WO2023274251A1 - 一类抑制rna解旋酶dhx33的多环化合物及其应用 - Google Patents
一类抑制rna解旋酶dhx33的多环化合物及其应用 Download PDFInfo
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- WO2023274251A1 WO2023274251A1 PCT/CN2022/102010 CN2022102010W WO2023274251A1 WO 2023274251 A1 WO2023274251 A1 WO 2023274251A1 CN 2022102010 W CN2022102010 W CN 2022102010W WO 2023274251 A1 WO2023274251 A1 WO 2023274251A1
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- Prior art keywords
- compound
- alkyl
- formula
- halogen
- pharmaceutically acceptable
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 251
- -1 Polycyclic compound Chemical class 0.000 title claims abstract description 73
- 230000002401 inhibitory effect Effects 0.000 title abstract description 13
- 108060004795 Methyltransferase Proteins 0.000 title description 14
- 101000901934 Homo sapiens ATP-dependent RNA helicase DHX33 Proteins 0.000 claims abstract description 50
- 102100022423 ATP-dependent RNA helicase DHX33 Human genes 0.000 claims abstract description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 201000010099 disease Diseases 0.000 claims abstract description 21
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- 125000000217 alkyl group Chemical group 0.000 claims description 85
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 34
- 150000002431 hydrogen Chemical class 0.000 claims description 29
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
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- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 8
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- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 230000001404 mediated effect Effects 0.000 claims description 7
- 239000002207 metabolite Substances 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
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- 239000012453 solvate Substances 0.000 claims description 6
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
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- 230000000155 isotopic effect Effects 0.000 claims description 5
- 125000002971 oxazolyl group Chemical group 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000000335 thiazolyl group Chemical group 0.000 claims description 5
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 4
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
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- 238000002360 preparation method Methods 0.000 abstract description 25
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- 239000000243 solution Substances 0.000 description 141
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- FPWCPEHIOHVWFT-UHFFFAOYSA-N tert-butyl n-(2,4-dimethyl-1,3-thiazol-5-yl)carbamate Chemical compound CC1=NC(C)=C(NC(=O)OC(C)(C)C)S1 FPWCPEHIOHVWFT-UHFFFAOYSA-N 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A61K31/425—Thiazoles
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- 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
- A61K31/437—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 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
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- 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
- C07D403/02—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 two hetero rings
- C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
- C07D471/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and relates to a small molecule inhibitor of DHX33, a pharmaceutical composition containing it, a preparation method thereof, and a medical application for preventing and/or treating DHX33-related diseases.
- the present invention relates to compounds that inhibit the RNA helicase activity of DHX33.
- DHX33 belongs to the DEAD/H box-containing RNA helicase protein family. Among them, DEAD/H stands for the abbreviation of amino acid Asp-Glu-Ala-Asp/His. This sequence, together with other conservative amino acid sequences, appears in the protein sequence of RNA helicase family members and is highly involved in nucleic acid substrates. Binding and ATP hydrolysis. Although these family members share these same sequences, each RNA helicase has its own specific specificity and unique biological function. The molecular weight of human DHX33 protein is about 72kDa, and it has the function of unwinding nucleic acid.
- RNA uses the bioenergy released by ATP hydrolysis to drive and change the conformation of RNA and protein complexes, and then participates in the metabolic activities of various RNAs.
- RNA A series of biological processes such as transcription, splicing, editing, translation and degradation.
- the function of DHX33 is not limited to the modification of RNA molecules. Studies have shown that in addition to unwinding RNA double strands, DHX33 protein is also involved in DNA metabolism. Specifically, the DHX33 protein can unwind the double-strand structure of DNA and play an important role in the process of gene expression.
- DHX33 affects the methylation status of DNA by binding to the promoters of various cancer-related genes, and then regulates the expression of various cancer genes and the signaling pathways related to tumor development at the genome level, and has a significant effect on cell growth, proliferation, It plays a vital role in various cellular activities such as migration, apoptosis, and glucose metabolism.
- DHX33 can sense the invasion of foreign double-stranded RNA molecules and play an important role in the innate immunity of cells.
- DHX33 is highly expressed in various cancers, such as lung cancer, lymphoma, glioblastoma, breast cancer, colon cancer, liver cancer and so on.
- DHX33 protein The genetic knockout of DHX33 can significantly inhibit the occurrence and development of lung cancer driven by RAS oncogene; in vivo and in vitro experiments have confirmed that after inhibiting DHX33 protein, the occurrence and development of various cancers such as breast cancer, colon cancer, glioma, lymphoma, etc. were significantly suppressed.
- the present invention provides structures and synthesis methods of various compounds with enzyme activity inhibiting DHX33, and these compounds are used in the preparation of medicines for treating diseases or diseases at least partially mediated by DHX33.
- the present invention has discovered a series of small molecular compounds that can inhibit the RNA helicase activity of DHX33, and have potential value in preventing and/or treating DHX33-related diseases.
- the present invention provides a compound of formula I or a pharmaceutically acceptable form thereof:
- X 1 is selected from N or CR 1
- X 2 is selected from N or CR 2
- X 3 is selected from N or CR 3
- X 4 is selected from N or CR 4 ;
- Each R 6 is independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl or C 6-10 aryl;
- Ring A is selected from 5-10 membered heteroaryl or 3-8 membered heterocyclic group, ring A is optionally substituted by one or more R 7 ;
- Each R 7 is independently selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
- L 2 is selected from single bond, O, S or CR 8 R 9 ;
- R 8 and R 9 are each independently selected from hydrogen, halogen or C 1-6 alkyl
- Ring B is selected from C 6-10 aryl, 5-12 membered heteroaryl or 3-8 membered heterocyclic group, ring B is optionally substituted by one or more R 10 ;
- the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitroxides, isotopic labels, metabolites and prodrugs.
- each of R 1 , R 2 , R 3 and R 4 in the compound of formula I above or a pharmaceutically acceptable form thereof is independently selected from hydrogen, halogen, amino, nitro, hydroxyl, C 1- 6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 or C 1-6 hydroxyalkyl.
- R 1 , R 2 , R 3 and R 4 in the compound of formula I above or a pharmaceutically acceptable form thereof are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy.
- R 1 , R 2 , R 3 and R 4 in the compound of formula I above or a pharmaceutically acceptable form thereof are each independently selected from hydrogen, halogen, amino, nitro, hydroxyl, Methyl, methoxy or trifluoromethoxy.
- R in the compound of formula I above or a pharmaceutically acceptable form thereof is selected from hydrogen, halogen or methyl.
- ring A in the compound of formula I above or a pharmaceutically acceptable form thereof is selected from 5-10 membered heteroaryl, ring A is optionally substituted by one or more R 7 , each R 7 independently selected from halogen, C 1-4 alkyl or C 1-4 haloalkyl.
- ring A in the above-mentioned compound of formula I or its pharmaceutically acceptable form is selected from pyrrolyl, pyrazolyl, imidazolyl, thiazolyl or oxazolyl, and ring A is optionally replaced by one or a plurality of R 7 substituted, each R 7 independently selected from halogen, methyl, ethyl or trifluoromethyl.
- ring A in the compound of formula I above or a pharmaceutically acceptable form thereof is selected from pyrrolyl or imidazolyl, ring A is optionally substituted by one or more R 7 , each R 7 is independently selected from halogen or methyl.
- ring A in the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is selected from
- L 2 in the compound of formula I above or a pharmaceutically acceptable form thereof is selected from a single bond or CR 8 R 9 ;
- R 8 and R 9 are each independently selected from hydrogen, halogen or C 1-4 alkyl.
- L 2 in the compound of formula I above or a pharmaceutically acceptable form thereof is selected from a single bond, -CH 2 - or -CH(CH 3 )-.
- ring B in the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof is selected from
- the above-mentioned compound of formula I or a pharmaceutically acceptable form thereof has formula I-1, formula I-2, formula I-3, formula I-4, formula I-5, formula I-6, A compound of formula I-19 or formula I-20 or a pharmaceutically acceptable form thereof:
- R 1 , R 2 , R 3 , R 4 , R 6 , L 1 , L 2 and ring B are as defined in formula I.
- the above-mentioned compound of formula I or its pharmaceutically acceptable form has formula I-7, formula I-8, formula I-9, formula I-10, formula I-11, formula I- 12.
- R 1 , R 2 , R 3 , R 4 , R 6 and ring B are as defined in formula I.
- the present invention also provides the following compounds or pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotope labels, metabolites or prodrugs thereof:
- the present invention provides a pharmaceutical composition, which comprises at least one compound or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
- the present invention provides the above-mentioned compound or its pharmaceutically acceptable form, or the above-mentioned pharmaceutical composition, which is used as a DHX33 inhibitor for preventing and/or treating diseases or conditions at least partially mediated by DHX33.
- the present invention provides the use of the above-mentioned compound or its pharmaceutically acceptable form or the above-mentioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or condition at least partially mediated by DHX33.
- the present invention provides a method for preventing and/or treating a disease or condition mediated at least in part by DHX33, which comprises the following steps: administering a preventive and/or therapeutically effective amount of the above-mentioned compound or its pharmaceutical An acceptable form or pharmaceutical composition as described above is administered to an individual in need thereof.
- compositions, methods, or device comprising a list of elements is not necessarily limited to the elements explicitly listed, but may also include other elements not explicitly listed or inherent to the composition, method, or device described above.
- 5-10 yuan should be understood as covering any sub-range and every point value, such as 5-6 yuan, 5-7 yuan, 5-8 yuan, 5-9 yuan, 6-7 yuan, 6-8 yuan, etc., and 5, 6, 7, 8, 9, 10 yuan, etc.
- composition refers to a composition that can be used as a medicine, which comprises a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers.
- pharmaceutically acceptable carrier refers to an excipient that is administered with a therapeutic agent and that is suitable within the scope of sound medical judgment for contacting human and/or other animal tissues without undue toxicity, irritation, Anaphylaxis or other problems or complications with a reasonable benefit/risk ratio.
- the pharmaceutically acceptable carrier that can be used in the present invention includes but not limited to: a) diluent; b) lubricant; c) binder; d) disintegrating agent; and/or sweeteners; f) emulsifying or dispersing agents; and/or g) substances which enhance the absorption of the compound, etc.
- compositions may act systemically and/or locally.
- they can be administered by suitable routes, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or administered as an inhalant.
- Dosage forms that can be used in the present invention include, but are not limited to: tablets, capsules, lozenges, hard lozenges, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments elixirs, aqueous suspensions, injectable solutions, elixirs, syrups, etc.
- the above pharmaceutical composition can be made into any orally acceptable preparation form, including but not limited to tablets, capsules, aqueous solutions, aqueous suspensions and the like.
- the above pharmaceutical composition can also be administered in the form of sterile injection, including sterile injectable water or oil suspension, or sterile injectable water or oil solution.
- the carrier that can be used includes but not limited to: water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils such as mono- or diglycerides, can be employed as a solvent or suspending medium.
- the above-mentioned pharmaceutical composition may contain 0.01 mg to 1000 mg of at least one of the above-mentioned compounds or a pharmaceutically acceptable form thereof.
- disease or disorder at least partially mediated by DHX33 refers to a disease whose pathogenesis at least partially includes factors related to DHX33, such as cancer, viral infection, and inflammation.
- an effective amount refers to a dose capable of inducing biological or medical responses in cells, tissues, organs or organisms (eg, individuals) and sufficient to achieve desired preventive and/or therapeutic effects.
- Dosage regimens may be adjusted to provide the optimum desired response. For example, it can be administered as a single dose, divided doses can be administered over time, or the dose can be proportionally reduced or increased according to the actual situation. It will be appreciated that for any particular individual, the specific dosing regimen will be adjusted according to the needs and professional judgment of the person administering the composition or supervising the administration of the composition.
- needle for refers to a physician's or other caregiver's judgment that an individual needs or will benefit from prophylactic and/or therapeutic procedures, based on the physician's or other caregiver's various factors.
- the term "individual" refers to a human or non-human animal.
- Individuals of the present invention include individuals with diseases and/or conditions (patients) and normal individuals.
- Non-human animals of the present invention include all vertebrates, such as non-mammals, such as birds, amphibians, reptiles, etc., and mammals, such as non-human primates, livestock and/or domesticated animals (such as sheep, dogs, cats, cows, pigs, etc.).
- treating means alleviating or eliminating the targeted disease or condition. If the subject receives a therapeutic amount of a compound of the present invention or a pharmaceutically acceptable form thereof or a pharmaceutical composition of the present invention, at least one indicator and symptom of the subject exhibits observable and/or detectable Detected remission and/or improvement indicates that the subject has been successfully "treated". It is understood that treatment includes not only complete cure, but also not complete cure but achievement of some biologically or medically relevant result. Specifically, “treatment” means that the compound of the present invention or its pharmaceutically acceptable form or the pharmaceutical composition of the present invention can achieve at least one of the following effects, for example: prevent disease in animals experiencing or exhibiting disease pathology or symptomatology; (2) inhibit disease (i.e.
- pharmaceutically acceptable salt refers to a salt of a compound of the present invention that is substantially non-toxic to an organism.
- Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting compounds of the present invention with pharmaceutically acceptable inorganic/organic acids or inorganic/organic bases. Such salts are also called acid addition salts or base addition salts.
- a salt For a review of suitable salts see, e.g., Jusiak, Soczewinski, et al., Remington's Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley -VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to those skilled in the art.
- esters refers to an ester that is substantially non-toxic to the living body and hydrolyzed into the compound of the present invention or a salt thereof in the living body.
- Pharmaceutically acceptable esters generally include, but are not limited to, esters of compounds of the present invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters are also known as carboxylic acid esters or sulfonic acid esters.
- isomer refers to compounds that have the same molecular weight due to the same number and type of atoms, but differ in the arrangement or configuration of the atoms in space.
- stereoisomer means having at least one chiral element (including a chiral center, chiral axis, chiral plane, etc.) that has a perpendicular plane of asymmetry, Stable isomers that can thus rotate plane-polarized light. Due to the presence of asymmetric centers and other chemical structures which may give rise to stereoisomerism in the compounds of the present invention, the present invention also includes these stereoisomers and mixtures thereof. Unless otherwise indicated, all stereoisomeric forms of the compounds of the invention are within the scope of the invention.
- tautomer refers to structural isomers having different energies that are interconvertible through a low energy barrier. If tautomerism is possible (eg, in solution), then a chemical equilibrium of the tautomers can be achieved.
- proton tautomers include, but are not limited to, interconversions via migration of a proton, such as keto-enol isomerization, imine-enamine isomerization, Amide-iminoalcohol isomerization, etc. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
- solvate refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule through non-covalent intermolecular forces.
- solvates include, but are not limited to, hydrates (including hemihydrates, monohydrates, dihydrates, trihydrates, etc.), ethanolates, acetonates, and the like.
- nitrogen oxide refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or a nitrogen-containing (aromatic) heterocyclic compound.
- nitrogen atoms in the nucleus of the above compounds can form the corresponding nitrogen oxides.
- isotopic label refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotopic atom.
- the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as but not limited to 2 H(D), 3 H(T), 13 C, 14 C , 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S, 36 S and 37 Cl.
- the term "metabolite” refers to derivative compounds formed after metabolism of the compounds of the present invention. Further information on metabolism can be found in Goodman and Gilman's: The Pharmacological Basis of Therapeutics (9 th ed.) [M], McGraw-Hill International Editions, 1996.
- the present invention encompasses all possible metabolite forms of the compounds of the present invention, ie substances formed in the body of the individual administered the compounds of the present invention. Metabolites of compounds can be identified by techniques known in the art, and their activity can be characterized by assays.
- prodrug refers to a derivative compound capable of providing, directly or indirectly, a compound of the invention upon administration to an individual.
- Particularly preferred derivative compounds or prodrugs are compounds that, when administered to a subject, increase the bioavailability of the compounds of the invention (e.g., better absorption into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system) compound of.
- all prodrug forms of the compounds of the invention are within the scope of the invention and various prodrug forms are known in the art, see for example T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems[J],American Chemical Society,Vol.14,1975.
- the invention also encompasses compounds of the invention which contain protecting groups.
- protecting groups such as those described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
- the term "independently" means that at least two groups (or ring systems) present in the structure with the same or similar value range may have the same or different meanings under specific circumstances.
- the substituent X and the substituent Y are each independently hydrogen, halogen, hydroxyl, cyano, alkyl or aryl, then when the substituent X is hydrogen, the substituent Y can be either hydrogen or halogen, Hydroxyl, cyano, alkyl or aryl; Similarly, when the substituent Y is hydrogen, the substituent X can be either hydrogen or halogen, hydroxyl, cyano, alkyl or aryl.
- halogen as used herein alone or in combination with other groups refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
- alkyl refers to a straight or branched chain aliphatic hydrocarbon group.
- C 1-6 alkyl used in the present invention refers to an alkyl group having 1 to 6 carbon atoms.
- alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or t-butyl, and the like.
- Alkyl groups can be optionally substituted or unsubstituted.
- alkylene refers to a straight-chain or branched divalent saturated aliphatic hydrocarbon group, and the two groups (or fragments) connected by it can be connected with the same A carbon atom can be connected to different carbon atoms.
- C 1-6 alkylene refers to an alkylene group having 1-6 carbon atoms (such as methylene, 1,1-ethylene, 1,2-ethylene group, 1,2-propylene, 1,3-butylene, etc.). Alkylene groups can be optionally substituted or unsubstituted.
- haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms.
- C 1-6 haloalkyl used in the present invention refers to a haloalkyl group having 1 to 6 carbon atoms.
- haloalkyl includes, but is not limited to, -CH2F , -CHF2 , -CF3 , -CH2CF3 , -CF2CF3 , -CH2CH2CF3 , -CH2Cl , and the like.
- a haloalkyl group can be optionally substituted or unsubstituted.
- hydroxyalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups.
- C 1-6 hydroxyalkyl used in the present invention refers to a hydroxyalkyl group having 1 to 6 carbon atoms.
- hydroxyalkyl includes, but is not limited to Wait.
- a hydroxyalkyl group can be optionally substituted or unsubstituted.
- alkoxy refers to an alkyl group attached to the remainder of the molecule through an oxygen atom.
- alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
- Alkoxy groups can be optionally substituted or unsubstituted.
- haloalkoxy refers to a monovalent straight or branched chain haloalkyl-O- group which is replaced by at least one member selected from the group consisting of fluorine, chlorine, bromine and The iodine atom is substituted, may contain unsaturation, and is attached to another group through a single bond to the oxygen atom, such as a C1-6 haloalkoxy group.
- haloalkoxy includes, but is not limited to, fluoromethoxy (-OCH 2 F), difluoromethoxy (-OCHF 2 ), trifluoromethoxy (-OCF 3 ), 1-fluoroethoxy (- OCHFCH 3 ), 2-fluoroethoxy (-OCH 2 CH 2 F), 1,2-difluoroethoxy (-OCHFCH 2 F), 2,2-difluoroethoxy (-OCH 2 CHF 2 ), 1,2,2-trifluoroethoxy (-OCHFCHF 2 ), 2,2,2-trifluoroethoxy (-OCH 2 CF 3 ), etc.
- cycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (such as bicyclic) non-aromatic hydrocarbon group.
- C 3-6 cycloalkyl used in the present invention refers to a cycloalkyl group having 3 to 6 carbon atoms.
- cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, and the like. Cycloalkyl groups can be optionally substituted or unsubstituted.
- a heterocyclyl group can be attached to the rest of the molecule through any ring atom, provided the valence requirements are met.
- heterocyclic group refers to a heterocyclic group having 3 to 8 ring atoms.
- Common heterocyclyl groups include (but are not limited to) oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl, pyrrolidine , pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dithianyl or trithianyl.
- the heterocyclyl group in the present invention is optionally substituted with one or more substituents described herein.
- aryl refers to a monocyclic or fused polycyclic aromatic hydrocarbon group having a conjugated ⁇ -electron system.
- C 6-10 aryl used in the present invention refers to an aryl group having 6 to 10 carbon atoms.
- Common aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthrenyl, acenaphthyl, azulenyl, fluorenyl, indenyl, pyrenyl, and the like.
- Aryl groups in the present invention are optionally substituted with one or more substituents described herein.
- heteroaryl refers to a monocyclic or fused polycyclic aromatic group having a conjugated ⁇ -electron system, the ring atoms of which consist of carbon atoms and at least one It consists of heteroatoms selected from N, O and S.
- a heteroaryl group can be attached to the rest of the molecule through any ring atom, provided the valence requirements are met.
- the term “5-10 membered heteroaryl” used in the present invention refers to a heteroaryl group having 5 to 10 ring atoms.
- heteroaryl groups include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazole Base, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and its benzo derivatives, pyrrolopyridyl, pyrrolopyrazinyl, pyrazolopyridyl, imidazo Pyridyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, purinyl, etc.
- the heteroaryl group in the present invention is optionally substituted by one or more substituents described in the present invention (such as halogen, C 1-6 alkyl, etc.).
- cyano as used herein alone or in combination with other groups refers to -CN.
- amino as used herein alone or in combination with other groups refers to -NH2 .
- nitro as used herein alone or in combination with other groups refers to -NO2 .
- Figure 1 shows the result analysis of the recombinant DHX33 protein prepared by the method of the present invention after SDS-PAGE separation and staining with Coomassie Brilliant Blue.
- the reagents or instruments used in the examples are all commercially available conventional products. Those without specific conditions shall be carried out in accordance with the conventional conditions or the conditions suggested by the manufacturer.
- the term "room temperature” used in the present invention refers to 20°C ⁇ 5°C.
- the term “about” used in the present invention refers to the error range acceptable to those skilled in the art including the numerical value or numerical range and the numerical value or numerical range, such as the error The range is ⁇ 10%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, ⁇ 0.5%, etc.
- the measuring instrument of nuclear magnetic resonance uses Bruker 400MHz nuclear magnetic resonance instrument, and measuring solvent is deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ), hexadeuterio dimethyl sulfoxide (DMSO-d 6 ), The internal standard substance is tetramethylsilane (TMS). In 1 H NMR, some hydrogens may not appear as peaks due to interference from salts or solvents.
- Mass spectrometry was performed using an Agilent 6120B mass spectrometer, and the ion source was an electrospray ionization source (ESI).
- MS mass spectrometry
- ESI electrospray ionization source
- HPLC HPLC-based analytical chromatography
- Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5 ⁇ m chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18, 150X 4.6mm, 5 ⁇ m chromatographic column).
- the thin-layer chromatography silica gel plate uses Qingdao Haiyang GF254 silica gel plate, the specification of the silica gel plate used for thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin-layer chromatography separation and purification product is 0.4mm-0.5mm silicone board.
- the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), and the system of developing agent used in the reaction has A: methylene chloride and methanol system; B: sherwood oil and ethyl acetate system, and the volume ratio of solvent is according to The polarity of the compound is adjusted accordingly.
- TLC thin-layer chromatography
- the eluent system of column chromatography and the developing agent system of thin-layer chromatography used in the purification compound include A: dichloromethane and methanol system; B: petroleum ether and ethyl acetate system, and the volume ratio of the solvent is based on the compound It can be adjusted according to the polarity, and can also be adjusted by adding a small amount of triethylamine and acidic or alkaline reagents.
- Example 1 Compound AB29502 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-3H-imidazo[4,5-c]pyridine-2- base)-2,5-dimethyl-1H-pyrrole-3-carboxamide) synthesis
- Phosphorus oxychloride (2.48 g, 16.2 mmol, 2.0 eq) was added dropwise to dimethylformamide (30 mL) at 0 °C under nitrogen protection. The mixture was stirred at 0°C for 30 minutes and then allowed to warm to room temperature.
- Example 2 Compound AB29509 (1-(4-cyano-2-methylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2 , the preparation method of 5-dimethyl-1H-pyrrole-3-carboxamide)
- the mixture was cooled to room temperature, quenched with methanol (10 mL), and then adjusted to pH 3 with 3M hydrochloric acid.
- the mixture was diluted with water (30 mL), then extracted three times with 20 mL each of ethyl acetate.
- the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated.
- Example 4 Compound AB24387 (1-(3-carbamoyl-5-methylthiophen-2-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)- 2,5-dimethyl-1H-pyrrole-3-carboxamide) preparation method
- Example 5 Compound AB29505 (1-(2,4-dimethylthiazol-5-yl)-N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5 -Synthesis of dimethyl-1H-pyrrole-3-carboxamide)
- Example 7 Compound AB29513 (N-(6-methoxy-1H-benzo[d]imidazol-2-yl)-2,5-dimethyl-1-((1-methyl-1H-pyridine Synthesis of azole-4-yl)methyl)-1H-pyrrole-3-carboxamide)
- Embodiment 8 the synthesis of compound AB29522
- Embodiment 9 the synthesis of compound AB29553
- reaction solution was directly concentrated, water (100mL) was added to the concentrated residue, extracted three times with ethyl acetate (100mL*3), the combined organic phase was backwashed once with saturated brine (50.0mL), the organic phase was separated and washed with anhydrous After drying over sodium sulfate, it was concentrated by filtration.
- Embodiment 10 the synthesis of compound AB29556
- Embodiment 11 the synthesis of compound AB29557
- reaction solution was concentrated under the oil pump.
- the crude product was separated and purified by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH 4 HCO 3 )-ACN]; B%: 43%-73%, 2min) to obtain compound AB29557 (0.022g, 50.9umol, yield 26.5%, purity 94.9%) was a yellow solid.
- Embodiment 12 the synthesis of compound AB29558
- the first purification was performed by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(NH 3 H 2 O)-ACN]; B%: 25%-55%, 8min).
- the second purification was performed by high performance liquid chromatography (column: Welch Xtimate C18 150*25mm*5um; mobile phase: [water(HCl)-ACN]; B%: 16%-46%, 8min).
- Compound AB29558 (8.68 mg, 19.4 umol, 7.28% yield, 99% purity, hydrochloride) was obtained as a white solid.
- Embodiment 13 the synthesis of compound AB29559
- Embodiment 14 the synthesis of compound AB29560
- Methylamine hydrochloride (1.44g, 21.4mmol, 5.00eq, HCl) was dissolved in N-methylpyrrolidone (10.0mL), compound 1 (780mg, 4.27mmol, 1.00eq) and potassium carbonate (2.95g, 21.4 mmol, 5.00 eq). The mixture was stirred and reacted at 150° C. for 24 hours. LCMS showed that compound 1 was consumed and the desired molecular weight of the compound was detected.
- Embodiment 15 the synthesis of compound AB29561
- Tetrahydrofuran (0.5mL) and dimethyl sulfoxide (0.5mL) were added to compound 1 (100mg, 246umol, 1.00eq), potassium tert-butoxide (55.2mg, 493umol, 2.00eq) was added to the reaction solution, and then Chloromethyl methyl ether (29.8mg, 369umol, 28.1uL, 1.50eq) was added dropwise to the reaction solution, and the reaction solution was stirred and reacted at 20°C for 2 hours. LCMS showed that the starting material was consumed, and the formation of the target product peak was detected.
- Embodiment 19 Synthesis of compound AB29540
- RNA helicase gene (mouse DHX33 gene) is cloned between the BamH I/Not I restriction sites of the pET32M-3C vector. Then the plasmid was transformed into Escherichia coli strain BL-21pLysS(DE3), and 0.5 mM isopropyl 1-thio- ⁇ -D-galactopyranoside (IPTG) was added to induce the expression of the recombinant protein at 16°C for 16 hours.
- IPTG isopropyl 1-thio- ⁇ -D-galactopyranoside
- Cells were pelleted and resuspended in cell lysis buffer [50 mM Tris-HCl (pH 7.2), 150 mM NaCl, 1% Triton X-100 and 50 mM imidazole supplemented with protease inhibitors]. Cells were then sonicated and centrifuged at 13000 rpm for 25 minutes. The supernatant was incubated with Tris-buffer-equilibrated nickel-nitrilotriacetic acid beads followed by extensive washing. The purified protein was then eluted with 300 mM imidazole in Tris buffer and then dialyzed against imidazole-free Tris buffer overnight at 4 °C.
- Figure 1 shows the result analysis of the recombinant DHX33 protein prepared by the above method after separation by SDS-PAGE and stained with Coomassie Brilliant Blue.
- the arrow in the figure indicates the target recombinant DHX33 protein (containing thioredoxin tag), and the molecular weight of the target band is 90kDa.
- the helicase reaction was started after addition of 90 ⁇ L of reaction mixture [0.25 ⁇ g of purified full-length DHX33 protein dissolved in 25 mM 4-MOPS (pH 7.0), 5 mM ATP, 2 mM DTT, 3 mM MnCl 2 and 100 ⁇ g/mL BSA]. React at 37°C for 60 minutes. After washing, each well was incubated with blocking solution [10% (w/v) BSA in 0.1M maleic acid and 0.15M NaCl (pH7.5)] for 30 minutes, and then incubated with 20 ⁇ L of antibody solution (anti- DIG-AP, Roche, in blocking buffer) for 30 minutes.
- blocking solution [10% (w/v) BSA in 0.1M maleic acid and 0.15M NaCl (pH7.5)] for 30 minutes, and then incubated with 20 ⁇ L of antibody solution (anti- DIG-AP, Roche, in blocking buffer) for 30 minutes.
- One of the negative controls is the comparison under the condition that all other conditions are the same except ATP, and the other negative control refers to the comparison under the condition that the other conditions are the same except that DHX33 protein is not added.
- Positive controls are comparisons to wild-type DHX33 protein standards. Compared with the DHX33 protein standard, the results showed that the DHX33 protein prepared by the above method had helicase activity.
- the helicase activity of the DHX33 protein in vitro was determined using a series of concentrations of the compound (the concentration range was set at 1 nM, 5 nM, 10 nM, 20 nM, 50 nM, 100 nM, 250 nM, 500 nM, 1000 nM).
- Table 1 shows the half-inhibitory concentrations of the compounds of the present invention on the helicase activity of DHX33 protein. It can be seen from Table 1 that the compound of the present invention has significant inhibitory effect on the helicase activity of DHX33 protein.
- **** represents the half-inhibitory concentration ⁇ 20nM.
- U251-MG cells were purchased from the Cell Bank of the Chinese Academy of Sciences. Cultured in MEM medium containing 10% fetal bovine serum (FBS), 2mM L-glutamine, streptomycin and penicillin, the growth conditions were set at 37°C, 5% CO 2 in a cell culture incubator with humidity. Cells were passaged every 3 days and discarded after 10 passages.
- FBS fetal bovine serum
- 2mM L-glutamine 2mM L-glutamine
- streptomycin streptomycin
- penicillin penicillin
- DHX33 overexpressed cancer cell line U251-MG cells on a 96-well plate at 1 ⁇ 10 4 /100ul/well. Wait for the cells to adhere completely, add the compound to the cell culture medium at a concentration of 5nM, 10nM, 25nM, 50nM, 100nM, 250nM, 500nM, 1000nM, 2000nM, 5000nM, 10 ⁇ M, 20 ⁇ M, and mix evenly with a multi-channel exhaust gun.
- CCK-8 reagent (Yisheng Biotechnology (Shanghai) Co., Ltd.) to the medium of the 96-well plate according to the standard procedure, and after incubation for 2 hours, use the enzyme
- **** represents the half inhibitory concentration ⁇ 100nM.
Abstract
Description
Claims (13)
- 一种具有式I结构的化合物或其药学上可接受的形式:其中,X 1选自N或CR 1,X 2选自N或CR 2,X 3选自N或CR 3,X 4选自N或CR 4;R 1、R 2、R 3和R 4各自独立地选自氢、卤素、氨基、硝基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2、C 1-6羟基烷基、-O-(C 1-6亚烷基)-O-(C 1-6烷基)、-C(=O)-NH-(C 1-6烷基)、-C(=O)-NH-(C 1-6亚烷基)-N(C 1-6烷基) 2或-C(=O)-O-(C 1-6烷基);X 5选自N或CR 5,R 5选自氢、卤素或C 1-6烷基,所述C 1-6烷基任选地被一个或多个选自卤素、C 1-6烷基、-(C 1-6亚烷基)-O-(C 1-6烷基)或-(C 1-6亚烷基)-O-C(=O)-(C 1-6烷基)的取代基取代;L 1选自-NR 6C(=O)-、-NR 6S(=O) 2-、-NR 6S(=O)-、-C(=O)NR 6-、-S(=O) 2NR 6-或-S(=O)NR 6-;每个R 6独立地选自氢、C 1-6烷基、C 3-8环烷基或C 6-10芳基;环A选自5-10元杂芳基或3-8元杂环基,环A任选地被一个或多个R 7取代;每个R 7独立地选自卤素、C 1-6烷基或C 1-6卤代烷基;L 2选自单键、O、S或CR 8R 9;R 8和R 9各自独立地选自氢、卤素或C 1-6烷基;环B选自C 6-10芳基、5-12元杂芳基或3-8元杂环基,环B任选地被一个或多个R 10取代;每个R 10独立地选自卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-6环烷基、-C(=O)-O-(C 1-6烷基)、苯基、苄基、吡啶基、-C(=O)-NH 2、或-NH-C(=O)-(C 1-6烷基),所述苯基、苄基、吡啶基任选地被一个或多个选自氢、卤素、氰基、氨基、羟基、C 1-6烷基或C 1-6烷氧基的取代基取代;所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、溶剂化物、氮氧化物、同位素标记物、代谢物和前药。
- 根据权利要求1所述的化合物或其药学上可接受的形式,其中R 1、R 2、R 3和R 4各自独立地选自氢、卤素、氨基、硝基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、-NH(C 1-6烷基)、-N(C 1-6烷基) 2或C 1-6羟基烷基;优选地,R 1、R 2、R 3和R 4各自独立地选自氢、卤素、氨基、硝基、羟基、C 1-4烷基、C 1-4卤代烷基、C 1-4烷氧基或C 1-4卤代烷氧基;更优选地,R 1、R 2、R 3和R 4各自独立地选自氢、卤素、氨基、硝基、羟基、甲基、甲氧基或三氟甲氧基。
- 根据权利要求1或2所述的化合物或其药学上可接受的形式,其中R 5选自氢、卤素或C 1-4烷基,所述C 1-4烷基任选地被一个或多个选自卤素、C 1-4烷基、-(C 1-4亚烷基)-O-(C 1-4烷基)或-(C 1-4亚烷基)-O-C(=O)-(C 1-4烷基)的取代基取代;R 5选自氢、卤素或C 1-4烷基,所述C 1-4烷基任选地被一个或多个选自卤素、C 1-4烷基、-CH 2-O-CH 3或-CH 2-O-C(=O)-CH 3的取代基取代;优选地,R 5选自氢、卤素或甲基。
- 根据权利要求1-3中任一项所述的化合物或其药学上可接受的形式,其中L 1选自-NR 6C(=O)-、-NR 6S(=O) 2-、-C(=O)NR 6-或-S(=O) 2NR 6-,每个R 6独立地选自氢、C 1-4烷基或C 3-6环烷基;优选地,L 1选自-NR 6C(=O)-、-NR 6S(=O) 2-、-C(=O)NR 6-或-S(=O) 2NR 6-,每个R 6独立地选自氢或C 1-4烷基;更优选地,L 1选自-NHC(=O)-、-N(CH 3)-C(=O)-、-NHS(=O) 2-、-C(=O)NH-或-S(=O) 2NH-。
- 根据权利要求1-5中任一项所述的化合物或其药学上可接受的形式,其中L 2选自单键或CR 8R 9;R 8和R 9各自独立地选自氢、卤素或C 1-4烷基;优选地,L 2选自单键、-CH 2-或-CH(CH 3)-。
- 根据权利要求1-6中任一项所述的化合物或其药学上可接受的形式,其中环B选自C 6-10芳基或5-12元杂芳基,环B任选地被一个或多个R 10取代,每个R 10独立地选自卤素、氰基、氨基、硝基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6卤代烷氧基、C 3-6环烷基或-C(=O)-NH 2;优选地,环B选自C 6-10芳基或5-10元杂芳基,环B任选地被一个或多个R 10取代,每个R 10独立地选自卤素、氰基、氨基、硝基、羟基、C 1-4烷基、C 1-4烷氧基或-C(=O)-NH 2;更优选地,环B选自苯基、吡嗪基、吡啶基、嘧啶基、呋喃基、噁唑基、噻吩基、噻唑基、吡唑基或咪唑基,环B任选地被一个或多个R 10取代,每个R 10独立地选自卤素、氰基、氨基、硝基、羟基、甲基或-C(=O)-NH 2;
- 一种药物组合物,其包含根据权利要求1-10中任一项所述的化合物或其药学上可接受的形式,以及一种或多种药学上可接受的载体。
- 根据权利要求1-10中任一项所述的化合物或其药学上可接受的形式、或者权利要求11所述的药物组合物在制备用于预防和/或治疗至少部分由DHX33介导的疾病或病症的药物中的用途。
- 根据权利要求12所述的用途,所述疾病选自由DHX33介导的癌症、病毒感染及炎症。
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CN116036282B (zh) * | 2022-12-30 | 2023-12-26 | 深圳开悦生命科技有限公司 | Rna解旋酶dhx33抑制剂在制备用于治疗前列腺癌的药物中的应用 |
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