyl.
  • Q 1 , Q 2 , Q 3 and Q 4 are independently selected from C 3 -C 8 cycloalkylene or 5-10 membered heterocyclylene, wherein the C 3 -C 8 cycloalkylene or 5-10 membered heterocyclylene is optionally substituted by a group selected from halogen, OH, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 haloalkyl or C 1 -C 3 hydroxyalkyl.
  • the linker is selected from the following structures: bond, -O-, -C(O)-, -CH 2 -,
  • the linker is selected from: a bond, -O-, -C(O)-, -CH 2 -,
  • the Linker is selected from
  • the linker is selected from a bond, -CH 2 -, -C(O)-,
  • the DIM is selected from ligand compounds that are capable of binding to a cereblon-type E3 ubiquitin ligase.
  • the DIM is selected from the structure shown in formula (DIM-1) or (DIM-2):
  • Y is a chemical bond, or Y is selected from YA , O, NH, NR E , C(O)O, C(O)NR E ', NR E'C (O), YA- NH , YA -NR E , YA- C (O), YA- C (O)O, YA- OC (O), YA-C(O)NR E ' or YA- NR E'C (O), wherein YA is selected from C1 - C6 alkylene, C2 - C6 alkenylene or C2 - C6 alkynylene;
  • X is selected from C(O) or C( RA ) 2 ;
  • Each RA is independently selected from H or C 1 -C 3 alkyl, wherein the C 1 -C 3 alkyl is optionally substituted with C 6 -C 10 aryl or 5-10 membered heteroaryl;
  • Each RA ' is independently selected from C1 - C3 alkyl
  • Each RB is independently selected from H or C1 - C3 alkyl, or two RBs together with the atoms to which they are attached form C(O), C3 - C6 cycloalkyl, C3 - C6 cycloalkenyl or 4-6 membered heterocyclyl;
  • R C is selected from H, halogen or C 1 -C 3 alkyl
  • Each R D is independently selected from halogen, NO 2 , NH 2 , OH, COOH, C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
  • Each RE is independently selected from C1- C6 alkyl, C2 - C6 alkenyl, C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C(O)-C1- C6 alkyl , C(O) -C2 - C6 alkenyl, C(O) -C3 -C8 cycloalkyl or C(O)-3-8 membered heterocycloalkyl, said RE is optionally substituted by a group selected from halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6-C10 aryl or 5-10 membered heteroaryl, wherein said C3 - C8 cycloalkyl, 3-8 membered heterocycloalkyl, C6 - C10 aryl or 5-10 member
  • R E ' is selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by a group selected from the group consisting of halogen, N(R a ) 2 , NHC(O)R a , NHC(O)OR a , OR b , C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl, wherein the C 3 -C 8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6 -C 10 aryl or 5-10 membered heteroaryl is optionally further substituted
  • Each Ra is independently selected from H or C1 - C6 alkyl
  • R b is selected from H or p-toluenesulfonyl
  • t is selected from 0 or 1;
  • n 0, 1, 2 or 3;
  • p is selected from 0, 1 or 2.
  • the DIM is further selected from the structure shown in formula (DIM-3) or (DIM-4):
  • the DIM is further selected from the structures shown in formula (DIM-5), (DIM-6), (DIM-7) or (DIM-8):
  • Y, X, XA - XB , RA , RA ', RB , RC , RD , m and p are as defined above.
  • the DIM is further selected from the structure shown in formula (DIM-9) or (DIM-10):
  • Y, X, XA - XB , RA , RA ', RB , RC , RD , m and p are as defined above.
  • the DIM is selected from the structure shown in formula (DIM-11):
  • XC is selected from a chemical bond, -CH2- , -CH( CF3 )-, -SO2- , -S(O)-, -P(O)R'-, -P(O)(OR')-, -P(O)( NR'2 )-, -C(O)-, -C(S)- or
  • XD is selected from C, N or Si
  • X E is selected from a chemical bond, -CR' 2 -, -NR'-, -O-, -S- or -SiR' 2 -;
  • RF is absent or is selected from H, deuterium , halogen, CN, -OR', -SR', -S(O)R', -S(O) 2R ', -NR'2, -P(O)(OR') 2 , -P(O)( NR'2 )OR', -P(O)( NR'2 ) 2 , -Si(OH) 2R ', -Si(OH) R'2 , -SiR'3 , or C1 - C4 alkyl ;
  • Each RG is independently selected from H, deuterium, RH , halogen, CN, -NO2, -OR ', -SR', -NR'2 , -SiR'3 , -S(O) 2R ', -S(O) 2NR'2 , -S(O)R ' , -C(O)R', -C(O)OR', -C(O) NR'2 , -C(O)N(R')OR', -C(R') 2N (R')C(R')C(O)R', -C(R') 2N (R')C(O) NR'2 , -OC(O)R', -OC(O) NR'2 , -OP(O)R'2, -OP(O)(OR') 2 , -OP (O ) (OR') 2 , -OP (O ) (OR') 2 , -
  • Each RH is independently selected from C1 - C6 alkyl, phenyl, 4-7 membered heterocyclyl or 5-6 membered heteroaryl;
  • L 1 is selected from a chemical bond, a C 1 -C 3 alkylene group, a C 2 -C 3 alkenylene group or a C 2 -C 3 alkynylene group, wherein any one or two methylene groups in the C 1 -C 3 alkylene group, the C 2 -C 3 alkenylene group or the C 2 -C 3 alkynylene group are optionally replaced by the following groups: -O-, -C(O)-, -C(S)-, -C(R') 2 -, -CH(R')-, -C(F) 2 -, -N(R')-, -S- or -S(O) 2 -;
  • Each R' is independently selected from H, C 1 -C 6 alkyl, phenyl, 4-7 membered heterocyclic group or 5-6 membered heteroaryl, or two R' are connected to it The atoms together form a 4-7 membered heterocyclic group or a 5-6 membered heteroaryl group;
  • q is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16.
  • the DIM is selected from the structure shown in formula (DIM-11'):
  • the DIM is selected from the structure shown in formula (DIM-12):
  • k is selected from 0, 1, 2, 3 or 4;
  • X C , X D , X E , RF , RG , L 1 and ring E are as defined in formula (DIM-11).
  • the DIM is selected from the structure shown in formula (DIM-12'):
  • the DIM is selected from the structure shown in formula (DIM-13):
  • the DIM is selected from the structure shown in (DIM-13'):
  • the DIM is selected from the structure shown in formula (DIM-1), formula (DIM-3), formula (DIM-5), formula (DIM-12), formula (DIM-12'), formula (DIM-13) or formula (DIM-13').
  • the DIM is selected from the structure represented by formula (DIM-3), formula (DIM-5), formula (DIM-12), formula (DIM-12'), formula (DIM-13) or formula (DIM-13').
  • the DIM is selected from the following structures:
  • the DIM is selected from the following structures:
  • the DIM is selected from the following structures:
  • the compound of formula (I) of the present disclosure or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound represented by any of the above general formulae of the present disclosure or a specific compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the present disclosure provides a method for treating a disease mediated by IRAK4 in a mammal, comprising administering a therapeutically effective amount of a compound represented by any of the above general formulas or a specific compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides a method for treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases in mammals, comprising administering a therapeutically effective amount of a compound represented by any of the above general formulas or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to a mammal, preferably a human, in need of such treatment.
  • the present disclosure provides use of a compound represented by any of the above general formulas or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating an IRAK4-mediated disease.
  • the present disclosure provides the use of a compound represented by any of the above general formulas or a specific compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.
  • the present disclosure provides the use of the compound represented by any of the above general formulas or specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating IRAK4-mediated diseases.
  • the present disclosure provides the use of the compound represented by any of the above general formulas or specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.
  • the present disclosure provides any of the above-mentioned general formula compounds or specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof for preventing or treating IRAK4-mediated diseases.
  • the present disclosure provides any of the above general formula compounds or specific compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for preventing or treating tumors, inflammatory diseases, neurodegenerative diseases or autoimmune diseases.
  • the IRAK4-mediated disease is selected from a tumor, an inflammatory disease, a neurodegenerative disease, or an autoimmune disease.
  • capable of binding means capable of measurably binding to a target (eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine of an E3 ubiquitin ligase, etc.).
  • a target eg, a ligand of an E3 ubiquitin ligase is capable of forming a covalent bond with a cysteine of an E3 ubiquitin ligase, etc.
  • ubiquitin ligase refers to a family of proteins that facilitate the transfer of ubiquitin to a specific substrate protein to target the substrate protein for degradation.
  • E3 ubiquitin ligases alone or in complex with E2 ubiquitin ligases, are responsible for transferring ubiquitin to target proteins.
  • ubiquitin ligases participate in polyubiquitination, such that a second ubiquitin is attached to a first ubiquitin; a third ubiquitin is attached to a second ubiquitin, and so on.
  • Polyubiquitination marks proteins for degradation by the proteasome.
  • ubiquitination events that are limited to monoubiquitination, in which ubiquitin ligases only add a single ubiquitin to a substrate molecule.
  • Monoubiquitinated proteins are not targeted to the proteasome for degradation, but can change their cellular location or function, for example, by binding to other proteins with domains capable of binding ubiquitin.
  • E3 ubiquitin ligases can target different lysines on ubiquitin to make chains.
  • target protein refers to proteins and peptides having any biological function or activity, including structural, regulatory, hormonal, enzymatic, genetic, immune, contractile, storage, transport, and signal transduction.
  • the target protein refers to a protein or polypeptide that binds to a compound of the present disclosure and can be degraded.
  • tautomer refers to functional group isomers resulting from the rapid movement of an atom in two positions in a molecule.
  • the compounds of the present disclosure may exhibit tautomerism.
  • Tautomeric compounds may exist in two or more interconvertible species.
  • Tautomers generally exist in equilibrium, and attempts to separate a single tautomer usually produce a mixture whose physical and chemical properties are consistent with the mixture of compounds. The position of equilibrium depends on the chemical characteristics within the molecule. For example, in many aliphatic aldehydes and ketones such as acetaldehyde, the keto form predominates; while in phenols, the enol form predominates.
  • the present disclosure includes all tautomeric forms of the compounds.
  • stereoisomer refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and diastereomers.
  • the compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • Specific geometric or stereoisomeric forms may be cis and trans isomers, E-type and Z-type geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and their mixtures.
  • asymmetric carbon atoms such as alkyl groups
  • substituents such as alkyl groups
  • substituents such as alkyl groups
  • all of these isomers and their mixtures involved in all substituents are also within the definition of the compounds of the present invention.
  • the compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • an ethyl group is "optionally" substituted with a halogen, which means that the ethyl group may be unsubstituted (CH 2 CH 3 ), monosubstituted (CH 2 CH 2 F, CH 2 CH 2 Cl, etc.), polysubstituted (CHFCH 2 F, CH 2 CHF 2 , CHFCH 2 Cl, CH 2 CHCl 2 , etc.) or fully substituted (CF 2 CF 3 , CF 2 CCl 3 , CCl 2 CCl 3 , etc.). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and/or cannot be synthesized will be introduced.
  • substituted means that a specific atom or group can be replaced by another specified atom or group.
  • CH 2 in -CH 2 CH 2 CH 2 - can be replaced by O, S or NH to obtain -CH 2 OCH 2 -, -OCH 2 CH 2 -, -CH 2 SCH 2 -, -SCH 2 CH 2 -, -CH 2 NHCH 2 - or - NHCH 2 CH 2 -etc.
  • any variable e.g., Ra , Rb
  • its definition in each case is independent. For example, if a group is substituted by 2 Rb , each Rb has independent options; for the group N( C1 - C6 alkyl) 2 , when C1 - C6 alkyl is substituted by Rb , the two C1 - C6 alkyls have independent Rb options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a bond.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary.
  • L 1 When L 1 is selected from “C 1 -C 3 alkylene-O", L 1 can connect ring Q and R 1 from left to right to form “ring QC 1 -C 3 alkylene-OR 1 ", or connect ring Q and R 1 from right to left to form “ring QOC 1 -C 3 alkylene-R 1 ".
  • Cm - Cn herein refers to an integer number of carbon atoms in the range of mn or m to n.
  • C1 - C10 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms or 10 carbon atoms.
  • n-membered to n-membered means that the number of ring atoms is m to n, for example, 5-14-membered ring includes 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, 12-membered ring, 13-membered ring and 14-membered ring, and also includes any range from n to m, for example, 5-14-membered ring includes 6-14-membered ring, 6-11-membered ring, 5-10-membered ring, 6-10-membered ring, 6-8-membered ring, etc.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n +1 , which is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms.
  • C1 - C10 alkyl is understood to mean a straight or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • alkyl group examples include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc.; the term "C 1 - ...
  • C 1 -C 4 alkyl may be understood to mean an alkyl group having 1 to 6 carbon atoms, specific examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, and the like.
  • C 1 -C 4 alkyl may be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms.
  • C 1 -C 3 alkyl may be understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms.
  • the “C 1 -C 10 alkyl” may include “C 1 -C 6 alkyl”, “C 1 -C 4 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 6 alkyl” may further include “C 1 -C 4 alkyl” or “C 1 -C 3 alkyl”, and the “C 1 -C 4 alkyl” may further include “C 1 -C 3 alkyl”.
  • heteroalkyl refers to an alkyl group in which one or more -CH2- are replaced by a heteroatom selected from NH, O and S, or one or more -CH- are replaced by N; wherein the alkyl group is as defined above.
  • haloalkyl refers to a group obtained by further replacing the alkyl with halogen, such as "C 1 -C 6 haloalkyl” refers to a C 1 -C 6 alkyl further replaced with halogen.
  • hydroxyalkyl refers to a group obtained by further replacing the alkyl with OH.
  • alkylene refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of an alkane radical by removing two hydrogen atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, and more preferably an alkylene group containing 1 to 6 carbon atoms.
  • Non-limiting examples of alkylene groups include, but are not limited to, methylene, -CH(CH 3 )-, -CH 2 CH 2 -, -CH(CH 2 CH 3 )-, -CH 2 CH(CH 3 )-, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 - , and the like.
  • the term "C 1 -C 6 alkylene group” is understood to mean an alkylene group having 1 to 6 carbon atoms.
  • C 1 -C 3 alkylene is understood to mean an alkylene group having 1 to 3 carbon atoms.
  • C 1 -C 6 alkylene may include "C 1 -C 3 alkylene”.
  • heteroalkylene refers to an alkylene group in which one or more -CH 2 - groups are substituted by heteroatoms selected from N, O and S; wherein the alkylene group is as defined above.
  • alkoxy refers to a monovalent group generated by the loss of a hydrogen atom from a hydroxyl group of a straight or branched alcohol, and can be understood as “alkyloxy” or “alkyl-O-", wherein the definition of alkyl is as described above.
  • C 1 -C 10 alkoxy can be understood as “C 1 -C 10 alkyloxy” or “C 1 -C 10 alkyl-O-"; the term “C 1 -C 6 alkoxy” can be understood as “C 1 -C 6 alkyloxy” or "C 1 -C 6 alkyl-O-".
  • the "C 1 -C 10 alkoxy” can include “C 1 -C 6 alkoxy” and “C 1 -C 3 alkoxy” and the like, and the “C 1 -C 6 alkoxy” can further include “C 1 -C 3 alkoxy”.
  • haloalkoxy refers to a group obtained by further substituted with halogen by the alkoxy group, such as "C 1 -C 6 haloalkoxy” refers to a C 1 -C 6 alkoxy group further substituted with halogen.
  • alkenyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing 2 to 20 carbon atoms and having at least one double bond.
  • C2 - C10 alkenyl is understood to mean a linear or branched unsaturated monovalent hydrocarbon group containing one
  • C 2 -C 6 alkenyl is understood to mean a linear or branched unsaturated monovalent hydrocarbon group containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C 10 alkenyl is preferably “C 2 -C 6 alkenyl” or “C 2 -C 4 alkenyl", “C 2 -C 6 alkenyl” is further preferably “C 2 -C 4 alkenyl”, and further preferably C 2 or C 3 alkenyl. It should be understood that in the case where the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other.
  • alkenyl group examples include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl, etc.
  • alkenylene refers to a residue derived from the same carbon atom or two different carbon atoms of a parent alkene by removing two hydrogen atoms, wherein alkenyl is as defined above.
  • C 2 -C 6 alkenylene is understood as an alkenylene having 2 to 6 carbon atoms.
  • C 2 -C 3 alkenylene is understood as an alkenylene having 2 or 3 carbon atoms.
  • C 2 -C 6 alkenylene includes "C 2 -C 3 alkenylene”.
  • alkynyl refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, containing 2 to 20 carbon atoms and having at least one triple bond.
  • C 2 -C 10 alkynyl may be understood to mean a linear or branched unsaturated monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • C 2 -C 6 alkynyl may be understood to mean a linear or branched unsaturated monovalent hydrocarbon group containing one or more triple bonds and having 2, 3, 4, 5 or 6 carbon atoms.
  • C 2 -C 6 alkynyl examples include, but are not limited to, ethynyl (-C ⁇ CH 3 , -CH 2 C ⁇ CH 3 , -CH 2 C ⁇ CH ), but-1-ynyl, but-2-ynyl or but-3-ynyl.
  • C 2 -C 10 alkynyl may include “C 2 -C 6 alkynyl” or “C 2 -C 3 alkynyl”
  • C 2 -C 6 alkynyl may include “C 2 -C 3 alkynyl”.
  • Examples of “C 2 -C 3 alkynyl” include ethynyl (—C ⁇ CH), prop-1-ynyl (—C ⁇ CCH 3 ) or prop-2-ynyl (propargyl).
  • alkynylene refers to a residue derived from the same carbon atom or two different carbon atoms of a parent alkyne by removing two hydrogen atoms, wherein the definition of alkynyl is as shown above.
  • C 2 -C 6 alkynylene is to be understood as an alkynylene having 2 to 6 carbon atoms.
  • C 2 -C 3 alkynylene is to be understood as an alkynylene having 2 or 3 carbon atoms.
  • C 2 -C 6 alkynylene includes "C 2 -C 3 alkynylene".
  • cycloalkyl refers to a fully saturated carbocyclic ring that exists in the form of a monocyclic, cyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3- to 10-membered ring.
  • C 3 -C 10 cycloalkyl is understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 10 carbon atoms.
  • C 3 -C 8 cycloalkyl is understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 8 carbon atoms.
  • C 3 -C 6 cycloalkyl is understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 3 to 6 carbon atoms, and specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 5 -C 9 cycloalkyl is understood to mean a saturated monovalent monocyclic, cyclic, spirocyclic or bridged ring having 5 to 9 carbon atoms.
  • C5 - C7 cycloalkyl is understood to mean a saturated monovalent monocyclic, cyclopentyl, spirocyclic or bridged ring having 5 to 7 carbon atoms.
  • Specific examples of the cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, adamantyl, spiro[4.5]decyl, and the like.
  • C3 - C10 cycloalkyl may include “ C3 - C8 cycloalkyl”, “ C3 - C6 cycloalkyl”, “ C5 - C9 cycloalkyl” or “ C5 - C7 cycloalkyl”, the term “ C3 - C8 cycloalkyl” may include “ C3 - C6 cycloalkyl” or “ C5 - C7 cycloalkyl”, the term “ C5 - C9 cycloalkyl” may include “ C5 - C7 cycloalkyl”.
  • cycloalkyloxy may be understood as “cycloalkyl-O-".
  • C 3 -C 6 cycloalkyloxy may be understood as “C 3 -C 6 cycloalkyl-O-”.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic ring, a cyclic ring, a bridged ring or a spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is generally a 3-10 membered ring. Specific examples of the cycloalkenyl include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl or cycloheptadienyl.
  • C 5 -C 10 cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic ring, a cyclic ring, a bridged ring or a spirocyclic ring, and has 5-10 carbon atoms.
  • C 5 -C 9 cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic ring, a cyclic ring, a bridged ring or a spirocyclic ring, and has 5, 6, 7, 8 or 9 carbon atoms.
  • C 5 -C 7 cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic ring, a cyclic ring, a bridged ring or a spirocyclic ring, etc., and has 5, 6 or 7 carbon atoms.
  • C 3 -C 6 cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and exists in the form of a monocyclic ring, a cyclic ring, a bridged ring or a spirocyclic ring, etc., and has 3, 4, 5 or 6 carbon atoms.
  • C 5 -C 10 cycloalkenyl may include “C 5 -C 9 cycloalkenyl” or “C 5 -C 7 cycloalkenyl”, and the term “C 5 -C 9 cycloalkenyl” may include “C 5 -C 7 cycloalkenyl”.
  • 4-14 membered heterocyclyl refers to a heterocyclyl having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, and the ring atoms contain 1 to 5 heteroatoms or heteroatom groups independently selected from the above.
  • “4-14 membered heterocyclyl” may include “6-14 membered heterocyclyl", “6-11 membered heterocyclyl”, “6-10 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-10 membered heterocyclyl”, “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “5-10 membered heterocyclyl”, “5-9 membered heterocyclyl”
  • the term “5-10 membered heterocyclyl” may include “5-9 membered heterocyclyl”, “5-8 membered heterocyclyl”, “5-7 membered heterocyclyl”, “6-10 membered heterocyclyl” or “6-8 membered heterocyclyl”.
  • 4-10 membered heterocyclyl refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms.
  • “4-10 membered heterocyclyl” includes “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl” or “4-6 membered heterocyclyl”, wherein specific examples of 4 membered heterocyclyl include but are not limited to azetidinyl or oxetanyl; specific examples of 5 membered heterocyclyl include but are not limited to tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6 membered heterocyclyl include but are not limited to tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,
  • the heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include, but are not limited to, hexahydrocyclopenta[c]pyrrole-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include, but are not limited to, hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl.
  • the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic group, specific examples of which include, but are not limited to, dihydroisoquinolinyl and the like.
  • the “4-10 membered heterocyclyl” may include the ranges of “5-10 membered heterocyclyl”, “5-9 membered heterocyclyl”, “5-8 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “6-10 membered heterocyclyl”, “6-8 membered heterocyclyl”, “4-8 membered heterocyclyl”, “4-7 membered heterocyclyl”, “4-6 membered heterocyclyl”, “4-10 membered heterocycloalkyl”, “5-10 membered heterocycloalkyl”, “4-7 membered heterocycloalkyl”, “5-6 membered heterocycloalkyl”, “6-8 membered heterocycloalkyl”, and the like, and the “4-7 membered heterocyclyl” may further include the ranges of “4-6 membered heterocyclyl”, “5-7 membered heterocyclyl”, “5-6 membered heterocyclyl”, “4-7 membered heterocycly
  • heterocyclyloxy may be understood as “heterocyclyl-O-”.
  • heterocycloalkyl refers to a fully saturated monovalent cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1, 2, 3, 4 or 5 heteroatoms or heteroatomic groups (i.e., an atomic group containing heteroatoms).
  • heterocycloalkyl refers to a heterocycloalkyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms.
  • “3-10 membered heterocycloalkyl” includes “3-8 membered heterocycloalkyl”, wherein specific examples of 4 membered heterocycloalkyl include but are not limited to azetidinyl, oxetanyl or thietanyl; specific examples of 5 membered heterocycloalkyl include but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl or tetrahydropyrazolyl; specific examples of 6 membered heterocycloalkyl include but are not limited to piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxanyl, 1,4-dioxane, thi
  • heterocycloalkyloxy may be read as “heterocycloalkyl-O-”.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group with a conjugated ⁇ electron system.
  • the aryl group may have 6-20 carbon atoms, 6-14 carbon atoms or 6-12 carbon atoms.
  • C 6 -C 20 aryl is understood to mean a monovalent aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms.
  • C 6 aryl such as phenyl
  • C 9 aryl such as indanyl or indenyl
  • 10 carbon atoms such as tetrahydronaphthyl, dihydronaphthyl or naphthyl
  • C 13 aryl such as fluorenyl
  • C 14 aryl such as anthracenyl
  • C 6 -C 10 aryl is understood to mean a monovalent aromatic all-carbon monocyclic or bicyclic group having 6 to 10 carbon atoms, in particular a ring having 6 carbon atoms (“C 6 aryl”), such as phenyl; or a ring having 9 carbon atoms (“C 9 aryl”), such as indenyl; or a ring having 10 carbon atoms (“C 10 aryl”), such as naphthyl.
  • aryloxy may be understood as “aryl-O-”.
  • heteroaryl refers to a monocyclic or fused polycyclic system with aromaticity, which contains at least one, preferably 1, 2, 3 or 4 ring atoms selected from N, O, S, and the remaining ring atoms are carbon 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered aromatic ring radical. Heteroaryl is preferably a 5-10-membered, more preferably a 5- or 6-membered heteroaryl.
  • 5-10-membered heteroaryl is understood to include such monovalent monocyclic or bicyclic aromatic ring systems: it has 5, 6, 7, 8, 9 or 10 ring atoms, in particular 5 or 6 or 9 or 10 ring atoms, and it contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S.
  • the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or azinyl, in
  • 5-6 membered heteroaryl refers to an aromatic ring system having 5 or 6 ring atoms and containing 1 to 3, preferably 1 to 2 independent
  • 6-membered heteroaryl refers to an aromatic ring system having 6 ring atoms, and it contains 1-3, preferably 1-2 heteroatoms independently selected from N, O and S.
  • the term “5-10 membered heteroaryl” may include “5-6 membered heteroaryl” or "6 membered heteroaryl”
  • the term “5-6 membered heteroaryl” may include “6 membered heteroaryl”.
  • halo or halogen refers to fluorine, chlorine, bromine or iodine.
  • hydroxy refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH2 group.
  • nitro refers to the -NO2 group.
  • terapéuticaally effective amount means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.
  • the amount of a compound of the present disclosure that constitutes a “therapeutically effective amount” varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their own knowledge and this disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or an organic acid, and a salt formed between a compound and an inorganic base or an organic base.
  • composition refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient.
  • the purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no significant irritation to the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number commonly found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl, etc., respectively.
  • isotopically labeled compounds of the present disclosure are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present disclosure can generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an unlabeled reagent.
  • compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, for example, they can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into particles to obtain a tablet or dragee core.
  • suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants or flavoring agents, etc.
  • the pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.
  • a suitable daily dosage of the compound of formula (I) described herein is 0.01 mg/kg to 1000 mg/kg.
  • the compounds disclosed herein can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitution methods known to those skilled in the art.
  • the preferred embodiments include but are not limited to the embodiments disclosed herein.
  • the ratios expressed for mixed solvents are volume mixing ratios. Unless otherwise specified, % means wt%.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the unit of NMR shift is 10 -6 (ppm).
  • the solvents for NMR determination are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, D 2 O, CF 3 COOD, etc., and the internal standard is tetramethylsilane (TMS); "IC 50 " refers to the half inhibitory concentration, which refers to the concentration when half of the maximum inhibitory effect is achieved.
  • t-Bu tert-butyl
  • t-BuOK potassium tert-butoxide
  • t-BuNO 2 tert-butyl nitrite
  • TEA triethylamine
  • THF tetrahydrofuran
  • Me methyl
  • MeOH methanol
  • MeI methyl iodide
  • EtOH ethanol
  • DCM dichloromethane
  • DCE dichloroethane
  • DMF N,N-dimethylformamide
  • DIEA N,N-diisopropylethylamine
  • NMP N-methylpyrrolidone
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • Boc tert-butyloxycarbonyl
  • Bn benzyl
  • NaBH(OAc) 3 sodium triacetoxyborohydride
  • AcOH ter
  • the eluent mentioned below may be a mixed eluent formed by two or more solvents, the ratio of which is the volume ratio of each solvent.
  • 6-bromo-5-isopropoxybenzo[d]thiazole-2-amine (A-5, 1.4 g, 4.87 mmol) and cupric chloride (1.0 g, 7.46 mmol) were dissolved in acetonitrile (20 mL), and tert-butyl nitrite (754 mg, 7.31 mmol) was slowly added under stirring, and the mixture was stirred for 30 min at room temperature, and then heated to 65°C and stirred for 1 hour.
  • reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (30 mL ⁇ 3), and the organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 6 Synthesis of tert-butyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A-7)
  • 6-bromo-2-chloro-5-isopropoxybenzo[d]thiazole (A-6, 530 mg, 1.73 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (535 mg, 1.73 mmol), potassium carbonate (478 mg, 3.46 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (73 mg, 0.10 mmol) were dissolved in dioxane (12 mL) and water (2 mL), replaced with nitrogen three times, and then heated to 100°C and stirred for 4 hours.
  • reaction solution was cooled to room temperature, diluted with water (50 mL), and then extracted with ethyl acetate (30 mL ⁇ 3), and the organic phase was collected, washed with saturated brine, and dried over anhydrous sodium sulfate.
  • Step 7 Synthesis of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxybenzo[d]thiazole-6-carboxylate (A-8)
  • tert-butyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (A-7, 530 mg, 1.17 mmol), triethylamine (237 mg, 2.34 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (88 mg, 0.12 mmol) were dissolved in methanol (40 mL), placed in a high pressure reactor, filled with carbon monoxide gas to 5 MPa, heated to 80°C and stirred for 16 hours.
  • Step 8 Synthesis of methyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-isopropoxybenzo[d]thiazole-6-carboxylate (A-9)
  • Step 9 Synthesis of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)-5-isopropoxybenzo[d]thiazole-6-carboxylic acid (A-10)
  • Step 10 Synthesis of tert-butyl 4-(5-isopropoxy-6-((1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperidine-1-carboxylate (A-11)
  • Step 11 Synthesis of 5-isopropoxy-N-(1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)-2-(piperidin-4-yl)benzo[d]thiazole-6-carboxamide (Intermediate A)
  • tert-butyl 4-(5-isopropoxy-6-((1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperidine-1-carboxylate (A-11, 25 mg, 0.047 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid dioxane solution (1 mL, 4 N) was slowly added dropwise and stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered and the filter cake was freeze-dried to obtain the title compound (16 mg).
  • Step 1 Synthesis of tert-butyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (B-1)
  • Step 2 Synthesis of methyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-isopropoxybenzo[d]thiazole-6-carboxylate (B-2)
  • tert-butyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (B-1, 713 mg, 1.56 mmol), triethylamine (316 mg, 3.12 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (117 mg, 0.16 mmol) were dissolved in methanol (40 mL), and the gas was replaced by a carbon monoxide bag for 3 times, and the temperature was raised to 80°C and refluxed for 16 hours.
  • Step 3 Synthesis of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-isopropoxybenzo[d]thiazole-6-carboxylic acid (B-3)
  • Step 4 Synthesis of tert-butyl 4-(5-isopropoxy-6-((1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (B-4)
  • Step 5 Synthesis of 5-isopropoxy-N-(1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide (Intermediate B)
  • tert-butyl 4-(5-isopropoxy-6-((1-methyl-2-carbonyl-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (B-4, 40 mg, 0.076 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid dioxane solution (1 mL, 4 N) was slowly added dropwise and stirred at room temperature for 2 h. After the reaction was completed, the mixture was concentrated and purified by preparative liquid phase to obtain the title compound (18 mg).
  • Step 3 Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (D-4)
  • Step 4 Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidine-4-carbaldehyde (Intermediate D)
  • tert-butyl 7-(hydroxymethyl)-2-azaspiro[3.5]nonane-2-carboxylate (E-1, 800 mg, 3.13 mmol) was dissolved in dichloromethane (4 mL). Hydrochloric acid dioxane solution (2 mL, 4 N) was added dropwise at room temperature and stirred at room temperature for 2 hours. The solvent was concentrated in vacuo to obtain the crude title compound, which was used directly in the next step.
  • Step 2 Synthesis of 2-(2,6-dioxopiperidin-3-yl)-5-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)isoindoline-1,3-dione (E-3)
  • Step 3 Synthesis of 2-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde (Intermediate E)
  • reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • the organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (F-4)
  • Step 4 Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (F-5)
  • Step 5 Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-6-yl)piperidine-4-carbaldehyde (Intermediate F)
  • Step 4 Synthesis of 1-(4-((2,6-dioxopiperidin-3-yl)oxy)phenyl)piperidine-4-carbaldehyde (Intermediate G)
  • Step 2 Synthesis of 3-(6-(7-(hydroxymethyl)-2-azaspiro[3.5]nonan-2-yl)pyridin-3-yl)piperidine-2,6-dione (H-3)
  • Step 3 Synthesis of 2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-azaspiro[3.5]nonane-7-carbaldehyde
  • Step 1 Synthesis of methyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)cyclohex-3-ene-1-carboxylate (I-1)
  • 6-bromo-2-chloro-5-isopropoxybenzo[d]thiazole (A-6, 6.30 g, 20.55 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylic acid methyl ester (4.92 g, 18.50 mmol), potassium carbonate (5.68 g, 41.10 mmol) and [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (0.75g, 1.03mmol) was dissolved in 1,4-dioxane (120mL) and water (20mL), and the nitrogen was replaced 3 times, and then the temperature was raised to 100°C and stirred for 5 hours.
  • Step 2 Synthesis of 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)cyclohex-3-ene-1-carbaldehyde (I-2)
  • methyl 4-(6-bromo-5-isopropoxybenzo[d]thiazol-2-yl)cyclohex-3-ene-1-carboxylate (I-1, 2.0 g, 4.87 mmol) was dissolved in dry tetrahydrofuran (30 mL), and the nitrogen was replaced 3 times. Then, the temperature was lowered to below -60°C in a dry ice ethanol bath, and a tetrahydrofuran solution of lithium aluminum hydride (5.0 mL, 5.00 mmol, 1 M) was slowly added with a syringe and stirred for 1 hour.
  • lithium aluminum hydride 5.0 mL, 5.00 mmol, 1 M
  • Step 3 Synthesis of 6-bromo-2-(4-(dimethoxymethyl)cyclohex-1-en-1-yl)-5-isopropoxybenzo[d]thiazole (I-3)
  • Step 4 Synthesis of 6-bromo-2-(4-(dimethoxymethyl)cyclohexyl)-5-isopropoxybenzo[d]thiazole (I-4)
  • Step 5 Synthesis of methyl 2-(4-(dimethoxymethyl)cyclohexyl)-5-isopropoxybenzo[d]thiazole-6-carboxylate (I-5)
  • Step 6 Synthesis of 2-(4-(dimethoxymethyl)cyclohexyl)-5-isopropoxybenzo[d]thiazole-6-carboxylic acid (I-6)
  • Step 7 Synthesis of 2-(4-(dimethoxymethyl)cyclohexyl)-5-isopropoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzo[d]thiazole-6-carboxamide (I-7)
  • Step 8 Synthesis of 2-(4-formylcyclohexyl)-5-isopropoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzo[d]thiazole-6-carboxamide (Intermediate I)
  • Step 1 Synthesis of tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (K-2)
  • Step 2 Synthesis of tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-1-carboxylate (K-3)
  • Step 3 Synthesis of tert-butyl 4-[5-(2,6-dibenzyloxypyridin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (K-4)
  • Step 4 Synthesis of tert-butyl 4-[5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl]piperazine-1-carboxylate (K-5)
  • Step 5 Synthesis of 3-(6-piperazin-1-yl-pyridin-3-yl)piperidine-2,6-dione (Intermediate K)
  • Step 2 Synthesis of 1-(6-bromopyrazolo[1,5-a]pyridin-3-yl)-3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (L-3)
  • 6-bromo-3-iodopyrazolo[1,5-a]pyridine (L-2,5g, 15.48mmol) and 3-[(4-methoxyphenyl)methyl]hexahydropyrimidine-2,4-dione (3.63g, 15.48mmol) were dissolved in dioxane (40mL) solution, potassium phosphate (6.57g, 30.97mmol) was added, 1,2-diaminocyclohexane (353.61mg, 3.10mmol) and cuprous iodide (589.76mg, 3.10mmol) were added after replacing nitrogen, and then the temperature was raised to 100°C, and the reaction solution was stirred overnight.
  • Step 3 Synthesis of tert-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]pyrazolo[1,5-a]pyridin-6-yl]piperazine-1-carboxylate (L-4)
  • reaction solution was cooled to room temperature and diluted with dichloromethane, and 5% acetic acid solution was added to adjust the pH to 6-7. It was extracted with dichloromethane, and the organic phase was dried over saturated brine and anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of the title compound (1.2g,).
  • Step 4 Synthesis of 1-(6-piperazin-1-ylpyrazolo[1,5-a]pyridin-3-yl)hexahydropyrimidine-2,4-dione (Intermediate L)
  • tert-butyl 4-[3-[3-[(4-methoxyphenyl)methyl]-2,4-dioxo-hexahydropyrimidin-1-yl]pyrazolo[1,5-a]pyridin-6-yl]piperazine-1-carboxylate (L-4, 600 mg, 1.12 mmol) was dissolved in trifluoroacetic acid (6 mL), and then trifluoromethanesulfonic acid (5.05 g, 33.67 mmol) was added. The reaction solution was heated to 60°C and stirred for 1 hour.
  • Step 1 Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (M-2)
  • Step 2 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidine-4-carboxaldehyde (Intermediate M)
  • intermediate M-1 was replaced with 3-(5-bromo-1-oxo-isoindolin-2-yl)piperidine-2,6-dione, and intermediate N was prepared in the same manner.
  • reaction solution was cooled to room temperature, diluted with water (50mL), and extracted with ethyl acetate (50mL ⁇ 3).
  • the organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of 3-(2,6-di(benzyloxy)pyridin-3-yl)-7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazole (O-5)
  • Step 5 Synthesis of 3-(7-(4-(dimethoxymethyl)piperidin-1-yl)-1-methyl-1H-indazol-3-yl)piperidine-2,6-dione (O-6)
  • Step 6 Synthesis of 1-(3-(2,6-dioxopiperidin-3-yl)-1-methyl-1H-indazol-7-yl)piperidine-4-carbaldehyde (Intermediate O)
  • Step 1 Synthesis of tert-butyl 4-(5-isopropoxy-6-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (P-1)
  • Step 2 Synthesis of 5-isopropoxy-2-(piperazin-1-yl)-N-(pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazole-6-carboxamide (Intermediate P)
  • tert-butyl 4-(5-isopropoxy-6-(pyrazolo[1,5-a]pyrimidin-3-ylcarbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (P-1, 165 mg, 0.307 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid dioxane solution (2 mL, 4 N) was slowly added dropwise and stirred at room temperature for 2 h. After the reaction was completed, the mixture was filtered and freeze-dried to obtain a crude product of the title compound (130 mg).
  • intermediate P the pyrazolo[1,5-a]pyrimidine-3-amine hydrochloride was replaced with 3-amino-1-((1S,2R)-2-fluorocyclopropyl)pyridin-2(1H)-one, and intermediate Q was prepared in the same manner.
  • Step 1 Synthesis of tert-butyl 2-[1-(5-bromo-3-fluoro-pyridin-2-yl)-4-hydroxy-piperidin-4-yl]acetate (R-2)
  • Step 2 Synthesis of tert-butyl 2-(1-(5-(2,6-dibenzyloxy-pyridin-3-yl)-3-fluoro-pyridin-2-yl)-4-hydroxy-piperidin-4-yl)acetate (R-3)
  • tert-butyl 2-[1-(5-bromo-3-fluoro-pyridin-2-yl)-4-hydroxy-piperidin-4-yl]acetate (R-2, 2.17 g, 5.57 mmol), 2,6-dibenzyloxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.26 g, 7.81 mmol), potassium carbonate (2.32 g, 16.75 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (326.92 mg, 446.80 ⁇ mol) were dissolved in 1,4-dioxane/water (10 mL/2 mL), nitrogen was replaced, the temperature was raised to 80°C, and the reaction mixture was stirred at 90°C for 16 hours.
  • reaction solution was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL ⁇ 3).
  • the organic phase was washed with saturated brine (20 mL x 2), separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of tert-butyl 2-[1-[5-(2,6-dioxo-piperidin-3-yl)-3-fluoro-pyridin-2-yl]-4-hydroxy-piperidin-4-yl]acetate (R-4)
  • tert-butyl 2-(1-(5-(2,6-dibenzyloxy-pyridin-3-yl)-3-fluoro-pyridin-2-yl)-4-hydroxy-piperidin-4-yl)acetate (1.07 g, 1.79 mmol) was dissolved in ethyl acetate (10 mL), followed by the addition of palladium carbon (110 mg) and palladium hydroxide carbon (110 mg), hydrogen replacement, and the reaction mixture was stirred at 25 ° C for 12 hours.
  • the reaction solution was filtered through diatomaceous earth, the filter cake was rinsed with ethyl acetate (60 mL), and the filtrate was concentrated under reduced pressure. The residue obtained was the title compound (641 mg).
  • Step 4 Synthesis of 2-(1-(5-(2,6-dioxopiperidin-3-yl)-3-fluoropyridin-2-yl)-4-hydroxypiperidin-4-yl)acetic acid (Intermediate R)
  • tert-butyl 2-[1-[5-(2,6-dioxo-piperidin-3-yl)-3-fluoro-pyridin-2-yl]-4-hydroxy-piperidin-4-yl]acetate (641 mg, 1.52 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of trifluoroacetic acid (2 mL), and the reaction mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and separated and purified by reverse phase preparative chromatography (C18 column, mobile phase 5%-95% water/acetonitrile, 30 minutes) to obtain the title compound (400 mg).
  • Step 3 Synthesis of 3-(6-bromo-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (S-4)
  • Step 4 Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-4-methoxy-1-oxoisoindolin-2-yl)piperidine-2,6-dione (S-5)
  • reaction solution was stirred at 100° C. for 12 hours under a nitrogen atmosphere, and LCMS showed that the reaction was complete.
  • the reaction solution was concentrated to dryness under reduced pressure, and water (10 mL) was added for slurrying. The mixture was filtered and the filter cake was dried to obtain the title compound (110 mg).
  • Step 5 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-7-methoxy-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate S)
  • Step 1 Synthesis of (R)-tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)-3-methylpiperazine-1-carboxylate (T-2)
  • Step 3 Synthesis of tert-butyl (3R)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3-methylpiperazine-1-carboxylate (T-4)
  • (R)-4-(4-(tert-butoxycarbonyl)-2-methylpiperazine-1-yl)-2-fluorobenzoic acid (T-3, 796 mg, 2.35 mmol) and 3-aminopiperidine-2,6-dione (361.70 mg, 2.82 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (606.93 mg, 4.70 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (241.20 g, 634.73 mmol) were added.
  • Step 4 Synthesis of (3R)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3-methylpiperazine (Intermediate T)
  • tert-butyl (3R)-4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3-fluorophenyl)-3-methylpiperazine-1-carboxylate (T-3, 31 mg, 0.069 mmol) was dissolved in dichloromethane (4 mL), and hydrochloric acid-dioxane solution (4 M, 1 mL) was added and stirred at room temperature for 1 hour. After the reaction was completed, the crude title compound (24.1 mg) was obtained by spin drying and used directly in the next step without purification.
  • methyl 5-amino-4-fluoro-2-methylbenzoate (V-2, 6.5 g, 35.48 mmol) was dissolved in acetonitrile (25 mL), the temperature was lowered to 10 ° C, water (50 mL) was added to the reaction solution, the temperature was lowered to 5 ° C, concentrated sulfuric acid (10.44 g, 106.4 mmol, 5.67 mL) was added to the reaction solution. Then sodium nitrite (2.57 g, 37.25 mmol) was dissolved in water (8 mL) and added dropwise to the reaction solution.
  • the reaction mixture was stirred at 0 ° C for 0.5 hours, and then potassium iodide (6.48 g, 39.04 mmol) was dissolved in water (22 mL) and added dropwise to the reaction solution. The temperature was raised to 7 ° C, and the reaction mixture was stirred at 7 ° C for 2 hours. After the reaction was completed, water (100 mL) was added for dilution, ethyl acetate (200 mL ⁇ 3) was extracted, and saturated sodium thiosulfate aqueous solution (50 mL) was washed.
  • Step 4 Synthesis of 3-(5-fluoro-6-iodo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (V-5)
  • Step 5 Synthesis of 3-(6-(4-(dimethoxymethyl)piperidin-1-yl)-5-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione (V-6)
  • Step 6 Synthesis of 1-(2-(2,6-dioxopiperidin-3-yl)-6-fluoro-3-oxoisoindolin-5-yl)piperidine-4-carbaldehyde (Intermediate V)
  • Step 1 Synthesis of 3-(5-(4-(dimethoxymethyl)piperidin-1-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (W-2)
  • Step 2 Synthesis of 1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)piperidine-4-carbaldehyde (Intermediate W)
  • Step 1 Synthesis of 3-(6-(4-hydroxy-4-(hydroxymethyl)piperidin-1-yl)pyridin-3-yl)piperidine-2,6-dione (Z-1)
  • Step 2 Synthesis of 1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-4-hydroxypiperidine-4-carbaldehyde (Intermediate Z)
  • intermediate P the pyrazolo[1,5-a]pyrimidine-3-amine hydrochloride was replaced by 2-amino-6-(trifluoromethyl)pyridine, and intermediate AC was prepared in the same manner.
  • Step 1 Synthesis of tert-butyl 4-(6-carbamoyl-5-isopropoxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (AD-1)
  • Step 4 Synthesis of tert-butyl 4-(6-((3-cyanopyrrolo[1,2-b]pyridazin-7-yl)carbamoyl)-5-isopropoxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (AD-5)
  • Step 5 Synthesis of N-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-5-isopropoxy-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide (Intermediate AD)
  • tert-butyl 4-(6-((3-cyanopyrrolo[1,2-b]pyridazin-7-yl)carbamoyl)-5-isopropoxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (AD-5, 60 mg, 0.11 mmol) was dissolved in dichloromethane (8 mL), and a hydrochloric acid dioxane solution (2.0 mL, 4 N) was slowly added dropwise, and stirred at room temperature for 6 hours. After the reaction was completed, the mixture was filtered and the filter cake was freeze-dried to obtain the title compound (42 mg).
  • intermediate B the piperazine-1-carboxylic acid tert-butyl ester was replaced with 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, and intermediate AE was prepared in the same manner.
  • Step 3 Synthesis of tert-butyl 4-(6-(chlorocarbonyl)-5-hydroxybenzo[d]thiazol-2-yl)piperazine-1-carboxylate (AJ-3)
  • Step 4 Synthesis of tert-butyl 4-(5-hydroxy-6-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperazine-1-carboxylate (AJ-4)
  • Step 5 Synthesis of tert-butyl 4-(5-(2-hydroxy-2-methylpropoxy)-6-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)benzothiazol-2-yl)piperazine-1-carboxylate (AJ-5)
  • Step 6 Synthesis of 5-(2-hydroxy-2-methylpropoxy)-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(piperazin-1-yl)benzo[d]thiazole-6-carboxamide hydrochloride (Intermediate AJ)
  • tert-butyl 4-(5-(2-hydroxy-2-methylpropoxy)-6-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)benzothiazol-2-yl)piperazine-1-carboxylate (AJ-5, 12 mg, 0.02 mmol) was dissolved in dichloromethane (2 mL), and a hydrochloric acid dioxane solution (0.5 mL, 4 N) was slowly added dropwise, and the mixture was stirred at room temperature for 6 h. After the reaction was completed, the mixture was filtered and the filter cake was freeze-dried to obtain the title compound (9.8 mg).
  • intermediate P the pyrazolo[1,5-a]pyrimidine-3-amine hydrochloride was replaced with 3-aminopyrazolo[1,5-a]pyrimidine-6-carbonitrile, and intermediate AK was prepared in the same manner.
  • intermediate P the pyrazolo[1,5-a]pyrimidine-3-amine hydrochloride was replaced with 3-amino-1-cyclopropylpyridin-2-(1H)-one, and intermediate AL was prepared in the same manner.
  • Example 8 Synthesis of 2-(4-((2-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)-2-azaspiro[3.5]nonan-7-yl)methyl)piperazin-1-yl)-5-isopropoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzo[d]thiazole-6-carboxamide (Compound 8)
  • intermediate B was replaced by intermediate I
  • intermediate C was replaced by intermediate K
  • compound 10 was prepared in the same manner.
  • intermediate B was replaced by intermediate I
  • intermediate C was replaced by intermediate L
  • compound 11 was prepared in the same manner.
  • intermediate B was replaced by intermediate P
  • intermediate C was replaced by intermediate D
  • compound 16 was prepared in the same manner.
  • Example 17 Synthesis of 2-(4-((1-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-isopropoxybenzo[d]thiazole-6-carboxamide (Compound 17)
  • intermediate B was replaced by intermediate Q
  • intermediate C was replaced by intermediate D
  • compound 18 was prepared in the same manner.
  • intermediate B 32 mg, 74.85 ⁇ mol
  • intermediate R 32.82 mg, 89.82 ⁇ mol
  • 1-hydroxybenzotriazole 15.16 mg, 112.28 ⁇ mol
  • 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 21.56 mg, 112.28 ⁇ mol
  • N, N-diisopropylethylamine 28.97 mg, 224.55 ⁇ mol
  • intermediate B was replaced by intermediate Q
  • intermediate C was replaced by intermediate V
  • compound 24 was prepared in the same manner.
  • Step 1 Synthesis of tert-butyl 4-(4-(5-isopropoxy-6-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)piperidine-1-carboxylate (31a)
  • Step 2 Synthesis of 5-isopropoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-(piperidin-4-yl)piperazin-1-yl)-3a,4-dihydrobenzo[d]thiazole-6-carboxamide (31b)
  • tert-butyl 4-(4-(5-isopropoxy-6-((1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl)benzo[d]thiazol-2-yl)piperazin-1-yl)piperidine-1-carboxylate (31a, 40 mg, 0.07 mmol) was dissolved in dichloromethane (4 mL) and hydrochloric acid-dioxane (2 mL), and the reaction mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to give the title compound (35 mg).
  • Step 3 Synthesis of 2-(4-(1-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)azetidin-3-yl)methyl)piperidin-4-yl)piperazin-1-yl)-5-isopropoxy-N-(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)benzo[d]thiazole-6-carboxamide (Compound 31)
  • intermediate B was replaced by intermediate AC
  • intermediate C was replaced by intermediate D
  • compound 32 was prepared in the same manner.
  • intermediate B was replaced by intermediate AD
  • intermediate C was replaced by intermediate D
  • compound 33 was prepared in the same manner.
  • Example 36 Synthesis of 2-(4-((4-(3-(2,4-dioxo-tetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyridin-6-yl)piperazin-1-yl)methyl)cyclohexyl)-N-(1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-isopropoxybenzo[d]thiazole-6-carboxamide (Compound 36)
  • intermediate B was replaced by intermediate AG, and intermediate C was replaced by intermediate L, and compound 36 was prepared in the same manner.
  • intermediate B was replaced by intermediate AG
  • intermediate C was replaced by intermediate AH
  • compound 37 was prepared in the same manner.
  • Example 38 Synthesis of 2-(4-((1-(4-(2,6-dioxopiperidin-3-yl)-3,5-difluorophenyl)piperidin-4-yl)methyl)piperazin-1-yl)-N-(1-((1S,2R)-2-fluorocyclopropyl)-2-oxo-1,2-dihydropyridin-3-yl)-5-isopropoxybenzo[d]thiazole-6-carboxamide (Compound 38)
  • Example 40 Synthesis of 2-(4-((1-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)methyl)piperazin-1-yl)-5-isopropoxy-N-(pyrazolo[1,5-a]pyrimidin-3-yl)benzo[d]thiazole-6-carboxamide (Compound 40)
  • intermediate B was replaced by intermediate P
  • intermediate C was replaced by intermediate Y
  • compound 40 was prepared in the same manner.
  • intermediate B was replaced by intermediate Q
  • intermediate C was replaced by intermediate Z
  • compound 41 was prepared in the same manner.
  • intermediate B was replaced by intermediate P
  • intermediate C was replaced by intermediate M
  • compound 43 was prepared in the same manner.
  • Example 48 Synthesis of N-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-3-yl)-2-(4-((1-(5-(2,6-dioxopiperidin-3-yl)pyridin-2-yl)piperidin-4-yl)methyl)piperazin-1-yl)-5-isopropoxybenzo[d]thiazole-6-carboxamide (Compound 48)
  • intermediate B was replaced by intermediate AL
  • intermediate C was replaced by intermediate D
  • compound 48 was prepared in the same manner.
  • Test Example 1 HiBiT method to detect the degradation effect of compounds on IRAK4 in THP-1-HiBiT-IRAK4 overexpressing cells
  • THP-1-HiBiT-IRAK4 cells (constructed by Shanghai Medicilon) were inoculated in a 96-well flat-bottom white plate (Corning, Catalog No.: 3917) with a seeding density of 60,000 cells/25 ⁇ L/well. Then 25 ⁇ L/well of concentration gradient compounds were added (the final concentration of the compound was: starting concentration 5 ⁇ M, 5-fold gradient dilution, a total of 8 concentration points), mixed well and incubated in a 37°C, 5% CO 2 incubator for 24 hours.
  • sample treatment group cells + concentration gradient compounds
  • solvent control group cells + solvent control
  • blank control group only culture medium was added
  • 50 ⁇ L Nano-Glo HiBiT Lytic Detection buffer Promega, Catalog No.: N3040
  • the fluorescence value RLU was read by an enzyme reader (PE Envision).
  • the degradation rate of the compound on IRAK4 % (1-(RLU value of the sample treatment group-RLU value of the blank control group)/(RLU value of the solvent control group-RLU value of the blank control group)) ⁇ 100%, and the degradation rate and maximum degradation rate Dmax of the compound at each concentration were calculated.
  • the nonlinear fitting of compound concentration-degradation rate was performed using Graphpad Prism 9 software to obtain the degradation activity curve of the compound, and the half-degradation concentration (DC 50 ) of the compound was calculated.
  • the D max and DC 50 values of the tested compounds are shown in Table 1.
  • liver microsomes human liver microsomes (Corning 452117), CD-1 mouse liver microsomes (XENOTECH M1000)
  • the t 1/2 value calculated by the above formula is shown in Table 3.
  • the test data show that the disclosed compound has good liver microsome stability.
  • the water bath, incubator and ultracentrifuge are all set to 37°C, and the rotor is pre-incubated in the 37°C incubator for about 30 minutes.
  • Free rate % (peak area ratio of ultracentrifuged samples /peak area ratio of non-centrifuged control samples ) ⁇ 100%
  • Binding rate % 100% - free rate %
  • Test Example 4 Determination of membrane permeability and transport properties of the disclosed compounds
  • membrane permeability and transport properties of the disclosed compounds were determined using the following test methods.
  • Fetal bovine serum (FBS) (Sigma WXBD0055V), fluorescent yellow (Sigma MKCJ3738), NaHCO 3 (Sigma SLBZ4647)
  • HBSS Balanced Salt Solution
  • NEAA Non-Essential Amino Acids
  • Trpsin/EDTA Trypsin/EDTA
  • TEER value TEER ( ⁇ ) measured value ⁇ membrane area (cm 2 )
  • the resistance of the monolayer cell membrane is ⁇ 230 ⁇ cm 2 , indicating that the monolayer cell membrane has poor compactness and cannot be used for the experiment.
  • the fluorescence value of Caco-2 cell monolayer was calculated using the following formula:
  • I acceptor refers to the fluorescence density on the receiving side (0.3 mL), and I donor refers to the fluorescence density on the donating side (0.1 mL).
  • LY>1.0% indicates poor cell monolayer membrane tightness, and the corresponding results will be excluded from the evaluation.
  • VA is the volume of the receiving end solution (A ⁇ B is 0.3 mL, B ⁇ A is 0.1 mL), Area is the Transwell-96 plate membrane area (0.143 cm 2 ); incubation time is the incubation time (unit: s).
  • P app(BA) is the apparent permeability from the base to the apex
  • P app(AB) is the apparent permeability from the apex to the base.
  • the calculated apparent permeability coefficient and efflux ratio of the disclosed compound are shown in Table 5.
  • the test data show that the disclosed compound has good Caco-2 permeability.
  • Test Example 5 Inhibitory Effects of the Disclosed Compounds on CYP2C9, CYP2D6, and CYP3A4 Enzyme Activities
  • the inhibition of the disclosed compounds on the enzyme activities of CYP2C9, CYP2D6, and CYP3A4 was determined using the following test method.
  • Positive substrates diclofenac sodium (Dalian Meilun MB1277), dextromethorphan hydrobromide (Dalian Meilun MB1568) and midazolam (Cerilliant M-908)
  • IC 50 values of the disclosed compounds against CYP2C9, CYP2D6 and CYP3A4 were calculated by Excel XLfit 5.3.1.3 and are shown in Table 6.
  • the test data show that the disclosed compounds have no significant inhibitory effect on CYP2C9, CYP2D6 and CYP3A4.
  • Test Example 6 Determination of the Potential Inhibitory Effect of the Disclosed Compounds on Voltage-Gated Potassium Ion Channel hERG
  • This experiment uses Chinese hamster ovary (CHO) cells (B'SYS GmbH) that stably express hERG potassium channels.
  • the hERG-CHO cells were clamped with the SyncroPatch 384i/384 (Nanion) automatic patch clamp system to form a whole-cell voltage clamp mode, and the hERG current was induced with the corresponding voltage.
  • the test compound was tested: first, the cells were perfused 6 times with extracellular fluid containing 0.1% DMSO, and the measured stable hERG current was used as the detection baseline.
  • the baseline current value was the average of 5 stable sampling points (tail current size blank ).
  • tail current inhibition rate (%) [1-(tail current size compound -tail current size positive control )/(tail current size blank -tail current size positive control )] ⁇ 100 ⁇ , and then the dose-effect curve was fitted by Graphpad Prism 8.0 software, and the IC 50 value was calculated.
  • the inhibition of hERG by the disclosed compounds is shown in Table 7 below.
  • the test data show that the hERG inhibition activity of the disclosed compounds is poor and the potential safety risk in the future is relatively small.
  • K 2 EDTA anticoagulant tube was purchased from Jiangsu Xinkang Medical Instrument Co., Ltd.
  • Drug preparation Weigh a certain amount of the disclosed compound and dissolve it in 20% PEG400 + 4% 1M HCl + 76% (20% HP- ⁇ -CD) to prepare a 1 mg/mL solution for oral administration. Dilute the oral administration solution with 20% HP- ⁇ -CD to 0.2 mg/mL for intravenous administration.
  • Administration method Oral gavage group: CD-1 mice were given oral gavage without fasting, and the dosage was 10 mg/kg.
  • Intravenous group CD-1 mice were given intravenous administration without fasting, and the dosage was 1 mg/kg.
  • mice After oral or intravenous administration to mice, more than 20 ⁇ L of blood was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 h after administration and added to K 2 EDTA anticoagulant tubes. The plasma was separated by centrifugation at 12000 rpm, 4°C for 5 minutes and stored at -20°C.
  • NA stands for not applicable; * indicates the solvent is 5% NMP + 20% PEG400 + 2.5% 1N HCl + 72.5% 20% HP- ⁇ -CD; ** indicates the solvent is 5% NMP + 2.5% 1M HCl + 72.5% 20% HP- ⁇ -CD + 20% water.
  • K 2 EDTA anticoagulant tube was purchased from Jiangsu Xinkang Medical Instrument Co., Ltd.
  • Drug preparation Weigh a certain amount of the disclosed compound and dissolve it in 20% PEG400 + 4% 1M HCl + 76% (20% HP- ⁇ -CD) to prepare a 1 mg/mL solution for oral administration. Dilute the oral administration solution with 20% HP- ⁇ -CD to 0.2 mg/mL for intravenous administration.
  • NA stands for not applicable; * indicates the solvent is 5% NMP + 2.5% 1M HC1 + 72.5% 20% HP- ⁇ -CD + 20% water.
  • K 2 EDTA anticoagulant tube was purchased from Jiangsu Xinkang Medical Instrument Co., Ltd.
  • Drug preparation Weigh a certain amount of the disclosed compound, dissolve it in 5% NMP + 2.5% 1M HCl + 72.5% 20% HP- ⁇ -CD + 20% water to prepare a 1.5 mg/mL solution for oral administration. Weigh a certain amount of the disclosed compound, dissolve it in 99.5% 5% HP- ⁇ -CD + 0.5% 1M HCl for intravenous administration.
  • Administration method Intragastric administration group: the dosage was 3 mg/kg.
  • Intravenous administration group the dosage was 1 mg/kg.
  • NA stands for not applicable; * stands for the solvent is 99% 20% HP- ⁇ -CD + 1% 1M HCl.

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Abstract

L'invention concerne un composé d'agent de dégradation ciblant IRAK4 ayant une structure de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, ou une composition pharmaceutique comprenant le composé ou le sel pharmaceutiquement acceptable de celui-ci. Le composé ou le sel pharmaceutiquement acceptable de celui-ci ou la composition pharmaceutique peut être utilisé pour prévenir ou traiter des maladies médiées par IRAK4, comprenant, entre autres, des tumeurs, des maladies inflammatoires, des maladies neurodégénératives ou des maladies auto-immunes.
PCT/CN2024/124493 2023-10-13 2024-10-12 Composé d'agent de dégradation ciblant irak4, et son utilisation Pending WO2025077891A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021127283A2 (fr) * 2019-12-17 2021-06-24 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
CN114502158A (zh) * 2019-06-28 2022-05-13 凯麦拉医疗公司 Irak降解剂及其用途
CN115052627A (zh) * 2019-12-17 2022-09-13 凯麦拉医疗公司 Irak降解剂和其用途
CN115710274A (zh) * 2021-08-23 2023-02-24 上海领泰生物医药科技有限公司 Irak4降解剂及其制备方法和应用
CN116410204A (zh) * 2021-12-31 2023-07-11 爱科诺生物医药(香港)有限公司 具有irak4抑制活性的化合物，包含其的药物组合物，及其应用
CN116867758A (zh) * 2020-12-30 2023-10-10 凯麦拉医疗公司 Irak降解剂和其用途

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114502158A (zh) * 2019-06-28 2022-05-13 凯麦拉医疗公司 Irak降解剂及其用途
WO2021127283A2 (fr) * 2019-12-17 2021-06-24 Kymera Therapeutics, Inc. Agents de dégradation d'irak et leurs utilisations
CN115052627A (zh) * 2019-12-17 2022-09-13 凯麦拉医疗公司 Irak降解剂和其用途
CN116867758A (zh) * 2020-12-30 2023-10-10 凯麦拉医疗公司 Irak降解剂和其用途
CN115710274A (zh) * 2021-08-23 2023-02-24 上海领泰生物医药科技有限公司 Irak4降解剂及其制备方法和应用
CN116410204A (zh) * 2021-12-31 2023-07-11 爱科诺生物医药(香港)有限公司 具有irak4抑制活性的化合物，包含其的药物组合物，及其应用

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