WO2023165493A1 - Naphthyridine derivative and use thereof - Google Patents
Naphthyridine derivative and use thereof 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
- Prior art date
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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.
Abstract
Disclosed are a naphthyridine derivative and use thereof. The naphthyridine derivative can well inhibit ATR kinase activity and can be used in the preparation of an ATR kinase inhibitor, particularly in the preparation of a medicament against a related disease mediated by ATR kinase in which the inhibition of ATR kinase may contribute to the amelioration of conditions and/or symptoms of the disease, and more particularly in the preparation of a medicament for treating a hyperproliferative disease, a solid tumor, or leukemia.
Description
本发明属于药物化学领域，更具体地，涉及一种萘啶衍生物及其应用。The invention belongs to the field of medicinal chemistry, and more specifically relates to a naphthyridine derivative and its application.
基因组稳定性维持是一切生命活动的基础，然而，多种外源和内源因素产生的广泛DNA损伤和复制压力，构成了基因组不稳定的主要来源。ATM和ATR(ataxia telangiectasia and Rad3-related protein)激酶分别启动细胞对DNA双链断裂损伤和DNA单链断裂损伤或不稳定复制叉的DNA损伤应答响应。The maintenance of genome stability is the basis of all life activities. However, extensive DNA damage and replication stress caused by various exogenous and endogenous factors constitute the main source of genome instability. 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.
而与正常细胞相反，肿瘤细胞的一个基本特征是基因组不稳定性和易突变，它们通常伴随着大量稳定和修复基因组DNA的功能缺失，因此癌细胞更依赖ATR激酶修复自己，ATR及其参与的信号通路对基因组稳定以及肿瘤的发生、发展和治疗至关重要，事实上，ATR功能的破坏如基因缺失，已被显示在有和没有DNA损伤剂的存在下都促进癌细胞死亡；而ATR抑制剂作为单一成分和作为辐射疗法或遗传毒性化学疗法的强力增敏剂一直是研究的热点，寻找一种强效的和选择性ATR抑制剂对癌症的治疗具有重要意义。Contrary to normal cells, one of the basic characteristics of tumor cells is genome instability and mutation, which are usually accompanied by a large number of functional loss of stabilizing and repairing genomic DNA, so cancer cells rely more on ATR kinase to repair themselves, ATR and its involved Signaling pathways are critical for genome stability as well as tumor initiation, progression, and treatment. In fact, disruption of ATR function, such as gene deletion, has been shown to promote cancer cell death in the presence and absence of DNA-damaging agents; whereas ATR inhibits As a single component and as a powerful sensitizer for radiation therapy or genotoxic chemotherapy, it has always been a research hotspot. Finding a potent and selective ATR inhibitor is of great significance for the treatment of cancer.
发明内容Contents of the invention
针对现有技术的以上缺陷或改进需求，本发明提供了一种萘啶衍生物及其应用，其目的在于发现该萘啶衍生物对于ATR激酶的抑制作用，可作为ATR激酶的抑制剂，应用于制备抗ATR激酶介导的相关疾病的药物。In view of the above defects or improvement needs of the prior art, 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.
为实现上述目的，按照本发明的一个方面，提供了一种萘啶衍生物，其为具有通式(I)的化合物、其异构体、和/或可药用盐：
To achieve the above object, according to one aspect of the present invention, a naphthyridine derivative is provided, which is a compound with general formula (I), its isomer, and/or a pharmaceutically acceptable salt:
To achieve the above object, according to one aspect of the present invention, a naphthyridine derivative is provided, which is a compound with general formula (I), its isomer, and/or a pharmaceutically acceptable salt:
其中，in,
X为N或-CH-；X is N or -CH-;
Y为N或-CH-；Y is N or -CH-;
R1独立地选自氢、卤素、或甲基；R is independently selected from hydrogen, halogen, or methyl;
R2选自取代的杂环基、或-NR3R3；R 2 is selected from substituted heterocyclic groups, or -NR 3 R 3 ;
R3选自氢、卤代烷基、或烷基。R 3 is selected from hydrogen, haloalkyl, or alkyl.
优选地，所述萘啶衍生物，其具有以下分子式：
Preferably, the naphthyridine derivative has the following molecular formula:
Preferably, the naphthyridine derivative has the following molecular formula:
或其异构体或可药用盐。or an isomer or a pharmaceutically acceptable salt thereof.
优选地，所述萘啶衍生物，其所述具有通式(I)的化合物的异构体，包括具有通式(I)化合物的顺反异构体、对映异构体、非对映异构体、互变异构体、及其外消旋体；所述对映异构体，包括(-)-和(+)-对映体、(R)-和(S)-对映体、(D)-异构体、(L)-异构体；烷基等取代基中可存在另外的不对称碳原子；所述互变异构体，包括吡唑部分作为杂芳基的任何本发明的化合物，还可以以1H互变异构体或2H互变异构体或两者任意组合，其中1H互变异构体或2H互变异构体，如下式所示：
Preferably, 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:
Preferably, 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:
按照本发明的另一方面，提供了一种药物组合物，其活性成分包括本
发明所述的萘啶类化合物及其可药用的盐中的一种或多种的组合，还包括可药用载体或稀释剂。According to another aspect of the present invention, a kind of pharmaceutical composition is provided, 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.
按照本发明的另一方面，还提供了一种如本发明所述的萘啶衍生物在制备ATR激酶抑制剂中的应用；优选应用于制备抗ATR激酶介导的相关疾病的药物；所述ATR激酶介导的相关疾病为抑制ATR激酶有助于该疾病的病状和/或症候的疾病。According to another aspect of the present invention, there is also provided a use of 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.
优选地，所述萘啶衍生物在制备ATR激酶抑制剂中的应用，其应用于制备治疗过度增殖性疾病的药物；所述过度增殖性疾病，包括牛皮癣、瘢痕瘤、影响皮肤的其它增生、或良性***增生。Preferably, 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.
优选地，所述萘啶衍生物在制备ATR激酶抑制剂中的应用，其应用于制备治疗实体瘤的药物；所述实体瘤，包括乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼睛、肝、皮肤、头颈、甲状腺、甲状旁腺的肿瘤以及它们的远端转移，淋巴瘤、或者肉瘤。Preferably, 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.
优选地，所述萘啶衍生物在制备ATR激酶抑制剂中的应用，其应用于制备治疗白血病的药物。Preferably, 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.
优选地，所述萘啶衍生物在制备ATR激酶抑制剂中的应用，其所述药物，还包括药学上可接受的辅料；所述药学上可接受的辅料，包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂。Preferably, the application of the naphthyridine derivatives in the preparation of ATR kinase inhibitors, 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.
优选地，所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其所述药物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Preferably, the application of the naphthyridine derivatives in the preparation of ATR kinase inhibitors, 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.
总体而言，通过本发明所构思的以上技术方案与现有技术相比，能够取得下列有益效果：Generally speaking, compared with the prior art, the above technical solutions conceived by the present invention can achieve the following beneficial effects:
本发明提供的萘啶衍生物，能有效抑制ATR激酶活性，可应用于制备ATR激酶抑制剂，尤其是应用于制备抗ATR激酶介导的相关疾病的药物；
该化合物还能够显著抑制细胞活性增殖，能应用于制备治疗过度增殖性疾病、实体瘤、或白血病的药物。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.
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。此外，下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。In order to make the object, technical solution and advantages of the present invention more clear, the present invention will be further described in detail below in conjunction with the examples. It should be understood that the specific embodiments described here are only used to explain the present invention, not to limit the present invention. In addition, the technical features involved in the various embodiments of the present invention described below can be combined with each other as long as they do not constitute a conflict with each other.
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise stated, the following terms used in this application have the following meanings. A specific term should not be regarded as indeterminate or unclear if there is no special definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“烷基”是指具有1至7个碳原子(C1-7烷基)或1至4个碳原子(C1-4烷基)的支链或直链的烃基。烷基的代表性的实例包括但不限于甲基、乙基、正-丙基、异-丙基、正-丁基、仲-丁基、异-丁基、叔丁基、正-戊基、异戊基、新戊基、正-己基、3-甲基己基、2，2-二甲基戊基、2，3-二甲基戊基、正-庚基等。被取代的烷基是含一个或多个诸如1、2或3个选自卤素、羟基或烷氧基的取代基的烷基。卤素取代的烷基和卤素取代的烷氧基可以是直链或支链的，并包括甲氧基、乙氧基、二氟甲基、三氟甲基、五氟乙基、二氟甲氧基、三氟甲氧基等。The term "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.
术语“卤代烷基”是指具有一或多个卤素取代基的被取代的烷基。例如，“卤代烷基”包括单-、二-和三氟甲基。The term "haloalkyl" refers to a substituted alkyl group having one or more halo substituents. For example, "haloalkyl" includes mono-, di- and trifluoromethyl.
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族)并且可以以单环、桥环或螺环存在的非芳族环。杂环基的非限制性实例包括但不限于四氢呋喃基、二氢呋喃基、吡咯烷基、N-甲基吡咯烷基、
二氢吡咯基、哌啶基、哌嗪基、吡唑烷基、4H-吡喃基、吗啉基、硫代吗啉基、四氢噻吩基等。The term "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.
本发明提供的一种萘啶衍生物，为具有通式(I)的化合物、其异构体和/或药学上可接受的盐：
A kind of naphthyridine derivative provided by the present invention is a compound with general formula (I), its isomer and/or pharmaceutically acceptable salt:
A kind of naphthyridine derivative provided by the present invention is a compound with general formula (I), its isomer and/or pharmaceutically acceptable salt:
其中，in,
X是N或-CH-；X is N or -CH-;
Y为N或-CH-；Y is N or -CH-;
R1独立地选自氢；卤素或甲基；R is independently selected from hydrogen; halogen or methyl;
R2选自取代的杂环基；或-NR3R3；R 2 is selected from substituted heterocyclic groups; or -NR 3 R 3 ;
R3选自氢；卤代烷基；或烷基； R is selected from hydrogen; haloalkyl; or alkyl;
优选地，所述萘啶衍生物，具有以下分子式：
Preferably, the naphthyridine derivative has the following molecular formula:
Preferably, the naphthyridine derivative has the following molecular formula:
或其异构体或可药用盐。or an isomer or a pharmaceutically acceptable salt thereof.
所述异构体，包括具有通式(I)化合物的顺反异构体、对映异构体、非对映异构体、互变异构体、及其外消旋体；所述对映异构体，包括(-)-和(+)-对映体、(R)-和(S)-对映体、(D)-异构体、(L)-异构体；烷基等取代基中可存在另外的不对称碳原子。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.
所述萘啶衍生物还包括与本发明中记载的那些相同的，但一个或多个
原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的萘啶衍生物。可结合到萘啶衍生物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。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. Examples of 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.
某些同位素标记的所述萘啶衍生物(例如用3H及14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即3H)和碳-14(即14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序，通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的所述萘啶衍生物。Certain isotopically labeled such naphthyridine derivatives (eg, those labeled with3H and14C ) 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.
此外，用较重同位素(诸如氘(即2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代，所有这样的形式的化合物包含于本申请的范围内。Furthermore, substitution with heavier isotopes such as deuterium (i.e. 2 H) 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 The following may be preferred, wherein 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.
所述萘啶衍生物还可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括在本发明的保护范围之内，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。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.
本发明的化合物可以以互变异构体形态存在。例如，包含吡唑部分作为杂芳基的任何本发明的化合物，例如，可以以1H互变异构体或2H互变异构体或任何数量的两个互变异构体的混合物的形态存在，即：
The compounds of the present invention may exist in the form of tautomers. For example, 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 of the present invention may exist in the form of tautomers. For example, 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:
因此，所述化合物可以作为异构体的混合物或优选纯的异构体存在。Thus, the compounds may exist as mixtures of isomers or, preferably, as pure isomers.
本发明提供的一种药物组合物，其活性成分包括本发明所述的萘啶衍生物及其可药用的盐中的一种或多种的组合，优选还包括药学上可接受的辅料，所述药学上可接受的辅料包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂；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;
所述赋形剂为配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The 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.
给予所述药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。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.
所述药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。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.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, 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.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。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.
所述药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶
液剂、混悬剂或冻干产品。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.
所述药物组合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。所述萘啶衍生物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供所述萘啶衍生物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验***导出的剂量-反应曲线外推，得到有效剂量。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. For example, 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 μg/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.
本发明还提供了一种萘啶衍生物在制备ATR激酶抑制剂中的应用，所述萘啶衍生物，包括本发明所述的化合物及其前药衍生物、其衍生物、和/或其可药用的盐。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.
所述萘啶衍生物在制备ATR激酶抑制剂中的应用，优选应用于制备抗ATR激酶介导的相关疾病的药物；所述ATR激酶介导的相关疾病为抑制ATR激酶有助于该疾病的病状和/或症候的疾病。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.
进一步地；所述ATR激酶介导的相关疾病，包括过度增殖性疾病、实体瘤和白血病；所述过度增殖性疾病，包括牛皮癣、瘢痕瘤及影响皮肤的其它增生、良性***增生(BPH)；所述实体瘤，包括乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼睛、肝、皮肤、头颈、甲状腺、甲状旁腺的肿瘤以及它们的远端转移、淋巴瘤和肉瘤。Further; 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.
本发明所述的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
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.
本发明具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本发明的化学变化及其所需的试剂和物料。为了获得本发明所述的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present invention are completed in a suitable solvent, and the solvent must be suitable for the chemical changes of the present invention and the required reagents and materials. In order to obtain the compounds described in the present invention, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes on the basis of existing implementations.
在一些实施方案中，本发明所述的化合物可以由有机合成领域技术人员参考以下路线来制备：In some embodiments, 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:
方案一：
Option One:
Option One:
X，Y，R1，R2定义同前述。X, Y, R 1 , R 2 have the same definitions as above.
本发明采用下述缩略词：The following abbreviations are used in the present invention:
DMSO代表二甲亚砜；NMP代表N-甲基吡咯烷酮；DMF代表N，N-二甲基甲酰胺；DIPEA代表二异丙基乙胺；10％Pd/C代表10％含量钯/碳。DMSO stands for dimethylsulfoxide; NMP stands for N-methylpyrrolidone; DMF stands for N,N-dimethylformamide; DIPEA stands for diisopropylethylamine; 10% Pd/C stands for 10% palladium/carbon.
以下为实施例：The following are examples:
实施例1：(R)-1-(4-甲基-5-(2-((R)-3-甲基吗啉)-8-(1H-吡唑-5-基)-1,7-萘啶-4-基)嘧啶-2-基)吡咯烷-3-醇(化合物1)
Example 1: (R)-1-(4-methyl-5-(2-((R)-3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7 -Naphthyridin-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol (compound 1)
Example 1: (R)-1-(4-methyl-5-(2-((R)-3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7 -Naphthyridin-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol (compound 1)
(1)化合物1-c的制备(1) Preparation of compound 1-c
向100ml反应器中加入(R)-3-羟基吡咯烷(1g)、5-溴-2-氟-4-甲基嘧啶(1.1g)、碳酸钾(2.38g)和N-甲基吡咯烷酮(20mL)。加热升温至135℃反应4小时。将反应液用100mL乙酸乙酯稀释，用100mL水洗2次，100mL饱和食盐水洗2次，无水硫酸钠干燥，过滤，滤液浓缩至干，得到化合物1-c(1.4g)。ESI-MS:m/z＝258.02[M+H]+。(R)-3-hydroxypyrrolidine (1 g), 5-bromo-2-fluoro-4-methylpyrimidine (1.1 g), potassium carbonate (2.38 g) and N-methylpyrrolidone ( 20mL). Heat up to 135°C for 4 hours. The reaction solution was diluted with 100 mL of ethyl acetate, washed twice with 100 mL of water and twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain compound 1-c (1.4 g). ESI-MS: m/z=258.02 [M+H]+.
(2)化合物1-d的制备(2) Preparation of compound 1-d
向100ml反应器中加入1-c(1.0g)、联硼酸频那醇酯(1.18g)、醋酸钾(580mg)和1,4-二氧六环(12mL)，搅拌，N2保护，再加入1,1'-双二苯基膦二茂铁二氯化钯(135mg)，升温至100℃反应2小时。反应液用100mL乙酸乙酯和100mL二氯甲烷的混合溶液稀释，用50mL水洗2次，50mL饱和食盐水洗3次，无水硫酸钠干燥，抽滤，滤液浓缩干。然后加入20mL正己烷搅拌20分钟，抽滤，向滤饼中加入40mL正己烷，搅拌15分钟，过
滤，滤液浓缩至干，得到化合物1-d(1.0g)。Add 1-c (1.0g), pinacol diborate (1.18g), potassium acetate (580mg) and 1,4-dioxane (12mL) into a 100ml reactor, stir, N2 protection, and then add 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (135mg), heated to 100°C for 2 hours. The reaction solution was diluted with a mixed solution of 100 mL of ethyl acetate and 100 mL of dichloromethane, washed twice with 50 mL of water and three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness. Then add 20mL of n-hexane and stir for 20 minutes, suction filter, add 40mL of n-hexane in the filter cake, stir for 15 minutes, pass After filtration, the filtrate was concentrated to dryness to obtain compound 1-d (1.0 g).
(3)化合物1-f的制备(3) Preparation of compound 1-f
向100ml反应器中加入1-d(1.0g)、1-e(1.44g)(参照中国专利CN106795156B第83页中间体10的制备方法制备)、碳酸钾(567mg)、1,1'-双二苯基膦二茂铁二氯化钯(125mg)、乙腈(20mL)和纯净水(10mL)，搅拌，升温至130℃反应20分钟。将反应液用150mL二氯甲烷稀释，用100mL水洗一次，100mL饱和食盐水洗4次，无水硫酸钠干燥，抽滤，滤液浓缩干，得到化合物1-f(984mg)。Add 1-d (1.0g), 1-e (1.44g) (prepared with reference to the preparation method of intermediate 10 on page 83 of Chinese patent CN106795156B), potassium carbonate (567mg), 1,1'-bis Diphenylphosphinoferrocenepalladium dichloride (125mg), acetonitrile (20mL) and purified water (10mL) were stirred and heated to 130°C for 20 minutes to react. The reaction solution was diluted with 150 mL of dichloromethane, washed once with 100 mL of water and four times with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness to obtain compound 1-f (984 mg).
(4)化合物1的制备(4) Preparation of compound 1
向100ml反应器中加入1-f(0.5mg)和13mL氯化氢甲醇溶液，室温搅拌1小时。将反应液减压浓缩干，再加入20mL乙腈，减压浓缩干，再加入20mL二氯甲烷，减压浓缩干，通过制备液相得到化合物1(50mg)。ESI-MS:m/z＝473.44[M+H]+。Add 1-f (0.5 mg) and 13 mL methanolic hydrogen chloride solution into a 100 ml reactor, and stir at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then 20 mL of acetonitrile was added, concentrated to dryness under reduced pressure, 20 mL of dichloromethane was added, concentrated to dryness under reduced pressure, and compound 1 (50 mg) was obtained by preparing the liquid phase. ESI-MS: m/z=473.44 [M+H]+.
1H NMR(500MHz,DMSO-d6):d[ppm]＝1.30(dd,3H)，1.96–1.89(m,1H),2.08–2.01(m,1H),2.11(d,3H),3.38–3.31(m,1H),3.58(dt,4H),3.69–3.64(m,1H),3.72(dd,1H),3.82(dd,1H),4.05(dd,1H),4.25–4.16(m,1H),4.42(d,1H),4.61(s,1H),4.99(s,1H),7.19(d,1H),7.47–7.40(m,2H),7.64(d,1H),8.22(s,1H),8.30(d,1H),13.33(s,1H)。 1 H NMR (500MHz, DMSO-d6): d[ppm]=1.30(dd,3H), 1.96–1.89(m,1H), 2.08–2.01(m,1H), 2.11(d,3H),3.38– 3.31(m,1H),3.58(dt,4H),3.69–3.64(m,1H),3.72(dd,1H),3.82(dd,1H),4.05(dd,1H),4.25–4.16(m, 1H), 4.42(d, 1H), 4.61(s, 1H), 4.99(s, 1H), 7.19(d, 1H), 7.47–7.40(m, 2H), 7.64(d, 1H), 8.22(s ,1H), 8.30(d,1H), 13.33(s,1H).
实施例2：(R)-4-甲基-5-(2-(3-甲基吗啉)-8-(1H-吡唑-5-基)-1,7-萘啶-4-基)-N-(2,2,2-三氟甲基)嘧啶-2-胺(化合物2)
Example 2: (R)-4-methyl-5-(2-(3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl )-N-(2,2,2-trifluoromethyl)pyrimidin-2-amine (compound 2)
Example 2: (R)-4-methyl-5-(2-(3-methylmorpholine)-8-(1H-pyrazol-5-yl)-1,7-naphthyridin-4-yl )-N-(2,2,2-trifluoromethyl)pyrimidin-2-amine (compound 2)
(1)化合物2-c的制备(1) Preparation of compound 2-c
向100ml反应器中加入2-a(1.0g)、5-溴-2-氟-4-甲基嘧啶(2.0g)、碳酸钾(1.37g)和N-甲基吡咯烷酮(20mL)。加热升温至135℃反应4小时。将反应液用100mL乙酸乙酯稀释，用100mL水洗2次，100mL饱和食盐水洗2次，无水硫酸钠干燥，过滤，滤液浓缩至干，得到化合物2-c(2.7g)。ESI-MS:m/z＝270.02[M+H]+。2-a (1.0 g), 5-bromo-2-fluoro-4-methylpyrimidine (2.0 g), potassium carbonate (1.37 g) and N-methylpyrrolidone (20 mL) were added to a 100 ml reactor. Heat up to 135°C for 4 hours. The reaction solution was diluted with 100 mL of ethyl acetate, washed twice with 100 mL of water and twice with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain compound 2-c (2.7 g). ESI-MS: m/z=270.02 [M+H]+.
(2)化合物2-d的制备(2) Preparation of compound 2-d
向100ml反应器中加入2-c(1.0g)、联硼酸频那醇酯(1.1g)、醋酸钾(545mg)和1,4-二氧六环(10mL)，搅拌，N2保护，再加入1,1'-双二苯基膦二茂铁二氯化钯(135mg)，升温至100℃反应2小时。反应液用100mL乙酸乙酯和100mL二氯甲烷的混合溶液稀释，用50mL水洗2次，50mL饱和食盐水洗3次，无水硫酸钠干燥，抽滤，滤液浓缩干。然后加入20mL正己烷搅拌20分钟，抽滤，向滤饼中加入40mL正己烷，搅拌15分钟，过滤，滤液浓缩至干，得到化合物2-d(996mg)。
Add 2-c (1.0g), biboronic acid pinacol ester (1.1g), potassium acetate (545mg) and 1,4-dioxane (10mL) into the 100ml reactor, stir, N2 protection, then add 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (135mg), heated to 100°C for 2 hours. The reaction solution was diluted with a mixed solution of 100 mL of ethyl acetate and 100 mL of dichloromethane, washed twice with 50 mL of water and three times with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness. Then 20 mL of n-hexane was added and stirred for 20 minutes, suction filtered, 40 mL of n-hexane was added to the filter cake, stirred for 15 minutes, filtered, and the filtrate was concentrated to dryness to obtain compound 2-d (996 mg).
(3)化合物2-f的制备(3) Preparation of compound 2-f
向100ml反应器中加入2-d(0.5g)、1-e(0.7g)、碳酸钾(650mg)、1,1'-双二苯基膦二茂铁二氯化钯(50mg)、乙腈(12mL)和纯净水(46mL)，搅拌，升温至130℃反应20分钟。将反应液用150mL二氯甲烷稀释，用100mL水洗一次，100mL饱和食盐水洗4次，无水硫酸钠干燥，抽滤，滤液浓缩干，得到化合物2-f(780mg)。Into a 100ml reactor was added 2-d (0.5g), 1-e (0.7g), potassium carbonate (650mg), 1,1'-bisdiphenylphosphinoferrocenepalladium dichloride (50mg), acetonitrile (12mL) and purified water (46mL), stirred and heated to 130°C for 20 minutes. The reaction solution was diluted with 150 mL of dichloromethane, washed once with 100 mL of water and four times with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness to obtain compound 2-f (780 mg).
(4)化合物2的制备(4) Preparation of Compound 2
向100ml反应器中加入2-f(500mg)和12mL氯化氢甲醇溶液，室温搅拌1小时。将反应液减压浓缩干，再加入20mL乙腈，减压浓缩干，再加入20mL二氯甲烷，减压浓缩干，通过制备液相得到化合物2(70mg)。ESI-MS:m/z＝485.40[M+H]+。Add 2-f (500 mg) and 12 mL methanolic hydrogen chloride solution into a 100 ml reactor, and stir at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then 20 mL of acetonitrile was added, concentrated to dryness under reduced pressure, 20 mL of dichloromethane was added, concentrated to dryness under reduced pressure, and compound 2 (70 mg) was obtained by preparing the liquid phase. ESI-MS: m/z=485.40 [M+H]+.
1H NMR(500MHz,DMSO-d6):d[ppm]＝1.34–1.25(m,3H),2.13(d,3H),3.38–3.31(m,1H),3.58(t,1H),3.76–3.67(m,1H),3.87–3.77(m,1H),4.09–3.99(m,1H),4.22(d,3H),4.62(s,1H),7.16(dd,1H),7.42(s,1H),7.50(d,1H),7.65(d,1H),8.03(s,1H),8.27(s,1H),8.31(d,1H),13.37(s,1H)。 1 H NMR (500MHz, DMSO-d6):d[ppm]=1.34–1.25(m,3H),2.13(d,3H),3.38–3.31(m,1H),3.58(t,1H),3.76– 3.67(m,1H),3.87–3.77(m,1H),4.09–3.99(m,1H),4.22(d,3H),4.62(s,1H),7.16(dd,1H),7.42(s, 1H), 7.50(d,1H), 7.65(d,1H), 8.03(s,1H), 8.27(s,1H), 8.31(d,1H), 13.37(s,1H).
根据方案1并类似于实施例1、实施例2制备化合物3、化合物4、化合物5及化合物6，如表1所示。Compound 3, Compound 4, Compound 5 and Compound 6 were prepared according to Scheme 1 and similarly to Example 1 and Example 2, as shown in Table 1.
表1 化合物3-6
Table 1 Compounds 3-6
Table 1 Compounds 3-6
实验1：ATR激酶抑制活性测定Experiment 1: ATR Kinase Inhibitory Activity Assay
ATR/ATPIP激酶溶液(50ng/μl)，按每孔5.8μl加入至检测孔中，加入0.2ul不同浓度的化合物，2个复孔，同时设对照。室温孵育60min后，将ATP(5μM)与p53底物(50nM)，按1:1混合，按每孔4μl加入检测孔中；室温反应60min后，EDTA终止反应，再加入5μl检测抗体Mab Anti-phospho p53和Mab Anti GST-d2(perkinelmer公司产品)，室温孵育60min；酶标仪进行读板检测(激发620nm，发射665nm)，采用四参数拟合，计算IC50。结果见表2。ATR/ATPIP kinase solution (50ng/μl), 5.8μl 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. After incubating at room temperature for 60 minutes, ATP (5 μM) and p53 substrate (50 nM) were mixed at a ratio of 1:1, and 4 μl per well was added to the detection well; after 60 minutes of reaction at room temperature, EDTA terminated the reaction, and then 5 μl of the detection antibody Mab Anti- Phospho p53 and Mab Anti GST-d2 (product of Perkinelmer Company) were incubated at room temperature for 60 min; the microplate reader was used for plate reading detection (excitation 620nm, emission 665nm), and four-parameter fitting was used to calculate IC 50 . The results are shown in Table 2.
表2 ATR激酶抑制活性(HTRF法)
Table 2 ATR kinase inhibitory activity (HTRF method)
Table 2 ATR kinase inhibitory activity (HTRF method)
由表2可知，本发明提供的化合物对ATR激酶有较强的抑制作用，可用于制备ATR激酶抑制剂。It can be seen from Table 2 that the compounds provided by the present invention have a strong inhibitory effect on ATR kinase and can be used to prepare ATR kinase inhibitors.
实验2 TMD-8细胞增殖抑制活性测定Experiment 2 Determination of TMD-8 cell proliferation inhibitory activity
取处于生长状态良好的TMD-8细胞，收集至离心管，调整细胞密度约5×104个/ml，按100μl/孔接种于96孔板，CO2细胞培养箱中培养过夜后加入不同浓度的化合物，2个复孔，同时设正常对照。CO2培养箱中继续培养72小时，按10μl/孔加入检测试剂CCK-8(同仁化学公司产品)，细胞培养箱中孵育约4小时，酶标仪450nm处检测其吸光值，四参数分析，拟合量效曲线，计算IC50。结果见表3。Take 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 μl/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. Continue culturing in the CO2 incubator for 72 hours, add detection reagent CCK-8 (product of Tongren Chemical Co., Ltd.) at 10 μl/well, incubate in the cell incubator for about 4 hours, detect the absorbance value at 450 nm with a microplate reader, and analyze with four parameters. Based on the dose-effect curve, calculate the IC 50 . The results are shown in Table 3.
表3 细胞增殖活性(TMD8)
Table 3 Cell proliferation activity (TMD8)
Table 3 Cell proliferation activity (TMD8)
由表3可知，本发明提供的化合物对TMD8细胞的增殖有显著抑制作用，可见，其有很好的抗肿瘤成药前景。It can be seen from Table 3 that the compound provided by the present invention has a significant inhibitory effect on the proliferation of TMD8 cells, and it can be seen that it has a good prospect for anti-tumor drug production.
实验例3 对TMD-8细胞CHK1磷酸化抑制活性测定Experimental Example 3 Determination of Inhibitory Activity of CHK1 Phosphorylation in TMD-8 Cells
取处于生长状态良好的TMD-8细胞，收集至离心管，调整细胞密度约1×107个/ml，按5μl/孔接种于384孔板，每孔加入不同浓度的化合物，2个复孔，同时设对照。CO2细胞培养箱中继续培养30min，按5μl/孔加入10mM HU，室温孵育2h后，使用p-CHK1(Ser345)检测试剂盒(perkinelmer公司产品)，酶标仪AlphaLISA程序检测，四参数分析，拟合量效曲线，计算IC50。
Take 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 μl/well, add different concentrations of compounds to each well, and make 2 duplicate wells , while setting up a control. Continue culturing in the CO2 cell incubator for 30 min, add 10 mM HU at 5 μl/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.
表4 TMD-8细胞CHK1磷酸化抑制活性
Table 4 Inhibitory activity of CHK1 phosphorylation in TMD-8 cells
Table 4 Inhibitory activity of CHK1 phosphorylation in TMD-8 cells
试验例4 体外肝微位体稳定性Test Example 4 Stability of Liver Microsites in Vitro
化合物(终浓度1μM)与PBS缓冲液(PH7.4)、肝微粒体溶液(0.5mg/ml)、NADPH+MgCl2溶液于37℃、300rpm孵育1小时。同时将受试化合物(终浓度1μM)与PBS缓冲液(PH7.4)、肝微粒体溶液(0.5mg/ml)混合作为0小时对照。样本用含内标的乙腈溶液进行蛋白沉淀离心后制备上清液，稀释后用于LC/MS/MS测定。结果见表5。Compounds (final concentration 1 μM) were incubated with PBS buffer (pH 7.4), liver microsome solution (0.5 mg/ml), NADPH+MgCl 2 solution at 37° C., 300 rpm for 1 hour. At the same time, the test compound (final concentration 1 μM) was mixed with PBS buffer (pH 7.4) and liver microsome solution (0.5 mg/ml) as a 0-hour control. The samples were centrifuged for protein precipitation with an internal standard-containing acetonitrile solution to prepare the supernatant, which was diluted for LC/MS/MS determination. The results are shown in Table 5.
表5 在肝微粒体中的稳定性结果
Table 5 Stability results in liver microsomes
Table 5 Stability results in liver microsomes
试验例5 小鼠体内药代动力学Test Example 5 Pharmacokinetics in mice
ICR小鼠，适应3～5天，体重20～24g，随机分组，每组9只，按10mg/kg
剂量分别灌胃化合物。给化合物前禁食12h，给药后4h给食物，自由饮水。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.
灌胃给药后，15min、30min、1h、2h、3h、4h、6h、8h、10h、24h等时间点取血样。每只小鼠采集3～4个时间点，每个时间点3只小鼠，每只取血约0.1ml，EDTA-K2抗凝，30min内4℃、4000rpm离心10min分离血浆。20μl待测血浆样品或标曲样品，加入含内标的乙腈溶液，经蛋白沉淀得到上清液，稀释后用于LC/MS/MS测定。采用非房室模型拟合。结果见表6。Blood samples were taken at 15min, 30min, 1h, 2h, 3h, 4h, 6h, 8h, 10h, 24h after intragastric administration. 3 to 4 time points were collected from each mouse, 3 mice at each time point, about 0.1 ml of blood was collected from each mouse, anticoagulated with EDTA-K2, and the plasma was separated by centrifugation at 4°C and 4000 rpm for 10 min within 30 min. Add 20 μl of the plasma sample or standard song sample to be tested, add the acetonitrile solution containing the internal standard, obtain the supernatant through protein precipitation, and use it for LC/MS/MS determination after dilution. A non-compartmental model was fitted. The results are shown in Table 6.
表6 化合物小鼠药代参数
Table 6 Pharmacokinetic parameters of compounds in mice
Table 6 Pharmacokinetic parameters of compounds in mice
试验例6 体内药效评价(TMD-8人弥漫大B淋巴瘤细胞皮下移植瘤模型中的药效学评价)Test Example 6 In vivo drug efficacy evaluation (pharmacodynamic evaluation in TMD-8 human diffuse large B lymphoma cell subcutaneous xenograft model)
将约1×107个TMD-8细胞接种于SPF级雌性NOD-SCID小鼠右侧腋窝皮下。肿瘤平均体积达200mm3左右时，将动物分以下几组，模型对照组(溶媒对照)、阳性对照组(20mpk、40mpk)、化合物1组(20mpk、40mpk)、化合物2组(20mpk、40mpk)，每组8只。About 1× 107 TMD-8 cells were inoculated subcutaneously in the right axilla of SPF female NOD-SCID mice. When the average volume of the tumor reaches about 200mm3, divide the animals into the following groups, model control group (vehicle control), positive control group (20mpk, 40mpk), compound 1 group (20mpk, 40mpk), compound 2 group (20mpk, 40mpk) , 8 in each group.
分组当天(d0天)开始灌胃给药，给药体积为4ml/kg。每日灌胃给药两次连续给药，每周测2-3次瘤体积，同时称重；每日观察与记录小鼠一般表现。实验结束时取瘤并称重、拍照。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.
计算公式：Calculation formula:
肿瘤体积，TV(mm3)＝1/2×(a×b2)；a为长径，b为短径。Tumor volume, TV (mm 3 )=1/2×(a×b 2 ); a is the long axis, b is the short axis.
相对肿瘤体积，RTV＝TVt/TV0；TV0为d0天肿瘤体积，TVt为每一次
测量时的肿瘤体积。Relative tumor volume, RTV=TV t /TV 0 ; TV 0 is the tumor volume on day d0, TV t is each time Tumor volume at time of measurement.
相对肿瘤增殖率，T/C(％)＝TRTV/CRTV×100％，TRTV：治疗组RTV；CRTV：对照组RTV。Relative tumor proliferation rate, T/C (%)=T RTV /C RTV ×100%, T RTV : RTV of the treatment group; C RTV : RTV of the control group.
肿瘤抑制率，TGI％＝(1-治疗组瘤重量/对照组瘤重量)×对照组瘤重量。Tumor inhibition rate, TGI%=(1-tumor weight of treatment group/tumor weight of control group)×tumor weight of control group.
试验结果见表7。The test results are shown in Table 7.
表7 化合物对TMD-8人弥漫大B淋巴瘤细胞皮下移植瘤的影响(d9)
Table 7 Effects of compounds on subcutaneous transplantation of TMD-8 human diffuse large B lymphoma cells (d9)
Table 7 Effects of compounds on subcutaneous transplantation of TMD-8 human diffuse large B lymphoma cells (d9)
注：elimusertib为拜耳公司处于临床试验阶段的ATR抑制剂，又名：BAY1895344。Note: elimusertib is an ATR inhibitor in clinical trials by Bayer, also known as: BAY1895344.
本领域的技术人员容易理解，以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
It is easy for those skilled in the art to understand that the above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements and improvements made within the spirit and principles of the present invention, All should be included within the protection scope of the present invention.
Claims (10)
- 一种萘啶衍生物，其特征在于，为具有通式(I)的化合物、其异构体、和/或可药用盐：
A naphthyridine derivative is characterized in that it is a compound of general formula (I), its isomer, and/or a pharmaceutically acceptable salt:
其中，in,X为N或-CH-；X is N or -CH-;Y为N或-CH-；Y is N or -CH-;R1独立地选自氢、卤素、或甲基；R is independently selected from hydrogen, halogen, or methyl;R2选自取代的杂环基、或-NR3R3；R 2 is selected from substituted heterocyclic groups, or -NR 3 R 3 ;R3选自氢、卤代烷基、或烷基。R 3 is selected from hydrogen, haloalkyl, or alkyl. - 如权利要求1所述的萘啶衍生物，其特征在于，所述萘啶类化合物具有以下分子式：
The naphthyridine derivative as claimed in claim 1, wherein the naphthyridine compound has the following molecular formula:
或其异构体或可药用盐。or an isomer or a pharmaceutically acceptable salt thereof. - 如权利要求1或2所述的萘啶衍生物，其特征在于，所述具有通式(I)的化合物的异构体，包括具有通式(I)化合物的顺反异构体、对映异构体、非对映异构体、互变异构体、及其外消旋体；所述对映异构体，包括(-)-和(+)-对映体、(R)-和(S)-对映体、(D)-异构体、(L)-异构体；烷基等取代基中可存在另外的不对称碳原子；所述互变异构体，包括吡唑部分作为杂芳 基的任意如权利要求1或2所述的萘啶衍生物、1H互变异构体、2H互变异构体以及1H互变异构体和2H互变异构体的组合。Naphthyridine derivatives as claimed in claim 1 or 2, characterized in that, the isomers of the compound of general formula (I) include cis-trans isomers, enantiomers of the compound of general formula (I) Isomers, diastereomers, tautomers, and racemates thereof; said enantiomers, including (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, (D)-isomers, (L)-isomers; additional asymmetric carbon atoms may be present in substituents such as alkyl groups; said tautomers, including pyridine azole moiety as heteroaryl Any of the naphthyridine derivatives, 1H tautomers, 2H tautomers and combinations of 1H tautomers and 2H tautomers as claimed in claim 1 or 2.
- 一种药物组合物，其特征在于，其活性成分包括如权利要求1至3任意一项所述的萘啶类化合物及其可药用的盐中的一种或多种的组合，还包括可药用载体或稀释剂。A pharmaceutical composition, characterized in that its active ingredient comprises one or more combinations of the naphthyridine compounds and pharmaceutically acceptable salts thereof as claimed in any one of claims 1 to 3, and also includes Pharmaceutical carrier or diluent.
- 一种如权利要求1至3任意一项所述的萘啶衍生物在制备ATR激酶抑制剂中的应用；优选应用于制备抗ATR激酶介导的相关疾病的药物；所述ATR激酶介导的相关疾病为抑制ATR激酶有助于该疾病的病状和/或症候的疾病。Application of a naphthyridine derivative as described in any one of claims 1 to 3 in the preparation of ATR kinase inhibitors; preferably used in the preparation of medicines for the related diseases mediated by anti-ATR kinases; said ATR kinases mediated A relevant disease is one in which inhibition of ATR kinase contributes to the condition and/or symptoms of the disease.
- 如权利要求5所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其特征在于，应用于制备治疗过度增殖性疾病的药物；所述过度增殖性疾病，包括牛皮癣、瘢痕瘤、影响皮肤的其它增生、或良性***增生。The application of naphthyridine derivatives as claimed in claim 5 in the preparation of ATR kinase inhibitors is characterized in that it is applied to the preparation of medicines for the treatment of hyperproliferative diseases; said hyperproliferative diseases include psoriasis, keloids, Other growths of the skin, or benign prostatic hyperplasia.
- 如权利要求5所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其特征在于，应用于制备治疗实体瘤的药物；所述实体瘤，包括乳腺、呼吸道、脑、生殖器官、消化道、泌尿道、眼睛、肝、皮肤、头颈、甲状腺、甲状旁腺的肿瘤以及它们的远端转移，淋巴瘤、或者肉瘤。The use of naphthyridine derivatives as claimed in claim 5 in the preparation of ATR kinase inhibitors is characterized in that it is applied to the preparation of drugs for the treatment of solid tumors; said solid tumors include breast, respiratory tract, brain, reproductive organs, digestive Tumors of the tract, urinary tract, eyes, liver, skin, head and neck, thyroid, parathyroid glands and their distant metastases, lymphoma, or sarcoma.
- 如权利要求5所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其特征在于，应用于制备治疗白血病的药物。The use of the naphthyridine derivatives as claimed in claim 5 in the preparation of ATR kinase inhibitors is characterized in that it is used in the preparation of medicaments for treating leukemia.
- 如权利要求5至8任意一项所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其特征在于，所述药物，还包括药学上可接受的辅料；所述药学上可接受的辅料，包括赋形剂、溶剂、分散剂、稳定剂、乳化剂、粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和/或矫味剂。The application of the naphthyridine derivatives as described in any one of claims 5 to 8 in the preparation of ATR kinase inhibitors, characterized in that the medicine also includes pharmaceutically acceptable adjuvants; the pharmaceutically acceptable Excipients, including excipients, solvents, dispersants, stabilizers, emulsifiers, binders, diluents, disintegrants, lubricants, glidants, sweeteners and/or flavoring agents.
- 如权利要求9所述的所述的萘啶衍生物在制备ATR激酶抑制剂中的应用，其特征在于，所述药物的典型途径包括但不限于口服、直肠、局部、吸入、肠 胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。 The use of the naphthyridine derivatives according to claim 9 in the preparation of ATR kinase inhibitors, wherein the typical route of the drug includes but not limited to oral, rectal, topical, inhalation, intestinal Parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106795156A (en) * | 2014-08-04 | 2017-05-31 | 拜耳制药股份公司 | 2 (base of morpholine 4) 1,7 naphthyridines |
| WO2018153970A1 (en) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Solid forms of 2-[(3r)-3-methylmorpholin-4-yl]-4-(1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphthyridine |
| WO2018153973A1 (en) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors with parp inhibitors |
| CN108699057A (en) * | 2016-01-14 | 2018-10-23 | 拜耳医药股份公司 | 2- (morpholine -4- bases) -1,7- naphthyridines of 5- substitutions |
| WO2019025440A1 (en) * | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and pd-1/pd-l1 inhibitors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106795156A (en) * | 2014-08-04 | 2017-05-31 | 拜耳制药股份公司 | 2 (base of morpholine 4) 1,7 naphthyridines |
| CN108699057A (en) * | 2016-01-14 | 2018-10-23 | 拜耳医药股份公司 | 2- (morpholine -4- bases) -1,7- naphthyridines of 5- substitutions |
| WO2018153970A1 (en) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Solid forms of 2-[(3r)-3-methylmorpholin-4-yl]-4-(1-methyl-1h-pyrazol-5-yl)-8-(1h-pyrazol-5-yl)-1,7-naphthyridine |
| WO2018153973A1 (en) * | 2017-02-24 | 2018-08-30 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors with parp inhibitors |
| WO2019025440A1 (en) * | 2017-08-04 | 2019-02-07 | Bayer Pharma Aktiengesellschaft | Combination of atr kinase inhibitors and pd-1/pd-l1 inhibitors |
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