WO2023165493A1 - Dérivé de naphtyridine et son utilisation - Google Patents
Dérivé de naphtyridine et son utilisation Download PDFInfo
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- WO2023165493A1 WO2023165493A1 PCT/CN2023/078898 CN2023078898W WO2023165493A1 WO 2023165493 A1 WO2023165493 A1 WO 2023165493A1 CN 2023078898 W CN2023078898 W CN 2023078898W WO 2023165493 A1 WO2023165493 A1 WO 2023165493A1
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- naphthyridine
- compound
- atr kinase
- atr
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- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- LJXQPZWIHJMPQQ-UHFFFAOYSA-N pyrimidin-2-amine Chemical compound NC1=NC=CC=N1 LJXQPZWIHJMPQQ-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- JHHZLHWJQPUNKB-UHFFFAOYSA-N pyrrolidin-3-ol Chemical compound OC1CCNC1 JHHZLHWJQPUNKB-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 230000005783 single-strand break Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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
- A61K31/535—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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- the invention belongs to the field of medicinal chemistry, and more specifically relates to a naphthyridine derivative and its application.
- ATM and ATR ataxia telangiectasia and Rad3-related protein kinases initiate the DNA damage response of cells to DNA double-strand breaks and DNA single-strand breaks or unstable replication forks, respectively.
- the present invention provides a naphthyridine derivative and its application, the purpose of which is to discover the inhibitory effect of the naphthyridine derivative on ATR kinase, which can be used as an inhibitor of ATR kinase, application It is used for the preparation of drugs against related diseases mediated by ATR kinase.
- a naphthyridine derivative is provided, which is a compound with general formula (I), its isomer, and/or a pharmaceutically acceptable salt:
- X is N or -CH-
- Y is N or -CH-
- R is independently selected from hydrogen, halogen, or methyl
- R 2 is selected from substituted heterocyclic groups, or -NR 3 R 3 ;
- R 3 is selected from hydrogen, haloalkyl, or alkyl.
- the naphthyridine derivative has the following molecular formula:
- the naphthyridine derivatives, the isomers of the compound of the general formula (I), include cis-trans isomers, enantiomers, diastereomers of the compound of the general formula (I) Isomers, tautomers, and racemates thereof; said enantiomers, including (-)- and (+)-enantiomers, (R)- and (S)-enantiomers tautomers, (D)-isomers, (L)-isomers; additional asymmetric carbon atoms may be present in substituents such as alkyl groups; said tautomers, including pyrazole moieties as heteroaryls Any compound of the present invention can also be a 1H tautomer or a 2H tautomer or any combination of the two, wherein the 1H tautomer or the 2H tautomer is shown in the following formula:
- a kind of pharmaceutical composition is provided, its active ingredient comprises this
- its active ingredient comprises this
- the combination of one or more of the naphthyridine compounds and their pharmaceutically acceptable salts also includes a pharmaceutically acceptable carrier or diluent.
- the naphthyridine derivatives as described in the present invention in the preparation of ATR kinase inhibitors; preferably used in the preparation of drugs against related diseases mediated by ATR kinases; the A related disease mediated by ATR kinase is one in which inhibition of ATR kinase contributes to the condition and/or symptoms of the disease.
- the application of the naphthyridine derivatives in the preparation of ATR kinase inhibitors is used in the preparation of drugs for the treatment of hyperproliferative diseases;
- the hyperproliferative diseases include psoriasis, keloids, other hyperplasia affecting the skin, or benign prostatic hyperplasia.
- the application of the naphthyridine derivatives in the preparation of ATR kinase inhibitors is applied to the preparation of drugs for the treatment of solid tumors;
- the solid tumors include breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, Tumors of the eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases, lymphoma, or sarcoma.
- the application of the naphthyridine derivative in the preparation of an ATR kinase inhibitor is used in the preparation of a drug for treating leukemia.
- the drug also includes pharmaceutically acceptable auxiliary materials;
- the pharmaceutically acceptable auxiliary materials include excipients, solvents, dispersion agent, stabilizer, emulsifier, binder, diluent, disintegrant, lubricant, glidant, sweetener and/or flavoring agent.
- the typical routes of the drug include but not limited to oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal , Intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
- the naphthyridine derivatives provided by the invention can effectively inhibit the activity of ATR kinase, and can be applied to the preparation of ATR kinase inhibitors, especially to the preparation of drugs against related diseases mediated by ATR kinase;
- the compound can also significantly inhibit the active proliferation of cells, and can be applied to the preparation of drugs for treating hyperproliferative diseases, solid tumors, or leukemia.
- halo or halogen refers to fluorine, chlorine, bromine and iodine.
- alkyl refers to a branched or straight chain hydrocarbon group having 1 to 7 carbon atoms (C 1-7 alkyl) or 1 to 4 carbon atoms (C 1-4 alkyl).
- Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl, tert-butyl, n-pentyl , isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, etc.
- a substituted alkyl group is an alkyl group containing one or more substituents, such as 1, 2 or 3, selected from halogen, hydroxy or alkoxy.
- Halogen-substituted alkyl and halogen-substituted alkoxy may be straight or branched and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy group, trifluoromethoxy group, etc.
- haloalkyl refers to a substituted alkyl group having one or more halo substituents.
- haloalkyl includes mono-, di- and trifluoromethyl.
- heterocyclyl refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and that can exist as a monocyclic, bridged, or spiro ring.
- Non-limiting examples of heterocyclyl include, but are not limited to, tetrahydrofuryl, dihydrofuryl, pyrrolidinyl, N-methylpyrrolidinyl, Dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl and the like.
- a kind of naphthyridine derivative provided by the present invention is a compound with general formula (I), its isomer and/or pharmaceutically acceptable salt:
- X is N or -CH-
- Y is N or -CH-
- R is independently selected from hydrogen; halogen or methyl
- R 2 is selected from substituted heterocyclic groups; or -NR 3 R 3 ;
- R is selected from hydrogen; haloalkyl; or alkyl;
- the naphthyridine derivative has the following molecular formula:
- Said isomers include cis-trans isomers, enantiomers, diastereoisomers, tautomers and racemates thereof of the compound of general formula (I); Enantiomers, including (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, (D)-isomers, (L)-isomers; alkyl Additional asymmetric carbon atoms may be present in such substituents.
- the naphthyridine derivatives also include the same as those described in the present invention, but one or more Isotopically labeled derivatives of naphthyridine in which atoms are replaced by atoms of an atomic mass or mass number different from that normally found in nature.
- isotopes that can be incorporated into naphthyridine derivatives include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
- Certain isotopically labeled such naphthyridine derivatives are useful in compound and/or substrate tissue distribution assays.
- Tritiated ( ie3H ) and carbon-14 ( ie14C ) isotopes are especially preferred for their ease of preparation and detectability.
- Positron-emitting isotopes such as 15 O, 13 N, 11 C, and 18 F, can be used in positron emission tomography (PET) studies to determine substrate occupancy.
- Isotopically labeled said naphthyridine derivatives can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- substitution with heavier isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability (e.g. increased in vivo half-life or reduced dosage requirements), and thus in some cases
- deuterium substitution may be partial or complete, partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium, and all such forms of compounds are included within the scope of the present application.
- the naphthyridine derivatives may also be asymmetric, eg, have one or more stereoisomers. Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers, are included within the scope of the invention.
- the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
- the compounds of the present invention may exist in the form of tautomers.
- any compound of the invention comprising a pyrazole moiety as a heteroaryl for example, may exist as a 1H tautomer or a 2H tautomer or any number of mixtures of the two tautomers ,Right now:
- the compounds may exist as mixtures of isomers or, preferably, as pure isomers.
- the present invention provides a pharmaceutical composition, the active ingredient of which includes the combination of one or more of the naphthyridine derivatives and their pharmaceutically acceptable salts described in the present invention, and preferably also includes pharmaceutically acceptable excipients,
- the pharmaceutically acceptable auxiliary materials include excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents agent;
- excipients are formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, Microspheres and aerosols, etc.
- Typical routes of administration of the pharmaceutical composition include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
- the pharmaceutical composition can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, freeze-drying and the like.
- the pharmaceutical composition is in oral form.
- the pharmaceutical compositions can be formulated by mixing the active compounds with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc. for oral administration to patients.
- Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets Or the core of the sugar coating.
- Suitable auxiliary materials include but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc.
- the pharmaceutical composition may also be adapted for parenteral administration, such as a sterile solution in a suitable unit dosage form. Liquids, suspensions or freeze-dried products.
- Therapeutic dosages of the pharmaceutical compositions may depend, for example, on the particular use for treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
- the ratio or concentration of said naphthyridine derivatives in the pharmaceutical composition may vary depending on various factors including dosage, chemical properties (eg hydrophobicity) and route of administration.
- the naphthyridine derivatives may be provided for parenteral administration in an aqueous physiological buffer solution containing about 0.1-10% w/v of the compound.
- Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
- the dosage will likely depend on such variables as the type and extent of the disease or disorder, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
- the present invention also provides an application of a naphthyridine derivative in the preparation of an ATR kinase inhibitor.
- the naphthyridine derivative includes the compound of the present invention and its prodrug derivative, derivative thereof, and/or its pharmaceutically acceptable salt.
- the application of the naphthyridine derivatives in the preparation of ATR kinase inhibitors is preferably applied to the preparation of medicines against related diseases mediated by ATR kinases; Conditions and/or symptoms of disease.
- the related diseases mediated by the ATR kinase include hyperproliferative diseases, solid tumors and leukemia;
- the hyperproliferative diseases include psoriasis, keloids and other hyperplasia affecting the skin, benign prostatic hyperplasia (BPH);
- the solid tumors include tumors of breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eyes, liver, skin, head and neck, thyroid gland, parathyroid gland and their distant metastases, lymphoma and sarcoma.
- the compounds described in 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 the synthetic methods well known to those skilled in the art Preferred implementations include but are not limited to the examples of the present invention.
- the compounds described in the present invention can be prepared by those skilled in the art of organic synthesis with reference to the following routes:
- X, Y, R 1 , R 2 have the same definitions as above.
- DMSO dimethylsulfoxide
- NMP N-methylpyrrolidone
- DMF N,N-dimethylformamide
- DIPEA diisopropylethylamine
- 10% Pd/C stands for 10% palladium/carbon.
- ATR/ATPIP kinase solution 50ng/ ⁇ l
- 5.8 ⁇ l per well was added to the detection wells, 0.2ul of compounds with different concentrations were added, and 2 duplicate wells were set up, and controls were set at the same time.
- ATP 5 ⁇ M
- p53 substrate 50 nM
- EDTA terminated the reaction, and then 5 ⁇ l of the detection antibody
- Mab Anti- Phospho p53 and Mab Anti GST-d2 product of Perkinelmer Company
- TMD-8 cells in a good growth state, collect them into centrifuge tubes, adjust the cell density to about 5 ⁇ 104 cells/ml, inoculate 100 ⁇ l/well in 96-well plates, culture them overnight in a CO2 cell incubator, and then add different concentrations of Compounds, 2 duplicate wells, and a normal control was set at the same time.
- detection reagent CCK-8 product of Tongren Chemical Co., Ltd.
- CCK-8 product of Tongren Chemical Co., Ltd.
- TMD-8 cells in a good growth state, collect them into a centrifuge tube, adjust the cell density to about 1 ⁇ 10 7 cells/ml, inoculate them in a 384-well plate at 5 ⁇ l/well, add different concentrations of compounds to each well, and make 2 duplicate wells , while setting up a control.
- a control Continue culturing in the CO2 cell incubator for 30 min, add 10 mM HU at 5 ⁇ l/well, and incubate at room temperature for 2 h, use the p-CHK1 (Ser345) detection kit (product of PerkinElmer), detect with the AlphaLISA program of the microplate reader, and analyze with four parameters.
- Combined dose-effect curve calculate IC50.
- ICR mice adapted for 3-5 days, body weight 20-24g, divided into random groups, 9 mice in each group, 10mg/kg Doses of compounds were administered orally respectively. Fasting for 12 hours before administration of the compound, food and free drinking water 4 hours after administration.
- Test Example 6 In vivo drug efficacy evaluation (pharmacodynamic evaluation in TMD-8 human diffuse large B lymphoma cell subcutaneous xenograft model)
- TMD-8 cells were inoculated subcutaneously in the right axilla of SPF female NOD-SCID mice.
- model control group vehicle control
- positive control group (20mpk, 40mpk
- compound 1 group (20mpk, 40mpk
- compound 2 group (20mpk, 40mpk)
- intragastric administration On the day of grouping (d0 day), intragastric administration was started, and the administration volume was 4ml/kg. Two consecutive doses were given by intragastric administration every day, the tumor volume was measured 2-3 times a week, and weighed at the same time; the general performance of the mice was observed and recorded daily. At the end of the experiment, tumors were removed, weighed, and photographed.
- Tumor volume, TV (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ); a is the long axis, b is the short axis.
- TV 0 is the tumor volume on day d0,
- TV t is each time Tumor volume at time of measurement.
- T/C (%) T RTV /C RTV ⁇ 100%, T RTV : RTV of the treatment group; C RTV : RTV of the control group.
- TGI% (1-tumor weight of treatment group/tumor weight of control group) ⁇ tumor weight of control group.
- elimusertib is an ATR inhibitor in clinical trials by Bayer, also known as: BAY1895344.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Sont divulgués un dérivé de naphtyridine et son utilisation. Le dérivé de naphtyridine peut bien inhiber l'activité de la kinase ATR et peut être utilisé dans la préparation d'un inhibiteur de kinase ATR, en particulier dans la préparation d'un médicament contre une maladie associée médiée par la kinase ATR dans laquelle l'inhibition de la kinase ATR peut contribuer à l'atténuation d'états et/ou de symptômes de la maladie, et plus particulièrement dans la préparation d'un médicament pour le traitement d'une maladie hyperproliférative, d'une tumeur solide ou d'une leucémie.
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CN202210193164.5A CN116731011A (zh) | 2022-03-01 | 2022-03-01 | 一种萘啶衍生物及其应用 |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106795156A (zh) * | 2014-08-04 | 2017-05-31 | 拜耳制药股份公司 | 2‑(吗啉‑4‑基)‑1,7‑萘啶 |
WO2018153973A1 (fr) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combinaison d'inhibiteurs de la kinase atr et d'inhibiteurs de parp |
WO2018153970A1 (fr) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Formes solides de 2-[(3r)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphtyridine |
CN108699057A (zh) * | 2016-01-14 | 2018-10-23 | 拜耳医药股份公司 | 5-取代的2-(吗啉-4-基)-1,7-萘啶 |
WO2019025440A1 (fr) * | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combinaison d'inhibiteurs de kinase atr et d'inhibiteurs de pd-1/pd-l1 |
-
2022
- 2022-03-01 CN CN202210193164.5A patent/CN116731011A/zh active Pending
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2023
- 2023-03-01 WO PCT/CN2023/078898 patent/WO2023165493A1/fr unknown
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106795156A (zh) * | 2014-08-04 | 2017-05-31 | 拜耳制药股份公司 | 2‑(吗啉‑4‑基)‑1,7‑萘啶 |
CN108699057A (zh) * | 2016-01-14 | 2018-10-23 | 拜耳医药股份公司 | 5-取代的2-(吗啉-4-基)-1,7-萘啶 |
WO2018153973A1 (fr) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combinaison d'inhibiteurs de la kinase atr et d'inhibiteurs de parp |
WO2018153970A1 (fr) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Formes solides de 2-[(3r)-3-méthylmorpholin-4-yl]-4-(1-méthyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphtyridine |
WO2019025440A1 (fr) * | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combinaison d'inhibiteurs de kinase atr et d'inhibiteurs de pd-1/pd-l1 |
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