WO2021204111A1 - 作为dna-pk抑制剂的氨基嘧啶化合物及其衍生物 - Google Patents
作为dna-pk抑制剂的氨基嘧啶化合物及其衍生物 Download PDFInfo
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- WO2021204111A1 WO2021204111A1 PCT/CN2021/085643 CN2021085643W WO2021204111A1 WO 2021204111 A1 WO2021204111 A1 WO 2021204111A1 CN 2021085643 W CN2021085643 W CN 2021085643W WO 2021204111 A1 WO2021204111 A1 WO 2021204111A1
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- 230000029087 digestion Effects 0.000 description 1
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- 239000005457 ice water Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- XMBWDFGMSWQBCA-YPZZEJLDSA-N iodane Chemical compound [125IH] XMBWDFGMSWQBCA-YPZZEJLDSA-N 0.000 description 1
- 229940044173 iodine-125 Drugs 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
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- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- GVOISEJVFFIGQE-YCZSINBZSA-N n-[(1r,2s,5r)-5-[methyl(propan-2-yl)amino]-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 GVOISEJVFFIGQE-YCZSINBZSA-N 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
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- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 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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- 150000003384 small molecules Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
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- 238000010189 synthetic method Methods 0.000 description 1
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- 235000002906 tartaric acid Nutrition 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
- 231100000331 toxic Toxicity 0.000 description 1
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- 231100000419 toxicity Toxicity 0.000 description 1
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- 229910052722 tritium Inorganic materials 0.000 description 1
- JQSHBVHOMNKWFT-DTORHVGOSA-N varenicline Chemical compound C12=CC3=NC=CN=C3C=C2[C@H]2C[C@@H]1CNC2 JQSHBVHOMNKWFT-DTORHVGOSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
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Classifications
-
- 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
-
- 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
- A61K31/527—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim spiro-condensed
-
- 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
- A61K31/529—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim forming part of bridged ring systems
-
- 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
- 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
- C07D471/12—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 three hetero rings
- C07D471/18—Bridged systems
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/20—Spiro-condensed systems
-
- 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
- C07D471/22—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 systems contains four or more hetero rings
-
- 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
Definitions
- the present invention relates to a DNA-PK inhibitor, in particular to a compound represented by formula (II) 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 which belongs to the PI3K-related kinase (PIKK) family, mainly targets non-homologous DNA double-strand breaks End join (NHEJ) repair is an important member of DNA damage repair.
- NHEJ non-homologous DNA double-strand breaks End join
- the Ku70/Ku80 heterodimer specifically connects to the double-stranded damage through a pre-formed channel, recognizes double-strand breaks and binds to the broken ends separately, and then follows the DNA in an ATP-dependent manner. The strands slid a certain distance to both ends to form a KU-DNA complex and recruit DNA-PKcs to bind to the double-strand break.
- 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 DNA-PK small molecule inhibitor of the present invention can not only be used as a single drug to exert a therapeutic effect on tumors with defects in other DNA repair pathways. It can also be used in combination 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 invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
- T 1 and T 2 are each independently selected from CH and N;
- E 1 is selected from -C(R 1 )(R 2 )- and -N(R 3 )-;
- R 1 and R 2 together with the carbon atoms they are connected to form cyclopentyl, cyclohexyl, piperidinyl and The cyclopentyl, cyclohexyl, piperidinyl and Optionally substituted by one R a;
- R 3 is selected from 8-oxa-3-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-8-aza Heterobicyclo[3.2.1]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 4-oxa-7-azaspiro[2.5]octyl and 3-azabicyclo[ 3.1.0] Hexyl;
- R a is selected from H, C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl and butyl ethylene, said C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl And epoxybutyl are optionally substituted with 1, 2 or 3 R;
- R is selected from H and F
- 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;
- Y 2 is selected from F, Cl, Br, I, cyclopropyl and C 1-3 alkyl, said C 1-3 alkyl optionally substituted by OH or 4 or 5 F.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T 1 and T 2 are each independently selected from CH and N;
- E 1 is selected from -C(R 1 )(R 2 )- and -N(R 3 )-;
- R 1 and R 2 together with the carbon atoms they are connected to form cyclopentyl, cyclohexyl, piperidinyl and The cyclopentyl, cyclohexyl, piperidinyl and Optionally substituted by one R a;
- R 3 is selected from 8-oxa-3-azabicyclo[3.2.1]octyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 3-oxa-8-aza Heterobicyclo[3.2.1]octyl, 5-oxa-8-azaspiro[3.5]nonyl, 4-oxa-7-azaspiro[2.5]octyl and 3-azabicyclo[ 3.1.0] Hexyl;
- R a is selected from H, C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl and butyl ethylene, said C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl And epoxybutyl are optionally substituted with 1, 2 or 3 R;
- R is selected from H and F.
- R a is selected from H, CH 3 O, CF 3 CH 2, Other variables are as defined in the present invention.
- R 1 and R 2 together with the carbon atom to which they are connected together form Said R a is optionally substituted by one, the other variables are as defined in the present invention.
- R 1 and R 2 together with the carbon atom to which they are connected together form Said R a is optionally substituted by one, the other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- R 3 is selected from Other variables are as defined in the present invention.
- the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from
- T 1, T 2, R 3 and R a are as defined in the present invention.
- the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
- T 1 and T 2 are each independently selected from CH and N;
- E 1 is selected from -C(R 1 )(R 2 )- and -N(R 3 )-;
- R 1 and R 2 together with the carbon atoms they are connected to form cyclohexyl, piperidinyl and The cyclohexyl, piperidinyl and Optionally substituted by one R a;
- R 3 is selected from 8-oxa-3-azabicyclo[3.2.1]octyl, 3-oxa-8-azabicyclo[3.2.1]octyl, 5-oxa8-aza Spiro[3.5]nonyl, 4-oxa-7-azaspiro[2.5]octyl and 3-azabicyclo[3.1.0]hexyl;
- R a is selected from H, C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl and butyl ethylene, said C 1-3 alkyl, C 1-3 alkoxy, cyclopropyl And epoxybutyl are optionally substituted with 1, 2 or 3 R;
- R is selected from H and F.
- the present invention also provides a compound represented by 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.
- the compound of the present invention has a significant anti-tumor effect, and tumor-bearing mice all show good tolerance to the compound of the present invention.
- the PK results show that the compound of the present invention has excellent pharmacokinetic properties and good brain exposure, and is a good molecule that can be developed for oral administration.
- 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, the organic acid includes, for example, 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
- the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, 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 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 an appropriate 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 uses 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 can reduce toxic side effects and increase 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 a substituent.
- the substituent may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the compound after substitution Is stable.
- 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 Express.
- 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;
- 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) .
- Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
- C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through an oxygen atom.
- the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
- Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), 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, also including any one of n + m to n ranges, for example C 1- 3 comprises a C 1-12 , 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 from 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, 9-membered ring , 10-membered ring, 11-member
- 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 art.
- the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
- 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
- EDTA ethylenediaminetetraacetic acid
- DNA stands for deoxyribonucleic acid
- ATP adenosine triphosphate
- PEG polyethylene glycol
- GST glutathion Glycine S transferase
- Balb/c represents the mouse strain.
- N,N'-carbonyldiimidazole (1.62g, 10mmol, 2eq) was added to the acetonitrile (20mL) solution of compound 11 (1.28g, 5mmol, 1eq), and the reaction solution was added and reacted at 80°C for 2 hours.
- N-dimethylformamide (40mL) solution of compound 2g (1.24g, 4.4mmol, 1eq) was added cesium carbonate (2.15g, 6.6mmol, 1.5eq) and methyl iodide (780mg, 5.5mmol, 1.25eq), after adding the reaction solution, react at 21°C for 4 hours.
- reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain a crude product.
- reaction solution was cooled to 30°C, diluted with ethyl acetate (20 mL), filtered through Celite, and the filter cake was washed with ethyl acetate.
- the resulting filtrate was concentrated under reduced pressure to obtain a crude product.
- reaction solution is diluted with water (300mL), extracted with dichloromethane (300mL*2), dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure and purified by silica gel column chromatography (pure petroleum ether) to obtain compound 17c .
- reaction solution was cooled to 30°C, diluted with ethyl acetate (20 mL), filtered through a pad of diatomaceous earth, and the filter cake was washed with ethyl acetate.
- the resulting filtrate was concentrated under reduced pressure to obtain a crude product.
- 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.
- 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 0.08 mg/mL, which was filtered through a microporous membrane for use.
- the test compound was mixed with 10% dimethyl sulfoxide/50% polyethylene glycol 200/40% water, vortexed and sonicated to prepare a 0.2 mg/mL approximately clear solution, which was filtered with a microporous membrane for use.
- IV intravenous injection
- PO oral administration
- C 0 instantaneous required concentration after intravenous injection
- C max the 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 proportional constant 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.
- 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.
- SD male rats were selected, and the candidate compound solution was orally administered at a dose of 40 mg/kg.
- 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.
- mice Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams.
- 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 131mm 3 , group administration was started .
- the compound was formulated as a 10 mg/mL suspension solution, and the solvent was 0.5% HPMC+1% Tween 80.
- the tumor diameter was measured with vernier calipers twice a week.
- TGI percent of tumor growth rate
- T/C percent of tumor proliferation rate
- 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 the 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. 4.6 Experimental results and conclusions
- the supplier of the experimental animals used in compound 2 and the blank control was Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd. (Zhejiang Branch Company); e.
- the supplier of the experimental animals used for compound 1 and its blank control is Shanghai Sipuer-Bikai Laboratory Animal Co., Ltd.
- the compound of the present invention has a significant anti-tumor effect, and the tumor-bearing mice showed good tolerance to the compound, and the treatment group had no significant weight loss.
Abstract
Description
供试品 | DNA-PK激酶抑制活IC 50(nM) | 供试品 | DNA-PK激酶抑制活IC 50(nM) |
化合物1 | 0.8 | 化合物14 | 0.5 |
化合物2 | 0.7 | 化合物15 | 2 |
化合物3 | 0.5 | 化合物16 | 2 |
化合物4 | 0.4 | 化合物17 | 1 |
化合物5 | 0.4 | 化合物18 | 2 |
化合物6 | 0.4 | 化合物19 | 0.5 |
化合物9 | 0.3 | 化合物20 | 2 |
化合物10 | 0.4 | 化合物21 | 0.8 |
化合物12 | 9 | 化合物22 | 5 |
化合物13 | 3 | 化合物23 | 1 |
Claims (11)
- 式(II)所示化合物或其药学上可接受的盐,其中,T 1、T 2各自独立地选自CH和N;E 1选自-C(R 1)(R 2)-和-N(R 3)-;R 3选自8-氧杂-3-氮杂双环[3.2.1]辛烷基、6-氧杂-3-氮杂双环[3.1.1]庚烷基、3-氧杂-8-氮杂双环[3.2.1]辛烷基、5-氧杂8-氮杂螺[3.5]壬烷基、4-氧杂-7-氮杂螺[2.5]辛烷基和3-氮杂双环[3.1.0]己烷基;R a选自H、C 1-3烷基、C 1-3烷氧基、环丙基和环氧丁基,所述C 1-3烷基、C 1-3烷氧基、环丙基和环氧丁基任选被1、2或3个R取代;R选自H和F;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;Y 2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、3、4或5个F取代。
- 根据权利要求1~8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9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修复途径缺陷的肿瘤中发挥治疗效果。
- 根据权利要求9所述的应用,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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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 |
WO2022135360A1 (zh) * | 2020-12-21 | 2022-06-30 | 江苏恒瑞医药股份有限公司 | 嘌呤酮衍生物、其制备方法及其在医药上的应用 |
EP4067359A4 (en) * | 2019-11-25 | 2024-01-10 | Zai Lab Shanghai Co Ltd | PYRIMIDOIMIDAZOLE COMPOUNDS AS DNA-PK INHIBITORS |
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US20230055321A1 (en) * | 2019-11-22 | 2023-02-23 | Medshine Discovery Inc. | Pyrimidopyrrole spiro compounds and derivatives thereof as dna-pk inhibitors |
TWI807228B (zh) * | 2019-11-25 | 2023-07-01 | 大陸商南京明德新藥研發有限公司 | 作為dna-pk抑制劑的嘧啶并吡咯類化合物 |
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WO2022135360A1 (zh) * | 2020-12-21 | 2022-06-30 | 江苏恒瑞医药股份有限公司 | 嘌呤酮衍生物、其制备方法及其在医药上的应用 |
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 |
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