WO2021104277A1 - 作为dna-pk抑制剂的嘧啶并咪唑类化合物 - Google Patents
作为dna-pk抑制剂的嘧啶并咪唑类化合物 Download PDFInfo
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
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- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to a DNA-PK inhibitor, in particular to a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, and its application in the preparation of drugs related to DNA-PK inhibitors.
- DNA breaks especially double-strand breaks (DSBs) are extremely serious damages that can cause loss of genetic material, gene recombination, and lead to cancer or cell death.
- Eukaryotic cells have evolved a variety of mechanisms to deal with the serious threats caused by DNA double-strand breaks. This is the DNA damage response mechanism (DDR), which mainly includes DNA damage detection, signal transduction, and damage repair.
- DDR DNA damage response mechanism
- DNA double-strand break repair mainly includes homologous end joining (HR) repair and non-homologous end joining (NHEJ) repair. In higher eukaryotes, NHEJ repair, which is preferentially used during the early G1/S phase, is the main mechanism.
- DDR initial damage factors such as MRN will detect and recognize the damage site, recruit phosphoinositide kinase family members (ATM, ATR, DNA-PK), phosphorylate H2AX to promote the formation of ⁇ H2AX, guide downstream signal transduction and recruit related proteins to complete the receptor. Repair of damaged DNA.
- DNA-PK catalytic subunit belongs to the PI3K-related kinase (PIKK) family, mainly for non-homologous DNA double-strand breaks End join (NHEJ) repair is an important member of DNA damage repair.
- PIKK PI3K-related kinase
- NHEJ non-homologous DNA double-strand breaks End join
- DNA-damaging chemotherapeutics such as bleomycin, topoisomerase II inhibitors such as etoposide and doxorubicin
- DNA-PK DNA-damaging chemotherapeutics
- bleomycin bleomycin
- topoisomerase II inhibitors such as etoposide and doxorubicin
- doxorubicin DNA-damaging chemotherapeutics
- DNA-PK inhibitors can inhibit the activity of DNA-PKcs, thereby greatly reducing tumor DNA repair, inducing cells to enter the apoptosis process, and achieving better therapeutic effects.
- DNA-PK inhibitors can also be used as single drugs to exert therapeutic effects in tumors with defects in other DNA repair pathways.
- the present invention aims to discover a DNA-PK small molecule inhibitor, which can not only be used as a single drug to exert a therapeutic effect in tumors with defects in other DNA repair pathways. It can also be combined with radiotherapy and chemotherapy drugs to enhance the sensitivity of tumor tissues to radiotherapy and chemotherapy, overcome the problem of drug resistance, and enhance the inhibitory effect on a variety of solid tumors and hematomas. Such compounds have good activity and show excellent effects and functions, and have broad prospects.
- the present invention provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
- E 1 is selected from a single bond, -O- and -C(R 6 R 7 )-;
- R 1 , R 2 , R 3 , R 4 , R'and R" are each independently selected from H, F and Cl;
- R 1 and R 2 are connected together to make the structural unit Selected from
- R 3 and R 4 are connected together to make the structural unit Selected from
- R 1 and R 4 are connected together to make the structural unit Selected from
- R 2 , R" and the carbon atom to which they are connected together form a C 3-5 cycloalkyl group
- R 5 is selected from F, Cl, Br, I, cyclopropyl and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by OH, or two, or three R a;
- R 6 and R 7 are each independently selected from H, F, Cl, Br, I and CN;
- R 6 , R 7 and the carbon atoms to which they are connected together form a cyclopropyl group or a 4-membered oxetanyl group;
- Ring A is selected from C 3-5 cycloalkyl
- Y 1 is selected from cyclopropyl and C 1-3 alkyl, the C 1-3 alkyl is optionally substituted with 1, 2, 3, 4 or 5 F;
- R a is selected from H, F, Cl, Br and I.
- the present invention provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
- E 1 is selected from a single bond, -O- and -C(R 6 R 7 )-;
- R 1 , R 2 , R 3 , R 4 , R'and R" are each independently selected from H, F and Cl;
- R 1 and R 2 are connected together to make the structural unit Selected from
- R 3 and R 4 are connected together to make the structural unit Selected from
- R 1 and R 4 are connected together to make the structural unit Selected from
- R 2 , R" and the carbon atom to which they are connected together form a C 3-5 cycloalkyl group
- R 5 is selected from F, Cl, Br, I, cyclopropyl and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by OH, or two, or three R a;
- R 6 and R 7 are each independently selected from H, F, Cl, Br, I and CN;
- R 6 , R 7 and the carbon atoms to which they are connected together form a cyclopropyl group or a 4-membered oxetanyl group;
- Ring A is selected from C 3-5 cycloalkyl
- R a is selected from H, F, Cl, Br and I.
- the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- E 1 is selected from a single bond, -O- and -C(R 6 R 7 )-;
- R 1 , R 2 , R 3 , R 4 , R'and R" are each independently selected from H, F and Cl;
- R 1 and R 2 are connected together to make the structural unit Selected from
- R 3 and R 4 are connected together to make the structural unit Selected from
- R 1 and R 4 are connected together to make the structural unit Selected from
- R 2 , R" and the carbon atom to which they are connected together form a C 3-5 cycloalkyl group
- R 5 is selected from F, Cl, Br, I, cyclopropyl and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by OH, or two, or three R a;
- R 6 and R 7 are each independently selected from H, F, Cl, Br, I and CN;
- R 6 , R 7 and the carbon atoms to which they are connected together form a cyclopropyl group or a 4-membered oxetanyl group;
- Ring A is selected from C 3-5 cycloalkyl
- R a is selected from H, F, Cl, Br, I.
- the invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof
- R 1 , R 2 , R 3 and R 4 are each independently selected from H, F and Cl;
- R 1 and R 2 are connected together to make the structural unit for
- R 3 and R 4 are connected together to make the structural unit for
- R 5 is selected from F, Cl, Br, I, cyclopropyl and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by OH, or two, or three R a;
- R a is selected from H, F, Cl, Br, I.
- the above-mentioned compound is selected from
- ring B is selected from C 3-5 cycloalkyl
- Ring C is cyclopropyl or 4-membered oxetanyl group
- n is selected from 0 and 1;
- Ring A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined in the present invention.
- the above-mentioned compound is selected from
- R 5 is as defined in the present invention.
- R 1 and R 2 are connected together so that the structural unit Selected from Other variables are as defined in the present invention.
- R 3 and R 4 are connected together to make the structural unit Selected from Other variables are as defined in the present invention.
- R 1 and R 4 are connected together so that the structural unit Selected from Other variables are as defined in the present invention.
- the above-mentioned ring A is selected from Other variables are as defined in the present invention.
- R 6 and R 7 form together with the carbon atom to which they are connected together
- Other variables are as defined in the present invention.
- R 1 and R 2 are connected together so that the structural unit for Other variables are as defined in the present invention.
- R 3 and R 4 are connected together to make the structural unit for Other variables are as defined in the present invention.
- R 5 is selected from F, Cl, CH 2 OH, CF 3 and CH 3 , and other variables are as defined in the present invention.
- R 5 is selected from F, Cl and CH 3 , and other variables are as defined in the present invention.
- the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is used in the preparation of drugs related to DNA-PK inhibitors.
- the above-mentioned DNA-PK inhibitor-related drugs as a single drug exert a therapeutic effect on tumors with defects in other DNA repair pathways.
- the above-mentioned DNA-PK inhibitor-related drugs are combined with radiochemotherapeutic drugs to enhance the inhibitory effect on solid tumors and hematomas.
- the compound of the present invention exhibits significant DNA-PK kinase inhibitory activity.
- PK results show that the compound of the present invention has a longer half-life, lower clearance rate and higher drug exposure, and has excellent pharmacokinetic properties, and is a good molecule that can be developed for oral administration.
- results of in vivo pharmacodynamics show that the compound of the present invention has a significant anti-tumor effect.
- pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
- pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from a compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
- a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
- the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
- Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid.
- Certain specific compounds of the present invention contain basic and acidic functional groups
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods.
- such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both.
- the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
- the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
- Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
- enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
- cis-trans isomer or “geometric isomer” is caused by the inability to rotate freely because of double bonds or single bonds of ring-forming carbon atoms.
- diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
- wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a three-dimensional center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
- the term “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refers to one of the isomers or pairs of
- the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
- the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
- optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide pure The desired enantiomer.
- the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with a suitable optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
- the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which employs a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
- the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
- compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
- deuterium can be substituted for hydrogen to form deuterated drugs.
- the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
- deuterated drugs have reduced toxic side effects and increased drug stability. , Enhance the efficacy, extend the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
- substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
- oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
- optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
- any variable such as R
- its definition in each case is independent.
- the group can optionally be substituted with up to two Rs, and R has independent options in each case.
- combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
- linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
- the substituent can be bonded with any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
- substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
- a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
- the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the opposite direction to the reading order from left to right
- Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
- any one or more sites of the group can be connected to other groups through chemical bonds.
- the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
- the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
- the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
- the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
- the wavy line in indicates that the phenyl group is connected to other groups through the 1 and 2 carbon atoms;
- the number of atoms in a ring is generally defined as the number of ring members.
- “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
- C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
- the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
- Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
- C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a monocyclic ring system, and the C 3-5 cycloalkyl includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or multivalent.
- Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and the like.
- C n-n+m or C n -C n+m includes any specific case of n to n+m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , including any range from n to n+m, for example, C 1- 12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.; similarly, from n to n +m member means that the number of atoms in the ring is n to n+m, for example, 3-12 membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, and 9-membered ring, and 9
- the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
- the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the field.
- SXRD single crystal X-ray diffraction
- the cultured single crystal is collected with a Bruker D8venture diffractometer to collect diffraction intensity data
- the light source is CuK ⁇ radiation
- the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
- the solvent used in the present invention is commercially available.
- eq stands for equivalent
- DMSO dimethyl sulfoxide
- ATP adenosine triphosphate
- EDTA ethylenediaminetetraacetic acid
- DNA stands for deoxyribonucleic acid
- PEG polyethylene glycol
- Balb/c stands for Mouse strain.
- reaction solution was filtered through celite and concentrated under reduced pressure to obtain a crude product.
- the crude product was dissolved in tetrahydrofuran (100 mL), 3N hydrochloric acid (20 mL) was added thereto and stirred at 20°C for 0.5 hour.
- water 100mL was added to the reaction solution, extracted with ethyl acetate (100mL*3), and the organic phase was discarded; the aqueous phase was added with ammonia (30mL) to adjust the pH to alkalinity, and ethyl acetate (100mL) was added to the aqueous phase.
- MS m/z 430.0[M+Na] + ;
- MS m/z 407.3 [M+H] + .
- MS m/z 407.3 [M+H] + .
- reaction solution was concentrated under reduced pressure, followed by adding tetrahydrofuran (10mL) and 3mol/L hydrochloric acid solution (3mL), stirring at 20°C for 0.5 hours, and then adding water (20mL) to dilute, ethyl acetate (15mL*2) Extract and discard the organic phase.
- Chloroacetaldehyde (5.26g, 26.80mmol, 670.12 ⁇ L, 40% purity, 1.2eq) was added to the mixed solution of compound 23a (4.2g, 22.34mmol, 1eq) in ethanol (42mL) and water (17.5mL). The reaction solution was reacted at 100°C for 16 hours.
- Experimental example 1 DNA-dependent protein kinase (DNA-PK) inhibitory activity screening experiment
- HTRF uniform time-resolved fluorescence
- the compound of the present invention has significant DNA-PK kinase inhibitory activity.
- Test compound and 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water (compounds 1, 4, 10, 17) or 20% N,N-dimethylacetamide/80% water ( Compound 5) was mixed, vortexed and sonicated to obtain 0.08 mg/mL (compound 1, 4, 10, 17) or 0.50 mg/mL (compound 5) approximately clear solution, which was filtered with a microporous membrane for use.
- Test compound and 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water (compound 1,4,10,17) or 20%-hydroxypropyl- ⁇ -cyclodextrin (compound 5) Mix, vortex and sonicate to prepare a 0.2 mg/mL (compound 1, 4, 10, 17) or 1 mg/mL (compound 5) approximately clear solution, which is filtered through a microporous membrane for use.
- Collect whole blood for a certain period of time prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate pharmacokinetic parameters.
- IV intravenous injection
- PO oral
- C 0 instantaneous required concentration after intravenous injection
- C max highest blood concentration after administration
- T max time required to reach peak drug concentration after administration
- T 1/2 the time required for the blood concentration to drop by half
- V dss the apparent volume of distribution, which refers to the constant proportionality between the amount of the drug in the body and the concentration of the blood when the drug reaches dynamic equilibrium in the body.
- the compound of the present invention exhibits a longer half-life, lower clearance rate and higher drug exposure, and has better pharmacokinetic properties in vivo.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a 0.4mg/mL (compound 5) approximately clear solution, which was filtered through a microporous membrane. use.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare an approximately clear solution of 1 mg/mL, which was filtered with a microporous membrane for use.
- the compound of the present invention exhibits a longer half-life, lower clearance rate and higher drug exposure, and has better pharmacokinetic properties in vivo.
- test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare 0.5 mg/mL (compound 5) or 1 mg/mL (compound 17) approximately clear
- the solution is filtered by a microporous membrane for use.
- Select SD male rats and give the candidate compound solution intravenously at a dose of 1 mg/kg (compound 5) or 2 mg/kg (compound 17).
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a 4 mg/mL homogeneous suspension (compound 5) or 1 mg/mL approximately clear solution (Compound 17).
- SD male rats were selected and the candidate compound solution was orally administered with a dose of 40 mg/kg (compound 5) or 10 mg/kg (compound 17).
- the compound of the present invention exhibits a longer half-life, a lower clearance rate and a higher drug exposure, and has better pharmacokinetic properties in vivo. At the same time, the compound has a better brain exposure.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare an approximately clear solution of 1 mg/mL, which was filtered with a microporous membrane for use.
- a male Beagle dog was selected and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare an approximately clear solution of 1 mg/mL, which was filtered with a microporous membrane for use.
- Beagle male dogs were selected and the candidate compound solution was orally administered at a dose of 5 mg/kg. Collect whole blood for a certain period of time, prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate pharmacokinetic parameters.
- the compound of the present invention exhibits a longer half-life, lower clearance rate and higher drug exposure, and has better pharmacokinetic properties in vivo.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare an approximately clear solution of 1 mg/mL, which was filtered with a microporous membrane for use.
- Male cynomolgus monkeys were selected and the candidate compound solution was administered intravenously at a dose of 1 mg/kg.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare an approximately clear solution of 1 mg/mL, which was filtered with a microporous membrane for use.
- Male cynomolgus monkeys were selected and the candidate compound solution was orally administered at a dose of 5 mg/kg. Collect whole blood for a certain period of time, prepare plasma, analyze drug concentration by LC-MS/MS method, and use Phoenix WinNonlin software (Pharsight, USA) to calculate pharmacokinetic parameters.
- the compound of the present invention exhibits a longer half-life, lower clearance rate, higher drug exposure, and higher oral bioavailability, and has better pharmacokinetic properties in vivo.
- mice Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams; Supplier: Shanghai Xipuer-Bikai Laboratory Animal Co., Ltd.
- NCI-H1703 cells Human non-small cell lung cancer NCI-H1703 cells were cultured in vitro. RPMI1640 medium was supplemented with 10% fetal bovine serum, 100U/mL penicillin and 100 ⁇ g/mL streptomycin, and cultured in a 5% CO 2 incubator at 37°C. Use pancreatin-EDTA for routine digestion and passage twice a week. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
- NCI-H1703 cells (with matrigel, volume ratio 1:1) were subcutaneously inoculated on the right back of each mouse. When the average tumor volume reached about 130mm 3 , group administration was started .
- Compound 5 was formulated as 3 mg/mL, 6 mg/mL, 9 mg/mL suspension solutions, compound 17 was formulated as 9 mg/mL suspension, and the solvent was 0.5% HPMC+1% Tween 80.
- the tumor diameter was measured with vernier calipers twice a week.
- TGI total tumor growth rate
- T/C relative tumor growth rate
- Relative tumor proliferation rate T/C (%) T RTV /C RTV ⁇ 100%
- TRTV average RTV of the treatment group
- C RTV average RTV of the negative control group
- RTV relative tumor volume
- TGI (%) reflects the tumor growth inhibition rate.
- TGI(%) [1-(Average tumor volume at the end of a certain treatment group-average tumor volume at the start of the treatment group)/(Average tumor volume at the end of treatment in the solvent control group-average tumor volume at the start of treatment in the solvent control group Tumor volume)] ⁇ 100%.
- the tumor weight will be detected and the T/weight percentage will be calculated.
- T weight and C weight represent the tumor weights of the administration group and the vehicle control group, respectively.
- the statistical analysis is based on the RTV data at the end of the experiment using SPSS software for analysis.
- the treatment group showed the best treatment effect on the 21st day after administration at the end of the trial, so statistical analysis was performed based on this data to evaluate the differences between the groups.
- the comparison between two groups is analyzed by T-test, and the comparison between three or more groups is analyzed by one-way ANOVA. If the variance is uniform (the F value is not significantly different), the analysis should be performed by Tukey's method; if the variance is not uniform (There is a significant difference in the F value), using the Games-Howell method to test. p ⁇ 0.05 considered a significant difference.
- compound 5 at doses of 60 mg/kg and 90 mg/kg (dose twice a day), compound 17 at doses of 90 mg/kg (dose twice a day), compared with the blank control, significantly inhibited tumors. effect.
- Compound 5 has a certain anti-tumor effect at a dose of 30 mg/kg (administered twice a day).
- the curative effects of compound 5 are all dose-dependent, and the experimental results are shown in Table 7.
- the tumor weight and tumor photo results on the 21st day are shown in Table 8 and Figure 1.
- the p value is obtained by using one-way ANOVA to analyze the relative tumor volume value (RTV).
- the p value is obtained by analyzing the tumor weight by one-way ANOVA and the vehicle treatment group.
- the F value is significantly different, and the Games-Howell method is used for analysis.
Abstract
Description
供试品 | DNA-PK激酶抑制IC 50(nM) |
化合物1 | 2 |
化合物4 | 1 |
化合物5 | 1 |
化合物6 | 1 |
化合物7 | 2 |
化合物8 | 7 |
化合物9 | 3 |
化合物10 | 2.5 |
化合物11 | 5 |
化合物12 | 4 |
化合物13 | 2 |
化合物14 | 5 |
化合物15 | 1 |
化合物16 | 0.5 |
化合物17 | 0.5 |
化合物18 | 0.9 |
化合物19 | 0.6 |
化合物20 | 0.9 |
化合物21 | 0.5 |
化合物22 | 0.4 |
化合物23 | 10 |
化合物24 | 68 |
Claims (14)
- 本发明提供了式(IV)所示化合物或其药学上可接受的盐,其中,E 1选自单键、-O-和-C(R 6R 7)-;R 1、R 2、R 3、R 4、R’和R”各自独立地选自H、F和Cl;或者R 2、R”与它们共同连接的碳原子一起形成C 3-5环烷基;R 5选自F、Cl、Br、I、环丙基和C 1-3烷基,所述C 1-3烷基任选被OH或1、2或3个R a取代;R 6和R 7各自独立地选自H、F、Cl、Br、I和CN;或者R 6、R 7与它们共同连接的碳原子一起形成环丙基或4元氧杂环丁基;环A选自C 3-5环烷基;Y 1选自环丙基和C 1-3烷基,所述C 1-3烷基任选被1、2、3、4或5个F取代;R a选自H、F、Cl、Br和I。
- 根据权利要求1-9任意一项所述化合物或其药学上可接受的盐,其中,R 5选自F、Cl、CH 2OH、CF 3和CH 3。
- 根据权利要求1-11任意一项所述的化合物或其药学上可接受的盐在制备DNA-PK抑制剂相关药物上的应用。
- 根据权利要求12所述的应用,其中,所述DNA-PK抑制剂相关药物作为单一药物在具有其他DNA修复途径缺陷时的肿瘤中发挥治疗效果。
- 根据权利要求12所述的应用,其中,所述DNA-PK抑制剂相关药物通过与放化疗药物联用,增强对实体瘤和血液瘤的抑制作用。
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IL293318A IL293318A (en) | 2019-11-25 | 2020-11-25 | Pyrimidoimidazole compounds used as dna-pk inhibitors |
EP20892868.9A EP4067359A4 (en) | 2019-11-25 | 2020-11-25 | PYRIMIDOIMIDAZOLE COMPOUNDS AS DNA-PK INHIBITORS |
JP2022530844A JP7383818B2 (ja) | 2019-11-25 | 2020-11-25 | Dna-pk阻害剤としてのピリミドイミダゾル系化合物 |
US17/779,322 US20230026616A1 (en) | 2019-11-25 | 2020-11-25 | Pyrimidoimidazole compounds used as dna-pk inhibitors |
KR1020227021633A KR20220106799A (ko) | 2019-11-25 | 2020-11-25 | Dna-pk 억제제로서의 피리미도이미다졸계 화합물 |
AU2020390962A AU2020390962B2 (en) | 2019-11-25 | 2020-11-25 | Pyrimidoimidazole compounds used as DNA-PK inhibitors |
CA3159290A CA3159290A1 (en) | 2019-11-25 | 2020-11-25 | Pyrimidoimidazole compounds used as dna-pk inhibitors |
CN202080081020.XA CN114728969B (zh) | 2019-11-25 | 2020-11-25 | 作为dna-pk抑制剂的嘧啶并咪唑类化合物 |
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CN202010911879 | 2020-09-02 | ||
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JP (1) | JP7383818B2 (zh) |
KR (1) | KR20220106799A (zh) |
CN (1) | CN114728969B (zh) |
AU (1) | AU2020390962B2 (zh) |
CA (1) | CA3159290A1 (zh) |
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CN114249753A (zh) * | 2020-09-22 | 2022-03-29 | 山东轩竹医药科技有限公司 | 三唑并吡啶类激酶抑制剂 |
WO2022135555A1 (zh) * | 2020-12-24 | 2022-06-30 | 江苏恒瑞医药股份有限公司 | 嘌呤酮类化合物、其制备方法及其在医药上的应用 |
WO2022242658A1 (zh) * | 2021-05-19 | 2022-11-24 | 南京明德新药研发有限公司 | 杂环取代的嘌呤酮衍生物的盐型及晶型 |
WO2023274310A1 (zh) * | 2021-06-29 | 2023-01-05 | 成都百裕制药股份有限公司 | 嘌呤衍生物的晶型及其药物组合物 |
WO2023165603A1 (en) * | 2022-03-03 | 2023-09-07 | Zai Lab (Shanghai) Co., Ltd. | Dna-pk inhibitor and combination use thereof |
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CN113121573A (zh) * | 2019-12-31 | 2021-07-16 | 成都百裕制药股份有限公司 | 嘌呤衍生物及其在医药上的应用 |
TWI765640B (zh) * | 2020-04-10 | 2022-05-21 | 大陸商南京明德新藥研發有限公司 | 作為dna-pk抑制劑的氨基嘧啶化合物及其衍生物 |
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WO2022135555A1 (zh) * | 2020-12-24 | 2022-06-30 | 江苏恒瑞医药股份有限公司 | 嘌呤酮类化合物、其制备方法及其在医药上的应用 |
WO2022242658A1 (zh) * | 2021-05-19 | 2022-11-24 | 南京明德新药研发有限公司 | 杂环取代的嘌呤酮衍生物的盐型及晶型 |
WO2023274310A1 (zh) * | 2021-06-29 | 2023-01-05 | 成都百裕制药股份有限公司 | 嘌呤衍生物的晶型及其药物组合物 |
WO2023165603A1 (en) * | 2022-03-03 | 2023-09-07 | Zai Lab (Shanghai) Co., Ltd. | Dna-pk inhibitor and combination use thereof |
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AU2020390962B2 (en) | 2023-09-28 |
IL293318A (en) | 2022-07-01 |
CA3159290A1 (en) | 2021-06-03 |
CN114728969A (zh) | 2022-07-08 |
US20230026616A1 (en) | 2023-01-26 |
EP4067359A4 (en) | 2024-01-10 |
TWI807228B (zh) | 2023-07-01 |
JP7383818B2 (ja) | 2023-11-20 |
CN114728969B (zh) | 2024-03-08 |
AU2020390962A1 (en) | 2022-07-14 |
TW202120506A (zh) | 2021-06-01 |
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