WO2024021957A1 - Inhibiteur de prmt5, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Inhibiteur de prmt5, son procédé de préparation et son utilisation pharmaceutique Download PDF

Info

Publication number
WO2024021957A1
WO2024021957A1 PCT/CN2023/102508 CN2023102508W WO2024021957A1 WO 2024021957 A1 WO2024021957 A1 WO 2024021957A1 CN 2023102508 W CN2023102508 W CN 2023102508W WO 2024021957 A1 WO2024021957 A1 WO 2024021957A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
substituted
deuterium
halogen
group
Prior art date
Application number
PCT/CN2023/102508
Other languages
English (en)
Chinese (zh)
Inventor
邓海兵
刘建
杨飞
喻红平
陈椎
徐耀昌
Original Assignee
上海和誉生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海和誉生物医药科技有限公司 filed Critical 上海和誉生物医药科技有限公司
Publication of WO2024021957A1 publication Critical patent/WO2024021957A1/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and specifically relates to a PRMT5 inhibitor, its preparation method and pharmaceutical application.
  • Epigenetic gene regulation is an important biological regulatory mechanism for protein synthesis and cell differentiation, and plays an important role in many human diseases.
  • Epigenetic regulation involves the modulation of inheritable genetic material without changing its nucleic acid sequence.
  • epigenetic regulation is controlled by selective and reversible modifications (such as methylation) of DNA and proteins (such as histones) to control the transition between transcriptionally active and inactive states in chromatin conformation. Modification of these covalent bonds can be controlled by enzymes such as methyltransferases (such as PRMT5), many of which are associated with specific genetic changes in many human disease-causing genes.
  • PRMT5 plays an important role in many diseases such as tumors, metabolic diseases and hematological diseases.
  • Homozygous deletions of tumor suppressor genes are tumor drivers and often result in deletions of passenger genes near the suppressor genes. Loss of these passenger genes creates tumor cell-specific vulnerabilities that can be targeted with targeted therapies.
  • Homozygous deletions of chromosome 9p21 which contains the well-known tumor suppressor gene CDKN2A, occur in 15% of tumors and often contain deletions of the passenger gene MTAP.
  • MTAP is a key enzyme in the methionine and adenine recycling pathway. The absence of MTAP leads to the accumulation of its substrate, MTA. MTA is structurally similar to S-adenosylmethionine (SAM), which is a methyl substrate donor for type II methyltransferase PRMT5.
  • SAM S-adenosylmethionine
  • PRMT5 is a very important gene for cells. Studies on conditional knockout of PRMT5 or siRNA knockout all suggest that inhibiting PRMT5 in normal tissues will have significant side effects. (For example, blood cell reduction, infertility, skeletal muscle loss, cardiac hypertrophy, etc.). Therefore, new strategies are needed to apply and explore this metabolic susceptibility, selectively targeting PRMT5 in MTAP-deficient tumors and avoiding the effects of PRMT5 in normal tissues (MTAP wild-type).
  • Small molecule inhibitors targeting PRMT5 that work together with MTA can selectively target only PRMT5 in the MTA-bound state, and this kind of PRMT5 is only enriched in tumor cells with MTAP deficiency, so in normal cells with intact MTAP When MTA levels are very low in cells, PRMT5 will not be targeted, providing a better therapeutic window.
  • the object of the present invention is to provide a PRMT5 inhibitor, its preparation method and pharmaceutical application.
  • the series of compounds of the present invention have a strong inhibitory effect on PRMT5 and can be widely used in the preparation of drugs for treating and/or preventing PRMT5-mediated diseases, thereby promising to develop a new generation of PRMT5 inhibitors.
  • a first aspect of the invention provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof:
  • X 1 is CR 6 or N
  • X 2 is CR 7 or N
  • X 3 is CR 8 or N
  • Ring A is C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • Ring B is selected from a 4-10-membered nitrogen-containing heterocyclyl group or a 5-10-membered nitrogen-containing heteroaryl group, and the nitrogen atom is connected to a carbonyl group, wherein,
  • ring B is selected from a 4-membered nitrogen-containing heterocyclic group, an 8-10-membered nitrogen-containing heterocyclic group or an 8-10-membered nitrogen-containing heteroaryl group,
  • Ring C is C 3-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, and the C 3-12 cycloalkyl or 4-12 membered heterocycle
  • the base is optionally condensed on a C 6-10 aryl group or a 5-10 membered heteroaryl group, and the C 6-10 aryl group or 5-10 membered heteroaryl group is optionally condensed on a C 3-12 cycloalkyl group or 4-12 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alky
  • ring B is selected from a 5-7 membered nitrogen-containing heterocyclyl group or a 5-7 membered nitrogen-containing heteroaryl group
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O) R 11 , -C 0-8 alkyl-OC(O)R 11 , -C 0-8 alky
  • R 1 ' is selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -10 aryl, 5-10 membered heteroaryl, -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)R 11 and -C(O)NR 12 R 13 , the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered hetero Aryl,
  • Each R 1 ′′ is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS (O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , - C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl Base-OC(O)R 11 , -C 0-8 al
  • Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is selected from CR 1 , wherein at least one R 1 is -C 0-8 alkyl -NR 14 R 15 or - OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, C 2-10 chain Alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl- SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-
  • Each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0 -8alkyl -SF 5 , -C 0-8alkyl -OS(O) 2 R 9 , -C 0-8alkyl -S(O) r R 9 , -C 0-8alkyl -OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0- 8alky
  • Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS( O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl-OR 10 , -C 0-8 alkyl-C(O)OR 10 , -C 0-8 alkyl-C(O)SR 10 , -C 0-8 alkyl-SC(O)R 11 , -C 0-8 alkyl-C(O)R 11 , -C 0-8 alkyl -OC(O)R 11 , -C 0-8 alky
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azide, C 1-10 alkyl, halogen-substituted C 1-10 alkyl, deuterium-substituted C 1- 10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl , -C 0-8 alkyl-SF 5 , -C 0-8 alkyl-OS(O) 2 R 9 , -C 0-8 alkyl-S(O) r R 9 , -C 0-8 alkyl Base -OR 10 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -SC(O)R 11 ,
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-10 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl base, -C 0-8 alkyl -SF 5 , -C 0-8 alkyl -C(O)OR 10 , -C 0-8 alkyl -C(O)SR 10 , -C 0-8 alkyl -C(O)R 11 , -C 0-8 alkyl-P(O)(R 11 ) 2 and -C 0-8 alkyl-C(O)NR 12 R 13 , or, R 14 and R 15
  • the nitrogen atom directly connected to it together forms a 4-10-membered heterocyclyl group or a 5-10-membered heteroaryl group, and the above-mentioned groups are independently optionally further optionally substituted by one or more members selected from the group consisting of deuterium,
  • Each r is independently 0, 1, or 2;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • p is selected from 0, 1, 2, 3, 4 or 5.
  • R 3 and R 4 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 Alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl and 3-6 membered hetero ring base.
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, and cyano. , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-
  • R 6 , R 7 and R 8 are each independently selected from hydrogen, deuterium, halogen, cyanide base, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl , 3-6 membered heterocyclic group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl- C(O)OR 10 , -C 0-4 alkyl-C(O)SR 10 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-P(O)( R 11 ) 2 and -C 0-4 alkyl -C(O)NR 12 R 13 , or R 14 and R 15 together with the nitrogen atom directly connected to form a 4-6 membered heterocyclic group or 5-8 membered Heteroaryl, the above groups are independently optionally further substituted by one or more selected from deuterium,
  • R 14 and R 15 are each independently selected from hydrogen, deuterium, C 1-4 alkyl , Halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -SF 5 , -C(O)OR 10 , -C(O)SR 10 , -C(O)R 11 , -P(O)(R 11 ) 2 and -C(O)NR 12 R 13 ; where , R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl , -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl Base -OR 10 , -C 0-4 alkyl -C(O)OR 10 , -C 0-4 alkyl -C(O)SR 10 , -C 0-4 alkyl -SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -
  • each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1 -4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl Base, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted
  • each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, C 1- 4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 yuan Heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0- 4alkyl -S(O) r R 9 , -C 0-4alkyl -OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)OR 10 , -C 0-4alkyl -C(O)SR 10 , -C 0-4 alkyl-SC(
  • ring B is selected from a 4-membered nitrogen-containing heterocyclic group
  • Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle
  • the base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl
  • the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • ring B is selected from an 8-10 membered nitrogen-containing heterocyclic group
  • Ring C is C 3-6 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl, and the C 3-6 cycloalkyl or 4-8 membered heterocycle
  • the base is optionally fused to C 6-8 aryl or 5-8 membered heteroaryl
  • the C 6-8 aryl or 5-8 membered heteroaryl is optionally fused to C 3-6 cycloalkyl or 4-8 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m
  • Y 1 and Y 2 are each independently CR 1 or N
  • Y 3 is O
  • Y 4 and Y 5 are each independently CR 1 " or N;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 alkyl -OS(O) 2 R 9 , - C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl-C (O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -
  • Each R 1 ′′ is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl-SF 5 , -C 0-4 alkyl-OS(O) 2 R 9 , -C 0-4 alkyl-S(O) r R 9 , -C 0-4 alkyl-OR 10 , -C 0-4 alkyl-C(O)OR 10 , -C 0-4 alkyl- C(O)SR 10 , -C 0-4 alkyl-SC(O)R 11 , -C 0-4 alkyl-C(O)R 11 , -C 0-4 alkyl-OC(O)R 11 , -C 0-4alkyl -P(O
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • Ring B is selected from 5-7 membered nitrogen-containing heterocyclic groups, and ring C is formed together with -(R 1 ) m
  • Y 6 , Y 7 , Y 8 and Y 9 are each independently CR 1 or N, and at least one is CR 1 , wherein at least one R 1 is -C 0-4 alkyl -NR 14 R 15 or -OC 1-4 alkyl-NR 14 R 15 , each other R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, -C 0-4 alkyl -SF 5 , -C 0-4 Alkyl-OS(O) 2 R 9
  • R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 and r are as described for the compound of formula (I).
  • X 1 is CR 6 or N
  • X 2 is CR 7 or N
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • Each R 7 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • Each R 8 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • the compound of formula (I) has the following compound structure of formula (II):
  • Y 1 and Y 2 are each independently CR 1 or N, and Y 3 is O, S or NR 1 ';
  • Ring A is C 4-8 cycloalkyl, 4-8 membered heterocyclyl, C 6-8 aryl or 5-8 membered heteroaryl;
  • Ring B together with -(R 2 ) p forms the following structure:
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl, C 6-8 aryl, 5-8-membered heteroaryl, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C (O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , - NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 , the above groups are independently optionally further substituted by one or more selected from deuterium, halogen, cyano group , C 1-4 al
  • Each R 2 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl , C 2-4 alkynyl group, C 3-6 cycloalkyl group, 3-6 membered heterocyclyl group, C 6-8 aryl group, 5-8 membered heteroaryl group, -SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , -C(O)R 11 , -OC (O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R 12 )-C(O)R 11 ;
  • R 2 ' is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl base and 3-6 membered heterocyclyl;
  • Each R 5 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, hydroxyl-substituted C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl Base, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, - SF 5 , -OS(O) 2 R 9 , -S(O) r R 9 , -OR 10 , -C(O)OR 10 , -C(O)SR 10 , -SC(O)R 11 , - C(O)R 11 , -OC(O)R 11 , -P(O)(R 11 ) 2 , -NR 12 R 13 , -C(O)NR 12 R 13 and -N(R
  • R 6 is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 Alkynyl, C 1-4 alkoxy, halogen-substituted C 1-4 alkoxy, deuterium-substituted C 1-4 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, 3 -6-membered heterocyclyl, 3-6-membered heterocyclicoxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, hydroxyl and -NR 12 R 13 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 , n, p and r are as described in the compound of formula (I).
  • X 1 is CR 6 or N
  • X 2 is CH or N
  • Each R 6 is independently selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl, C 3-6 cycloalkyl , 3-6 membered heterocyclyl, -SF 5 and -OR 10 ;
  • R 9 , R 10 , R 11 , R 12 , R 13 and r are as described for the compound of formula (I).
  • the compound of formula (I) has the following compound structure of formula (III 1 ) or formula (III 2 ):
  • Ring A together with its directly connected parts forms the following structure:
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, dimethyl amino, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, dimethylaminoethoxy, cyclopropyl, cyclobutyl, piperidyl, piperazinyl, morpholinyl, methyl base-substituted piperidinyl, ethyl-substituted piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
  • R 1 ' is selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, dimethylamino-substituted methyl, dimethylamino-substituted ethyl, cyclopropyl , cyclobutyl, piperidinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl and tetrahydropyranyl;
  • Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF 5 and hydroxyl;
  • Each R is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, cyclopropyl, -SF and hydroxyl;
  • p is selected from 0, 1 or 2.
  • Ring A together with its directly connected parts forms the following structure:
  • R 1 is selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methylamino, Dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidinyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted piperidinyl , cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazine and tetrahydropyranyl;
  • Each R 2 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  • the compound of formula (I) has the following formula (IV 1 ), formula (IV 2 ), formula ( IV 3 ) or compound structure of formula (IV 4 ):
  • Each R 1 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, ethyl, isopropyl, trifluoromethyl, trideuteromethyl, methoxy, trifluoromethoxy, amino, methyl amino, dimethylamino-substituted ethyl, dimethylamino-substituted ethoxy, cyclopropyl, piperidyl, piperazinyl, morpholinyl, methyl-substituted piperidinyl, ethyl-substituted Piperidinyl, cyclopropyl-substituted piperidinyl, methyl-substituted piperazinyl, cyclopropyl-substituted piperazinyl and tetrahydropyranyl;
  • Each R 2a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 2b is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5a is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5b is independently selected from hydrogen, deuterium, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 5c is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl and cyclopropyl;
  • Each R 6 is independently selected from hydrogen, deuterium, fluorine, chlorine, methyl, trifluoromethyl, trideuteromethyl, and cyclopropyl.
  • the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt includes but is not limited to the following compounds:
  • a second aspect of the present invention provides a method for preparing a compound of formula (I), its stereoisomer, or a pharmaceutically acceptable salt thereof, which includes the following steps: reacting a compound of formula (Ia) with a compound of formula (Ib) to generate a compound of formula ( I) compound, the reaction formula is as follows:
  • X is hydroxyl or halogen
  • ring A, ring B, ring C, R 1 , R 2 , R 3 , R 4 , R 5 , X 1 , X 2 , ) compound is defined.
  • the third aspect of the present invention provides a pharmaceutical composition, including a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the fourth aspect of the present invention provides a use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of drugs for treating MATP-related tumors.
  • the tumor is selected from the group consisting of cell tumor, lymphoma, leukemia, osteoma, malignant teratoma, intraepithelial carcinoma, adenoma, fibroma, melanoma, fallopian tube cancer, bladder cancer, and teratoma , embryonal carcinoma, choriocarcinoma, lipoma, liver cancer, cholangiocarcinoma, lung cancer, gastric cancer, hemangioma, gallbladder cancer, ampullary cancer, malignant melanoma, nevus, dysplastic nevus, myeloproliferative diseases, Hodgkin's disease, Chordoma, myxoma, rhabdomyomas, leiomyoma, hamartoma, mesothelioma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, viperoma, granuloma, xanthoma, de
  • the cell tumor is selected from the group consisting of granulosa-theca cell tumor, Sertoli cell tumor, germ cell tumor, nephroblastoma, seminoma, hepatoblastoma, malignant fibrous histiocytoma, chondroblastoma, blastoma, giant cell tumor, astrocytoma, medulloblastoma, glioblastoma multiforme, oligodendrogliomas, retinoblastoma, squamous cell carcinoma, clear cell carcinoma, transitional cell carcinoma , stromal cell carcinoma and basal cell carcinoma;
  • the lymphoma is selected from malignant lymphoma and non-Hodgkin lymphoma;
  • the leukemia is selected from the group consisting of acute and chronic myeloid leukemia, acute lymphoblastic leukemia and chronic lymphocytic leukemia;
  • the osteoma is selected from the group consisting of osteochondroma, benign enchondroma, osteoid osteoma, chondromatoid hamartoma, multiple myeloma and cranioma;
  • the adenoma is selected from the group consisting of fibroadenoma, adenomatoid tumor, hepatocellular adenoma, bronchial adenoma, tubular adenoma, villous adenoma, breast cancer, pancreatic cancer, endometrial adenocarcinoma, prostate cancer, ductal adenoma carcinoma and colorectal adenocarcinoma;
  • the fibroma is selected from the group consisting of fibroma, chondromyxofibroma, neurofibroma and spinal neurofibroma;
  • the myeloproliferative disease is selected from the group consisting of multiple myeloma and myelodysplastic syndrome;
  • the lung cancer is selected from bronchial lung cancer and alveolar cancer;
  • the sarcoma is selected from the group consisting of fibrosarcoma, botryoid sarcoma, angiosarcoma, Kaposi's sarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, liposarcoma, leiomyosarcoma and meningiosarcoma.
  • the present invention also relates to the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, which is used as a PRMT5 inhibitor drug.
  • the present invention also relates to the use of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt in the preparation of medicaments for the treatment and/or prevention of PRMT5-mediated diseases.
  • the present invention also relates to a method for treating and/or preventing PRMT5-mediated diseases, which comprises administering to a patient in need a therapeutically effective amount of the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof .
  • a PRMT5 inhibitor with the following formula (I) structure.
  • the series of compounds of the present invention can be widely used in the preparation of drugs for the treatment and/or prevention of PRMT5-mediated diseases. , is expected to be developed into a new generation of PRMT5 inhibitors. On this basis, the present invention was completed.
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group, preferably including a linear alkyl group and a branched alkyl group of 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-Dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl Propyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methyl
  • C 1-10 alkyl refers to straight-chain alkyl groups and branched-chain alkyl groups having 1 to 10 carbon atoms
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms. Containing branched chain alkyl groups, "C 0-8 alkyl” refers to straight-chain alkyl groups containing 0 to 8 carbon atoms and branched-chain alkyl groups, and “C 0-4 alkyl groups” refers to containing 0 to 4 carbon atoms straight-chain alkyl groups and branched-chain alkyl groups.
  • the alkyl group may be optionally substituted or unsubstituted.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ electron system.
  • the cycloalkyl group is divided into a monocyclic cycloalkyl group and a polycyclic cycloalkyl group, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups with to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, and "C 4-8 cycloalkyl” refers to cycloalkyl groups including 4 to 8 carbon atoms.
  • C 3-8 cycloalkyl refers to a cycloalkyl group including 3 to 8 carbon atoms
  • C 3-6 cycloalkyl refers to a cycloalkyl group including 3 to 6 carbon atoms, in:
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cycloctyl et al.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to a polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings. These may contain one or more (preferably 1, 2 or 3) double bonds, but no single ring has A fully conjugated ⁇ electron system. According to the number of shared spiro atoms between the rings, spirocycloalkyl groups are divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups. Spirocycloalkyl groups include but are not limited to:
  • Condensed cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, in which one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups.
  • the fused ring alkyl groups include but are not limited to:
  • Bridged cycloalkyl refers to an all-carbon polycyclic group in which any two rings share two non-directly connected carbon atoms. These may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated ⁇ electron system. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Bridged cycloalkyl groups include but are not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Cycloalkyl or “carbocycle” may be optionally substituted or unsubstituted.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a fully conjugated ⁇ electron system, and one or more (preferably 1, 2, 3 or 4) ring atoms in the heterocyclyl group are selected from N, O, N ⁇ O or heteroatoms of S(O) r (where r is an integer 0, 1, 2), excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon.
  • Preferred heterocyclyl groups include 3 to 12 or 3 to 8 or 3 to 6 ring atoms.
  • 3-6 membered heterocyclyl refers to heterocyclyl groups containing 3 to 6 ring atoms
  • 3- "8-membered heterocyclyl” refers to a heterocyclic group containing 3 to 8 ring atoms
  • 4-8-membered heterocyclyl refers to a heterocyclic group containing 4 to 8 ring atoms
  • “4-10-membered heterocyclyl” refers to a heterocyclic group containing 4 to 10 ring atoms
  • 5-8-membered heterocyclyl refers to a heterocyclic group containing 5 to 8 ring atoms
  • 3-12-membered heterocyclyl refers to a heterocyclic group containing 3 to 12 ring atoms.
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between single rings, in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O , N ⁇ O or S(O) r (where r is an integer 0, 1, 2) heteroatoms, and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but no ring has a fully conjugated pi electron system.
  • spiroheterocyclyl groups are divided into single spiroheterocyclyl groups, double spiroheterocyclyl groups or polyspiroheterocyclyl groups.
  • Spiroheterocyclyl groups include, but are not limited to:
  • Condensed heterocyclyl refers to a polycyclic heterocyclyl in which each ring in the system shares an adjacent pair of atoms with every other ring in the system group, one or more (preferably 1, 2, 3 or 4) rings may contain one or more (preferably 1, 2 or 3) double bonds, but no ring has a fully conjugated ⁇ electron system, where One or more (preferably 1, 2, 3 or 4) ring atoms are selected from heteroatoms of N, O, N ⁇ O or S(O) r (where r is an integer 0, 1, 2), and the remaining ring atoms for carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups.
  • the fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. These may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings Having a fully conjugated ⁇ electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from N, O, N ⁇ O or S(O) r (where r is an integer 0, 1 , 2) heteroatoms, and the remaining ring atoms are carbon. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups. Bridged heterocyclyl groups include but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Heterocyclyl or “heterocycle” may be optionally substituted or unsubstituted.
  • Aryl or "aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a common Polycyclic (i.e., rings with adjacent pairs of carbon atoms) groups of the yoke ⁇ electron system, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, "C 6-10 aromatic "Basic” refers to an all-carbon aryl group containing 6-10 carbons, including but not limited to phenyl and naphthyl, and "C 6-8 aryl” refers to an all-carbon aryl group containing 6-8 carbons.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Aryl or "aromatic ring” may be substituted or unsubstituted.
  • Heteroaryl or “heteroaryl ring” refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms, including N, O, N ⁇ O and S (O) Heteroatom of r (where r is an integer 0, 1, 2), preferably a heteroaromatic system containing 5-10 or 5-8 or 5-6 ring atoms, for example, "5-8 membered”"Heteroaryl” refers to a heteroaromatic system containing 5-8 ring atoms, and "5-10-membered heteroaryl” refers to a heteroaromatic system containing 5-10 ring atoms, including but not limited to furyl and thienyl.
  • heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • Heteroaryl or “heteroaryl ring” may be optionally substituted or unsubstituted.
  • Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight chain or branched alkenyl group containing 2 to 10 or 2 to 4 carbons.
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl group containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl group containing 2-4 carbons.
  • Branched alkenyl Including but not limited to vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc.
  • Alkenyl may be substituted or unsubstituted.
  • Alkynyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight chain or branched chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight-chain or branched alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight-chain or branched alkynyl group containing 2-4 carbons.
  • Alkynyl Including but not limited to ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, etc.
  • Alkynyl may be substituted or unsubstituted.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, for example, “C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons, and “C 1-2 alkoxy” refers to an alkyloxy group containing 1-2 carbons, including but not limited to methoxy and ethoxy. , propoxy, butoxy, etc.
  • Alkoxy may be optionally substituted or unsubstituted.
  • Cycloalkoxy or “cycloalkyloxy” refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a group containing 3-12 Carbon cycloalkyloxy, “C 3-6 cycloalkoxy” refers to cycloalkyloxy containing 3-6 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy , cyclohexyloxy, etc.
  • Heterocyclyloxy or “heterocyclyloxy” refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy base, azetanyloxy group, nitrogen, oxanyloxy group, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group remaining after removing the hydroxyl group from C 1-10 alkyl acid. It is also usually expressed as “C 0-9 alkyl-C(O)-", for example, “C 1 "Alkyl-C(O)-” refers to acetyl; “C 2alkyl -C(O)-” refers to propionyl; “C 3alkyl -C(O)-” refers to butyryl or isobutyl acyl group.
  • -C 0-8 alkyl-C(O)SR 10 means that the carbonyl group in -C(O)SR 10 is attached to a C 0-8 alkyl group, wherein C 0-8 alkyl group is as defined above.
  • Halo-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy group refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, etc.
  • Deuterium-substituted C 1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally replaced by a deuterium atom. Including but not limited to monodeuterium methyl, dideuterium methyl, trideuterium methyl, etc.
  • Halogen refers to fluorine, chlorine, bromine or iodine
  • EA refers to ethanol
  • PE refers to petroleum ether
  • EtOAc refers to ethyl acetate
  • MeOH methyl alcohol
  • DCM dichloromethane
  • DMSO dimethyl sulfoxide
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes situations where the event or circumstance does or does not occur, that is, whether it is substituted or not. .
  • a heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but need not be present. This description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted means that one or more "hydrogen atoms" in a group are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with the chemical valence bond theory, which the person skilled in the art can determine without undue effort (either experimentally or theoretically) what is possible or impossible replacement. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated bond, such as an alkene.
  • Steps whose English name is stereoisomers, refer to isomers produced by the different spatial arrangements of atoms in the molecule. They can be divided into two types: cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers caused by the rotation of single bonds are called conformational isomers, sometimes also called rotamers. Stereoisomers caused by bond length, bond angle, double bonds in the molecule, rings, etc. are called configuration isomers (configuration stereo-isomers). Configuration isomers are divided into two categories.
  • the isomers caused by the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely become geometric isomers (geometric isomers), also called cis-trans isomers (cis-trans isomers), which are divided into Z, E two configurations.
  • geometric isomers also called cis-trans isomers (cis-trans isomers)
  • cis-trans isomers which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers.
  • the stereoisomers with different optical properties caused by the lack of anti-axial symmetry in the molecules are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" mentioned in the present invention can be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers.
  • “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts, including inorganic acid salts and organic acid salts. These salts can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or physiologically/pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. drug The purpose of the composition is to facilitate administration to the organism and facilitate the absorption of the active ingredients to exert biological activity.
  • the structure of the compound of the present invention is determined by nuclear magnetic resonance (NMR) or/and liquid mass spectrometry (LC-MS). NMR chemical shifts ( ⁇ ) are given in parts per million (ppm) units. NMR was measured using a Bruker AVANCE-400/500 nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), and the internal standard was It is tetramethylsilane (TMS).
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS tetramethylsilane
  • LC-MS was measured using an Agilent 6120 mass spectrometer.
  • HPLC was measured using Agilent 1200DAD high-pressure liquid chromatograph (Sunfire C18 150 ⁇ 4.6mm column) and Waters 2695-2996 high-pressure liquid chromatograph (Gimini C18 150 ⁇ 4.6mm column).
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for thin layer chromatography separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai Silica Gel 200 ⁇ 300 mesh silica gel as the carrier.
  • the starting materials in the embodiments of the present invention are known and can be purchased on the market, or can be synthesized using or according to methods known in the art.
  • 2-Amino-4-chlorobenzenethiol (3.00g, 18.8mmol), 1-methylpiperidine-4-carboxylic acid (2.69g, 18.8mmol), N,N-diisopropylethylamine (6.55 mL, 37.6 mmol) and 50% 1-propylphosphonic anhydride (12.0 g, 18.8 mmol) were dissolved in a 100 mL round-bottomed flask, replaced with nitrogen three times and stirred at 100°C overnight.
  • Intermediates 2 to 6 can be prepared by referring to all or part of the synthesis method of intermediate 1 and selecting corresponding raw materials:
  • Step 2 Synthesis of tert-butyl 4-methyl-2-oxopiperidine-1-carboxylate
  • Step 4 Synthesis of tert-butyl 4-methyl-6-(2-methylbenzo[d]thiazol-5-yl)-3,4-dihydropyridine-1(2H)-carboxylate
  • Intermediates 8 to 15 can be prepared by referring to all or part of the synthesis method of intermediate 7 and selecting corresponding raw materials:
  • Step 1 Synthesis of tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
  • Step 2 Synthesis of tert-butyl 5-(2-methylbenzo[d]thiazol-5-yl)-2,3-dihydro-4H-1,4-oxazine-4-carboxylate
  • Intermediates 17 to 19 can be prepared by referring to all or part of the synthesis method of intermediate 16 and selecting corresponding raw materials:
  • Step 1 Synthesis of methyl 4-amino-5-bromo-2-fluorobenzoate
  • Step 2 Synthesis of methyl 4-amino-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate
  • Step 3 Synthesis of methyl 4-amino-7-fluoro-1-methyl-1H-pyrazolo[4,3-c]quinoline-8-carboxylate
  • Intermediates 21-26 can be prepared by selecting corresponding raw materials by referring to all or part of the synthesis method of intermediate 20:
  • the reaction solution was diluted with water and extracted with tert-butyl methyl ether.
  • the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated by rotary evaporation.
  • the crude product was separated by normal phase column to obtain methyl 4-methyl-5-oxopentanoate (6.22g, yield 47.6%).
  • Step 3 Synthesis of: (S)-1-((R)-2-hydroxy-1-phenylethyl)-5-methylpiperidin-2-one
  • Step 6 Synthesis of tert-butyl (S)-5-methyl-2-oxopiperidine-1-carboxylate
  • Step 8 Synthesis of tert-butyl (S)-6-(benzo[d]thiazol-5-yl)-3-methyl-3,4-dihydropyridine-1(2H)-carboxylate
  • Embodiments 2 to 87 can be prepared by selecting corresponding raw materials with reference to all or part of the synthesis methods of Embodiments 1, 1-1, and 1-2:
  • HCT 116MTAP knockout and MTAP wild-type cells in a 96-well flat-bottom plate, and culture them in McCoy's 5A containing 10% fetal calf serum + 1% penicillin-streptomycin at 37°C and 5% CO2 . overnight.
  • the cell plate treated with the compound was continuously cultured at 37°C and 5% CO 2 for 6 days.
  • the series of compounds of the present invention have a strong inhibitory effect on the proliferation of human colon cancer HCT116 MTAP knockout cells at the cellular level.
  • the purpose of this test is to study the pharmacokinetic behavior of some compounds of the present invention.
  • the administration methods are: single oral administration (PO) to ICR mice, and the dosage is 10 mg/kg.
  • the compounds used in this test are derived from the specific example compounds of the present invention.
  • ICR mouse male N 3 Original source: Shanghai Sipur-Bika Experimental Animal Co., Ltd.
  • the blood collection time points are the 1st, 4th and 24th hour.
  • the samples are stored in a refrigerator at minus 20 degrees Celsius.
  • Kp is calculated from the AUC or concentration in brain or plasma measured by the above method. Kp refers to the relationship between drug concentrations in the brain and blood and is used to evaluate the ability of a drug to penetrate the blood-brain barrier. Kp after administration is calculated using the following formula:

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un inhibiteur de PRMT5, son procédé de préparation et son utilisation pharmaceutique. En particulier, la présente invention concerne un inhibiteur de PRMT5 ayant une structure de composé représentée dans la formule (I), son procédé de préparation, une composition pharmaceutique le contenant, son utilisation en tant qu'inhibiteur de PRMT5, et son utilisation dans le traitement et/ou la prévention d'une maladie médiée par PRMT5. La définition de chaque substituant dans le composé représenté par la formule (I) est la même que celle dans la description.
PCT/CN2023/102508 2022-07-26 2023-06-26 Inhibiteur de prmt5, son procédé de préparation et son utilisation pharmaceutique WO2024021957A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210885964 2022-07-26
CN202210885964.3 2022-07-26

Publications (1)

Publication Number Publication Date
WO2024021957A1 true WO2024021957A1 (fr) 2024-02-01

Family

ID=89705221

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/102508 WO2024021957A1 (fr) 2022-07-26 2023-06-26 Inhibiteur de prmt5, son procédé de préparation et son utilisation pharmaceutique

Country Status (1)

Country Link
WO (1) WO2024021957A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (fr) * 2020-02-12 2021-08-19 Amgen Inc. Nouveaux inhibiteurs de prmt5
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci

Similar Documents

Publication Publication Date Title
EP2604610B1 (fr) Dérivé de phtalazinone cétone, son procédé de préparation et utilisation pharmaceutique
WO2021129824A1 (fr) Nouvel inhibiteur du k-ras g12c
WO2020259432A1 (fr) Inhibiteur de kras-g12c
WO2021027911A1 (fr) Nouvel inhibiteur de k-ras g12c spirocyclique
TW201833108A (zh) 醯胺類衍生物抑制劑及其製備方法和應用
JP6034877B2 (ja) Ｐａｒｐ阻害剤としての縮合四環式または縮合五環式ジヒドロジアゼピノカルバゾロン
WO2021027943A1 (fr) Dérivé de pyrimidinopyridazinone et son utilisation médicale
WO2023098439A1 (fr) Dérivé de pyrazole, son procédé de préparation et son utilisation en médecine
TW201111356A (en) Nitrogen-containing compound and pharmaceutical composition
EP2928466B1 (fr) Utilisation de dérivés de maléimide pour la prévention et le traitement de la leucémie
TW201917129A (zh) 含吡唑基的三并環類衍生物、其製備方法和應用
JP2019515932A (ja) チロシンキナーゼｂｃｒ−ａｂｌ阻害剤としての新規複素環化合物
WO2023280136A1 (fr) Dérivé de pyrazino pyrazino quinolinone substitué par un trideutérométhyle, son procédé de préparation et son utilisation en médecine
WO2021249533A1 (fr) Composé modulateur du récepteur des oestrogènes et son utilisation
CN116462676A (zh) 一种多稠环prmt5抑制剂及其制备方法和应用
CN116462677A (zh) 一种多稠环prmt5抑制剂及其制备方法和应用
WO2023280182A1 (fr) Composé servant d'inhibiteur de kat6
CN110407854B (zh) 新的四环化合物
CN115427407B (zh) 一种新型n-杂环bet溴结构域抑制剂、其制备方法及医药用途
WO2024021957A1 (fr) Inhibiteur de prmt5, son procédé de préparation et son utilisation pharmaceutique
WO2022100738A1 (fr) Forme cristalline d'une base libre d'inhibiteur contenant un dérivé à noyau bicyclique, procédé de préparation et utilisation de la forme cristalline
CN113336774B (zh) 作为trk抑制剂的取代的手性二芳基大环化合物
CN115322158A (zh) 作为krasg12c蛋白抑制剂的取代喹唑啉类化合物
WO2022063333A1 (fr) Composé de pyrimidine carboxamide et son utilisation
WO2021249417A1 (fr) Composé hétérocyclique et son dérivé

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23845170

Country of ref document: EP

Kind code of ref document: A1