CN112898284B - Compound for inhibiting RNA helicase DHX33 and application thereof - Google Patents
Compound for inhibiting RNA helicase DHX33 and application thereof Download PDFInfo
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- CN112898284B CN112898284B CN202110225711.9A CN202110225711A CN112898284B CN 112898284 B CN112898284 B CN 112898284B CN 202110225711 A CN202110225711 A CN 202110225711A CN 112898284 B CN112898284 B CN 112898284B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C07—ORGANIC CHEMISTRY
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- 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
Abstract
The invention relates to a compound for inhibiting RNA helicase DHX33 and application thereof. In particular, the invention relates to a compound shown in formula I or a pharmaceutically acceptable form thereof, a pharmaceutical composition containing the compound, a preparation method thereof and medical application thereof in preventing and/or treating DHX33 related diseases.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and relates to a small molecule inhibitor of DHX33, a pharmaceutical composition containing the small molecule inhibitor, a preparation method of the small molecule inhibitor, and medical application of the small molecule inhibitor in preventing and/or treating diseases related to DHX 33.
Background
The present invention relates to compounds that inhibit DHX33 RNA helicase activity. DHX33 belongs to the family of RNA helicase proteins that contain DEAD/H cassettes. Among them, DEAD/H represents the amino acid abbreviation Asp-Glu-Ala-Asp/His, which occurs, along with many other conserved amino acid sequences, in protein sequences of members of the RNA helicase family, highly involved in nucleic acid substrate binding and ATP hydrolysis. Although these family members share these same sequences, each RNA helicase has its own specific and unique biological functions. The molecular weight of the DHX33 protein is 72kDa, and the DHX33 protein has the function of unwinding nucleic acid, utilizes the bioenergy released by ATP hydrolysis to drive the change of the conformation of RNA and protein complexes, and further participates in a series of biological processes of RNA transcription, shearing, editing, translation to degradation and the like. The function of DHX33 is not limited to the modification of RNA molecules, and studies have shown that DHX33 protein is involved in DNA metabolism in addition to unwinding RNA duplexes. Specifically, the DHX33 protein can unravel the double-stranded structure of DNA and play an important role in the gene expression process.
Research shows that DHX33 influences the methylation state of DNA by combining with gene promoters related to various cancers, further regulates the expression of various cancer genes and signal paths related to tumor development at the genome level, and has important effects on various cell activities such as cell growth, proliferation, migration, apoptosis, carbohydrate metabolism and the like. In addition, DHX33 was found to 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, etc., as an important cell growth regulatory gene. The development of various cancers is dependent on the high expression of DHX33 protein. The genetic knockout of DHX33 can obviously inhibit the generation and development of the lung cancer driven by RAS oncogene; in vivo and in vitro experiments prove that after DHX33 protein is inhibited, the occurrence and the development of various cancers such as breast cancer, colon cancer, brain glioma, lymphoma and the like are obviously inhibited.
Studies have shown that DHX33 protein function is dependent on its helicase activity. The helicase activity deletion mutant of DHX33 does not have the function of DHX33 protein, and cannot replace the function of wild-type DHX33 gene. The invention provides a plurality of compound structures with DHX33 enzyme activity inhibition and a synthesis method, and has potential value for treating various cancers.
Disclosure of Invention
Through a large number of researches, a series of small molecule compounds capable of inhibiting the RNA helicase activity of DHX33 are discovered, and the small molecule compounds have potential values of preventing and/or treating DHX33 related diseases (such as cancers like glioblastoma).
In a first aspect, the present invention provides a compound having the structure of formula I:
wherein the content of the first and second substances,
ring A is selected from carbazole ring and benzo [4,5] imidazo [1,2-a ] pyridine ring;
each R1Independently selected from halogen, amino, nitro, hydroxy, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -NH (C)1-4Alkyl), -N (C)1-4Alkyl radical)2Or C1-4A hydroxyalkyl group;
each R2Independently selected from halogen, C1-4Alkyl or C1-4A haloalkyl group;
each R3Independently selected from halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A haloalkoxy group;
m is selected from 0, 1,2, 3 or 4;
n and p are independently selected from 0, 1,2 or 3;
the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.
In some embodiments, ring a in the above-described compound of formula I or a pharmaceutically acceptable form thereof is selected from 
In some embodiments, each R in the above compounds of formula I or pharmaceutically acceptable forms thereof1Independently selected from halogen, amino, nitro, hydroxyl, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A haloalkoxy group.
In some preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof1Independently selected from fluoro, chloro, bromo, amino, nitro, hydroxy, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy.
In some more preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof1Independently selected from methyl or methoxy.
In some embodiments, each of the compounds of formula I, or pharmaceutically acceptable forms thereof, described aboveR is2Independently selected from halogen or C1-4An alkyl group.
In some preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof2Independently selected from fluorine, chlorine, bromine, methyl, ethyl or isopropyl.
In some more preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof2Independently selected from methyl.
In some embodiments, each R in the above compounds of formula I or pharmaceutically acceptable forms thereof3Independently selected from halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl or C1-4An alkoxy group.
In some preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof3Independently selected from fluoro, chloro, bromo, cyano, amino, nitro, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy.
In some more preferred embodiments, each R in the above-described compound of formula I or a pharmaceutically acceptable form thereof3Independently selected from cyano or methyl.
In some embodiments, m in the above compound of formula I or a pharmaceutically acceptable form thereof is selected from 0, 1, 2, or 3.
In some preferred embodiments, m in the above compound of formula I or a pharmaceutically acceptable form thereof is selected from 0, 1 or 2.
In some embodiments, n in the above compound of formula I or a pharmaceutically acceptable form thereof is selected from 0, 1 or 2.
In some embodiments, p in the above compound of formula I or a pharmaceutically acceptable form thereof is selected from 0, 1, or 2.
In some embodiments, the present invention provides a compound having the structure of formula I or a pharmaceutically acceptable form thereof:
Wherein the content of the first and second substances,
ring A is selected from
Each R1Independently selected from fluoro, chloro, bromo, amino, nitro, hydroxy, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or trifluoromethoxy;
each R2Independently selected from fluoro, chloro, bromo, methyl, ethyl or isopropyl;
each R3Independently selected from fluoro, chloro, bromo, cyano, amino, nitro, hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy or isopropoxy;
m is selected from 0, 1, 2 or 3;
n and p are independently selected from 0, 1 or 2;
the pharmaceutically acceptable form is selected from the group consisting of pharmaceutically acceptable salts, esters, stereoisomers, tautomers, solvates, nitrogen oxides, isotopic labels, metabolites and prodrugs.
In some embodiments, the above-described compound of formula I, or a pharmaceutically acceptable form thereof, is a compound of formula I-1 through formula I-3, or a pharmaceutically acceptable form thereof:
wherein R is1、R2、R3N and p are as defined in formula I; q is selected from 0, 1 or 2.
It will be understood by those skilled in the art that the present invention encompasses compounds resulting from any combination of the various embodiments. Embodiments resulting from the combination of features from one embodiment or preferred features with features from another embodiment or preferred features are also included within the scope of the present invention.
In a second aspect, the present invention also provides the following compounds, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, nitrogen oxide, isotopic label, metabolite, or prodrug thereof:
in a third aspect, the present invention provides a pharmaceutical composition comprising at least one compound of formula I, formula I-1 through formula I-3, or a pharmaceutically acceptable form thereof, as described above, and one or more pharmaceutically acceptable carriers.
In a fourth aspect, the present invention provides a compound of formula I, formula I-1 to formula I-3, or a pharmaceutically acceptable form thereof, as described above, or a pharmaceutical composition as described above, for use as a DHX33 inhibitor for the prevention and/or treatment of a disease or disorder (e.g., cancer such as glioblastoma) mediated at least in part by DHX 33.
In a fifth aspect, the present invention provides the use of a compound of formula I, formula I-1 to formula I-3, or a pharmaceutically acceptable form thereof, as described above, or a pharmaceutical composition as described above, in the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by DHX33 (e.g., a cancer such as glioblastoma).
In a sixth aspect, the present invention provides a method for preventing and/or treating a disease or disorder (e.g., cancer such as glioblastoma) mediated at least in part by DHX33, comprising the steps of: administering to a subject in need thereof a prophylactically and/or therapeutically effective amount of a compound of formula I, formula I-1 through formula I-3, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition as described above.
The present invention is not limited to the specific embodiments described herein; it is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Definition of terms
The following terms have the following meanings in the present invention unless otherwise specified.
The terms "comprises," "comprising," "includes," "including," "has," "having" or "containing," or any other variation thereof, are intended to cover a non-exclusive or open-ended inclusion. For example, a composition, method, or apparatus that comprises a list of elements is not necessarily limited to only those elements explicitly listed, but may include other elements not explicitly listed or inherent to such composition, method, or apparatus.
When the lower and upper limits of a range of values are disclosed, any value or any sub-range falling within the range is specifically disclosed. In particular, each numerical range of parameters disclosed herein (e.g., in the form of "about a to b," or equivalently "about a-b") is to be understood to encompass each number and subrange therein. For example, "C1-4"is to be understood to cover any subrange therein as well as each point value, e.g. C2-4、C3-4、C1-2、C1-3、C1-4Etc. and C 1、C2、C3、C4And so on.
The term "pharmaceutical composition" refers to a composition that can be used as a medicament, comprising a pharmaceutically active ingredient (or therapeutic agent) and optionally one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" refers to an excipient that is administered with a therapeutic agent, and which is, within the scope of sound medical judgment, suitable for contact with the tissues of humans and/or other animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable carriers that may be used in the present invention include, but are not limited to: a) a diluent; b) a lubricant; c) a binder; d) a disintegrant; e) absorbents, coloring, flavoring and/or sweetening agents; f) an emulsifier or dispersant; and/or g) substances that enhance the absorption of the compounds, and the like.
The pharmaceutical compositions described above may act systemically and/or locally. For this purpose, they may be administered by a suitable route, for example by parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular routes or as an inhalant.
The above administration route can be achieved by a suitable dosage form. Dosage forms that may be used in the present invention include, but are not limited to: tablets, capsules, troches, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
When administered orally, the above pharmaceutical compositions may be formulated into any orally acceptable dosage form, including, but not limited to, tablets, capsules, aqueous solutions, aqueous suspensions, and the like.
The pharmaceutical compositions described above may also be administered in the form of sterile injectable preparations, including sterile injectable aqueous or oleaginous suspensions, or sterile injectable aqueous or oleaginous solutions. Among the carriers that can be used are, but not limited to: water, ringer's solution and isotonic sodium chloride solution. In addition, the sterilized fixed oil may also be employed as a solvent or suspending medium, such as a monoglyceride or diglyceride.
The pharmaceutical composition may comprise from 0.01mg to 1000mg of at least one compound of formula I, formula I-1 to formula I-3 above or a pharmaceutically acceptable form thereof.
The term "a disease or disorder mediated at least in part by DHX 33" refers to a disease that comprises at least a portion of the factors involved in DHX33 in the pathogenesis, such as cancer, e.g., glioblastoma.
The term "effective amount" refers to a dose that is capable of inducing a biological or medical response in a cell, tissue, organ or organism (e.g., an individual) and is sufficient to achieve a desired prophylactic and/or therapeutic effect.
The dosing regimen may be adjusted to provide the best desired response. For example, it may be administered in a single dose, may be administered in divided doses over time, or may be administered after proportionally decreasing or increasing the dose as the case may be. It will be appreciated that for any particular individual, the specific dosage regimen will be adjusted as needed and as the professional judgment of the person administering the composition or supervising it.
The term "in need thereof" refers to a judgment by a physician or other caregiver that an individual needs or will benefit from a prophylactic and/or therapeutic procedure, the judgment being made based on various factors of the physician or other caregiver in their area of expertise.
The term "individual" (or subject) refers to a human or non-human animal. The subject of the present invention includes both subjects (patients) suffering from a disease and/or disorder and normal subjects. Non-human animals of the invention include all vertebrates, e.g., non-mammals, such as birds, amphibians, reptiles, and the like, and mammals, e.g., non-human primates, livestock, and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, and the like).
The term "treating" refers to alleviating or eliminating a disease or disorder in question. A subject is successfully "treated" if the subject receives a therapeutic amount of a compound of the invention or a pharmaceutically acceptable form thereof, or a pharmaceutical composition of the invention, and the subject exhibits an observable and/or detectable remission and/or improvement of at least one of the indications and symptoms. It is understood that treatment includes not only complete treatment, but also less than complete treatment, but achieves some biologically or medically relevant result. In particular, "treatment" means that the compound of the invention or a pharmaceutically acceptable form thereof or the pharmaceutical composition of the invention can achieve at least one of the following effects, for example: (1) preventing disease from occurring in an animal that may be predisposed to the disease but has not yet experienced or exhibited disease pathology or symptomology; (2) inhibiting disease in an animal experiencing or exhibiting disease pathology or symptomatology (i.e., arresting further development of pathology and/or symptomatology); (3) ameliorating the disease (i.e., reversing pathology and/or symptomatology) in an animal experiencing or exhibiting disease pathology or symptomatology.
The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention that are substantially non-toxic to organisms. Pharmaceutically acceptable salts generally include, but are not limited to, salts formed by reacting a compound of the invention with a pharmaceutically acceptable inorganic/organic acid or inorganic/organic base, such salts also being referred to as acid addition salts or base addition salts. For reviews of suitable Salts see, for example, 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 present invention are known to those skilled in the art.
The term "pharmaceutically acceptable ester" refers to an ester that is substantially non-toxic to an organism and that hydrolyzes in vivo to a compound of the invention or a salt thereof. Pharmaceutically acceptable esters generally include, but are not limited to, esters of the compounds of the present invention with pharmaceutically acceptable carboxylic or sulfonic acids, such esters also being referred to as carboxylic or sulfonic esters.
The term "isomers" refers to compounds having the same molecular weight, but differing in the spatial arrangement or configuration of the atoms, due to the same number and type of atoms.
The term "stereoisomer" (or "optical isomer") refers to a stable isomer having perpendicular asymmetric planes due to having at least one chiral factor (including chiral centers, chiral axes, chiral planes, etc.) that is capable of rotating plane polarized light. Because of the presence of asymmetric centers as well as other chemical structures that may lead to stereoisomers of the compounds of the present invention, these stereoisomers and mixtures thereof are also encompassed by the present invention. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
The term "tautomer" (or "tautomeric form") refers to structural isomers having different energies that can interconvert by a low energy barrier. If tautomerism is possible (e.g., in solution), then the chemical equilibrium of the tautomer can be reached. For example, proton tautomers (or proton transfer tautomers) include, but are not limited to, interconversions by proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-iminoalcohol isomerization, and the like. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
The term "solvate" refers to a substance formed by the binding of a compound of the invention (or a pharmaceutically acceptable salt thereof) to at least one solvent molecule by non-covalent intermolecular forces. For example, solvates include, but are not limited to, hydrates (including hemihydrate, monohydrate, dihydrate, trihydrate, and the like), ethanolates, acetonates, and the like.
The term "nitroxide" refers to a compound formed by oxidation of a nitrogen atom in the structure of a tertiary amine or nitrogen (aryl) containing heterocyclic compound. For example, the nitrogen atom in the parent nucleus of a compound of formula I may form the corresponding nitroxide.
The term "isotopic label" refers to a derivatized compound formed by replacing a particular atom in a compound of the invention with its isotopic atom. Unless otherwise indicated, the compounds of the present invention include various isotopes of H, C, N, O, F, P, S, Cl, such as, but not limited to2H(D)、3H(T)、13C、14C、15N、17O、18O、18F、31P、32P、35S、36S and37Cl。
the term "metabolite" refers to a derivative compound formed after the compounds of the present invention are metabolized. Further information on metabolism can be found in Goodman and Gilman's: The pharmaceutical Basis of Therapeutics (9)thed.)[M]McGraw-Hill International proportions, 1996. The present invention encompasses all possible metabolite forms of the compounds of the invention, i.e. substances formed in the body of the individual to whom the compounds of the invention are administered. Metabolites of a compound can be identified by techniques well known in the art, and their activity can be characterized by assays.
The term "prodrug" refers to a derivative compound that is capable of providing, directly or indirectly, a compound of the invention upon administration to a subject. Particularly preferred derivative compounds or prodrugs are those that increase the bioavailability of the compounds of the invention when administered to a subject (e.g., more readily absorbed into the blood), or facilitate delivery of the parent compound to the site of action (e.g., the lymphatic system). Unless otherwise indicated, all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, see, e.g., T.Higuchi, V.Stella, Pro-drugs as Novel Drug Delivery Systems [ J ], American Chemical Society, Vol.14, 1975. Furthermore, the present invention also encompasses compounds of the present invention containing protecting groups. In any process for the preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned, thereby forming a chemically protected form of the compounds of the present invention. This may be achieved by conventional 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 may be removed at a suitable subsequent stage using methods known in the art.
The term "independently" means that at least two groups (or ring systems) present in a structure that are the same or similar in value can have the same or different meaning in a particular instance. For example, substituent X and substituent Y are independently hydrogen, halogen, hydroxy, cyano, alkyl or aryl, and when substituent X is hydrogen, substituent Y may be either hydrogen, halogen, hydroxy, cyano, alkyl or aryl; similarly, when the substituent Y is hydrogen, the substituent X may be hydrogen, or may be halogen, hydroxy, cyano, alkyl or aryl.
The term "halogen", when used herein alone or in combination with other groups, refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).
The term "alkyl", when used herein alone or in combination with other groups, refers to a straight or branched chain aliphatic hydrocarbon group. For example, the term "C" as used in the present invention1-4Alkyl "refers to an alkyl group having 1 to 4 carbon atoms. For example, alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and the like.
The term "haloalkyl" as used herein, alone or in combination with other groups, means substituted with one or more (such as 1 to 3) substituents which may or may not be the same Alkyl substituted with the same halogen atom. For example, the term "C" as used in the present invention1-4Haloalkyl "refers to haloalkyl having 1 to 4 carbon atoms. For example, haloalkyl includes, but is not limited to, -CH2F、-CHF2、-CF3、-CH2CF3、-CF2CF3、-CH2CH2CF3、-CH2Cl, and the like.
The term "hydroxyalkyl", when used herein alone or in combination with other groups, refers to an alkyl group substituted with one or more (such as 1 to 3) hydroxy groups. For example, the term "C" as used in the present invention1-4Hydroxyalkyl "refers to hydroxyalkyl groups having 1 to 4 carbon atoms. For example, hydroxyalkyl includes, but is not limited to
And so on.
The term "alkoxy" as used herein alone or in combination with other groups, refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. For example, alkoxy includes, but is not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.
The term "haloalkoxy", as used herein alone or in combination with other groups, refers to a monovalent straight or branched chain haloalkyl-O-group which is substituted with at least one atom selected from fluorine, chlorine, bromine and iodine, which may contain unsaturation, and which is attached to other groups by a single bond to an oxygen atom, e.g., C 1-4A haloalkoxy group. For example, haloalkoxy includes, but is not limited to, fluoromethoxy (-OCH)2F) Difluoromethoxy (-OCHF)2) Trifluoromethoxy (-OCF)3) 1-fluoroethoxy (-OCHFCH)3) 2-fluoroethoxy (-OCH)2CH2F) 1, 2-Difluoroethoxy (-OCHFCH)2F) 2, 2-difluoroethoxy (-OCH)2CHF2) 1,2, 2-trifluoroethoxy (-OCHFCHF)2) 2,2, 2-trifluoroethoxy (-OCH)2CF3) And the like.
The term "hydroxy" when used herein alone or in combination with other groups means-OH.
The term "cyano," when used herein alone or in combination with other groups, refers to — CN.
The term "amino" as used herein, alone or in combination with other groups, refers to-NH2。
Detailed Description
In order to make the objects and technical solutions of the present invention clearer, embodiments of the present invention will be described in detail below with reference to examples. It will be understood by those skilled in the art that the following examples are illustrative of the present invention only and should not be taken as limiting the scope of the invention.
The reagents or instruments used in the examples are all conventional products which are commercially available. Those who do not have specific conditions noted are conducted under conventional conditions or conditions recommended by the manufacturer. The term "room temperature" used in the present invention means 20 ℃. + -. 5 ℃. As used herein, the term "about" when used in conjunction with a modification of a value or range of values means that the value or range of values and the range of errors acceptable to those skilled in the art are included, for example, within the range of ± 10%, 5%, 4%, 3%, 2%, 1%, 0.5%, etc.
The structures of the compounds described in the following examples were confirmed by Nuclear Magnetic Resonance (NMR) and/or Mass Spectrometry (MS).
Nuclear Magnetic Resonance (NMR) measuring apparatus Bruker 400MHz NMR was used, and deuterated methanol (CD) was used as a measuring solvent3OD), deuterated chloroform (CDCl)3) Hexa-deuterated dimethyl sulfoxide (DMSO-d)6) The internal standard substance is Tetramethylsilane (TMS).
Abbreviations in the Nuclear Magnetic Resonance (NMR) data in the following examples represent the following meanings:
s: singlet, d: doublet, t: triplet, q: quartet, dd: doublet, qd: quartet, ddd: double doublet, ddt: double triplet, dddd: double doublet, m: multiplet, br: broad peak, J: coupling constant, Hz: hertz, δ: chemical shift.
All chemical shift (δ) values are given in parts per million (ppm).
Mass Spectrometry (MS) was performed using an Agilent 6120B mass spectrometer with an electrospray ion source (ESI).
HPLC measurements were carried out using an Agilent 1200DAD high pressure liquid chromatograph (Sunfirc C18, 150X 4.6mm, 5 μm, column) and a Waters 2695-.
The thin layer chromatography silica gel plate is Qingdao sea GF254 silica gel plate, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15mm-0.2mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5 mm.
Column chromatography generally uses Qingdao ocean 200-mesh and 300-mesh silica gel as a carrier.
The progress of the reaction in the examples was monitored by Thin Layer Chromatography (TLC) using a system of developing reagents, A: dichloromethane and methanol systems; b: petroleum ether and ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound.
The system of eluents for column chromatography and developing agents for thin layer chromatography used for purifying compounds include a: dichloromethane and methanol systems; b: the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of triethylamine and acidic or basic reagents can be added for adjustment.
Synthesis of Compounds
Example 1: synthesis of compound AB24350(2- (3- (7-methoxy-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
(1) Preparation of compound 3 (2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazole)
Compound 1 (2-bromo-7-methoxycarbazole) (300mg, 1.08mmol, 1eq) was dissolved in 1, 4-dioxane (2mL), and compound 2 (pinacolate diboron) (331mg, 1.30mmol, 1.2eq), potassium acetate (213mg, 2.17mmol, 2.0eq) and 1,1' -bis (diphenylphosphino) ferrocene (24mg, 0.032mmol, 0.03eq) were added. The mixture was heated to 90 ℃ for 16 hours under nitrogen protection. After the completion of the reaction, the mixture was purified by flash column chromatography (petroleum ether/ethyl acetate ═ 50/1 to 25/1 to 10/1) to obtain 3 (2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazole) as a yellow solid (314mg, yield: 89%). MS (ESI) M/z 324[ M + H ] +]. TLC: petroleum ether/ethyl acetate (5/1); rf(compound 1) ═ 0.4; rf(compound 2) ═ 0.3;1H NMR(400MHz,CDCl3)δ7.98-7.93(m,3H),7.85(s,1H),7.65(d,J＝7.2Hz,1H),6.91(s,1H),6.84(d,J＝8.4Hz,1H),3.89(s,3H),1.38(s,12H)。
(2) synthesis of Compound 5(2- (3-bromo-2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
The crude compound 4(2- (2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) (300mg, 1.38mmol, 1.0eq) was dissolved in tetrahydrofuran (10mL) and N-bromosuccinimide (269mg, 1.51mmol, 1.09eq) was added at-78 ℃. The mixture was stirred at-78 ℃ for 0.5 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried, filtered and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate ═ 10/1) to give compound 5(2- (3-bromo-2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) as a yellow solid (216mg, yield: 53%). MS (ESI) M/z 295[ M + H ]+]. TLC: petroleum ether/ethyl acetate (10/1); rf(compound 4) ═ 0.6; rf(compound 5) ═ 0.5.
(3) Preparation of compound AB24350(2- (3- (7-methoxy-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
Compound 3 ((2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazole)) (164mg, 0.508mmol, 1.5eq) was dissolved in a mixture of 1, 4-dioxane and water (1.5mL/0.3mL), and compound 5(2- (3-bromo-2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) (100mg, 0.339mmol, 1.0eq), cesium carbonate (221mg, 0.678mmol, 2.0eq), palladium acetate (4mg, 0.0169mmol, 0.05eq), and 1,1' -bis (diphenylphosphino) ferrocene (19mg, 0.0339mmol, 0.3eq) were added. The mixture was stirred in a closed tube at-78 ℃ for 3 hours. After completion of the reaction, the mixture was concentrated and purified by flash column chromatography (petroleum ether/ethyl acetate. cndot. 20/1 to 10/1) to obtain AB24350(2- (3- (7-methoxy-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) as an off-white solid (27mg, yield: 19.3%). MS (ESI) M/z 412[ M + H +]。1H NMR(400MHz,DMSO-d6)δ11.05(s,1H),7.95-7.90(m,2H),7.38(s,1H),7.28(s,1H),7.15(d,J＝7.6Hz,1H),6.93(s,1H),6.73(d,J＝8Hz,1H),6.28(s,1H),3.81(S,3H),2.51(s,3H),2.21(s,3H),2.09(s,3H)。
Example 2: synthesis of compound AB24374(2- (3- (7-methoxy-3-methyl-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
(1) Synthesis of Compound 7 (4-bromo-5-methyl-2-nitrophenyldiazonium tetrafluoroborate)
Compound 6 (4-bromo-5-methyl-2-nitroaniline) (1g, 4.33mmol, 1eq) was dissolved in dichloromethane (100mL), boron trifluoride etherate (737mg, 5.19mmol, 1.2eq) was added at 0 ℃ followed by tert-butyl nitrite (669mg, 6.49 mmol)1.5 eq). The reaction was stirred at room temperature for 40 minutes. After completion of the reaction, the mixture was filtered, and the solid was dried in vacuo to obtain Compound 7 (4-bromo-5-methyl-2-nitrophenyldiazotetrafluoroborate) (1.03g, yield: 72.1%) as a white solid. MS (ESI) M/z 330.0[ M-H ]+]. TLC: petroleum ether/ethyl acetate (10/1); rf(compound 6) ═ 0.2; rf(compound 7) ═ 0.7.
(2) Preparation of compound 9 (4-bromo-4 '-methoxy-5-methyl-2-nitro-1, 1' -biphenyl)
Compound 7 (4-bromo-5-methyl-2-nitrophenyldiazonium tetrafluoroborate) (1.03g, 3.16mmol, 1.1eq) and compound 8 ((4-methoxyphenyl) boronic acid) (436mg, 2.87mmol, 1.0eq) were dissolved in 1, 4-dioxane (100mL), and palladium acetate (19mg, 0.08mmol, 0.03eq) was added. The mixture was stirred at room temperature for two hours under nitrogen protection. After the reaction was completed, the mixture was purified by flash column chromatography (petroleum ether/ethyl acetate ═ 10/1) to obtain compound 9 (4-bromo-4 '-methoxy-5-methyl-2-nitro-1, 1' -biphenyl) (611mg, yield: 60.2%) as a yellow solid. MS (ESI) M/z 322.1[ M + H ] +]. TLC: petroleum ether/ethyl acetate (10/1); rf(compound 7) ═ 0.7; rf(compound 9) ═ 0.6.
(3) Preparation of compound 10 (2-bromo-7-methoxy-3-methyl-9H-carbazole)
Compound 9 (4-bromo-4 '-methoxy-5-methyl-2-nitro-1, 1' -biphenyl) (300mg, 0.93mmol, 1eq) was added to triethyl phosphate (3mL), the reaction was heated to 200 ℃ and stirred for 30 min. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the obtained solid was dried in vacuo to obtain compound 10 (2-bromo-7-methoxy-3-methyl-9H-carbazole) (120mg, yield: 60.2%) as a white solid. MS (ESI) M/z 290.1[ M ]+H+]. TLC: petroleum ether/ethyl acetate (10/1); rf(compound 9) ═ 0.6; rf(compound 10) ═ 0.4.
(4) Preparation of compound 11 (7-methoxy-3-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -9H-carbazole)
The compounds 10 (2-bromo-7-methoxy-3-methyl-9H-carbazole) (120mg, 0.40mmol, 1eq) and (Bpin)2(123mg, 0.49mmol, 1.2eq) was dissolved in 1, 4-dioxane (10mL), and potassium acetate (79mg, 0.81mmol, 2eq) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (34mg, 0.04mmol, 0.1 eq). The mixture was heated to 90 ℃ with nitrogen blanket and stirred for two hours. After the reaction was completed, the mixture was purified by flash column chromatography (dichloromethane/methanol ═ 100/1) to obtain compound 11 (7-methoxy-3-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -9H-carbazole) (130mg, yield: 94.2%) as a white solid. MS (ESI) M/z 338.1[ M + H +]. TLC: petroleum ether/ethyl acetate (5/1); r isf(compound 10) ═ 0.3; r isf(compound 11) ═ 0.2.
(5) Preparation method of compound AB24374(2- (3- (7-methoxy-3-methyl-9H-carbazole-2-yl) -2, 5-dimethyl-1H-pyrrole-1-yl) -5-methylthiophene-3-carbonitrile)
Compound 11 ((7-methoxy-3-methyl-2- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -9H-carbazole)) (100mg, 0.30mmol, 1.5eq) and compound 5(2- (3-bromo-2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) (60mg, 0.20mmol, 1.0eq) were dissolved in a mixture of 1, 4-dioxane and water (3mL/0.6mL), followed by addition of cesium carbonate (130mg, 0.40mmol, 2eq), palladium acetate (24mg, 0.10mmol, 0.5eq) and 1,1' -bisdiphenylphosphinoferrocene (110mg, 0.20mmol, 0.1 eq). In the presence of nitrogenThe reactants were heated to 100 ℃ under a gas blanket and stirred for two hours. After the reaction was complete, the mixture was diluted with water (20mL) and then extracted three times with dichloromethane (20 mL. times.3). The organic layer was dried, filtered and concentrated. After the residue was purified by preparative thin layer chromatography (petroleum ether/ethyl acetate ═ 5:1), the compound AB24374(2- (3- (7-methoxy-3-methyl-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) was obtained as a white solid (6mg, yield: 6.9%). MS (ESI) M/z 426.15[ M + H ] +]。1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.88(d,J＝4Hz,1H),7.82(s,1H),7.27(s,1H),7.15(s,1H),6.91(s,1H),6.71(s,1H),6.06(s,1H),3.81(s,3H),2.30(s,3H),2.11(s,3H),1.93(s,3H),1.21(s,3H)。
Example 3: synthesis of compound AB24375(2- (3- (6-methoxy-9H-carbazol-2-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
Compound AB24375 (yield: 8.5%) was obtained in the same manner as in example 2,1H NMR(400MHz,CDCl3)δ8.01(d,J＝4Hz,1H),7.92(s,1H),7.53(s,1H),7.33(s,1H),7.31(s,1H),7.04(s,1H),6.91(s,1H),6.24(s,1H),3.93(s,3H),2.54(s,3H),2.29(s,3H),2.18(s,3H)。
example 4: synthesis of compound AB24385(2- (3- (2-methoxybenzo [4,5] imidazo [1,2-a ] pyridin-7-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
(1) Synthesis of Compound 14 (7-bromo-2-methoxybenzo [4,5] imidazo [1,2-a ] pyridine)
Compound 12 (4-bromo-2-iodobenzylamine) (5g, 16.78mmol, 1eq) and compound 13 (2-bromo-5-methoxypyridine) (4.7g, 25.17mmol, 1.5eq) were dissolved in xylene (50mL), and cuprous iodide (639mg, 3.35mmol, 0.2eq), cesium carbonate (16.4g, 50.34mmol, 2eq), and 1, 10-phenanthroline (1.2g, 6.71mmol, 0.4eq) were added. The mixture was heated to 120 ℃ and stirred for 16 hours. After the reaction is completed, the mixture is subjected to flash column chromatographyPurification by chromatography (dichloromethane/methanol ═ 300/1 to 250/1) gave compound 14 (7-bromo-2-methoxybenzo [4, 5) as a black oil]Imidazo [1,2-a ]]Pyridine) (390mg, yield: 8.3%). MS (ESI) M/z 277.1[ M + H ]+]. TLC: dichloromethane/methanol (20/1); rf(compound 12) ═ 0.8; r f(compound 14) ═ 0.3.
(2) Synthesis of Compound 16 (2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [4,5] imidazo [1,2-a ] pyridine)
Reacting compound 14 (7-bromo-2-methoxybenzo [4,5]]Imidazo [1,2-a ]]Pyridine) (330mg, 1.19mmol, 1eq) and compound 15 (pinacolato diboron) (906mg, 3.57mmol, 3eq) were dissolved in 1,4 dioxane (10mL), and potassium carbonate (350mg, 3.57mmol, 3eq) and [1,1' -bis (diphenylphosphino) ferrocene were added]Palladium dichloride (44mg, 0.059mmol, 0.05eq) and 1,1' -bis (diphenylphosphino) ferrocene (66mg, 0.119mmol, 0.1 eq). The reaction was heated to 100 ℃ and stirred for 16 hours. After completion of the reaction, the mixture was purified by flash column chromatography (dichloromethane/methanol ═ 100/1) to obtain compound 16 (2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [4, 5-dioxaborane-2-yl) benzene [4,5] as a black oil]Imidazo [1,2-a ]]Pyridine) (210mg crude extract). MS (ESI) M/z 415.10[ M + H ]+]. TLC: dichloromethane/methanol (30/1); rf(compound 14) ═ 0.4; rf(compound 16) ═ 0.4.
(3) Preparation of compound AB24385(2- (3- (2-methoxybenzo [4,5] imidazo [1,2-a ] pyridin-7-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
To compound 16 (2-methoxy-7- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzo [4,5]Imidazo [1,2-a ]]Pyridine) (210mg, 0.648mmol, 1eq) and compound 5(2- (3-bromo-2, 5-dimethyl-1H-pyrrol-1-yl)) -5-methylthiophene-3-carbonitrile) (247mg, 0.842mmol, 1.3eq) to a mixture of 1, 4-dioxane/water (5mL/0.5mL) was added cesium carbonate (422mg, 1.29mmol, 2eq), palladium acetate (8mg, 0.032mmol, 0.05eq) and 1, 2-bis (diphenylphosphino) ethane (36mg, 0.064mmol, 0.1 eq). The mixture was heated to 100 ℃ and stirred for 16 hours. After the reaction was complete, the mixture was diluted with water (20mL) and extracted three times with dichloromethane (20 mL. times.3). The organic layer was dried, filtered and concentrated, and the residue was purified by preparative high pressure liquid chromatography to give AB24385(2- (3- (2-methoxybenzo [4,5] methyl ethyl acetate) as a yellow solid]Imidazo [1,2-a ]]Pyridin-7-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile) (9mg, yield: 3.3%). MS (ESI) M/z 413.1[ M + H ]+]。1H NMR(400MHz,CD3OD-d4):δ8.48(s,1H),8.17(d,J＝6.8Hz,1H),7.73(s,1H),7.58(d,J＝8.4Hz,1H),7.46(d,J＝8.4Hz,1H),7.41(d,J＝8.0Hz,1H),7.09(s,1H),6.25(s,1H),3.95(s,3H),2.56(s,3H),2.25(s,3H),2.16(s,3H)。
Example 5: synthesis of Compound AB24379(2- (3- (3-methoxybenzo [4,5] imidazo [1,2-a ] pyridin-7-yl) -2, 5-dimethyl-1H-pyrrol-1-yl) -5-methylthiophene-3-carbonitrile)
Compound AB24379 (yield: 2.0%) was obtained in the same manner as in example 4, 1H NMR(400MHz,CD3OD-d4):δ8.70(s,1H),8.48(s,1H),7.64(s,1H),7.35(s,1H),7.09(s,1H),6.93(s,1H),6.74(s,1H),6.24(s,1H),3.97(s,3H),2.56(s,3H),2.25(s,3H),2.16(s,3H)。
Pharmacological Activity test
Preparation of recombinant RNA helicase DHX33
Protein isolation and purification see Wang X, Ge W, and Zhang y. recombinant DHX33 Protein metals Dual DNA/RNA help activity. biochemistry.2019; 58(4):250-8. Several different RNA helicase genes (mouse DHX33 gene) were cloned into pET32M-3C vector between the BamH I/Not I cleavage sites. The plasmid was then transformed into E.coli strain BL-21pLysS (DE3), and 0.5mM isopropyl 1-thio-. beta. -D-galactopyranoside (IPTG) was added to induce recombinant protein expression for 16 hours at 16 ℃. The cells were pelleted and resuspended in cell lysis buffer [50mM Tris-HCl (pH7.2), 150mM NaCl, 1% Triton X-100 and 50mM imidazole with protease inhibitors added ]. The cells were then sonicated and centrifuged at 13000rpm 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 300mM imidazole in Tris buffer, followed by dialysis against Tris buffer without imidazole overnight at 4 ℃.
DHX33 helicase Activity assay
Helicase activity reaction components were added to 96-well opaque white plates. The method is summarized as follows: neutravidin (neutravidin) was coated onto 96-well plates at a final concentration of 10. mu.g/mL (100. mu.L/well) overnight at 4 ℃. The neutravidin coated plates were then blocked with 100. mu.L of 0.1% (w/v) BSA (in conventional PBS) for 2 hours at 22 ℃. After washing, a DNA duplex [2.5ng ] annealed by two oligo DNA single strands (one single strand having the sequence of 5'-GCTGACCCTGCTCCCAATCGTAATCTATAG-3' labeled with biotin; and the other single strand having the sequence of 5'-CGATTGGGAGCAGGGTCAGC-3' labeled with DIG) was added, and the annealing reaction was carried out in 1M PBS (pH7.0) containing 1M NaCl ]And incubated at 22 ℃ for 4 hours. The helicase reaction was started after the addition of 90. mu.L of the reaction mixture [ 0.25. mu.g of purified full-length DHX33 protein, dissolved in 25mM 4-MOPS (pH 7.0), 5mM ATP, 2mM DTT, 3mM MnCl2And 100. mu.g/mL BSA]. The reaction was carried out at 37 ℃ for 60 minutes. After washing, each well was washed with blocking solution [ 10% (w/v) BSA in 0.1M maleic acid and 0.15M NaCl (pH7.5) ]]Incubate for 30 min, then incubate with 20 μ L antibody solution (anti-DIG-AP, Roche, in blocking buffer) for 30 min. Using 100. mu.L of detection buffer [0.1M Tris-HCl and 0.1M NaCl (pH9.5)]After washing, 1 μ L of chemiluminescent substrate (CSPD-0.25mM) was then added to each well and the plates were incubated at 17 ℃ for 5 minutes. The plates were then patted dry and incubated at 37 ℃ for 30 minutes. The remaining DIG-AP marker control in each well was counted for 10 minutes by a luminescence multiwell plate reader (Enspire, Perkinelmer).
Semi inhibitory concentration (EC) of cells50) Measurement of
Cancer cell line U251-MG cells with DHX33 over-expression at 1X 104100 ul/wellSpread onto 96-well plates. After the cells were allowed to adhere completely, compounds were added to the cell culture medium at concentrations of 5nM, 10nM, 25nM, 50nM, 100nM, 250nM, 500nM, 1000nM, 2000nM, 5000nM, 10. mu.M, 20. mu.M and mixed well with a multichannel rifle. After waiting for 48 hours of incubation time of the compound and cells, the cells were added to the medium in a 96-well plate using CCK-8 reagent (saint biol, next, shanghai) according to standard procedures, after 2 hours of incubation, the plate was read with a microplate reader (OD 450nm), the experiment was repeated three times, inhibition curves of the compound at different concentrations were plotted, and the half-Inhibitory Concentration (IC) of the compound was calculated (IC) 50)。
Cell culture and source
U251-MG cells were purchased from a cell bank of the Chinese academy of sciences. Culturing in MEM medium containing 10% Fetal Bovine Serum (FBS), 2mM L-glutamine, streptomycin and penicillin, and culturing at 37 deg.C and 5% CO2A cell culture box with humidity. Cells were passaged every 3 days and discarded after 10 passages.
Test results and analysis
The half inhibitory concentrations of the compounds of the present invention on the helicase activity of DHX33 protein are shown in table 1. As can be seen from table 1, the compounds of the present invention have significant inhibitory effects on the helicase activity of DHX33 protein.
Table 1: helicase activity inhibition assay of compounds on DHX33 protein
Table 2: analysis of half inhibitory concentration of compound on U251-MG
As can be seen from Table 2, the compounds of the present invention have significant inhibitory effect on cancer cell strain U251-MG cells with DHX33 over-expression.
Claims (11)
1. A compound having the structure of formula I:
wherein the content of the first and second substances,
ring A is selected from carbazole ring and benzo [4,5] imidazo [1,2-a ] pyridine ring;
each R1Independently selected from halogen, amino, nitro, hydroxy, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy or C1-4A hydroxyalkyl group;
Each R2Independently selected from halogen, C1-4Alkyl or C1-4A haloalkyl group;
each R3Independently selected from halogen, cyano, amino, nitro, hydroxy, C1-4Alkyl or C1-4A haloalkyl group;
m is selected from 0, 1, 2, 3 or 4;
n and p are independently selected from 0, 1, 2 or 3.
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein
Ring A is selected from
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein
Each R1Independently selected from methyl or methoxy.
4. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein
Each R2Independently selected from methyl.
5. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein
Each R3Independently selected from cyano or methyl.
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound having the structure of formula I-1 to formula I-3:
wherein R is1、R2、R3N and p are as defined in claim 1; q is selected from 0, 1 or 2.
7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the following compounds, or a pharmaceutically acceptable salt thereof:
8. A pharmaceutical composition comprising a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.
9. Use of a compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the manufacture of a medicament for the prevention and/or treatment of a disease or condition mediated at least in part by DHX 33.
10. The use according to claim 9, wherein the disease is cancer.
11. The use according to claim 10, wherein the disease is glioblastoma multiforme.
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