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CN116731011A - Naphthyridine derivative and application thereof - Google Patents

Naphthyridine derivative and application thereof Download PDF

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CN116731011A
CN116731011A CN202210193164.5A CN202210193164A CN116731011A CN 116731011 A CN116731011 A CN 116731011A CN 202210193164 A CN202210193164 A CN 202210193164A CN 116731011 A CN116731011 A CN 116731011A
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preparation
atr kinase
naphthyridine
compound
pharmaceutically acceptable
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张玉慧
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Wuhan Zhongcheng Kangjian Biomedical Technology Co ltd
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Wuhan Zhongcheng Kangjian Biomedical Technology Co ltd
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Priority to PCT/CN2023/078898 priority patent/WO2023165493A1/en
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    • 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

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Abstract

The application discloses a naphthyridine derivative and application thereof, wherein the naphthyridine derivative can well inhibit ATR kinase activity, can be applied to preparation of ATR kinase inhibitors, and is especially applied to preparation of medicines for resisting ATR kinase-mediated related diseases; the ATR kinase mediated related diseases are diseases in which inhibiting ATR kinase contributes to the symptoms and/or signs of the diseases, and are particularly applied to the preparation of medicaments for treating hyperproliferative diseases, solid tumors or leukemia.

Description

Naphthyridine derivative and application thereof
Technical Field
The application belongs to the field of pharmaceutical chemistry, and in particular relates to a naphthyridine derivative and application thereof.
Background
Genome stability maintenance is the basis of all vital activities, however, the broad DNA damage and replication pressures created by a variety of exogenous and endogenous factors constitute the major sources of genome instability. ATM and ATR (ataxia telangiectasia and Rad3-related protein) kinases initiate DNA damage response responses of cells to DNA double strand break damage and DNA single strand break damage or unstable replication crosses, respectively.
In contrast to normal cells, a fundamental feature of tumor cells is genomic instability and susceptibility to mutation, which are often accompanied by a large number of functional deletions for 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 genomic stabilization and tumor development, development and treatment, indeed, disruption of ATR function such as gene deletion has been shown to promote cancer cell death both in the presence and absence of DNA damaging agents; whereas ATR inhibitors have been the focus of research as single components and as powerful sensitizers for radiation therapy or genotoxic chemotherapy, finding a potent and selective ATR inhibitor has great significance for the treatment of cancer.
Disclosure of Invention
In view of the above-mentioned drawbacks or improvements of the prior art, the present application provides a naphthyridine derivative and its use, which aims to find out the inhibition of ATR kinase by the naphthyridine derivative, and can be used as an inhibitor of ATR kinase, and applied to the preparation of drugs against ATR kinase mediated related diseases.
To achieve the above object, according to one aspect of the present application, there is provided a naphthyridine derivative which is a compound having the general formula (I):
wherein,,
x is N or-CH-;
R 1 independently selected from hydrogen, halogen, or methyl;
R 2 selected from substituted heterocyclyl, or-NR 3 R 3 ；
R 3 Selected from hydrogen, haloalkyl, or alkyl.
Preferably, the naphthyridine derivative has the formula:
or an isomer or pharmaceutically acceptable salt thereof.
Preferably, the naphthyridine derivative, isomers of the compound having the general formula (I), including cis-trans isomers, enantiomers, diastereomers, tautomers, and racemates thereof, of the compound having the general formula (I); the enantiomers include (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, (D) -isomers, (L) -isomers; additional asymmetric carbon atoms may be present in substituents such as alkyl groups; the tautomers, including any of the compounds of the application having a pyrazole moiety as a heteroaryl group, may also be in the form of a 1H tautomer or a 2H tautomer, or any combination of the two, wherein the 1H tautomer or the 2H tautomer is represented by the formula:
according to another aspect of the present application there is provided a pharmaceutical composition comprising as active ingredient a combination of one or more of the naphthyridines compounds of the application and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent.
According to a further aspect of the present application there is also provided the use of a naphthyridine derivative as described herein in the preparation of an ATR kinase inhibitor; preferably for the preparation of a medicament against ATR kinase mediated related diseases; the ATR kinase mediated related disease is a disease in which inhibition of ATR kinase contributes to the condition and/or symptoms of the disease.
Preferably, the naphthyridine derivative is used for preparing ATR kinase, and is applied to preparing medicines for treating hyperproliferative diseases; such hyperproliferative diseases include psoriasis, keloids, other hyperplasia affecting the skin, or benign prostatic hyperplasia.
Preferably, the naphthyridine derivative is used for preparing ATR kinase, and is applied to preparing medicines for treating solid tumors; the solid tumor comprises tumor of breast, respiratory tract, brain, genital organ, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid gland and distal metastasis thereof, lymphoma, or sarcoma.
Preferably, the naphthyridine derivative is used for preparing ATR kinase, and is applied to preparing medicines for treating leukemia.
Preferably, the naphthyridine derivative is applied to the preparation of ATR kinase, and the medicine also comprises pharmaceutically acceptable auxiliary materials; the pharmaceutically acceptable auxiliary materials comprise excipient, solvent, dispersing agent, stabilizer, emulsifier, binder, diluent, disintegrating agent, lubricant, glidant, sweetener and/or flavoring agent.
Preferably, the naphthyridine derivatives are used in the preparation of ATR kinase, typical routes of the drug including, but not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
In general, the above technical solutions conceived by the present application, compared with the prior art, enable the following beneficial effects to be obtained:
the naphthyridine derivative provided by the application can effectively inhibit ATR kinase activity, and can be applied to the preparation of ATR kinase inhibitors, in particular to the preparation of medicines for resisting ATR kinase-mediated related diseases; the compound can also obviously inhibit the active proliferation of cells, and can be applied to the preparation of medicaments for treating hyperproliferative diseases, solid tumors or leukemia.
Detailed Description
The present application will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present application more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application. In addition, the technical features of the embodiments of the present application described below may be combined with each other as long as they do not collide with each other.
The following terms used in the present application have the following meanings unless otherwise indicated. A particular term, unless otherwise defined, shall not be construed as being ambiguous or otherwise unclear, but shall be construed in accordance with the ordinary meaning in the art. When trade names are presented herein, it is intended to refer to their corresponding commercial products or active ingredients thereof.
The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The term "alkyl" refers to a radical having 1 to 7 carbon atoms (C 1-7 Alkyl) or 1 to 4 carbon atoms (C 1-4 Alkyl) branched or straight chain hydrocarbyl groups. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2-dimethylpentyl, 2, 3-dimethylpentyl, n-heptyl, and the like. Substituted alkyl is alkyl containing one or more substituents such as 1, 2 or 3 substituents selected from halogen, hydroxy or alkoxy. Halogen substituted alkyl and halogen substituted alkoxy groups may be straight or branched and include methoxy, ethoxy, difluoromethyl, trifluoromethyl, pentafluoroethyl, difluoromethoxy, trifluoromethoxy and the like.
The term "haloalkyl" refers to a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono-, di-and trifluoromethyl.
The term "heterocyclyl" refers to a non-aromatic ring that is fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic) and may exist as a single ring, bridged ring, or spiro ring. Non-limiting examples of heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, pyrrolidinyl, N-methylpyrrolidinyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyrazolidinyl, 4H-pyranyl, morpholinyl, thiomorpholinyl, tetrahydrothiophenyl, and the like.
The naphthyridine derivative provided by the application is a compound with a general formula (I), an isomer and/or a pharmaceutically acceptable salt thereof:
wherein,,
x is N or-CH-;
R 1 independently selected from hydrogen; halogen or methyl;
R 2 selected from substituted heterocyclyl; or-NR 3 R 3 ；
R 3 Selected from hydrogen; a haloalkyl group; or alkyl;
preferably, the naphthyridine derivative has the formula:
or an isomer or pharmaceutically acceptable salt thereof.
Such isomers, including cis-trans isomers, enantiomers, diastereomers, and racemates thereof, of the compounds having the general formula (I); the enantiomers include (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, (D) -isomers, (L) -isomers; additional asymmetric carbon atoms may be present in substituents such as alkyl groups;
the naphthyridine derivatives also include isotopically-labeled naphthyridine derivatives which are identical to those recited in the present application, but in which one or more atoms are replaced by an atom having an atomic weight or mass number different from the atomic weight or mass number usually found in nature. Examples of isotopes that can be bound to naphthyridine derivatives include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as respectively 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, and the like.
Certain isotopically labeled naphthyridine derivatives (e.g. with 3 H is H 14 C-labeled) can be used in compound and/or substrate tissue distribution analysis. Tritiation (i.e 3 H) And carbon-14 (i.e 14 C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O、 13 N、 11 C and C 18 F can be used in Positron Emission Tomography (PET) studies to determine substrate occupancy. Isotopically labeled naphthyridine derivatives may generally be prepared by the following procedures similar to those disclosed in the schemes and/or examples below, by substituting an isotopically labeled reagent for an non-isotopically labeled reagent.
In addition, the use of heavier isotopes (such as deuterium (i.e. 2 H) Substitution may provide certain therapeutic advantages resulting from higher metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements), and thus may be preferred in certain circumstances, wherein deuterium substitution may be partial or complete, partial deuterium substitution meaning that at least one hydrogen is substituted with at least one deuterium, all such forms of compounds are included within the scope of the present application.
The naphthyridine derivatives may also be asymmetric, e.g. have one or more stereoisomers. Unless otherwise indicated, all stereoisomers are included within the scope of the application, such as enantiomers and diastereomers. The compounds of the application containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms can be resolved from the racemic mixture or synthesized by using chiral starting materials or chiral reagents.
The compounds of the present application may exist in tautomeric forms. For example, any of the compounds of the application comprising a pyrazole moiety as heteroaryl group, for example, may exist in the form of a 1H tautomer or a 2H tautomer or any number of mixtures of two tautomers, namely:
thus, the compounds may exist as a mixture of isomers or, preferably, as pure isomers.
The active ingredient of the pharmaceutical composition provided by the application comprises one or more of the naphthyridine derivatives and pharmaceutically acceptable salts thereof, and preferably also comprises pharmaceutically acceptable auxiliary materials, wherein the pharmaceutically acceptable auxiliary materials comprise excipients, solvents, dispersing agents, stabilizers, emulsifying agents, adhesives, diluents, disintegrating agents, lubricants, glidants, sweeteners and/or flavoring agents;
the excipient is formulated into solid, semi-solid, liquid or gaseous preparation, such as tablet, pill, capsule, powder, granule, unguent, emulsion, suspension, suppository, injection, inhalant, gel, microsphere, aerosol, 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 may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
The pharmaceutical compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
The therapeutic dose of the pharmaceutical composition may be determined, for example, according to the following: the specific use of the treatment, the manner in which the compound is administered, the health and condition of the patient, and the discretion of the prescribing physician. The ratio or concentration of the naphthyridine derivative in the pharmaceutical composition may be variable, depending on a variety of factors including the dosage, chemical characteristics (e.g., hydrophobicity) and route of administration. The naphthyridine derivatives may be provided, for example, by a physiologically buffered aqueous solution containing about 0.1 to 10% w/v of the compound, for parenteral administration. Some typical dosages range from about 1 μg/kg to about 1g/kg body weight/day. In certain embodiments, the dosage ranges from about 0.01mg/kg to about 100mg/kg body weight/day. Dosages will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health of the particular patient, the relative biological efficacy of the compound selected, the excipient formulation and its route of administration. The effective dose can be obtained by extrapolation of the dose-response curve derived from in vitro or animal model test systems.
The application also provides application of naphthyridine derivatives in preparing ATR kinase inhibitors, wherein the naphthyridine derivatives comprise the compounds and prodrug derivatives thereof, derivatives thereof and/or pharmaceutically acceptable salts thereof.
The application of the naphthyridine derivative in preparing an ATR kinase inhibitor, preferably in preparing medicines for resisting ATR kinase-mediated related diseases; the ATR kinase mediated related disease is a disease in which inhibition of ATR kinase contributes to the condition and/or symptoms of the disease.
Further; the ATR kinase mediated related diseases, including hyperproliferative diseases, solid tumors and leukemias; such hyperproliferative diseases, including 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, parathyroid, and distal metastases, lymphomas and sarcomas thereof.
The compounds of the present application may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present application.
The chemical reactions of the embodiments of the present application are accomplished in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds according to the application, it is sometimes necessary for the person skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the embodiments already known.
In some embodiments, the compounds of the present application may be prepared by one skilled in the art of organic synthesis with reference to the following routes:
scheme one:
x and R are as defined above.
The application adopts the following abbreviations:
DMSO represents dimethylsulfoxide; NMP represents N-methylpyrrolidone; DMF represents N, N-dimethylformamide; DIPEA stands for diisopropylethylamine; 10% Pd/C represents a 10% palladium on carbon content.
The following are examples:
example 1 Compound 1
(1) Preparation of Compounds 1-c
To a 100mL reactor were added (R) -3-hydroxypyrrolidine (1 g), 5-bromo-2-fluoro-4-methylpyrimidine (1.1 g), potassium carbonate (2.38 g) and N-methylpyrrolidone (20 mL). Heating to 135 deg.c and reaction for 4 hr. The reaction solution was diluted with 100mL of ethyl acetate, washed 2 times with 100mL of water, 2 times with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 1-c (1.4 g). ESI-MS: m/z=258.02 [ m+h ] +.
(2) Preparation of Compounds 1-d
To a 100mL reactor was added 1-c (1.0 g), pinacol diboronate (1.18 g), potassium acetate (580 mg) and 1, 4-dioxane (12 mL), stirred, N2 protected, and 1,1' -bis (diphenylphosphino) ferrocene palladium dichloride (135 mg) added and the temperature was raised to 100℃for reaction for 2 hours. The reaction solution was diluted with a mixed solution of 100mL of ethyl acetate and 100mL of methylene chloride, washed with 50mL of water 2 times, 50mL of saturated brine 3 times, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to dryness. Then, 20mL of n-hexane was added and stirred for 20 minutes, suction filtration was performed, 40mL of n-hexane was added to the filter cake and stirred for 15 minutes, filtration was performed, and the filtrate was concentrated to dryness to obtain compound 1-d (1.0 g).
(3) Preparation of Compounds 1-f
To a 100mL reactor were added 1-d (1.0 g), 1-e (1.44 g) (see chinese patent CN106795156B, page 83, preparation method of intermediate 10), potassium carbonate (567 mg), 1' -bis-diphenylphosphino ferrocene palladium dichloride (125 mg), acetonitrile (20 mL) and purified water (10 mL), and the mixture was stirred and heated to 130 ℃ to react for 20 minutes. The reaction solution was diluted with 150mL of methylene chloride, washed once with 100mL of water, washed 4 times with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated to dryness to give compound 1-f (984 mg).
(4) Preparation of Compound 1
To a 100mL reactor were added 1-f (0.5 mg) and 13mL of a methanol solution of hydrogen chloride, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then 20mL of acetonitrile was added thereto, concentrated to dryness under reduced pressure, then 20mL of methylene chloride was added thereto, concentrated to dryness under reduced pressure, and Compound 1 (50 mg) was obtained by preparing a liquid phase. ESI-MS: m/z=473.44 [ m+h ] +.
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)。
Example 2 Compound 2
(1) Preparation of Compound 2-c
To a 100mL reactor were added 2-a (1.0 g), 5-bromo-2-fluoro-4-methylpyrimidine (2.0 g), potassium carbonate (1.37 g), and N-methylpyrrolidone (20 mL). Heating to 135 deg.c and reaction for 4 hr. The reaction solution was diluted with 100mL of ethyl acetate, washed 2 times with 100mL of water, 2 times with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give compound 2-c (2.7 g). ESI-MS: m/z=270.02 [ m+h ] +.
(2) Preparation of Compound 2-d
To a 100mL reactor was added 2-c (1.0 g), pinacol biborate (1.1 g), potassium acetate (545 mg) and 1, 4-dioxane (10 mL), stirred, N2 protected, and 1,1' -bis-diphenylphosphino ferrocene palladium dichloride (135 mg) was further added, and the temperature was raised to 100℃for reaction for 2 hours. The reaction solution was diluted with a mixed solution of 100mL of ethyl acetate and 100mL of methylene chloride, washed with 50mL of water 2 times, 50mL of saturated brine 3 times, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated to dryness. Then, 20mL of n-hexane was added and stirred for 20 minutes, suction filtration was performed, 40mL of n-hexane was added to the filter cake, stirring was performed for 15 minutes, filtration was performed, and the filtrate was concentrated to dryness to obtain compound 2-d (996 mg).
(3) Preparation of Compound 2-f
To a 100mL reactor were added 2-d (0.5 g), 1-e (0.7 g), potassium carbonate (650 mg), 1' -bis-diphenylphosphino ferrocene palladium dichloride (50 mg), acetonitrile (12 mL) and purified water (46 mL), and the mixture was stirred and heated to 130℃for reaction for 20 minutes. The reaction solution was diluted with 150mL of methylene chloride, washed once with 100mL of water, washed 4 times with 100mL of saturated brine, dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate was concentrated to dryness to give compound 2-f (780 mg).
(4) Preparation of Compound 2
To a 100mL reactor were added 2-f (500 mg) and 12mL of a methanol solution of hydrogen chloride, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then 20mL of acetonitrile was added thereto, concentrated to dryness under reduced pressure, then 20mL of methylene chloride was added thereto, concentrated to dryness under reduced pressure, and Compound 2 (70 mg) was obtained by preparing a liquid phase. ESI-MS: m/z=485.40 [ m+h ] +.
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)。
Compound 3, compound 4 and compound 5 were prepared according to scheme 1 and analogously to example 1, example 2, as shown in table 1.
TABLE 1 Compounds 3-5
Experiment 1: ATR kinase inhibition Activity assay
ATR/ATPIP kinase solution (50 ng/. Mu.l) was added to the assay wells at 5.8. Mu.l per well, 0.2ul of compound at different concentrations was added, 2 wells were multiplexed, and a control was set. After incubation for 60min at room temperature, ATP (5. Mu.M) was mixed with p53 substrate (50 nM) at 1:1 and added to the assay wells at 4. Mu.l per well; after 60min at room temperature, EDTA was stopped, and 5. Mu.l of detection antibodies MabAnti-phospho p53 and MabAnti GST-d2 (perkinelmer Co.) were added and incubated at room temperature for 60min; plate is read to enzyme-labeling appearanceDetection (excitation 620nm, emission 665 nm), calculation of IC using four-parameter fitting 50 . The results are shown in Table 2.
TABLE 2 ATR kinase inhibitory Activity (HTRF method)
Compounds of formula (I) ATRIC 50 (nM)
Compound 1 201
Compound 2 333
Compound 3 40
Compound 4 152
Compound 5 69
As can be seen from Table 2, the compounds provided by the present application have an inhibitory effect on ATR kinase activity, and IC thereof 50 The value can reach 40nM, and the experimental result shows that the compound provided by the application has a strong inhibition effect on ATR kinase, and can be used for preparing ATR kinase inhibitors.
Experiment 3 determination of TMD-8 cell proliferation inhibitory Activity
Collecting TMD-8 cells in good growth state, collecting into centrifuge tube, and adjusting cell density to about 5×10 4 Inoculating 100 μl/well into 96-well plate, culturing in CO2 cell incubator overnightCompound of different concentration was then added, 2 duplicate wells were set up, and normal controls were set up. The culture was continued in a CO2 incubator for 72 hours, and a detection reagent CCK-8 (product of Tonic chemical Co.) was added at 10. Mu.l/well, incubated in the cell incubator for about 4 hours, and the absorbance was measured at 450nm with an ELISA reader, analyzed for four parameters, fitted with a quantitative response curve, and IC was calculated 50 . The results are shown in Table 3.
TABLE 3 cell proliferation Activity (TMD 8)
Compounds of formula (I) IC 50 (nM)
Compound 1 23
Compound 2 39
Compound 3 26
Compound 4 35
Compound 5 34
As shown in Table 3, the compound provided by the application can inhibit proliferation of human diffuse large B lymphoma cells (TMD 8), the IC50 value is lower than 40nM and even can reach 23nM, and experimental results show that the compound provided by the application has a remarkable inhibition effect on proliferation of TMD8 cells, and has a good anti-tumor patent medicine prospect.
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the application and is not intended to limit the application, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the application are intended to be included within the scope of the application.

Claims (10)

1. Naphthyridine derivatives characterized by being compounds having the general formula (I):
wherein,,
x is N or-CH-;
R 1 independently selected from hydrogen, halogen, or methyl;
R 2 selected from substituted heterocyclyl, or-NR 3 R 3 ；
R 3 Selected from hydrogen, haloalkyl, or alkyl.
2. The naphthyridine derivative according to claim 1, wherein the naphthyridine compound has the formula:
or an isomer or pharmaceutically acceptable salt thereof.
3. The naphthyridine derivative according to claim 1 or 2, wherein the isomer of the compound having the general formula (I) includes cis-trans isomers, enantiomers, diastereomers, tautomers, and racemates thereof, of the compound having the general formula (I); the enantiomers include (-) -and (+) -enantiomers, (R) -and (S) -enantiomers, (D) -isomers, (L) -isomers; additional asymmetric carbon atoms may be present in substituents such as alkyl groups.
4. A pharmaceutical composition comprising, as active principle, a combination of one or more of naphthyridines according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier or diluent.
5. Use of a naphthyridine derivative according to any one of claims 1 to 3 for the preparation of an ATR kinase inhibitor; preferably for the preparation of a medicament against ATR kinase mediated related diseases; the ATR kinase mediated related disease is a disease in which inhibition of ATR kinase contributes to the condition and/or symptoms of the disease.
6. Use of naphthyridine derivatives according to claim 5 for the preparation of ATR kinase, for the preparation of a medicament for the treatment of hyperproliferative diseases; such hyperproliferative diseases include psoriasis, keloids, other hyperplasia affecting the skin, or benign prostatic hyperplasia.
7. Use of naphthyridine derivatives according to claim 5 for the preparation of ATR kinase, for the preparation of a medicament for the treatment of solid tumors; the solid tumor comprises tumor of breast, respiratory tract, brain, genital organ, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid gland and distal metastasis thereof, lymphoma, or sarcoma.
8. Use of naphthyridine derivatives according to claim 5 for the preparation of ATR kinase, for the preparation of a medicament for the treatment of leukemia.
9. Use of naphthyridine derivatives according to any one of claims 5 to 8, for the preparation of ATR kinase, wherein the medicament further comprises pharmaceutically acceptable excipients; the pharmaceutically acceptable auxiliary materials comprise excipient, solvent, dispersing agent, stabilizer, emulsifier, binder, diluent, disintegrating agent, lubricant, glidant, sweetener and/or flavoring agent.
10. Use of naphthyridine derivatives as claimed in claim 9, in the preparation of ATR kinases, wherein typical routes of administration of the drug include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
CN202210193164.5A 2022-03-01 2022-03-01 Naphthyridine derivative and application thereof Pending CN116731011A (en)

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TWI656121B (en) * 2014-08-04 2019-04-11 德商拜耳製藥公司 2-(morpholin-4-yl)-1,7-naphthyridine
EP3402795B1 (en) * 2016-01-14 2019-10-30 Bayer Pharma Aktiengesellschaft 5-substituted 2-(morpholin-4-yl)-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
US11660301B2 (en) * 2017-02-24 2023-05-30 Bayer Pharma Aktiengesellschaft Combination of ATR kinase inhibitors with PARP inhibitors
EP3661560A1 (en) * 2017-08-04 2020-06-10 Bayer Pharma Aktiengesellschaft Combination of atr kinase inhibitors and pd-1/pd-l1 inhibitors

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