WO2020259478A1 - Composé tricyclique utilisé en tant qu'inhibiteur de prmt5 et son application - Google Patents

Composé tricyclique utilisé en tant qu'inhibiteur de prmt5 et son application Download PDF

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WO2020259478A1
WO2020259478A1 PCT/CN2020/097652 CN2020097652W WO2020259478A1 WO 2020259478 A1 WO2020259478 A1 WO 2020259478A1 CN 2020097652 W CN2020097652 W CN 2020097652W WO 2020259478 A1 WO2020259478 A1 WO 2020259478A1
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alkyl
acyl
group
amino
cycloalkyl
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Chinese (zh)
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王勇
赵立文
全旭
郑国闯
孙韡
詹康宁
杨婷婷
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南京圣和药物研发有限公司
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Publication of WO2020259478A1 publication Critical patent/WO2020259478A1/fr

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    • 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
    • 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
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
    • C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D471/08—Bridged systems
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention belongs to the field of medicinal chemistry, and specifically relates to tricyclic compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof as PRMT5 inhibitors, their preparation methods and pharmaceutical combinations containing these compounds And the use of these compounds or compositions for the treatment of PRMT5-mediated diseases.
  • DNA modification plays a central role in triggering gene expression programs at different stages of cell growth and development.
  • Arginine methylation plays an important role in cell processes, including signal transduction, transcription, RNA processing, DNA recombination and repair .
  • Protein arginine methyltransferases catalyze the methylation of specific arginine residues by transferring methyl groups from S-adenosylmethionine (SAM) to the guanidine nitrogen of arginine.
  • SAM S-adenosylmethionine
  • the different arginine methylation methods can divide PRMTs into three categories: Type I (PRMT 1, 2, 3, 4, 6 and 8) catalyzes monomethylation and asymmetric dimethylation, and type II (PRMT5). And PRMT9) catalyze monomethylation and symmetric dimethylation, while type III (PRMT7) only performs monomethylation.
  • PRMT5 specifically binds to methyltransferase complex protein 50 (MEP50), which can symmetrically methylate histones H3 and H4, and regulate the transcription of specific target genomes.
  • MEP50 methyltransferase complex protein 50
  • PRMT5 catalyzed histone H3 arginine 8 (R8) and H4R3 symmetric dimethylation has been shown to inhibit the expression of several tumor suppressor genes, such as tumor suppressor gene 7 (ST7), retinoblastoma (RB) tumor suppressor genes Family and receptor type O protein tyrosine phosphatase (PTPROt).
  • T7 tumor suppressor gene 7
  • RB retinoblastoma
  • PTPROt Family and receptor type O protein tyrosine phosphatase
  • PRMT5 can also methylate several important transcription factors, making it play an important role in cell regulation.
  • PRMT5 can methylate p53 and change its DNA binding activity, thereby triggering changes in the gene expression program controlled by p53.
  • PRMT5 has also been shown to methylate N-MYC and change its protein stability and enhance its oncogenic activity in neuroblastoma.
  • PRMT5 can also directly methylate transcription factors, including E2F-1 and NF- ⁇ B/p65, and induce the expression of its target genes.
  • PRMT5 can not only modify nuclear transcription factors, but also methylate cytoplasmic proteins such as golgin and ribosomal protein S10 (RPS10). Therefore, in addition to its ability to directly regulate its own target genes, PRMT5 can also indirectly affect global gene expression through symmetric methylation of key transcription factors, thereby affecting cell growth, proliferation and differentiation.
  • PRMT5 is overexpressed in different types and aggressive cancers, including B-cell and T-cell lymphoma, metastatic melanoma, neuroblastoma and glioblastoma, germ cell tumors, ovarian cancer, Nasopharyngeal cancer, breast cancer, colorectal cancer and gastric cancer.
  • Current research shows that PRMT5 plays an important role in controlling cell growth and proliferation, and its overexpression promotes cell transformation.
  • PRMT5 The enhanced expression of PRMT5 in cancer cells is related to the transcriptional silencing of its target tumor suppressor genes.
  • PRMT5 can promote the growth of cancer cells by methylation of the promoter histones H3R8 and H4R3 and by modifying specific arginine residues of key transcription factors including E2F1 and NF-kB/p65 to cause global chromatin changes.
  • PRMT5 also interacts with programmed cell death 4 (PDCD4), causing it to become methylated at R110 and lose its tumor suppressor activity in MCF-7 cells.
  • PDCD4 programmed cell death 4
  • the overexpression of PRMT5 may make it interact with growth promoting proteins and tumor suppressor proteins to facilitate the growth, survival and metastasis of cancer cells.
  • PRMT5 inhibitors have a clear mechanism in the treatment of tumors and other related diseases, and have great potential to become a new treatment method in the field of tumor treatment. Therefore, it is necessary to develop safer and more effective PRMT5 inhibitors to meet clinical needs. demand.
  • An object of the present invention is to provide a class of compounds with PRMT5 inhibitory activity represented by general formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof,
  • Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclic group may be one or more selected from halogen, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, amino Substitution of acyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl.
  • the aryl, heteroaryl, cycloalkyl, and heterocyclic group may be one or more selected from halogen, hydroxy, alkyl, and halogenated alkyl.
  • hydroxyalkyl alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, aminoacyl , Alkylamino acyl, dialkylamino, alkenyl, alkynyl, haloalkyl acyl, hydroxyalkyl acyl, cycloalkyl acyl, heterocyclyl acyl, cycloalkyl, heterocyclic, aryl, heteroaryl And oxo group substitution;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, Cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
  • R 5 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkylacyl, aminoacyl and alkylaminoacyl;
  • X 1 , X 2 , and X 3 are each independently selected from N and C (R 6 ), wherein R 6 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, Hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, and cycloalkyl; and
  • L is selected from -NH-, -S-, -O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -S(O ) 2 NH-, -NHS(O) 2 -, -C(O)- and -NHC(O)NH-.
  • Another object of the present invention is to provide a method for preparing the compound of general formula (I) of the present invention or its isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug.
  • Another object of the present invention is to provide a composition
  • a composition comprising the compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs and a pharmaceutically acceptable carrier, and The compound of the general formula (I) of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs and a combination of another or more drugs.
  • Another object of the present invention is to provide a method for treating PRMT5-mediated diseases with the compound of general formula (I) or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof of the present invention, and the present invention Application of the compound of general formula (I) or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs in the preparation of medicines for treating PRMT5-mediated diseases.
  • the present invention provides a compound represented by general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Ring A is selected from aryl, heteroaryl, cycloalkyl and heterocyclyl, and the aryl, heteroaryl, cycloalkyl and heterocyclic group may be one or more selected from halogen, hydroxy, alkyl, Haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, alkylsulfonyl, amino Substitution of acyl, alkylaminoacyl, dialkylamino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and oxo groups;
  • Cy is selected from the group consisting of aryl, heteroaryl, cycloalkyl, and heterocyclyl.
  • the aryl, heteroaryl, cycloalkyl, and heterocyclic group may be one or more selected from halogen, hydroxy, alkyl, and halogenated alkyl.
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, hydroxyalkoxy, nitro, carboxy, Cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl and dialkylamino;
  • R 5 is selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkylacyl, aminoacyl and alkylaminoacyl;
  • X 1 , X 2 , and X 3 are each independently selected from N and C (R 6 ), wherein R 6 is selected from hydrogen, halogen, hydroxy, alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, Hydroxyalkoxy, nitro, carboxy, cyano, amino, monoalkylamino, alkylacylamino, alkylacyl, aminoacyl, alkylaminoacyl, dialkylamino, and cycloalkyl; and
  • L is selected from -NH-, -S-, -O-, -C(O)NH-, -NHC(O)-, -OC(O)NH-, -NHC(O)O-, -S(O ) 2 NH-, -NHS(O) 2 -, -C(O)- and -NHC(O)NH-.
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Ring A is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclic group
  • the C 6-12 aryl, 5-12 membered heteroaryl Group, C 3-12 cycloalkyl and 3-12 membered heterocyclic group can be selected by one or more selected from halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 Alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, C 1-6 alkylsulfonyl, amino acyl, C 1-6 alkylamino acyl, bis C 1-6 alkylamino, C 2-10 Alkenyl, C 2-10 alkynyl, C 3-12 cycl
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 3-10 membered heterocyclic group, the C 6-10 aryl, 5-
  • the 10-membered heteroaryl group, C 3-10 cycloalkyl group and 3-10 membered heterocyclic group may be one or more selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkane amino, acylamino C 1-3 alkyl, C 1-3 alkyl group, C 1-3 alkyl sulfonyl, amino group, C 1-3 alkylamino group, a bis C 1-3 alkyl group, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cyclo
  • ring A is selected from C 6-8 aryl, 5-6 membered heteroaryl, C 3-6 cycloalkyl, 3-6 membered azaheterocyclyl, 3-6 membered oxoheterocyclyl, 3-6 membered sulfur heterocyclic group, the C 6-8 aryl group, 5-6 membered heteroaryl group, C 3-6 cycloalkyl group, 3-6 membered azacyclic group, 3-6 membered oxygen heterocyclic group Group, 3-6 membered sulfur heterocyclic group can be selected by one or more selected from halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 Alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino , C 1-3 alkyl acyl,
  • ring A is selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, aziridine Group, azetidinyl, tetrahydropyrrolyl, dihydropyrrolyl, pyrrolyl, piperidinyl, tetrahydropyridyl, dihydropyridyl, pyridyl, propylene oxide, oxetanyl , Tetrahydrofuranyl, dihydrofuranyl, furanyl, tetrahydropyranyl, dihydropyranyl, pyranyl, sulfiethane, sulfide cyclobutanyl, tetrahydrothienyl, dihydrothienyl, Thienyl, cyclopentanyl
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • Cy is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl and 3-12 membered heterocyclic group
  • the C 6-12 aryl, 5-12 membered heteroaryl , C 3-12 cycloalkyl and 3-12 membered heterocyclic group can be selected by one or more selected from halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkane Group, C 1-6 alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1 -6 alkyl acylamino, C 1-6 alkyl acyl, C 1-6 alkyl sulfonyl, amino acyl, C 1-6 alkyl amino acyl, double C 1-6 alkyl amino, C 2-10 alkene Group, C 2-10 alkynyl, halogenated
  • Cy is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl and 3-10 membered heterocyclic group, the C 6-10 aryl, 5-10
  • One or more membered heteroaryl groups, C 3-10 cycloalkyl groups and 3-10 membered heterocyclic groups may be selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkyl Amino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, C 1-3 alkyl sulfonyl, amino acyl, C 1-3 alkyl amino acyl, bis C 1-3 alkyl amino, C 2-6 alkenyl, C 2-6 alkynyl, halogenated
  • Cy is selected from phenyl, 5-6 membered heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-6 membered heterocyclyl
  • the phenyl, 5-6 Member heteroaryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-6 membered heterocyclic group can be selected by one or more selected from halogen, hydroxy, C 1-3 alkyl, halogenated C 1 -3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, Mono-C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, C 1-3 alkylsulfonyl, amino acyl, C 1-3 alkylamino
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 Alkoxy, halogenated C 1-6 alkoxy, hydroxy C 1-6 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino , C 1-6 alkyl acyl, amino acyl, C 1-6 alkyl amino acyl and double C 1-6 alkyl amino;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxyl C 1-3 alkoxy, nitro, carboxyl, cyano, amino, mono C 1-3 alkylamino, C 1-3 Alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl and bis C 1-3 alkylamino;
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxyl C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkane Alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkylamino acyl and bis C 1-3 alkylamino.
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 5 is selected from hydrogen, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylamino acyl;
  • R 5 is selected from hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkyl acyl, amino acyl, C 1-3 alkane Aminoacyl;
  • R 5 is selected from hydrogen, methyl, ethyl, propyl, trifluoromethyl, hydroxymethyl, hydroxyethyl, methylacyl, ethylacyl, propylacyl, aminoacyl, methyl Aminoacyl, ethylaminoacyl and propylaminoacyl.
  • the compound of the present invention is a compound of general formula (I) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, wherein:
  • R 6 is selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy Group, hydroxy C 1-6 alkoxy, nitro, carboxy, cyano, amino, mono C 1-6 alkylamino, C 1-6 alkyl acylamino, C 1-6 alkyl acyl, amino acyl, C 1-6 alkylaminoacyl, bis-C 1-6 alkylamino and C 3-12 cycloalkyl;
  • R 6 is selected from hydrogen, halogen, hydroxy, C 1-3 alkyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkoxy, halogenated C 1 -3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl , Aminoacyl, C 1-3 alkylamino acyl, double C 1-3 alkylamino and C 3-8 cycloalkyl;
  • R 6 is selected from hydrogen, halogen, hydroxy, methyl, ethyl, propyl, isopropyl, halogenated C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1-3 alkane Oxy, halogenated C 1-3 alkoxy, hydroxy C 1-3 alkoxy, nitro, carboxy, cyano, amino, mono C 1-3 alkylamino, C 1-3 alkyl acylamino, C 1-3 alkyl acyl, amino acyl, C 1-3 alkyl amino acyl, bis C 1-3 alkylamino and C 3-8 cycloalkyl.
  • the present invention provides a compound of general formula (Ia) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Cy, L and ring A have the definitions described in the general formula (I) above.
  • the present invention provides a compound of general formula (Ib) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Cy, L and ring A have the definitions described in the general formula (I) above.
  • the present invention provides a compound of general formula (Ic) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Cy, L and ring A have the definitions described in the general formula (I) above.
  • the present invention provides a compound of general formula (Id) or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof,
  • Cy, L and ring A have the definitions described in the general formula (I) above.
  • the compound of the present invention is a compound of general formula (I), (Ia), (Ib), (Ic) or (Id) or its isomers, pharmaceutically acceptable salts, solvents Compounds, crystals or prodrugs, of which:
  • the present invention provides the following specific compounds or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof:
  • the present invention provides a method for preparing the compound of general formula (I) of the present invention, which includes the step of reacting the compound of formula 1 and the compound of formula 2:
  • R 1 , R 2 , R 3 , R 4 , R 5 , Cy, L, X 1 , X 2 , X 3 , and ring A have the definitions described in the general formula (I), and the compound of formula 1 and formula 2
  • the compound of is a commercially available compound or can be synthesized by other technical means commonly used by those skilled in the art.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof.
  • the present invention provides the compound of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs and the compounds of the present invention or its isomers, pharmaceutically acceptable Pharmaceutical compositions of salts, solvates, crystals or prodrugs, said compounds or pharmaceutical compositions are used to treat PRMT5-mediated diseases.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, and a pharmaceutically acceptable carrier.
  • the compound of the present invention or its isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs can be mixed with pharmaceutically acceptable carriers, diluents or excipients to prepare pharmaceutical preparations suitable for oral administration or Parenteral administration.
  • Administration methods include, but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal and oral routes.
  • the preparation can be administered by any route, for example, by infusion or bolus injection, by the route of absorption through the epithelium or skin mucosa (such as oral mucosa or rectum, etc.). Administration can be systemic or local.
  • preparations for oral administration include solid or liquid dosage forms, specifically, tablets, pills, granules, powders, capsules, syrups, emulsions, suspensions, and the like.
  • the preparation can be prepared by a method known in the art, and contains a carrier, diluent or excipient conventionally used in the field of pharmaceutical preparations.
  • the present invention provides a compound represented by formula (I), (Ia), (Ib), (Ic) or (Id) or its isomers, pharmaceutically acceptable salts, solvates, crystals Or a prodrug, or a pharmaceutical composition containing the same for the method of treating PRMT5-mediated diseases and the use in the preparation of a medicine for treating PRMT5-mediated diseases.
  • the present invention provides a compound represented by formula (I), (Ia), (Ib), (Ic) or (Id) of the present invention or an isomer, pharmaceutically acceptable salt thereof, Solvates, crystals or prodrugs, or pharmaceutical compositions containing them are used to treat PRMT5-mediated diseases and their use in the preparation of drugs for the treatment of PRMT5-mediated diseases, wherein the PRMT5-mediated diseases include But not limited to: proliferative diseases, metabolic diseases or blood diseases.
  • the PRMT5-mediated disease of the present invention is cancer.
  • PRMT5-mediated diseases of the present invention include but are not limited to: acoustic neuroma, adenocarcinoma, adrenal carcinoma, anal cancer, angiosarcoma (eg, lymphangiosarcoma, lymphatic endothelial sarcoma, angiosarcoma) , Accessory cancer, benign monoclonal gammopathy, bile cancer (for example, cholangiocarcinoma), bladder cancer, breast cancer (for example, breast adenocarcinoma, breast papillary cancer, breast cancer, breast medullary cancer, triple negative breast cancer ), brain cancer (for example, meningioma; glioma, such as astrocytoma, oligodendroglioma; medulloblastoma), bronchial carcinoma, carcinoid tumor, cervical cancer (for example, cervical adenocarcinoma) , Choriocarcinoma, chordoma, craniopharyn
  • Gastrointestinal pancreatic neuroendocrine tumors GEP-NET
  • carcinoid tumors carcinoid tumors
  • osteosarcoma ovarian cancer
  • ovarian cancer e.g., cystadenocarcinoma, ovarian embryonic carcinoma, ovarian adenocarcinoma, ovarian clear cell carcinoma, ovarian serous cystadenocarcinoma ,
  • papillary adenocarcinoma pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary myxoma (IPMN), islet cell tumor)
  • penile cancer e.g., Paget's disease of the penis and scrotum
  • Pineal tumor e.g., Primary neuroectodermal tumor (PNT)
  • prostate cancer for example, prostate adenocarcinoma
  • rectal cancer rhabdomyosarcoma
  • salivary duct cancer for example, squam
  • the PRMT5-mediated diseases of the present invention include metabolic disorders such as diabetes or obesity.
  • the PRMT5-mediated diseases of the present invention include hemoglobinopathies such as sickle cell disease or ⁇ -thalassemia.
  • the PRMT5-mediated diseases of the present invention include inflammatory and autoimmune diseases.
  • the present invention provides a compound represented by general formula I of the present invention or an isomer, pharmaceutically acceptable salt, solvate, crystal or prodrug thereof, or a pharmaceutical composition containing it for use Method for treating PRMT5-mediated diseases and use in the preparation of drugs for treating PRMT5-mediated diseases, wherein the PRMT5-mediated diseases include but not limited to: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic system Cancer, lymphoma, medulloblastoma, medulloblastoma, rectal adenocarcinoma, colon cancer, stomach cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, prostate cancer, lung cancer, head and neck squamous cell carcinoma, brain Carcinoma, hepatocellular carcinoma, melanoma, oligodendroglioma, glioblastoma, testicular cancer, ovarian clear cell carcinoma, ovarian serous cystadenocarcino
  • hydrogen, carbon and oxygen in the compounds of the present invention include all their isotopes.
  • Isotopes should be understood to include those atoms having the same atomic number but different mass numbers.
  • hydrogen isotopes include protium, tritium, and deuterium
  • carbon isotopes include 12 C, 13 C, and 14 C
  • oxygen isotopes include 16 O and 18 O.
  • “Isomers” in the present invention refer to molecules with the same atomic composition and connection mode but different three-dimensional arrangements, including but not limited to diastereomers, enantiomers, cis-trans isomers, and their Mixtures, such as racemic mixtures.
  • Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to indicate the absolute configuration of the molecular chiral center.
  • the prefixes D, L or (+), (-) are used to name the symbols of the plane-polarized light rotation of the compound.
  • (-) or L means the compound is levorotatory, and the prefix (+) or D means the compound is dextrorotatory.
  • the chemical structures of these stereoisomers are the same, but their stereostructures are different.
  • a specific stereoisomer may be an enantiomer, and a mixture of isomers is usually called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is called a racemic mixture or a racemate, which may result in no stereoselectivity or stereospecificity during chemical reactions.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers, lacking optical activity.
  • the compound of the present invention can be one of the possible isomers or a mixture of them, such as racemates and diastereoisomer mixtures (depending on the number of asymmetric carbon atoms) The form exists.
  • Optically active (R)- or (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • Any resulting mixture of stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physical and chemical properties of the components, for example, by chromatography Method and/or fractional crystallization method.
  • halogen in the present invention means fluorine, chlorine, bromine, and iodine.
  • halo in the present invention refers to substitution by fluorine, chlorine, bromine or iodine.
  • alkyl in the present invention refers to a linear or branched saturated aliphatic hydrocarbon group, preferably a linear or branched group containing 1 to 6 carbon atoms, and more preferably a linear or branched group containing 1 to 3 carbon atoms
  • Chain groups non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethyl Propyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, etc.
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • the "sulfonyl group" in the present invention means -S(O) 2 -.
  • the "sulfonamide group" in the present invention means -S(O) 2 NH-.
  • haloalkyl in the present invention refers to an alkyl group substituted with at least one halogen.
  • hydroxyalkyl in the present invention refers to an alkyl group substituted with at least one hydroxy group.
  • Alkoxy in the present invention refers to -O-alkyl.
  • alkoxy groups include: methoxy, ethoxy, propoxy, n-propoxy, isopropoxy, isobutoxy, sec-butoxy and the like.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • cycloalkyl in the present invention refers to a cyclic saturated hydrocarbon group. Suitable cycloalkyl groups may be substituted or unsubstituted monocyclic, bicyclic or tricyclic saturated hydrocarbon groups with 3-12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • heterocyclic group refers to a 3- to 12-membered non-aromatic group having 1 to 4 ring heteroatoms (wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon) Groups of ring systems ("3-12 membered heterocyclyl").
  • heterocyclyl groups containing one or more nitrogen atoms the point of attachment may be a carbon or nitrogen atom, as long as the valence permits.
  • Heterocyclyl groups can either be monocyclic (“monocyclic heterocyclyl”) or fused, bridged or spiro ring systems (e.g.
  • bicyclic systems also known as "bicyclic heterocyclyl"
  • Suitable heterocyclic groups include but are not limited to piperidinyl, azetidinyl, aziridinyl, tetrahydropyrrolyl, piperazinyl, dihydroquinazolinyl, oxepanyl, oxa Cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, Wait.
  • Each instance of the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • aryl refers to an aromatic system that can contain a single ring or a fused polycyclic ring, preferably a single ring or a fused bicyclic aromatic system, which contains 6 to 12 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • Suitable aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, fluorenyl, indanyl.
  • the aryl group may be optionally substituted or unsubstituted, and when substituted, the substituent may be at any available point of attachment.
  • heteroaryl group in the present invention refers to an aryl group in which at least one carbon atom is replaced by a heteroatom, preferably composed of 5-12 atoms (5-12 membered heteroaryl), and more preferably composed of 5-10 atoms (5-10 membered heteroaryl), the heteroatoms are O, S, N.
  • heteroaryl groups include, but are not limited to, imidazolyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Tetrazolyl, indolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, isoindolyl, benzopyrazolyl, benzimidazolyl, benzofuranyl, benzopyridine Pyryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, Quinoxalinyl, benzoxazinyl, benzothiazinyl
  • the “pharmaceutically acceptable salt” of the present invention refers to the salt of the compound of the present invention. Such salt is safe and effective when used in mammals, and has due biological activity.
  • solvate in the present invention refers to a complex formed by the combination of a solute (such as an active compound, a salt of an active compound) and a solvent (such as water) in a conventional sense.
  • the solvent refers to a solvent known or easily determined by those skilled in the art. If it is water, the solvate is usually referred to as a hydrate, such as hemihydrate, monohydrate, dihydrate, trihydrate, or alternative amounts thereof.
  • the in vivo effects of the compound of formula (I) can be partly exerted by one or more metabolites formed in the body of the human or animal after the compound of formula (I) is administered. As described above, the in vivo effects of the compound of formula (I) can also be exerted through the metabolism of precursor compounds ("prodrugs").
  • the "prodrug” of the present invention refers to a compound that is converted into a compound of the invention by reaction with enzymes, gastric acid, etc. under physiological conditions in an organism, that is, a compound that is converted into a compound of the invention by enzyme oxidation, reduction, hydrolysis, etc. /Or a compound or the like that is converted into a compound of the invention by a hydrolysis reaction of gastric acid or the like.
  • the "crystalline" in the present invention refers to a solid whose internal structure is formed by repeating constituent atoms (or groups thereof) regularly in three dimensions, which is different from an amorphous solid that does not have such a regular internal structure.
  • the "pharmaceutical composition” of the present invention refers to containing any of the compounds of the present invention, including corresponding isomers, prodrugs, solvates, pharmaceutically acceptable salts or chemically protected forms thereof, and a Or a mixture of multiple pharmaceutically acceptable carriers and/or another one or more drugs.
  • the purpose of the pharmaceutical composition is to facilitate the administration of the compound to the organism.
  • the composition is generally used to prepare drugs for the treatment and/or prevention of diseases mediated by one or more kinases.
  • the "pharmaceutically acceptable carrier” in the present invention refers to a carrier that does not cause significant irritation to organisms and does not interfere with the biological activity and properties of the administered compound, and includes all solvents, diluents or other excipients, dispersants, and surface activities. Isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant, etc. Unless any conventional carrier medium is incompatible with the compound of the present invention.
  • pharmaceutically acceptable carriers include, but are not limited to, sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, And cellulose and cellulose acetate; malt, gelatin, etc.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a compound.
  • Excipients may include calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oil, and polyethylene glycol.
  • the "PRMT5" of the present invention may be any mutant or variant of wild-type PRMT5 or PRMT5, and the mutant or variant of PRMT5 contains one or more mutations (for example, conservative substitutions).
  • Step 3 Preparation of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one
  • Step 4 Preparation of 7'-amino-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one
  • Step 5 7'-((1-Acetylpiperidin-4-yl)amino)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]- Preparation of 1′-ketone
  • Step 6 (R)-7′-((1-Acetylpiperidin-4-yl)amino)-2′-(3-(3,4-dihydroisoquinolin-2(1H)-yl) -2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one
  • reaction solution was poured into 200 mL saturated ammonium chloride solution for quenching, extracted with ethyl acetate (100 mL ⁇ 3), the organic phases were combined, dried, the solvent was evaporated under reduced pressure, and the title compound was separated by column chromatography.
  • LC-MS m/z: [M+H] + 216.
  • Step 3 Preparation of 7'-nitro-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1'-one
  • Step 4 Preparation of 7'-amino-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1'-one
  • Step 6 (R)-7′-((1-Acetylpiperidin-4-yl)amino)-2′-(3-(3,4-dihydroisoquinolin-2(1H)-yl) -2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-1'-one
  • reaction solution was poured into 30mL saturated ammonium chloride solution for quenching, extracted with dichloromethane (20mL ⁇ 3), combined the organic phases, evaporated the solvent under reduced pressure to obtain the crude product, prepared and separated by prep-HPLC to obtain the title compound .
  • the preparation method is similar to the preparation method of Example 1, except that the raw material 1,2-dibromoethane in step 1 is replaced with 1,4-dibromobutane to obtain the title compound.
  • 1 H NMR 300MHz, DMSO-d 6 ) ⁇ 7.00-7.40 (m, 6H), 6.75 (d, 1H), 5.59 (d, 1H), 4.72 (brs, 1H), 4.18 (d, 1H), 4.02 (s, 1H), 3.70-3.80 (m, 2H), 3.62 (s, 2H), 3.45-3.51 (m, 2H), 3.30-3.41 (m, 2H), 3.10-3.20 (m, 2H), 2.60-2.80 (m, 5H), 2.30-2.50 (m, 2H), 2.00 (s, 3H), 1.80-1.95 (m, 2H), 1.50-1.80 (m, 7H), 1.10-1.30 (m, 2H) ).
  • Step 1 Preparation of N-(1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)benzamide
  • Step 2 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2' , 3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)benzamide
  • N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)benzamide (115mg, 0.394 mmol) was dissolved in 2mL of anhydrous N,N-dimethylformamide solution, sodium hydride (23.6mg, 0.591mmol) was added at 0°C, stirred for 30min, and (R)-2-(ethylene oxide-2 -Methyl)-1,2,3,4-tetrahydroisoquinoline (74.4mg, 0.394mmol) in N,N-dimethylformamide solution (2mL), moved to room temperature and reacted overnight.
  • Step 1 Preparation of N-(1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)benzenesulfonamide
  • Step 2 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2' Preparation of 3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)benzenesulfonamide
  • N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)benzenesulfonamide 80.0mg, 0.244mmol
  • sodium hydride (14.6mg, 0.366mmol) was added at 0°C, stirred for 30min, and (R)-2-(ethylene oxide- A solution (1 mL) of 2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (46.1 mg, 0.244 mmol) in N,N-dimethylformamide was moved to room temperature and reacted overnight.
  • Step 1 4-((1'-oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)piperidine Preparation of 1-tert-butyl carboxylate
  • Step 2 (R)-4-((2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2 Preparation of',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)amino)piperidine-1-carboxylic acid tert-butyl ester
  • Step 3 (R)-2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-7'-(piperidin-4-ylamino )-2',3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-1'-one
  • Step 2 7'-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-iso Preparation of quinoline]-1′-one
  • Step 3 (R)-7′-((1-(cyclopropanecarbonyl)piperidin-4-yl)amino)-2′-(3-(3,4-dihydroisoquinoline-2(1H) -Yl)-2-hydroxypropyl)-2',3'-dihydro-1'H-spiro[cyclopentane-1,4'-isoquinoline]-1'-one
  • Example 8 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2 ′,3′-Dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline]-7′-yl)-1-methyl-1H-pyrazole-4-carboxamide
  • Step 1 1-Methyl-N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline]-7′-yl ) Preparation of -1H-pyrazole-4-carboxamide
  • Step 2 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2' , 3′-Dihydro-1′H-spiro[cyclobutane-1,4′-isoquinoline]-7′-yl)-1-methyl-1H-pyrazole-4-carboxamide
  • Step 1 1-Methyl-N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl) Preparation of -1H-pyrazole-4-carboxamide
  • Step 2 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2' , 3′-Dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)-1-methyl-1H-pyrazole-4-carboxamide
  • Step 2 (R)-1-Acetyl-N-(2′-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1′- Preparation of oxo-2',3'-dihydro-1'H-spiro[cyclobutane-1,4'-isoquinoline]-7'-yl)piperidine-4-carboxamide
  • Step 2 (R)-1-Acetyl-N-(2′-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1′- Preparation of oxo-2',3'-dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)piperidine-4-carboxamide
  • reaction solution was poured into 10 mL saturated ammonium chloride solution and quenched, extracted with dichloromethane (15 mL ⁇ 3), combined the organic phases, evaporated the solvent under reduced pressure to obtain the crude product and separated by prep-HPLC to obtain the title compound.
  • Example 12 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2 ′,3′-Dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)tetrahydro-2H-pyran-4-carboxamide
  • Step 1 N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)tetrahydro-2H- Preparation of pyran-4-carboxamide
  • Step 2 (R)-N-(2'-(3-(3,4-Dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1'-oxo-2' , 3'-Dihydro-1'H-spiro[cyclopropane-1,4'-isoquinoline]-7'-yl)tetrahydro-2H-pyran-4-carboxamide
  • N-(1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-isoquinoline]-7′-yl)tetrahydro-2H-pyran -4-formamide 250mg, 0.830mmol was dissolved in 5mL of anhydrous N,N-dimethylformamide, sodium hydride (67mg, 1.67mmol) was added at 0°C, and the reaction was continued for 1 hour at 0°C; then added (R)-2-(Ethylene oxide-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (159mg, 0.83mmol) in N,N-dimethylformamide solution ( 2mL).
  • reaction was stirred overnight at room temperature, the reaction solution was poured into 10 mL of saturated ammonium chloride solution for quenching, extracted with dichloromethane, the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain the crude product, which was prepared and separated by prep-HPLC to obtain the title compound.
  • Example 1 of the present invention the compounds of Examples 13-34 were synthesized using different commercially available raw materials.
  • the characterization parameters of these compounds are shown in Table 1:
  • Reagents and consumables PRMT5, purchased from Active Motif, item number 31921; peptide substrate H4(1-21)S1ac, purchased from Gil Biochemical (Shanghai) Co., Ltd., item number 342095; [ 3 H]-SAM, Purchased from PerkinElmer, the article number is NET155V001MC; SAM, purchased from Sigma, the article number is A7007-100MG; SAH, purchased from Sigma Company, the article number is A9384-25MG; DTT, purchased from Shenggong Bioengineering (Shanghai) Co., Ltd. Limited company, the article number is A620058-0005.
  • Corning-3657 purchased from Corning Company, the article number is 3657; Echo Qualified 384-Well, purchased from Labcyte Company, the article number is P-05525; FlashPlate, purchased from Perkin Elmer, the article number is SMP410J001PK.
  • reaction buffer liquid components are 10mM Tris-HCl, pH 8.0; 0.01% Tween-20; 1mM DTT.
  • the composition of the reaction stop solution was 125 ⁇ M 3 H-SAM solution.
  • the compound was dissolved in 100% DMSO into a 10 mM stock solution, and then the compound was diluted to the required concentration on an Echo384-well plate.
  • the peptide substrate and [ 3 H]-SAM were added to the 1-fold reaction buffer to form a 2.5-fold substrate solution (final concentrations of 100 nM and 250 nM, respectively).
  • reaction stop solution 0.5 ⁇ L of reaction stop solution to each well of the 384-well reaction plate to stop the reaction. Take 25uL from each well of the test plate and transfer it to Flashplate, and place it at room temperature for 1h. Then wash the Flashpate plate 3 times with 0.1% Tween-20 solution.
  • Inhibition rate (%) (maximum-sample value)/(maximum-minimum) ⁇ 100%.

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Abstract

L'invention concerne un composé tricyclique tel que représenté par la formule (I) ou un isomère, un sel, un solvate, un cristal ou un promédicament pharmaceutiquement acceptables de celui-ci, des procédés de préparation de ceux-ci, et une composition pharmaceutique contenant les composés, et l'utilisation des composés ou de la composition pour le traitement de maladies médiées par PRMT5. Le composé présente une activité inhibitrice remarquable sur PRMT5.
PCT/CN2020/097652 2019-06-24 2020-06-23 Composé tricyclique utilisé en tant qu'inhibiteur de prmt5 et son application WO2020259478A1 (fr)

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WO2022206964A1 (fr) * 2021-04-02 2022-10-06 海思科医药集团股份有限公司 Inhibiteur de prmt5 et son utilisation
TW202400602A (zh) * 2022-05-31 2024-01-01 大陸商和記黃埔醫藥（上海）有限公司 三環類化合物及其用途

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