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RU-2861582-C2 - PRMT5 INHIBITOR, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL USE THEREOF

RU2861582C2RU 2861582 C2RU2861582 C2RU 2861582C2RU-2861582-C2

Abstract

FIELD: pharmacology. SUBSTANCE: invention relates to a compound of formula (IVa), a stereoisomer or a pharmaceutically acceptable salt thereof, which have the property of inhibiting PRMT5 and can be used for the treatment and/or prevention of PRMT5-mediated diseases. In formula (IVa), « » is selected from or , each R 1b independently is trifluoromethyl, trifluoromethoxy or methyl-substituted pyrazolyl; ring B together with the fragment « » to which it is directly attached is ; X 1 is CR 6 ; R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl; R 5a is hydrogen; R 2 is selected from the group consisting of cyclopropyl-substituted methyl, cyclobutyl-substituted methyl, thiazolyl-substituted methyl, pyrimidinyl-substituted methyl, cyclopropyl-substituted ethyl, cyclobutyl-substituted ethyl, thiazolyl-substituted ethyl, pyrimidinyl-substituted ethyl, cyclopropyl, methyl-substituted pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl and pyrimidinyl. EFFECT: invention relates to a method for producing said compound, a pharmaceutical composition containing same and its use for treating an MTAP-associated malignant neoplasm or tumour or as a PRMT5 inhibitor. 9 cl, 2 tbl, 238 ex

Inventors

  • DEN, Khajbin
  • Yan, Fej
  • LYU, Chzhaomin
  • LYU, Tszyan
  • YUJ, Khunpin
  • CHEN, Chzhuj
  • SYUJ, Yaochan

Dates

Publication Date
20260506
Application Date
20230703
Priority Date
20220715

Claims (20)

  1. 1. A compound of formula (IVa), its stereoisomer or pharmaceutically acceptable salt
  2. ,
  3. Where " » selected from the following structures: or , each R 1b is independently trifluoromethyl, trifluoromethoxy, or methyl-substituted pyrazolyl;
  4. ring B together with the fragment " ", to which it is directly attached, is
  5. ;
  6. X 1 represents CR 6 ;
  7. R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
  8. R 5a is hydrogen;
  9. R 2 is selected from the group consisting of cyclopropyl-substituted methyl, cyclobutyl-substituted methyl, thiazolyl-substituted methyl, pyrimidinyl-substituted methyl, cyclopropyl-substituted ethyl, cyclobutyl-substituted ethyl, thiazolyl-substituted ethyl, pyrimidinyl-substituted ethyl, cyclopropyl, methyl-substituted pyrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, and pyrimidinyl.
  10. 2. A compound of formula (IVa), its stereoisomer or a pharmaceutically acceptable salt according to claim 1, wherein the compound of formula (IVa) is a compound with a structure represented by formula (Va)
  11. ,
  12. Where " » selected from the following structures: or , each R 1b independently represents trifluoromethyl or trifluoromethoxy;
  13. R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, and methyl.
  14. 3. A compound of formula (IVa), its stereoisomer or pharmaceutically acceptable salt according to claims 1, 2, where it is selected from the following compounds:
  15. .
  16. 4. A method for producing a compound of formula (IVa), its stereoisomer or pharmaceutically acceptable salt according to claim 1, comprising the following steps:
  17. ,
  18. where X is fluorine, chlorine, bromine or hydroxy and ring B, X 1 , Y 1 , Z, R 1b , R 2 , R 5 , R 8 and n correspond to those in paragraph 1.
  19. 5. A pharmaceutical composition for inhibiting PRMT5 kinase activity, comprising a therapeutically effective amount of a compound of formula (IVa), its stereoisomer or pharmaceutically acceptable salt according to any one of claims 1-3 and a pharmaceutically acceptable carrier.
  20. 6. Use of a compound of formula (IVa), a stereoisomer thereof, or a pharmaceutically acceptable salt according to any one of claims 1 to 3 for the manufacture of preparations for the treatment of an MTAP-associated malignant neoplasm or tumor.

Description

AREA OF TECHNOLOGY The present invention relates to the field of pharmaceutical synthesis and, in particular, to a PRMT5 inhibitor, a method for producing it and its pharmaceutical use. LEVEL OF TECHNOLOGY Epigenetic regulation of genes is an important biological regulatory mechanism for protein synthesis and cell differentiation, and plays a significant role in many human diseases. Epigenetic regulation involves the regulation of hereditary genetic material without altering the nucleic acid sequence. Broadly speaking, epigenetic regulation is the selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) to control the switching between transcriptionally active and inactive conformational states of chromatin. Modifications to these covalent bonds can be controlled by enzymes such as methyltransferases (e.g., PRMT5), many of which are associated with specific gene alterations in numerous human pathogenic genes. PRMT5 plays an important role in the mechanisms of many diseases, including tumors, metabolic, and hematological diseases. Homozygous deletion of tumor suppressor genes is a factor in tumor development and often leads to the deletion of "passenger" genes located near the tumor suppressor genes. Deletion of these "passenger" genes creates tumor-cell-specific vulnerabilities that can be addressed by targeted therapy. Homozygous deletion of the chromosome 9p21 locus, which includes the well-known tumor suppressor gene CDKN2A, occurs in 15% of tumors and often contains a deletion of the "passenger" gene MTAP. MTAP is a key enzyme in the methionine and adenine recycling pathways. Deletion of MTAP leads to the accumulation of its substrate, MTA (methylthioadenosine). MTA and S-adenosylmethionine (SAM) have similar structures, with the latter being a methyl substrate donor for the type II methyltransferase PRMT5. Due to the increased MTA levels caused by MTAP deletion, it will selectively compete with SAM for PRMT5 binding, resulting in the methyltransferase remaining inactivated and the cell being more likely to be affected by PRMT5 inhibition. Screening of short hairpin RNA (shRNA) from a wide range of tumor cell lines across different genomic ranges demonstrated a correlation between MTAP deletion and cell line dependence on PRMT5, highlighting the impact of this metabolic vulnerability. However, PRMT5 is a very important gene for cells, and studies of conditional PRMT5 knockout or small interfering RNA (siRNA) knockout suggest that PRMT5 inhibition will cause significant side effects in normal tissues (e.g., cytopenia, infertility, decreased skeletal muscle mass, myocardial hypertrophy, etc.). Therefore, new strategies need to be developed to exploit and study this metabolic susceptibility in order to selectively target PRMT5 in MTAP-deleted tumors while sparing PRMT5 in normal tissues (wild-type MTAP). Small-molecule PRMT5 inhibitors acting in concert with MTA can selectively target PRMT5 only in its MTA-bound state, which is present in elevated levels only in tumor cells with MTAP deletion. Therefore, PRMT5 will not be targeted at the very low levels of MTA in normal cells with intact MTAP, providing a better therapeutic window. DISCLOSURE OF THE INVENTION The objective of the present invention is to develop a PRMT5 inhibitor, a method for its production, and its pharmaceutical use. A number of compounds related to the present invention exhibit potent inhibitory activity on PRMT5 and can be widely used to produce drugs for the treatment and/or prevention of PRMT5-mediated diseases, opening up prospects for the development of a new generation of PRMT5 inhibitors. The first aspect of the present invention relates to a compound of formula (I), a stereoisomer or a pharmaceutically acceptable salt: , where X 1 is CR 6 or N; X 2 is CR 7 or N; X 3 is CR 8 or N; ring A is C3-10 cycloalkyl, 4-10-membered heterocyclyl, C6-10 aryl, or 5-10-membered heteroaryl, and the C3-10 cycloalkyl or 4-10-membered heterocyclyl is further fused to C6-10 aryl or 5-10-membered heteroaryl; the C6-10 aryl or 5-10-membered heteroaryl is further fused to C3-10 cycloalkyl or 4-10-membered heterocyclyl; ring B is C 4-12 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl; each R 1 is independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, nitro, azido, 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 alkyl-P(O)(R 11 ) 2 , -C 0-8 alkyl-NR 12 R 13 , -C 0-8 alkyl-C(O)NR 12 R 13 and -C 0-8 alkyl-N(R 12 )-C(O)R 11 , and said groups are independently optionally substituted with one or more further substituents selected from the group consist