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EP-4736860-A2 - POLYCYCLIC COMPOUNDS FOR INHIBITING RNA HELICASE DHX33 AND USE THEREOF

EP4736860A2EP 4736860 A2EP4736860 A2EP 4736860A2EP-4736860-A2

Abstract

The present disclosure relates to a class of polycyclic compound inhibiting RNA helicase DHX33 and the application thereof. In particular, the present disclosure relates to a compound as represented by formula I or a pharmaceutically acceptable form thereof, a pharmaceutical composition comprising the same, a preparation method thereof, and a medical use thereof for preventing and/or treating DHX33-related diseases.

Inventors

  • ZHANG, YANDONG
  • LI, Xianglu

Assignees

  • Shenzhen Keye Life Technologies, Co., Ltd.

Dates

Publication Date
20260506
Application Date
20210901

Claims (13)

  1. A compound having the structure of formula I or a pharmaceutically acceptable form thereof: wherein each R 1 is independently halogen, amino, -NH(C 1-4 alkyl), -N(C 1-4 alkyl) 2 , nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkyl, -O-(C 1-4 alkylene)-O-(C 1-4 alkyl), -C(=O)-NH-(C 1-4 alkylene)-N(C 1-4 alkyl) 2 , or -C(=O)-O-(C 1-4 alkyl), alternatively, a plurality of R 1 and the atoms to which they are attached form a 5-7 membered ring; R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-O-(C 1-4 alkyl); X 1 is N or -CR 6 ; R 6 is hydrogen or C 1-4 alkyl; R 3 is hydrogen or C 1-4 alkyl; R 4 is hydrogen or C 1-4 alkyl; X 2 is N or -CR 7 · R 7 is hydrogen or C 1-4 alkyl; each R 5 is independently halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 cycloalkyl, -C(=O)-O-(C 1-4 alkyl), phenyl, benzyl, pyridyl, -C(=O)-NH 2 , or -NH-C(=O)-(C 1-4 alkyl), said phenyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, C 1-4 alkyl and C 1-4 alkoxy; m is 1, 2, 3 or 4; n is 0, 1, 2, or 3; and said pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a solvate, a N-oxide, and an isotopically labeled form.
  2. The compound or the pharmaceutically acceptable form thereof according to claim 1, wherein each R 1 is independently fluorine, chlorine, bromine, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, nitro, amino, -NH(CH 3 ), -NH(CH 2 CH 3 ), -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH, -O-(CH 2 ) 2 -OCH 3 , -C(=O)-NH-(CH 2 ) 2 -N(CH 3 ) 2 , -C(=O)-NH-(CH 2 ) 3 -N(CH 3 ) 2 , -C(=O)-OCH 3 , or -C(=O)-OCH 2 CH 3 , alternatively, two R 1 and the atoms to which they are attached form a 6 membered ring.
  3. The compound or the pharmaceutically acceptable form thereof according to claim 1 or 2, wherein R 2 is hydrogen, methyl, ethyl, isopropyl, -(CH 2 ) 2 -OCH 3 , or -CH 2 OCH 3 .
  4. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 3, wherein R 6 is hydrogen, methyl, ethyl, or isopropyl.
  5. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 3, wherein R 3 is hydrogen, methyl, ethyl, or isopropyl.
  6. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 4, wherein R 4 is hydrogen, methyl, ethyl, or isopropyl.
  7. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 5, wherein R 7 is hydrogen, methyl, ethyl, or isopropyl.
  8. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 7, wherein each R 5 is independently fluorine, chlorine, bromine, cyano, methyl, ethyl, isopropyl, tert-butyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, -C(=O)-OCH 3 , -C(=O)-OCH 2 CH 3 , phenyl, benzyl, pyridyl, -C(=O)-NH 2 , -NH-C(=O)-CH 3 , or -NH-C(=O)-CH 2 CH 3 .
  9. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 8, being a compound of formula Ia-1 or a pharmaceutically acceptable form thereof: wherein R 1 , R 2 , R 5 , m and n are as defined in claim 1 or 2.
  10. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 8, being a compound of formula Ib-1 or formula Ib-2 or a pharmaceutically acceptable form thereof: wherein R 1 , R 2 and m are as defined in claim 1 or 2.
  11. The compound or pharmaceutically acceptable form thereof according to any one of claims 1-10 selected from the group consisting of: said pharmaceutically acceptable form is selected from a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a solvate, a N-oxide, and an isotopically labeled form.
  12. A pharmaceutical composition, comprising the compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 11 and one or more pharmaceutically acceptable carriers.
  13. The compound or the pharmaceutically acceptable form thereof according to any one of claims 1 to 11 or the pharmaceutical composition of claim 12 for use in preventing and/or treating a disease or a disorder at least partially mediated by DHX33, the disease being selected from cancer, viral infection and inflammation that are mediated by DHX33.

Description

TECHNICAL FIELD The present disclosure belongs to the field of medicinal chemistry, and relates to a small molecule inhibitor of DHX33, a pharmaceutical composition comprising the same, a preparation method thereof and a medical use thereof for preventing and/or treating DHX33-related diseases. BACKGROUND The present disclosure relates to compounds that inhibit the RNA helicase activity of DHX33. DHX33 belongs to the DEAD/H-box protein family of RNA helicases, wherein DEAD/H represents the abbreviation of the amino acid sequence, i.e., Asp-Glu-Ala-Asp/His. This sequence, together with many other conservative amino acid sequences, appears in the protein sequences of the members of the RNA helicase family and is highly involved in the binding with nucleic acid substrates and ATP hydrolysis. Although these family members have these same sequences in common, each RNA helicase has particular specificity and unique biological function. Human DHX33 protein has a molecular weight of approximately 72 kDa and has the function of unwinding nucleic acids. It utilizes the biological energy released by ATP hydrolysis to drive changes in the conformation of the complex of RNA and protein, thus participating in a variety of metabolic activities of RNA, specifically, a series of biological processes such as the transcription, splicing, editing, translation and degradation of RNA. The function of DHX33 is not merely limited to the modification of RNA molecules. Studies have demonstrated that, in addition to unwinding the two strands of RNA, DHX33 protein is also involved in the metabolism of DNA. Specifically, DHX33 protein is capable of unwinding the double-stranded structure of DNA and playing an important role in the process of gene expression. Studies have demonstrated that, by binding to a variety of cancer-related gene promoters, DHX33 affects the methylation status of DNA and thus regulates the expression of a variety of cancer genes and the signaling pathways related to the development of tumor at genome level, which plays a crucial role in a variety of cellular activities such as the growth, proliferation, migration, apoptosis and glycometabolism of cells. In addition, it has been found that DHX33 is capable of sensing the invasion of foreign double-stranded RNA molecules and playing an important role in the innate immunity of cells. As a very important cell growth regulatory gene, DHX33 is highly expressed in a variety of cancers such as lung cancer, lymphoma, glioblastoma, breast cancer, colon cancer, liver cancer. The occurrence and development of a variety of cancers depend on the high expression of DHX33 protein. Genetic knockout of DHX33 is capable of significantly inhibiting the occurrence and development of the lung cancer driven by RAS oncogene. It has been confirmed by in-vivo and in-vitro experiments that, upon the inhibition of DHX33 protein, the occurrence and development of a variety of cancers such as breast cancer, colon cancer, brain glioma and lymphoma are inhibited significantly. Studies have demonstrated that the function of DHX33 protein depends on its helicase activity. A DHX33 mutant lacking the helicase activity does not have the function of DHX33 protein, and the function of the wild-type DHX33 gene cannot be replaced. The present disclosure provides the structures and the synthetic methods of a variety of compounds capable of inhibiting the enzymatic activity of DHX33, and these compounds possess uses in the preparation of a drug for treating a disease or a disorder at least partially mediated by DHX33. SUMMARY In the present disclosure, a series of small molecule compounds that inhibit the RNA helicase activity of DHX33 have been found through extensive studies, and these compounds have potential value in preventing and/or treating DHX33-related diseases. In a first aspect, the present disclosure provides a compound having the structure of formula I or a pharmaceutically acceptable form thereof: wherein each R1 is independently halogen, amino, -NH(C1-4 alkyl), -N(C1-4 alkyl)2, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 hydroxyalkyl, -O-(C1-4 alkylene)-O-(C1-4 alkyl), -C(=O)-NH-(C1-4 alkylene)-N(C1-4 alkyl)2, or -C(=O)-O-(C1-4 alkyl), alternatively, a plurality of R1 and the atoms to which they are attached form a 5-7 membered ring;R2 is hydrogen, C1-4 alkyl, or -(C1-4 alkylene)-O-(C1-4 alkyl);X1 is N or -CR6;R6 is hydrogen or C1-4 alkyl;R3 is hydrogen or C1-4 alkyl;R4 is hydrogen or C1-4 alkyl;X2 is N or -CR7;R7 is hydrogen or C1-4 alkyl;each R5 is independently halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C3-6 cycloalkyl, -C(=O)-O-(C1-4 alkyl), phenyl, benzyl, pyridyl, -C(=O)-NH2, or -NH-C(=O)-(C1-4 alkyl), said phenyl, benzyl and pyridyl are optionally substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, C1-4 alkyl and C1-4 alkoxy;m is 0, 1, 2, 3 or 4;n is 0, 1, 2, 3 or 4;provided that m is not 0