WO2023054759A1 - 2-aminoquinazoline derivative and anti-viral composition comprising same - Google Patents
2-aminoquinazoline derivative and anti-viral composition comprising same Download PDFInfo
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- WO2023054759A1 WO2023054759A1 PCT/KR2021/013418 KR2021013418W WO2023054759A1 WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1 KR 2021013418 W KR2021013418 W KR 2021013418W WO 2023054759 A1 WO2023054759 A1 WO 2023054759A1
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- 230000000840 anti-viral effect Effects 0.000 title claims abstract description 11
- 239000000203 mixture Substances 0.000 title claims description 21
- CZAAKPFIWJXPQT-UHFFFAOYSA-N quinazolin-2-amine Chemical class C1=CC=CC2=NC(N)=NC=C21 CZAAKPFIWJXPQT-UHFFFAOYSA-N 0.000 title abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
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- -1 tert-butanoyloxymethoxy group Chemical group 0.000 claims description 159
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052736 halogen Inorganic materials 0.000 claims description 16
- 150000002367 halogens Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 125000003277 amino group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 11
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- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 8
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000012744 reinforcing agent Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 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
- 230000035945 sensitivity Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 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
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/11—Esters of phosphoric acids with hydroxyalkyl compounds without further substituents on alkyl
Definitions
- the present invention relates to a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof and an antiviral pharmaceutical composition containing the same as an active ingredient.
- Coronavirus Infectious Disease-19 is a respiratory syndrome caused by SARS-CoV-2 infection, starting in Wuhan City, Hubei Province, China in December 2019, and spreading rapidly worldwide, The rapid increase in the number of deaths is causing a great social problem.
- the SARS-CoV-2 pathogen is an RNA virus belonging to the Coronaviridae, which has been associated with SARS-CoV, the pathogen of Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2015. It is very closely related to the MERS coronavirus (MERS-CoV), the pathogen of SARS-CoV-2 and SARS-CoV bind to the ACE2 (Angiotensin Converting Enzyme2) receptor, and MERS-CoV utilizes DPP4 (Dipeptidyl Peptidase4; CD26) as a receptor.
- SARS Severe Acute Respiratory Syndrome
- MERS Middle East Respiratory Syndrome
- SARS-CoV-2 and SARS-CoV spike proteins have a very similar shape (Walls et al., 2020, Structure, Function and antigenicity of the SARS-CoV-2 spike SARS -It was found that CoV-2 also attaches strongly to the surface of host cells through the ACE2 receptor, and the molecular structure of the spike protein and ACE2 complex was recently revealed (Zhou et al., 2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature.;Yan et al., 2020, Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.Science, DOI: 10.1126/science.abb2762).
- SARS-CoV-2 transmits and spreads more rapidly than SARS-CoV, which is why SARS-CoV-2 binds more strongly to ACE2 in host cells and makes parts of the spike protein more easily cut by protein scissors. It is presumed that this is because it is deformed.
- the present inventors have completed the present invention by finding that 2-aminoquinazoline derivatives introduced with various substituents are compounds having an inhibitory effect on COVID-19.
- An object of the present invention is to provide a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- an object of the present invention is to provide an antiviral pharmaceutical composition comprising a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- an object of the present invention is to provide a health food composition for preventing and improving viral infection, which includes a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- the present invention provides an antiviral pharmaceutical composition
- an antiviral pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the present invention provides a pharmaceutical composition for COVID-19 coronavirus antivirus.
- composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more known antiviral agents.
- the present invention relates to a compound according to Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
- composition containing a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the present invention has an excellent anti-proliferation activity against SARS-CoV-2 infected with Vero cell lines and It can be used as a virus treatment because of its low toxicity, and in particular, it can be used as a treatment for COVID-19 (Coronavirus Infectious Disease-19).
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- alkyl or “alkyl group” refers to an aliphatic hydrocarbon radical and includes both straight-chain and branched-chain hydrocarbon radicals.
- C 1 ⁇ C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like are all included.
- alkene or “alkenyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond
- alkyne or “alkynyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond.
- heterocycle or “heterocyclic group” includes one or more heteroatoms, includes at least one of a single ring and multiple rings, and includes heteroaliphatic and heteroaromatic rings, unless otherwise specified. It may also be formed by combining adjacent functional groups.
- aryl or “aryl group” refers to one or more hydrocarbon rings having a covalent pi electron system, and includes, for example, phenyl, naphthyl, biphenyl, and the like.
- halogen refers to elements belonging to group 17 of the periodic table, and may be specifically fluorine, chlorine, bromine, and iodine.
- alkoxy or “alkoxy group” means a radical in which the hydrogen atom of a hydroxy group is substituted with an alkyl, unless otherwise defined, and for example, C 1 to C 6 alkoxy is methoxy, ethoxy, propoxy, n- Butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like are all included.
- hydroxyl group means -OH.
- amino group means -NH 2 .
- benzyloxy group means a monovalent atomic group consisting of an oxy group and a benzyl group, that is, -O-CH 2 -C 6 H 5 .
- substitution means that one hydrogen atom is substituted, for example, when substituted with a hydroxyl group, -CH 3 is substituted with -CH 2 OH.
- the present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
- R 4 may be absent
- R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group,
- alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,
- R 1b is a C 1 ⁇ C 6 alkyl group; Or a substituted or unsubstituted C 6 ⁇ C 10 aryl group,
- R 1c is a hydroxyl group; C 1 ⁇ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;
- R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ⁇ C 6 alkyl group,
- n is an integer from 0 to 3;
- R 2 is hydrogen, a C 3 ⁇ C 6 cycloalkyl group; -(X) n -C 6 ⁇ C 10 An aryl group,
- R 1 and R 2 together may form a ring
- R 3a is a C 1 ⁇ C 6 alkanoyloxy group, o is 1 or 2;
- R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ⁇ C 6 Alkyl group; C 2 ⁇ C 6 Alkenyl group; A C 2 ⁇ C 6 alkynyl group; A C 1 ⁇ C 6 alkoxy group; C 1 ⁇ C 6 alkanoyloxy group; C 3 ⁇ C 6 Cycloalkyl group; C 6 ⁇ C 10 aryl group; A C 2 ⁇ C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,
- a is an integer from 0 to 4.
- R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ⁇ C 3 alkyl group;
- the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring.
- the present invention includes a compound in which Formula 1 is represented by Formula 2 below.
- R 1 , R 3 , R 4 , R 5 and a are the same as defined above,
- b is an integer from 0 to 5.
- the present invention includes a compound represented by any one of the following formulas 3 to 5 in the formula (1).
- R 1 , R 5 , R 6 , a and b are the same as defined above,
- R 7 is a C 1 ⁇ C 6 alkyl group; or a tert-butanoyloxymethoxy group.
- R 1a is a substituted or unsubstituted C 1 ⁇ C 6 alkyl group; or a substituted or unsubstituted C 2 ⁇ C 6 alkenyl group, where, when the C 1 ⁇ C 6 alkyl group is substituted, a C 1 ⁇ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,
- alkenyl group of C 2 ⁇ C 6 when substituted, it is substituted with a hydroxyl group, an amino group, a halogen or an acetoxy group.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
- the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
- the compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a substituent containing an asymmetric atom, in which case the compound of Formula 1 or a salt thereof is (R), (S), or racemic (RS) may exist as optical isomers. Therefore, unless otherwise indicated, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes all optical isomers such as (R), (S), or racemic (RS) forms.
- the compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt.
- Such salts include conventional acid addition salts, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxy acid.
- organic acids such as camphorsulfonic acid, capric acid, myristic acid, hypric acid or orotic acid.
- the salt is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethoxide, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, diethanol amines, triethanolamine, piperazine, morpholine, or salts derived from dicyclohexylamine.
- a pharmaceutically acceptable salt of the compound of Formula 1 can be prepared from the compound of Formula 1 by a conventional method.
- such salts can be prepared by reacting a compound of Formula 1 in free acid/base form with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or organic salt in a suitable solvent or various combinations of solvents.
- the present invention provides an antiviral pharmaceutical composition
- an antiviral pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
- the pharmaceutical composition may include a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent, and may be formulated into tablets, capsules, powders, granules, and suspensions according to conventional methods. It may be formulated into oral preparations such as emulsions or syrups or preparations for parenteral administration such as injections. The formulation may be formulated in a variety of forms, for example single dose or multiple dose dosage forms.
- a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent
- composition of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration.
- Compositions of the present invention are preferably administered orally.
- the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions.
- carriers such as lactose and corn starch and lubricants such as magnesium stearate may usually be added.
- lactose and/or dried corn starch may be used as diluents.
- the active ingredient may be combined with emulsifying and/or suspending agents.
- compositions according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4.
- a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.
- a pharmaceutical composition according to the present invention can be administered in a therapeutically effective amount. Therefore, the compound of formula 1 contained in the pharmaceutical composition; Or a pharmaceutically acceptable salt thereof may be administered to the patient in an effective amount of about 10 mg/kg to about 500 mg/kg per day. Of course, the dose may be changed according to the patient's age, body weight, sensitivity, symptoms or efficacy of the compound.
- the present invention also provides a therapeutically effective amount of the compound of Formula 1; Or a method for preventing or treating a virus, preferably a coronavirus, more preferably COVID-19, comprising administering a pharmaceutically acceptable salt thereof to a mammal, including a human.
- a virus preferably a coronavirus, more preferably COVID-19
- composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more antiviral agents.
- the present invention also relates to a compound of Formula 1 for the preparation of a drug for preventing or treating a virus; or a pharmaceutically acceptable salt thereof.
- the present invention relates to a treatment for coronavirus, particularly COVID-19, comprising a 2-aminoquinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. it's about
- the 2-Aminoquinazoline derivative of Chemical Formula 1 effectively inhibits SARS-CoV-2 in a drug efficacy test using Vero cells infected with SARS-CoV-2 and is expected to have a therapeutic effect on coronavirus due to its low cytotoxicity. It was confirmed that it can be used, and in particular, it was confirmed that it can be used as a treatment for COVID-19.
- the therapeutic agent or pharmaceutical composition for COVID-19 containing the compound of Formula 1 according to the present invention as an active ingredient is added to the compound of Formula 1 with a conventional non-toxic pharmaceutically acceptable carrier, reinforcing agent or excipient, etc. in the pharmaceutical field.
- Oral administration preparations such as tablets, capsules, troches, solutions, suspensions, etc. can be formulated in conventional preparations.
- a pharmaceutical composition may be provided by using the compound of Formula 1 according to the present invention as an active ingredient and further including other antiviral agents.
- it can be provided as a conventional preparation in the pharmaceutical field by adding the compound of Formula 1, other antiviral agents and pharmaceutically acceptable carriers to a COVID-19 treatment or pharmaceutical composition.
- the dosage of the compound of Formula 1 may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally 10 to 4,000 mg/day, and may be divided and administered once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
- the present invention is a compound of Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as shown in Reaction Scheme 1 below, but is not limited thereto.
- R 5 , R 6 , a and b have the same definition as above.
- Comp 1 (29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were placed in a 100 mL round bottom flask and heated at 150 °C for 2 hours. After the reaction was completed, the mixture was cooled at room temperature, 60 mL of water was added thereto, and the mixture was heated at 100° C. for 1 hour. Cooling the reactants precipitates a white solid. After filtering the white solid, it was washed with water and hexane and dried to obtain Comp 2 (yield: about 90%). Comp 2 was used in the next step without further purification.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-1 below, but is not limited thereto.
- the compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-3 below, but is not limited thereto.
- R 1a , R 5 , R 6 , a and b have the same definitions as above.
- Synthesis Examples 1, 2-1, 2-2, 2-3, and 2-4 are examples of the compound synthesis method according to the present invention, and include modification of some reagents, solvents, and chemical reaction sequences.
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
- Example 1-1 0.6 mmol, 200 mg
- potassium carbonate (0.72 mmol, 99.5 mg)
- dimethylacetamide (6 mL)
- iodomethyl pivalate 0.9 mmol, 140 ⁇ L
- work-up was performed with water and EA, and the organic layer was dried in MgSO 4 , filtered, and evaporated to obtain a crude product. .
- the crude product was purified with silica to obtain a product.
- Example 2-4 The reaction was carried out in the same manner as in Example 2-1, but using 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44). Thus, ((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-4) was obtained.
- Example 1-1 compound (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (2.94 mmol, 1000 mg) was added to 100 mL RBF, sodium eye Sodium iodide (1.76 mmol, 264 mg) and cesium carbonate (8.82 mmol, 2874 mg) were added, sealed, and nitrogen substitution was performed. After adding DMAc (29.4 mL) and stirring, di-tert-butyl chloromethyl phosphate (7.35 mmol, 1.73 mL) was added and heated to 60 ° C.
- Example 1-1 (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (10 mmol, 3 g) was added to 250 mL RBF. After adding acetic anhydride (100 mL) and stirring, TEA (30 mmoL, 4 mL) was slowly added dropwise. The reaction proceeded by heating the reactant to 85 ° C. After the reaction is completed, work-up is performed with brine and EA, and the organic layer is dried with MgSO 4 , filtered, and evaporated to obtain a crude product.
- Example 2-11 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one
- formic acid 100 ⁇ L
- acetic anhydride 500 ⁇ L
- work-up is performed using sodium bicarbonate and EA.
- the organic layer is dried over MgSO4, filtered, and evaporated to obtain a crude product.
- Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (200 mg, 0.587 mmol) was mixed with dichloromethane (3 mL) and triethylamine (164 mL. 1.174 mmL) and acetoxyacetyl chloride (195 mL, 1.761 mmol) was added. The reaction mixture was stirred at 40 ° C for 2.5 hours, and when the reaction was complete, it was diluted with dichloromethane (20 mL) and washed with water (20 mL).
- Example 1-1 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one) was used to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one (Example 2-27).
- Example 1-1 (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (500 mg, 1.468 mmol) was mixed with dichloromethane (12 mL) and triethylamine (307 mL, 2.20 mmol) and dimethylaminopyridine (18 mg, 0.147 mmol) and methanesulfonyl chloride (136 mL, 1.762 mmol) were added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours.
- 2-Amino-4-chloro-N-(2-(dimethylamino)ethyl)benzamide (0.2 g, 0.7 mmol) and 1,3-dichloro-5-isothiocyanatobenzene in DMF (6 mL) (0.143 g, 0.7 mmol) and a mixture of CuBr (0.05 g, 0.35 mmol) and triethylamine (0.05 mL, 0.36 mmol) was refluxed at 80 oC for 8 hours.
- Vero cells used in the present invention were purchased from the American Type Culture Collection (ATCC, CCL-81; Manassas, VA) and used, 10% heat inactivated fetal bovine serum and 1 ⁇ antibiotic-antimycotic , Gibco/Thermo Fisher Scientific, Waltham, MA) containing Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and incubated at 37°C under 5% carbon dioxide.
- ATCC American Type Culture Collection
- CCL-81 Manassas, VA
- DMEM Dulbecco's modified Eagle's medium
- SARS-CoV-2 Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was obtained from the Korea Centers for Disease Control and Prevention, National Institutes of Health , and proliferated in Vero cells according to the method presented in Kim et al., 2016 doi: 10.1093/cid/ciw239. All experiments using MERS-CoV were performed at the Pasteur Institute in Korea, which followed the enhanced Biosafety Level 3 (BL-3) containment procedures of the National Institutes of Health approved by the Korea Centers for Disease Control and Prevention.
- BL-3 Biosafety Level 3
- Chloroquine diphosphate (CQ; C6628), lopinavir (LPV; GP6351), and Remdesivir were purchased from SelleckChem (Houston, TX) and Glentham Life Science (UK), respectively.
- the anti-SARS-CoV-2 spike antibody used as the primary antibody was manufactured by Sino Biological Inc. (Beijing, China).
- Alexa Fluor 488 goat anti-rabbit IgG as a secondary antibody and Hoechst 33342 as a nuclear chromosome were purchased from Molecular Probes/Thermo Fisher Scientific (Waltham, MA).
- PFA Paraformaldehyde
- aqueous solution and normal goat serum were obtained from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc, respectively. (Burlingame, CA).
- cells infected with SARS-CoV-2 express viral proteins, it can be measured using antibodies that specifically bind to viral proteins.
- cells were stained using an antibody that binds to the spike protein of SARS-CoV-2, and infected cells were imaged through a microscope.
- the infection rate (number of cells expressing SARS-CoV-2 spike protein/total number of cells) was measured with an internally developed Image Mining 3.0 (IM 3.0) plug-in.
- infected cells treated with dimethyl sulfoxide (DMSO) were used as negative controls, and three compounds (CQ, LPV, Remdesivir) known to have antiviral activity against SARS-CoV-2 was used as a positive control to optimize the image-based assay.
- DMSO dimethyl sulfoxide
- Vero cells were plated at 1.2 ⁇ 10 4 cells per well in Opti-PROTM SFM containing 4 mM L-Glutamine and 1 ⁇ Antibiotic-Antimycotic in black, 384-well, microclear plates (Clear plates, Greiner bio-one, Kremsmunster, Austria). After 24 hours, small molecule compounds were added to each well using an automated liquid handling system (Apricot Designs, Covina, Calif.) prior to virus infection. The final concentration of the test compound was 2.5 to 28.2 ⁇ M, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625.
- the fixed cells were stained using Alexa Fluor 488 goat anti-rabbit IgG and Hoechst 33342. After fixation and staining of infected cells, they were imaged on a fluorescence imaging system (Perkin Elmer Operetta, 20 ⁇ , Waltham, MA) at 20 ⁇ magnification.
- the infection rate for SARS-CoV-2 of the cells treated with the small molecule compound was converted into the negative control group (0% infection inhibition rate) and the positive control group (100% infection inhibition rate) on each plate, resulting in an inhibitory effect of 90% or more A low-molecular-weight compound was identified.
- the inhibitory effect of viral infection according to the concentration of the compound can be seen through a concentration-response curve experiment.
- the highest concentration of the test compound is 5 mM, diluted 2 times with DMSO, and serially diluted up to 10 steps. This is treated with cells prepared in the same way as in 1-5 above.
- the highest concentration of the final concentration of the test compound was 25 ⁇ M, and the concentration of DMSO was maintained at 0.5%.
- the compound-treated group was moved to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625. 24 hours after infection, the infection rate was imaged and converted in the same manner as in 1-5 above.
- Example 1-1 0.269 >25 92.9
- Example 1-2 0.403 >25 62.085
- Example 1-3 5.13 >25 4.87
- Example 1-4 2.064 >25 12.113
- Example 1-5 0.328 >25 76.3
- Example 1-6 0.272 >25 92
- Examples 1-7 0.254 >25 98.241
- Examples 1-8 >25 >25 One Examples 1-9 >25 >25 One Examples 1-10 4.877 12.9 2.64
- Example 1-11 >25 >25 One Examples 1-12 0.41 >25 60.94
- Examples 1-13 0.511 >25 48.93
- Examples 1-14 1.513 >25 16.52
- Examples 1-15 >25 >25 One Examples 1-16 >25 >25 >25 One Examples 1-17 >25 >25 One Examples 1-18 0.362 >25 71
- Examples 1-19 0.991 >25 25.22
- Examples 1-20 >25 >25 >25 68.67
- Examples 1-22 0.89 >25 28.1
- Examples 1-24 0.308 14.046 45.55
- the compound according to one aspect of the present invention has excellent antiviral inhibitory activity against SARS-CoV-2, it can be seen that it can be used as a treatment for COVID-19 (coronavirus infection-19). there is.
- the present invention is useful in the field of medicine and medicine through antiviral effects through a novel pharmaceutical composition of a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
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Abstract
The present invention relates to a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof and, more specifically, to a compound represented by chemical formula 1 or a pharmaceutically acceptable salt thereof, and an anti-viral pharmaceutical composition comprising same as an active ingredient. [chemical formula 1]
Description
본 발명은 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염 및 이를 유효성분으로 함유하는 항바이러스용 약학 조성물에 관한 것이다.The present invention relates to a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof and an antiviral pharmaceutical composition containing the same as an active ingredient.
코로나바이러스감염증-19(COVID-19)는 사스-코로나바이러스-2(SARS-CoV-2) 감염에 의한 호흡기 증후군으로, 2019년 12월 중국 후베이성 우한시를 시작으로 전 세계적으로 빠르게 전파되어 감염자 및 사망자 수가 급증하면서 큰 사회적 문제를 야기하고 있다.Coronavirus Infectious Disease-19 (COVID-19) is a respiratory syndrome caused by SARS-CoV-2 infection, starting in Wuhan City, Hubei Province, China in December 2019, and spreading rapidly worldwide, The rapid increase in the number of deaths is causing a great social problem.
SARS-CoV-2 병원체는 Coronaviridae에 속하는 RNA 바이러스로, 그간 대규모 감염사태를 불러일으킨 2002년 중증급성호흡기증후군(SARS)의 병원체인 사스 코로나바이러스(SARS-CoV)와 2015년 중동호흡기증후군(MERS)의 병원체인 메르스 코로나바이러스(MERS-CoV)와 매우 밀접한 관련이 있다. SARS-CoV-2와 SARS-CoV는 ACE2 (Angiotensin Converting Enzyme2) 수용체에 결합하며, MERS-CoV는 DPP4 (Dipeptidyl Peptidase4; CD26)를 수용체로 활용한다. 3차원 분자구조 분석 결과, SARS-CoV-2와 SARS-CoV의 스파이크 단백질은 상당히 비슷한 형태를 가지고 있음이 확인되었으며(Walls et al., 2020, Structure, Function and antigenicity of the SARS-CoV-2 spike glycoprotein, Cell, DOI: 10.1016/j.cell.2020.02.058.; Wrapp et al., 2020, Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science.), 이러한 형태적 유사성으로 인해 SARS-CoV-2 역시 ACE2 수용체를 통해 숙주세포의 표면에 강하게 부착한다는 사실이 밝혀졌고, 스파이크 단백질과 ACE2의 결합체의 분자구조도 최근 밝혀졌다(Zhou et al., 2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature.; Yan et al., 2020, Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2. Science, DOI: 10.1126/science.abb2762). 그러나 SARS-CoV-2가 SARS-CoV보다 더 빠르게 전염, 확산되는데, 이는 SARS-CoV-2가 숙주세포의 ACE2에 더 강하게 결합하고, 스파이크 단백질의 일부분이 단백질가위에 의해 더 쉽게 잘라질 수 있도록 변형되어 있기 때문인 것으로 추정된다.The SARS-CoV-2 pathogen is an RNA virus belonging to the Coronaviridae, which has been associated with SARS-CoV, the pathogen of Severe Acute Respiratory Syndrome (SARS) in 2002 and Middle East Respiratory Syndrome (MERS) in 2015. It is very closely related to the MERS coronavirus (MERS-CoV), the pathogen of SARS-CoV-2 and SARS-CoV bind to the ACE2 (Angiotensin Converting Enzyme2) receptor, and MERS-CoV utilizes DPP4 (Dipeptidyl Peptidase4; CD26) as a receptor. As a result of 3D molecular structure analysis, it was confirmed that SARS-CoV-2 and SARS-CoV spike proteins have a very similar shape (Walls et al., 2020, Structure, Function and antigenicity of the SARS-CoV-2 spike SARS -It was found that CoV-2 also attaches strongly to the surface of host cells through the ACE2 receptor, and the molecular structure of the spike protein and ACE2 complex was recently revealed (Zhou et al., 2020 A pneumonia outbreak associated with a new coronavirus of probable bat origin.Nature.;Yan et al., 2020, Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2.Science, DOI: 10.1126/science.abb2762). However, SARS-CoV-2 transmits and spreads more rapidly than SARS-CoV, which is why SARS-CoV-2 binds more strongly to ACE2 in host cells and makes parts of the spike protein more easily cut by protein scissors. It is presumed that this is because it is deformed.
코로나바이러스감염증-19에 대한 예방 및 치료를 위한 연구개발이 활발히 진행중이며, 현재까지 개발된 코로나바이러스감염증-19 치료제가 없는 상황으로, 치료제의 개발이 요구되고 있다.Research and development for prevention and treatment of COVID-19 is actively underway, and as there is no treatment for COVID-19 developed so far, development of a treatment is required.
본 발명자는 다양한 치환기가 도입된 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체들이 코로나바이러스감염증-19에 대한 억제효과를 가지는 화합물임을 밝혀 본 발명을 완성하였다.The present inventors have completed the present invention by finding that 2-aminoquinazoline derivatives introduced with various substituents are compounds having an inhibitory effect on COVID-19.
본 발명은 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염을 제공하는 것을 목적으로 한다.An object of the present invention is to provide a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 항바이러스용 약학 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide an antiviral pharmaceutical composition comprising a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
또한, 본 발명은 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염을 포함하는 바이러스 감염증 예방 및 개선용 건강식품 조성물을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a health food composition for preventing and improving viral infection, which includes a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
또한, 본 발명은 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항바이러스용 약학 조성물을 제공한다.In addition, the present invention provides an antiviral pharmaceutical composition comprising the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
또 다른 예로, 본 발명은 코로나바이러스감염증-19 코로나바이러스 항바이러스용 약학 조성물을 제공한다.As another example, the present invention provides a pharmaceutical composition for COVID-19 coronavirus antivirus.
또한, 본 발명의 약학 조성물은 약학적으로 허용가능한 담체 하나 이상을 더 포함할 수 있으며, 공지의 항바이러스제 하나 이상을 더 포함할 수 있다.In addition, the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more known antiviral agents.
또 다른 예로, 본 발명은 상기 화학식 1에 따른 화합물; 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 바이러스 감염증 예방 및 개선용 건강식품 조성물을 제공한다.As another example, the present invention relates to a compound according to Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
본 발명에 따른 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염이 함유된 조성물은 Vero 세포주에 감염시킨 SARS-CoV-2에 대한 증식 억제작용이 우수하며 Vero 세포주에 대한 독성이 적어 바이러스 치료제로 사용될 수 있으며, 특히 COVID-19(코로나바이러스감염증-19) 치료제로서 사용될 수 있다.The composition containing a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof according to the present invention has an excellent anti-proliferation activity against SARS-CoV-2 infected with Vero cell lines and It can be used as a virus treatment because of its low toxicity, and in particular, it can be used as a treatment for COVID-19 (Coronavirus Infectious Disease-19).
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
이하, 본 발명을 상세히 설명한다. 본 명세서 및 청구범위에 사용되는 용어나 단어는 통상적이거나 사전적인 의미로 한정해서 해석되어서는 아니되며, 발명자는 그 자신의 발명을 가장 최선의 방법으로 설명하기 위해 용어의 개념을 적절하게 정의할 수 있다는 원칙에 입각하여 본 발명의 기술적 사상에 부합하는 의미와 개념으로 해석되어야만 한다.Hereinafter, the present invention will be described in detail. The terms or words used in this specification and claims should not be construed as being limited to ordinary or dictionary meanings, and the inventors may appropriately define the concept of terms in order to explain their invention in the best way. It should be interpreted as a meaning and concept consistent with the technical idea of the present invention based on the principle that there is.
본 명세서에서 사용된 용어에 대해 간략히 설명한다.The terms used in this specification are briefly described.
용어 “알킬” 또는 “알킬기”는 지방족 탄화수소 라디칼을 의미하며, 직쇄 또는 분지쇄 상의 탄화수소 라디칼을 모두 포함한다. 예를 들어 C1~C6의 알킬은 1 내지 6개의 탄소원자를 갖는 지방족 탄화수소로서, 메틸, 에틸, 프로필, n-부틸, n-펜틸, n-헥실, 아이소프로필, 아이소부틸, sec-부틸, tert-부틸, 네오펜틸, 아이소펜틸 등을 모두 포함한다.The term “alkyl” or “alkyl group” refers to an aliphatic hydrocarbon radical and includes both straight-chain and branched-chain hydrocarbon radicals. For example, C 1 ~ C 6 alkyl is an aliphatic hydrocarbon having 1 to 6 carbon atoms, methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and the like are all included.
용어 “알켄” 또는 “알켄일기”는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 이중 결합으로 이루어진 그룹을 의미하며, “알킨” 또는 “알킨일기”는 적어도 두 개의 탄소원자가 적어도 하나의 탄소-탄소 삼중 결합으로 이루어진 그룹을 의미한다.The term “alkene” or “alkenyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond, and “alkyne” or “alkynyl group” refers to a group in which at least two carbon atoms contain at least one carbon-carbon double bond. A group consisting of a triple bond.
용어 “헤테로고리” 또는 “헤테로고리기”는 다른 설명이 없는 한 하나 이상의 헤테로원자를 포함하고, 단일 고리 및 다중 고리 중 적어도 하나를 포함하며, 헤테로지방족 고리 및 헤테로방향족 고리를 포함한다. 이웃한 작용기가 결합하여 형성될 수도 있다.The term "heterocycle" or "heterocyclic group" includes one or more heteroatoms, includes at least one of a single ring and multiple rings, and includes heteroaliphatic and heteroaromatic rings, unless otherwise specified. It may also be formed by combining adjacent functional groups.
용어 “아릴” 또는 “아릴기”는 공유 파이 전자계를 가지는 하나 이상의 탄화수소 환을 의미하며, 그 예로, 페닐, 나프틸, 바이페닐 등을 포함한다.The term “aryl” or “aryl group” refers to one or more hydrocarbon rings having a covalent pi electron system, and includes, for example, phenyl, naphthyl, biphenyl, and the like.
용어 “할로겐”은 주기율표의 17족에 속하는 원소들로, 상세하게는 플루오르, 염소, 브롬, 요오드일 수 있다.The term “halogen” refers to elements belonging to group 17 of the periodic table, and may be specifically fluorine, chlorine, bromine, and iodine.
용어 “알콕시” 또는 “알콕시기”는 별도로 정의되지 않는 한 히드록시기의 수소 원자가 알킬로 치환된 라디칼을 의미하며, 예를 들어 C1~C6의 알콕시는 메톡시, 에톡시, 프로폭시, n-부톡시, n-펜틸옥시, 아이소프로폭시, sec-부톡시, tert-부톡시, 네오펜틸옥시, 아이소펜틸옥시 등을 모두 포함한다.The term “alkoxy” or “alkoxy group” means a radical in which the hydrogen atom of a hydroxy group is substituted with an alkyl, unless otherwise defined, and for example, C 1 to C 6 alkoxy is methoxy, ethoxy, propoxy, n- Butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, isopentyloxy and the like are all included.
용어 “알카노일옥시기”는 옥시기와 알카노일기가 결합되어 있는 원자단을 의미하며, 예를 들어, -O-C(=O)-R로 표현되며, C2 알카노일옥시기는 -O-C(=O)C2H5를 의미한다.The term “alkanoyloxy group” refers to an atomic group to which an oxy group and an alkanoyl group are bonded, and is expressed, for example, as -OC(=O)-R, and a C 2 alkanoyloxy group is -OC(=O ) C 2 H 5 .
용어 “아세틸기”는 메틸기와 카르보닐기로 이루어지는 1가 원자단을 의미하며, 즉, -C(=O)-CH3를 의미한다.The term “acetyl group” means a monovalent atomic group consisting of a methyl group and a carbonyl group, that is, -C(=O)-CH 3 .
용어 “히드록시기”는 -OH를 의미한다.The term "hydroxyl group" means -OH.
용어 “아미노기”는 -NH2를 의미한다.The term "amino group" means -NH 2 .
용어 “아세톡시기”는 알카노일옥시기의 일종으로, 옥시기와 아세틸기로 이루어지는 1가 원자단을 의미하며, 즉, -O-C(=O)-CH3를 의미한다.The term “acetoxy group” is a kind of alkanoyloxy group and means a monovalent atomic group consisting of an oxy group and an acetyl group, that is, -OC(=O)-CH 3 .
용어 “벤질옥시기”는 옥시기와 벤질기로 이루어지는 1가 원자단을 의미하며,즉, -O-CH2-C6H5를 의미한다.The term "benzyloxy group" means a monovalent atomic group consisting of an oxy group and a benzyl group, that is, -O-CH 2 -C 6 H 5 .
용어 “치환”은 하나의 수소 원자가 치환된 것을 의미하는 것으로, 예를 들어, 히드록시기로 치환되는 경우, -CH3가 -CH2OH로 치환된다.The term “substitution” means that one hydrogen atom is substituted, for example, when substituted with a hydroxyl group, -CH 3 is substituted with -CH 2 OH.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 제공한다.The present invention provides a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof.
[화학식 1][Formula 1]
{상기 화학식 1에서,{In Formula 1,
1) R1 및 R4는, 서로 독립적으로, 수소원자; C1~C3 알콕시기; C1~C6의 알킬기; -C(=O)R1a; -S(=O)2R1b; -(CH2)m-R1c; 또는 -(CH2)m-O-P(=O)(-OR1d)(-OR1e)이고, 1) R 1 and R 4 are, independently of each other, a hydrogen atom; C 1 ~ C 3 alkoxy group; C 1 ~ C 6 Alkyl group; -C(=0)R 1a ; -S(=0) 2 R 1b ; -(CH 2 ) m -R 1c ; or -(CH 2 ) m -OP(=0)(-OR 1d )(-OR 1e );
R4는 부존재할 수 있으며,R 4 may be absent;
상기 R1a는 치환되거나 비치환된 C1~C6의 알킬기; 또는 치환되거나 비치환된 C2~C6의 알켄일기이고, Wherein R 1a is a substituted or unsubstituted C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 2 ~ C 6 alkenyl group,
여기에서 C1~C6의 알킬기가 치환되는 경우, C1~C3의 알콕시기; 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되며,Here, when the C 1 ~ C 6 alkyl group is substituted, a C 1 ~ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,
여기에서, C2~C6의 알켄일기가 치환되는 경우, 히드록시기, 아미노기, 할로겐원자 또는 아세톡시기로 치환되고,Here, when the alkenyl group of C 2 ~ C 6 is substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,
상기 R1b는 C1~C6의 알킬기; 또는 치환되거나 비치환된 C6~C10의 아릴기이며,R 1b is a C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 6 ~ C 10 aryl group,
여기에서, C6~C10의 아릴기가 치환되는 경우, C1~C3의 알킬기로 치환되고,Here, when the C 6 ~ C 10 aryl group is substituted, it is substituted with a C 1 ~ C 3 alkyl group,
상기 R1c는 히드록시기; C1~C6의 알카노일옥시기; 벤질옥시기; 또는 NRaRb 이고, Wherein R 1c is a hydroxyl group; C 1 ~ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;
상기 R1d 및 R1e는 서로 독립적으로 수소; 소디움; 또는 C1~C6의 알킬기이며, R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ~ C 6 alkyl group,
m은 0 내지 3의 정수이고,m is an integer from 0 to 3;
2) R2는 수소, C3~C6의 시클로알킬기; -(X)n-C6~C10의 아릴기이며,2) R 2 is hydrogen, a C 3 ~ C 6 cycloalkyl group; -(X) n -C 6 ~ C 10 An aryl group,
상기 X는 -CH2; 카보닐(C=O); 또는 -C(=O)-CH=CH-;이며, n은 0 또는 1이고,X is -CH 2 ; carbonyl (C=O); or -C(=0)-CH=CH-; and n is 0 or 1;
3) 또는, R1 및 R2가 함께 고리를 형성할 수 있고3) or, R 1 and R 2 together may form a ring;
4) R3은 =O; C1~C6의 알킬기; NRcRd; 또는 -O-(CH)o-R3a이며,4) R 3 is =0; C 1 ~ C 6 Alkyl group; NR c R d ; or -O-(CH) o -R 3a ;
상기 R3a는 C1~C6의 알카노일옥시기이고, o는 1 또는 2이고,Wherein R 3a is a C 1 ~ C 6 alkanoyloxy group, o is 1 or 2;
5) R5는 수소; 할로겐; 시아노기; 니트로기; 히드록시기; 아미노기; C1~C6의 알킬기; C2~C6의 알켄일기; C2~C6의 알킨일기; C1~C6의 알콕시기; C1~C6의 알카노일옥시기; C3~C6의 시클로알킬기; C6~C10의 아릴기; O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기; NReRf; 이며, a가 1이상일 때 복수의 R5는 서로 동일하거나 상이하고,5) R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ~ C 6 Alkyl group; C 2 ~ C 6 Alkenyl group; A C 2 ~C 6 alkynyl group; A C 1 ~ C 6 alkoxy group; C 1 ~ C 6 alkanoyloxy group; C 3 ~ C 6 Cycloalkyl group; C 6 ~ C 10 aryl group; A C 2 ~C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,
6) a는 0 내지 4의 정수이며,6) a is an integer from 0 to 4;
7) 상기 Ra, Rb, Rc, Rd, Re 및 Rf는 서로 독립적으로 수소; 또는 C1~C3의 알킬기;이고,7) R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ~ C 3 alkyl group;
8) 
는 단일결합 또는 이중결합을 의미하며, 
는 단일결합 또는 결합이 형성되지 않음을 의미하고,8) Means a single bond or a double bond, Means that a single bond or no bond is formed,
9) 여기서, 상기 알킬기, 알켄일기, 알킨일기, 시클로알킬기, 알카노일옥시기, 아릴기 및 헤테로고리기는 각각 중수소; 할로겐; 히드록시기; 시아노기; 니트로기; C1~C6 알킬기; -C(=O)-C1~C6의 알킬기; -C(=O)NH2; C1~C6 알콕시기; 및 O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기;로 이루어진 군에서 선택된 하나 이상의 치환기로 더욱 치환될 수 있으며, 이들 치환기들은 서로 결합하여 고리를 형성할 수도 있고, 여기서 '고리'란 탄소수 3 내지 20의 지방족고리 또는 탄소수 6 내지 20의 방향족고리 또는 탄소수 2 내지 20의 헤테로고리 또는 이들의 조합으로 이루어진 융합 고리를 말하며, 포화 또는 불포화 고리를 포함한다.}9) Here, the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the alkanoyloxy group, the aryl group, and the heterocyclic group are each deuterium; halogen; hydroxy group; cyano group; nitro group; C 1 ~ C 6 alkyl group; -C(=O)-C 1 ~ C 6 Alkyl group; -C(=O)NH 2 ; C 1 ~ C 6 alkoxy group; And a C 2 ~ C 10 heterocyclic group containing at least one heteroatom of O, N, and S; may be further substituted with one or more substituents selected from the group consisting of, and these substituents may combine with each other to form a ring. Alternatively, the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring. }
또한, 본 발명은 상기 화학식 1이 하기 화학식 2로 표시되는 화합물을 포함한다.In addition, the present invention includes a compound in which Formula 1 is represented by Formula 2 below.
[화학식 2][Formula 2]
{상기 화학식 2에서,{In Formula 2,
1) R1, R3, R4, R5 및 a는 상기에서 정의한 바와 동일하며,1) R 1 , R 3 , R 4 , R 5 and a are the same as defined above,
2) R6은 수소; 할로겐; 히드록시기; 시아노기; 니트로기; C1~C6의 알킬기; C2~C6의 알켄일기; C2~C6의 알킨일기; C1~C6의 알콕시기; 또는 -C(=O)NH2;이고, b가 1이상일 때 복수의 R6은 서로 동일하거나 상이하며,2) R 6 is hydrogen; halogen; hydroxy group; cyano group; nitro group; C 1 ~ C 6 Alkyl group; C 2 ~ C 6 Alkenyl group; A C 2 ~C 6 alkynyl group; A C 1 ~ C 6 alkoxy group; or -C(=0)NH 2 ; and, when b is 1 or more, a plurality of R 6 are the same as or different from each other;
3) b는 0 내지 5의 정수이다.}3) b is an integer from 0 to 5.}
또한, 본 발명은 상기 화학식 1이 하기 화학식 3 내지 5 중 어느 하나로 표시되는 화합물을 포함한다.In addition, the present invention includes a compound represented by any one of the following formulas 3 to 5 in the formula (1).
[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
{상기 화학식 3 내지 5에서,{In Formulas 3 to 5,
1) R1, R5, R6, a 및 b는 상기 정의한 바와 동일하며,1) R 1 , R 5 , R 6 , a and b are the same as defined above,
2) R7은 C1~C6의 알킬기; 또는 tert-부타노일옥시메톡시기이다.}2) R 7 is a C 1 ~ C 6 alkyl group; or a tert-butanoyloxymethoxy group.}
본 발명의 일 양태에서, 상기 R1 및 R4 중 적어도 하나가 -C(=O)R1a이고, In one aspect of the present invention, at least one of R 1 and R 4 is -C(=0)R 1a ,
상기 R1a는 치환되거나 비치환된 C1~C6의 알킬기; 또는 치환되거나 비치환된 C2~C6의 알켄일기이며, 여기에서, 여기에서 C1~C6의 알킬기가 치환되는 경우, C1~C3의 알콕시기; 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되며,Wherein R 1a is a substituted or unsubstituted C 1 ~ C 6 alkyl group; or a substituted or unsubstituted C 2 ~ C 6 alkenyl group, where, when the C 1 ~ C 6 alkyl group is substituted, a C 1 ~ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,
여기에서, C2~C6의 알켄일기가 치환되는 경우, 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환된다.Here, when the alkenyl group of C 2 ~ C 6 is substituted, it is substituted with a hydroxyl group, an amino group, a halogen or an acetoxy group.
구체적으로, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염이 하기 화합물들 중 어느 하나일 수 있다.Specifically, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
또한, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 하기 화합물들 중 어느 하나일 수 있다.In addition, the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof may be any one of the following compounds.
상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 비대칭 원자를 포함하는 치환기를 가질 수 있으며, 이 경우 상기 화학식 1의 화합물 또는 이의 염은 (R), (S), 또는 라세믹체(RS) 등의 광학 이성질체로 존재할 수 있다. 따라서, 달리 표기하지 않는 한, 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염은 (R), (S), 또는 라세믹체(RS) 등의 광학 이성질체를 모두 포함한다.The compound of Formula 1 or a pharmaceutically acceptable salt thereof may have a substituent containing an asymmetric atom, in which case the compound of Formula 1 or a salt thereof is (R), (S), or racemic (RS) may exist as optical isomers. Therefore, unless otherwise indicated, the compound of Formula 1 or a pharmaceutically acceptable salt thereof includes all optical isomers such as (R), (S), or racemic (RS) forms.
본 발명의 화학식 1의 화합물은 약학적으로 허용가능한 염의 형태일 수 있다. 상기 염은 통상의 산부가염, 예를 들어 염산, 브롬화수소산, 황산, 설팜산, 인산, 또는 질산과 같은 무기산으로부터 유도된 염 및 아세트산, 프로피온산, 숙신산, 글리콜산, 스테아르산, 말레산, 히드록시말레산, 페닐아세트산, 글루탐산, 벤조산, 살리실산, 설파닐산, 2-아세톡시-벤조산, 푸마르산, 톨루엔술폰산, 메탄술폰산, 에탄술폰산, 옥살산, 트라이플루오로아세트산, 시트르산, 락트산, 타르타르산, 쿠마릭산, 알긴산, 캄포설폰산, 카프릭산, 미리스틱산, 히프릭산 또는 오로트산과 같은 유기산으로부터 유도된 염을 포함한다. 또한, 상기 염은 수산화나트륨, 수산화리튬, 수산화칼륨, 수산화 칼슘, 탄산칼륨, 탄산칼슘, 포타슘 t-부톡사이드, 소디움 에톡사이드, 트라이에틸아민, 암모니아, 구아니딘, 에틸렌다이아민, 에탄올아민, 다이에탄올아민, 트라이에탄올아민, 페페라진, 몰포린, 또는 다이사이클로헥실아민으로부터 유도된 염을 포함한다.The compound of Formula 1 of the present invention may be in the form of a pharmaceutically acceptable salt. Such salts include conventional acid addition salts, for example, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, or nitric acid, and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, maleic acid, hydroxy acid. Maleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, coumaric acid, alginic acid , salts derived from organic acids such as camphorsulfonic acid, capric acid, myristic acid, hypric acid or orotic acid. In addition, the salt is sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate, calcium carbonate, potassium t-butoxide, sodium ethoxide, triethylamine, ammonia, guanidine, ethylenediamine, ethanolamine, diethanol amines, triethanolamine, piperazine, morpholine, or salts derived from dicyclohexylamine.
상기 화학식 1의 화합물의 약학적으로 허용가능한 염은 화학식 1의 화합물로부터 통상적인 방법으로 제조할 수 있다. 일반적으로, 상기 염은 유리 산/염기 형태의 화학식 1의 화합물을 화학량론적 양 또는 과량의 목적하는 염-형성 무기산, 무기염, 유기산 또는 유기염과 적합한 용매 또는 용매들의 다양한 배합물 중에서 반응시켜 제조할 수 있다.A pharmaceutically acceptable salt of the compound of Formula 1 can be prepared from the compound of Formula 1 by a conventional method. In general, such salts can be prepared by reacting a compound of Formula 1 in free acid/base form with a stoichiometric amount or excess of the desired salt-forming inorganic acid, inorganic salt, organic acid or organic salt in a suitable solvent or various combinations of solvents. can
본 발명은 치료학적 유효량의 상기 화학식 1의 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항바이러스용 약학 조성물을 제공한다.The present invention provides an antiviral pharmaceutical composition comprising a therapeutically effective amount of the compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 약학 조성물은 통상적으로 사용되는 부형제, 붕해제, 감미제, 활택제 또는 향미제 등의 약학적으로 허용가능한 담체를 포함할 수 있으며, 통상의 방법에 따라 정제, 캅셀제, 산제, 과립제 및 현탁제, 유제 또는 시럽제와 같은 경구용 제제 또는 주사제 등의 비경구 투여용 제제로 제제화될 수 있다. 상기 제제는 다양한 형태, 예를 들어 단회 투여형 또는 수회 투여형 투여 형태(dosage form)로 제제화될 수 있다.The pharmaceutical composition may include a pharmaceutically acceptable carrier such as a commonly used excipient, disintegrant, sweetener, lubricant, or flavoring agent, and may be formulated into tablets, capsules, powders, granules, and suspensions according to conventional methods. It may be formulated into oral preparations such as emulsions or syrups or preparations for parenteral administration such as injections. The formulation may be formulated in a variety of forms, for example single dose or multiple dose dosage forms.
본 발명의 조성물은 경구 투여하거나, 정맥내, 근육내, 복강내, 피하, 직장 및 국소 투여를 포함한 비경구로 투여될 수 있다. 본 발명의 조성물은 바람직하게는 경구 투여될 수 있다. 따라서, 본 발명의 조성물은 정제, 캅셀제, 수성액제 또는 현탁제 등의 다양한 형태로 제제화될 수 있다. 경구용 정제의 경우 락토즈, 옥수수 전분 등의 담체 및 마그네슘 스테아레이트와 같은 활택제가 통상 가해질 수 있다. 경구투여용 캅셀제의 경우, 락토즈 및/또는 건조 옥수수 전분이 희석제로서 사용될 수 있다. 경구용 수성 현탁제가 필요할 경우, 활성성분을 유화제 및/또는 현탁화제와 결합시킬 수 있다. 필요할 경우, 특정 감미제 및/또는 향미제를 가할 수 있다. 근육내, 복강내, 피하 및 정맥내 투여의 경우, 활성성분의 멸균 용액이 통상 제조되며, 용액의 pH를 적합하게 조절하고 완충시켜야 한다. 정맥내 투여의 경우, 용질의 총 농도는 제제에 등장성이 부여되도록 조절되어야 한다. 본 발명에 따른 조성물은 pH가 7.4인 염수와 같은 약학적으로 허용되는 담체를 포함하는 수용액제의 형태일 수 있다. 상기 용액은 국소 주사(local bolus injection)로 환자의 근육내 혈류에 도입될 수 있다.The composition of the present invention may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical administration. Compositions of the present invention are preferably administered orally. Accordingly, the composition of the present invention may be formulated in various forms such as tablets, capsules, aqueous solutions or suspensions. In the case of tablets for oral use, carriers such as lactose and corn starch and lubricants such as magnesium stearate may usually be added. In the case of capsules for oral administration, lactose and/or dried corn starch may be used as diluents. When oral aqueous suspensions are required, the active ingredient may be combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring agents may be added. For intramuscular, intraperitoneal, subcutaneous and intravenous administration, sterile solutions of the active ingredients are usually prepared, the pH of the solutions suitably adjusted and buffered. For intravenous administration, the total concentration of solutes should be adjusted to impart isotonicity to the formulation. The composition according to the present invention may be in the form of an aqueous solution containing a pharmaceutically acceptable carrier such as saline having a pH of 7.4. The solution can be introduced into the patient's intramuscular bloodstream by local bolus injection.
본 발명에 따른 약학 조성물은 치료학적 유효량으로 투여될 수 있다. 따라서, 상기 약학 조성물에 함유되는 화학식 1의 화합물; 또는 이의 약학적으로 허용가능한 염은 환자에게 약 10 mg/kg 내지 약 500 mg/kg per day의 유효량으로 투여될 수 있다. 물론, 상기 용량은 환자의 나이, 체중, 감수성, 증상 또는 화합물의 약효에 따라 변경될 수 있다.A pharmaceutical composition according to the present invention can be administered in a therapeutically effective amount. Therefore, the compound of formula 1 contained in the pharmaceutical composition; Or a pharmaceutically acceptable salt thereof may be administered to the patient in an effective amount of about 10 mg/kg to about 500 mg/kg per day. Of course, the dose may be changed according to the patient's age, body weight, sensitivity, symptoms or efficacy of the compound.
본 발명은 또한, 치료학적 유효량의 상기 화학식 1의 화합물; 또는 이의 약학적으로 허용가능한 염을 인간을 포함한 포유동물에게 투여하는 것을 포함하는, 바이러스, 바람직하게는 코로나바이러스, 보다 바람직하게는 코로나바이러스감염증-19의 예방 또는 치료방법을 제공한다.The present invention also provides a therapeutically effective amount of the compound of Formula 1; Or a method for preventing or treating a virus, preferably a coronavirus, more preferably COVID-19, comprising administering a pharmaceutically acceptable salt thereof to a mammal, including a human.
또한, 본 발명의 약학 조성물은 약학적으로 허용가능한 담체 하나 이상을 더 포함할 수 있으며, 항바이러스제 하나 이상을 더 포함할 수 있다.In addition, the pharmaceutical composition of the present invention may further include one or more pharmaceutically acceptable carriers, and may further include one or more antiviral agents.
본 발명은 또한, 바이러스의 예방 또는 치료용 약제의 제조를 위한, 상기 화학식 1의 화합물; 또는 이의 약학적으로 허용가능한 염의 용도를 제공한다.The present invention also relates to a compound of Formula 1 for the preparation of a drug for preventing or treating a virus; or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 양태로서, 본 발명은 화학식 1의 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 코로나바이러스, 특히 코로나바이러스감염증-19 치료제에 관한 것이다.As another aspect of the present invention, the present invention relates to a treatment for coronavirus, particularly COVID-19, comprising a 2-aminoquinazoline derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient. it's about
화학식 1의 2-아미노퀴나졸린(2-Aminoquinazoline) 유도체는 SARS-CoV-2를 감염시킨 Vero cell을 활용한 약효시험에서 SARS-CoV-2를 효과적으로 저해하며 세포독성이 적어 코로나바이러스 치료효과를 기대할 수 있음을 확인하였으며, 특히, 코로나바이러스감염증-19 치료제로서 활용될 수 있음을 확인하였다.The 2-Aminoquinazoline derivative of Chemical Formula 1 effectively inhibits SARS-CoV-2 in a drug efficacy test using Vero cells infected with SARS-CoV-2 and is expected to have a therapeutic effect on coronavirus due to its low cytotoxicity. It was confirmed that it can be used, and in particular, it was confirmed that it can be used as a treatment for COVID-19.
따라서, 본 발명에 따른 화학식 1의 화합물을 유효성분으로 하는 코로나바이러스감염증-19 치료제 또는 약제 조성물은 화학식 1의 화합물에 통상의 무독성 약학적으로 허용가능한 담체, 보강제 또는 부형제 등을 첨가하여 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 트로키제, 액제, 현탁제 등의 경구투여용 제제로 제제화 할 수 있다.Therefore, the therapeutic agent or pharmaceutical composition for COVID-19 containing the compound of Formula 1 according to the present invention as an active ingredient is added to the compound of Formula 1 with a conventional non-toxic pharmaceutically acceptable carrier, reinforcing agent or excipient, etc. in the pharmaceutical field. Oral administration preparations such as tablets, capsules, troches, solutions, suspensions, etc. can be formulated in conventional preparations.
또한, 본 발명에 따른 화학식 1의 화합물을 유효성분으로 하고, 다른 항바이러스제를 더 포함하여 약학적 조성물을 제공할 수 있다. 또한, 코로나바이러스감염증-19 치료제 또는 약제 조성물로 화학식 1의 화합물과, 다른 항바이러스제 및 약학적으로 허용가능한 담체 등을 첨가하여 약제학적 분야에서 통상적인 제제로 제공할 수 있다.In addition, a pharmaceutical composition may be provided by using the compound of Formula 1 according to the present invention as an active ingredient and further including other antiviral agents. In addition, it can be provided as a conventional preparation in the pharmaceutical field by adding the compound of Formula 1, other antiviral agents and pharmaceutically acceptable carriers to a COVID-19 treatment or pharmaceutical composition.
또한, 화학식 1의 화합물의 인체에 대한 투여용량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 70 ㎏인 성인 환자를 기준으로 할 때 일반적으로 10 내지 4,000 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1일 1회 내지 수회로 분할 투여할 수 있다.In addition, the dosage of the compound of Formula 1 may vary depending on the patient's age, weight, sex, dosage form, health condition and disease degree, and is generally 10 to 4,000 mg/day, and may be divided and administered once or several times a day at regular time intervals according to the judgment of a doctor or pharmacist.
또한, 본 발명은 상기 화학식 1의 화합물; 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 바이러스 감염증 예방 및 개선용 건강식품 조성물을 제공한다.In addition, the present invention is a compound of Formula 1; Or it provides a health food composition for preventing and improving viral infection comprising a food chemically acceptable salt thereof as an active ingredient.
이하에서, 본 발명에 따른 화학식으로 표시되는 화합물의 합성예 및 실시예를 들어 구체적으로 설명하지만, 본 발명이 하기의 실시예로 한정되는 것은 아니다.Hereinafter, synthetic examples and examples of the compound represented by the formula according to the present invention will be described in detail, but the present invention is not limited to the following examples.
[합성예 1][Synthesis Example 1]
본 발명에 따른 화학식 1로 표시되는 화합물은 하기 반응식 1과 같이 반응하여 제조될 수 있으며, 이에 한정되는 것은 아니다.The compound represented by Formula 1 according to the present invention may be prepared by reacting as shown in Reaction Scheme 1 below, but is not limited thereto.
<반응식 1><Scheme 1>
상기 반응식 1에서, R5, R6, a 및 b는 상기 정의와 동일하다.In Reaction Scheme 1, R 5 , R 6 , a and b have the same definition as above.
Comp 5 (2-아닐리노퀴나졸린-4(Comp 5 (2-anilinoquinazoline-4(
3H3H
)-온 유도체) 합성예시) -one derivative) Synthesis example
1) Comp 2의 합성1) Synthesis of Comp 2
Comp 1 (29.1 mmol, 1 eq) 및 urea (582.8 mmol, 20 eq)를 100 mL 둥근바닥플라스크에 넣고 150℃에서 2시간 동안 가열하였다. 반응이 종결된 후 실온에서 냉각시킨 뒤 물 60 mL를 첨가하고 100℃에서 1시간 동안 가열하였다. 반응물을 냉각시키면 흰색 고체를 침전된다. 흰색 고체를 여과한 후 물과 헥산으로 세척한 뒤 건조시켜 Comp 2(수율: 약 90%)를 얻었다. Comp 2는 추가 정제 없이 다음 단계에 사용하였다.Comp 1 (29.1 mmol, 1 eq) and urea (582.8 mmol, 20 eq) were placed in a 100 mL round bottom flask and heated at 150 °C for 2 hours. After the reaction was completed, the mixture was cooled at room temperature, 60 mL of water was added thereto, and the mixture was heated at 100° C. for 1 hour. Cooling the reactants precipitates a white solid. After filtering the white solid, it was washed with water and hexane and dried to obtain Comp 2 (yield: about 90%). Comp 2 was used in the next step without further purification.
2) Comp 3의 합성2) Synthesis of Comp 3
상기 Comp 2 (28.3 mmol, 1 eq, 97%)를 트리에틸아민(triethylamine) (56.6 mmol, 2 eq)에 용해시킨 후 POCl3 (254.5 mmol, 9 eq)를 천천히 첨가한 후 115℃에서 17시간 동안 가열하였다. 반응이 종결된 후 용매를 톨루엔으로 여러 번 증발시켰다. 얼음물을 잔류물에 붓고 에틸아세테이트로 여러 번 추출하였다. 유기층을 황산나트륨으로 건조시키고, 여과한 후 진공에서 건조시켜 Comp 3을 얻었다. Comp 3은 추가 정제 없이 다음 단계에 사용하였다.After dissolving Comp 2 (28.3 mmol, 1 eq, 97%) in triethylamine (56.6 mmol, 2 eq), POCl 3 (254.5 mmol, 9 eq) was slowly added, followed by 17 hours at 115°C. heated while After the reaction was completed, the solvent was evaporated several times with toluene. Ice water was poured into the residue and extracted several times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and dried in vacuo to give Comp 3. Comp 3 was used in the next step without further purification.
3) Comp 4의 합성3) Synthesis of Comp 4
상기 Comp 3 (25.2 mmol)을 2 N NaOH 용액(75.6 mmol, 38 mL, 3 eq)에 실온에서 20시간 동안 용해시켰다. 반응이 종결된 후 acetic acid (75.6 mmol, 3 eq)를 붓고 에틸아세테이트와 염수로 추출하였다. 유기층을 황산나트륨으로 건조시키고, 여과한 후 진공에서 농축시켜 Comp 4 (19.4 mmol)를 얻었다.The above Comp 3 (25.2 mmol) was dissolved in 2 N NaOH solution (75.6 mmol, 38 mL, 3 eq) at room temperature for 20 hours. After the reaction was completed, acetic acid (75.6 mmol, 3 eq) was added, followed by extraction with ethyl acetate and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give Comp 4 (19.4 mmol).
4) Comp 5의 합성4) Synthesis of Comp 5
상기 Comp 4 (0.93 mmol)를 Comp 1-1 (2.8 mmol, 3 eq)과 함께 DMF (3.1 mL)에 용해시킨 후 85℃에서 16시간 동안 가열하였다. 반응이 종결된 후 실온에서 냉각시키면 침전물이 형성된다. 침전물을 물과 헥산으로 철저하게 세척한 후 수득한 Comp 5 (0.88 mmol, 94%)를 진공에서 건조시켰다. 침전물이 형성되지 않으면, 반응물을 prep HPLC (Shim-pack PREP-ODS, H2O:CH3CN:CH3OH=40:30:30 to H2O:CH3CN:CH3OH=1:49.5:49.5, flow rate=12 mL/min, 40℃, λnm, retention time : 30 min)로 정제하였다.The above Comp 4 (0.93 mmol) was dissolved in DMF (3.1 mL) together with Comp 1-1 (2.8 mmol, 3 eq) and heated at 85° C. for 16 hours. Upon completion of the reaction and cooling at room temperature, a precipitate is formed. After thoroughly washing the precipitate with water and hexane, the obtained Comp 5 (0.88 mmol, 94%) was dried in vacuo. If no precipitate formed, the reaction was prepared by prep HPLC (Shim-pack PREP-ODS, H 2 O:CH 3 CN:CH 3 OH=40:30:30 to H 2 O:CH 3 CN:CH 3 OH=1: 49.5:49.5, flow rate=12 mL/min, 40°C, λnm, retention time: 30 min).
[합성예 2-1][Synthesis Example 2-1]
본 발명에 따른 화학식 1로 표시되는 화합물은 하기 반응식 2-1와 같이 반응하여 제조될 수 있으며, 이에 한정되는 것은 아니다.The compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-1 below, but is not limited thereto.
<반응식 2-1><Scheme 2-1>
<반응식 2-2><Scheme 2-2>
상기 반응식 2-1 및 2-2에서, R1, R4, R5, R6, a 및 b는 상기 정의와 동일하다.In Schemes 2-1 and 2-2, R 1 , R 4 , R 5 , R 6 , a and b have the same definitions as above.
[합성예 2-2][Synthesis Example 2-2]
본 발명에 따른 화학식 1로 표시되는 화합물은 하기 반응식 2-3과 같이 반응하여 제조될 수 있으며, 이에 한정되는 것은 아니다.The compound represented by Formula 1 according to the present invention may be prepared by reacting as in Scheme 2-3 below, but is not limited thereto.
<반응식 2-3><Scheme 2-3>
<반응식 2-4><Scheme 2-4>
상기 반응식 2-3 및 2-4에서, R1a, R5, R6, a 및 b는 상기 정의와 동일하다.In Schemes 2-3 and 2-4, R 1a , R 5 , R 6 , a and b have the same definitions as above.
Comp 6 (2-아닐리노퀴나졸린-4(Comp 6 (2-anilinoquinazoline-4(
3H3H
)-온 유도체) 합성예시) -one derivative) Synthesis example
Comp 6의 합성Synthesis of Comp 6
Comp5 (200 mg, 0.587 mmol)을 디클로로메탄 (3 mL)과 트리에틸아민 (164 mL. 1.174 mmL)을 사용하여 녹이고 아세톡시아세틸 클로라이드 (195 mL, 1.761 mmol)를 첨가했다. 반응혼합물을 40 oC에서 2.5시간 동안 교반한 뒤 반응이 완료되면 디클로로메탄 (20 mL)을 사용하여 묽힌 뒤 물 (20 mL)로 씻어준다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 7)로 Comp 6 (162 mg, 63%)을 얻었다.Comp5 (200 mg, 0.587 mmol) was dissolved in dichloromethane (3 mL) and triethylamine (164 mL. 1.174 mmL) and acetoxyacetyl chloride (195 mL, 1.761 mmol) was added. The reaction mixture was stirred at 40 ° C for 2.5 hours, and when the reaction was complete, it was diluted with dichloromethane (20 mL) and washed with water (20 mL). Magnesium sulfate was added to the organic layer, filtered, and the filtrate was concentrated to obtain Comp 6 (162 mg, 63%) by silica gel chromatography (eluent ethyl acetate : hexane = 1 : 7).
상기 합성예 1, 2-1, 2-2, 2-3 및 2-4는 본 발명에 따른 화합물 합성방법의 일 예시로, 일부 시약, 용매, 화학반응순서 등의 변형을 포함한다.Synthesis Examples 1, 2-1, 2-2, 2-3, and 2-4 are examples of the compound synthesis method according to the present invention, and include modification of some reagents, solvents, and chemical reaction sequences.
실시예 1-1. 7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-1. 7-chloro-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 85%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 85%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.21 (s, 1H), 9.10 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 1.9 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.38 - 7.21 (m, 2H) ppm; 13C NMR (100 MHz, DMSO) δ161.01, 150.55, 148.00, 141.17, 139.18, 134.05, 127.89, 123.84, 121.78, 117.68, 114.68, 113.33 ppm; HRMS (FAB) calcd for [C14H8Cl3N3O]+ ([M]+):338.9733, found: 339.9813 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.21 (s, 1H), 9.10 (s, 1H), 7.97 (d, J = 8.5 Hz , 1H), 7.81 (d, J = 1.9 Hz, 2H ), 7.48 (d, J = 2.0 Hz, 1H), 7.38 - 7.21 (m, 2H) ppm; 13 C NMR (100 MHz, DMSO) δ 161.01, 150.55, 148.00, 141.17, 139.18, 134.05, 127.89, 123.84, 121.78, 117.68, 114.68, 113.33 ppm; HRMS (FAB) calcd for [C 14 H 8 Cl 3 N 3 O] + ([M] + ):338.9733, found: 339.9813 m/z [M+H] + .
실시예 1-2. 5,8-디클로로-2-((3,4-디클로로페닐)아미노)퀴나졸린-4(Example 1-2. 5,8-dichloro-2-((3,4-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 5,8-디클로로-2-((3,4-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 53%)을 얻었다.According to the synthesis method of Comp 5, 5,8-dichloro-2-((3,4-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 53%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.22 (s, 1H), 9.26 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H) ppm; LC/MS (ESI) 374.2 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.22 (s, 1H), 9.26 (s, 1H), 8.69 (d, J = 2.3 Hz , 1H), 7.81 (d, J = 8.5 Hz, 1H) ), 7.65 - 7.50 (m, 2H), 7.25 (d, J = 8.4 Hz, 1H) ppm; LC/MS (ESI) 374.2 m/z [M+H] + .
실시예 1-3. 5,8-디클로로-2-((2,4-디플로로페닐)아미노)퀴나졸린-4(Example 1-3. 5,8-dichloro-2-((2,4-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 녹색 고체의 5,8-디클로로-2-((2,4-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 77%)을 얻었다.According to the synthesis method of Comp 5, 5,8-dichloro-2-((2,4-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 77%) was obtained as a green solid.
1H NMR (400 MHz, DMSO) δ11.28 (s, 1H), 8.90 - 8.80 (m, 1H), 8.79 (s, 1H), 7.78 (dd, J = 8.5, 2.1 Hz, 1H), 7.39 (dd, J = 11.7, 8.7 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.16 (t, J = 9.1 Hz, 1H) ppm; LC/MS (ESI) 342.3 m/z [M+H]+. 1 H NMR (400 MHz, DMSO) δ11.28 (s, 1H), 8.90 - 8.80 (m, 1H), 8.79 (s, 1H), 7.78 (dd, J = 8.5, 2.1 Hz, 1H), 7.39 ( dd, J = 11.7, 8.7 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.16 (t, J = 9.1 Hz, 1H) ppm; LC/MS (ESI) 342.3 m/z [M+H] + .
실시예 1-4. 5,8-디클로로-2-((2,3,4-트리플로로페닐)아미노)퀴나졸린-4(3H)-온 합성예Example 1-4. Synthesis Example of 5,8-dichloro-2-((2,3,4-trifluorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 5의 합성방법에 따라 녹색 고체의 5,8-디클로로-2-((2,3,4-트리플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 78%)을 얻었다.5,8-dichloro-2-((2,3,4-trifluorophenyl)amino)quinazoline-4( 3H )-one (yield: 78%) as a green solid according to the synthesis method of Comp 5 above Got it.
1H NMR (400 MHz, DMSO) δ11.32 (s, 1H), 8.94 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.38 (t, J = 9.5 Hz, 1H), 7.26 - 7.23 (m, 1H) ppm; LC/MS (ESI) 360.3 m/z [M+H]+. 1 H NMR (400 MHz, DMSO) δ11.32 (s, 1H), 8.94 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 7.81 - 7.77 (m, 1H), 7.38 (t, J = 9.5 Hz, 1H), 7.26 - 7.23 (m, 1H) ppm; LC/MS (ESI) 360.3 m/z [M+H] + .
실시예 1-5. 5,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-5. 5,8-dichloro-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 5,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 45%)을 얻었다.According to the synthesis method of Comp 5, 5,8-dichloro-2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 45%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.22 (s, 1H), 9.29 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 10.1, 2.3 Hz, 2H), 7.26 (d, J = 8.5 Hz, 1H), 6.91 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C14H7Cl2F2N3O]+([M]+):340.9934, found: 340.9934. 1H NMR (300 MHz, DMSO- d6 ) δ11.22 (s, 1H) , 9.29 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 10.1, 2.3 Hz , 2H), 7.26 (d, J = 8.5 Hz, 1H), 6.91 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C 14 H 7 Cl 2 F 2 N 3 O] + ([M] + ):340.9934, found: 340.9934.
실시예 1-6. 7,8-디클로로-2-((3,4-디클로로페닐)아미노)퀴나졸린-4(Example 1-6. 7,8-dichloro-2-((3,4-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 옅은 노란색 고체의 7,8-디클로로-2-((3,4-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 23%)을 얻었다.According to the synthesis method of Comp 5, 7,8-dichloro-2-((3,4-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 23%) was obtained as a pale yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ11.25 (s, 1H), 9.27 (s, 1H), 8.64 (d, J = 2.1 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 7.67 - 7.50 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H) ppm; LC/MS (ESI) 373.9 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.25 (s, 1H), 9.27 (s, 1H), 8.64 (d, J = 2.1 Hz , 1H), 7.92 (d, J = 8.6 Hz, 1H) ), 7.67 - 7.50 (m, 2H), 7.46 (d, J = 8.6 Hz, 1H) ppm; LC/MS (ESI) 373.9 m/z [M+H] + .
실시예 1-7. 7,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-7. 7,8-dichloro-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 82%)을 얻었다.According to the synthesis method of Comp 5, 7,8-dichloro-2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 82%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.28 (s, 1H), 9.33 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.80 - 7.58 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 6.91 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C14H7Cl2F2N3O]+([M]+):340.9934, found: 340.9949. 1H NMR (300 MHz, DMSO- d6 ) δ11.28 (s, 1H) , 9.33 (s, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.80 - 7.58 (m, 2H), 7.47 (d, J = 8.6 Hz, 1H), 6.91 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C 14 H 7 Cl 2 F 2 N 3 O] + ([M] + ):340.9934, found: 340.9949.
실시예 1-8. 7,8-디클로로-2-(피페리딘-1-일)퀴나졸린-4(Example 1-8. 7,8-dichloro-2-(piperidin-1-yl)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7,8-디클로로-2-(피페리딘-1-일)퀴나졸린-4(3H)-온(수율: 55%)을 얻었다.According to the synthesis method of Comp 5, 7,8-dichloro-2-(piperidin-1-yl)quinazolin-4( 3H )-one (yield: 55%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.51 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.70 (t, J = 5.1 Hz, 4H), 1.58 (d, J = 7.8 Hz, 6H) ppm; LC/MS (ESI) 297.9 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.51 (s, 1H), 7.81 (d, J = 8.5 Hz , 1H), 7.25 (d, J = 8.5 Hz, 1H), 3.70 (t, J = 5.1 Hz, 4H), 1.58 (d, J = 7.8 Hz, 6H) ppm; LC/MS (ESI) 297.9 m/z [M+H] + .
실시예 1-9. 7-클로로-Example 1-9. 7-Chloro-
NN
-(3,5-디클로로페닐)-4-메틸퀴나졸린-2-아민 합성예-(3,5-dichlorophenyl)-4-methylquinazolin-2-amine Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-N-(3,5-디클로로페닐)-4-메틸퀴나졸린-2-아민(수율: 56%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro- N- (3,5-dichlorophenyl)-4-methylquinazolin-2-amine (yield: 56%) was obtained as a white solid.
1H NMR (300 MHz, Chloroform-d) δ7.86 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 1.8 Hz, 3H), 7.32 (dd, J = 8.8, 2.1 Hz, 1H), 7.04 (t, J = 1.8 Hz, 1H), 2.82 (s, 3H) ppm; LC/MS (ESI) 339.9 m/z [M+H]+. 1 H NMR (300 MHz, Chloroform- d ) δ7.86 (d, J = 8.8 Hz, 1H), 7.80 (t, J = 1.8 Hz, 3H), 7.32 (dd, J = 8.8, 2.1 Hz, 1H) , 7.04 (t, J = 1.8 Hz, 1H), 2.82 (s, 3H) ppm; LC/MS (ESI) 339.9 m/z [M+H] + .
실시예 1-10. 7-클로로-Example 1-10. 7-Chloro-
N2N2
-(3,5-디클로로페닐)퀴나졸린e-2,4-디아민 합성예- (3,5-dichlorophenyl) quinazoline e-2,4-diamine Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-N2-(3,5-디클로로페닐)퀴나졸린e-2,4-디아민(수율: 85%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-N 2 -(3,5-dichlorophenyl)quinazoline-2,4-diamine (yield: 85%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ10.22 (s, 1H), 8.64 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.91 - 7.76 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H) ppm; LC/MS (ESI) 339.3 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ10.22 (s, 1H), 8.64 (s, 1H), 8.22 (d, J = 8.8 Hz, 1H), 7.91 - 7.76 (m, 2H), 7.52 (d, J = 2.0 Hz, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.25 (s, 1H) ppm; LC/MS (ESI) 339.3 m/z [M+H] + .
실시예 1-11. 2-((3,5-디클로로페닐)아미노)-7-모르폴리노퀴나졸린-4(Example 1-11. 2-((3,5-dichlorophenyl)amino)-7-morpholinoquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-7-모르폴리노퀴나졸린-4(3H)-온(수율: 19%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-7-morpholinoquinazolin-4( 3H )-one (yield: 19%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ9.02 (s, 1H), 7.82 (s, 3H), 7.78 (s, 1H), 7.21 (t, J = 1.9 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 3.73 (d, J = 4.9 Hz, 4H), 3.30 (d, J = 6.5 Hz, 4H) ppm; LC/MS (ESI) 391.4 m/z [M+H]+. 1H NMR (300 MHz, DMSO) δ9.02 (s, 1H), 7.82 (s, 3H), 7.78 (s, 1H), 7.21 (t, J = 1.9 Hz, 1H), 6.97 (d, J = 9.2 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 3.73 (d, J = 4.9 Hz, 4H), 3.30 (d, J = 6.5 Hz, 4H) ppm; LC/MS (ESI) 391.4 m/z [M+H] + .
실시예 1-12. 2-((3,5-디플로로페닐)아미노)-7-니트로퀴나졸린-4(Example 1-12. 2-((3,5-difluorophenyl)amino)-7-nitroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 노란색 고체의 2-((3,5-디플로로페닐)아미노)-7-니트로퀴나졸린-4(3H)-온(수율: 65%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-7-nitroquinazolin-4( 3H )-one (yield: 65%) was obtained as a yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ11.40 (s, 1H), 9.27 (s, 1H), 8.26 - 8.15 (m, 2H), 7.98 (dd, J = 8.7, 2.3 Hz, 1H), 7.54 (d, J = 8.9 Hz, 2H), 6.92 (tt, J = 9.4, 2.3 Hz, 1H) ppm; LC/MS (ESI) 319.4 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.40 (s, 1H) , 9.27 (s, 1H), 8.26 - 8.15 (m, 2H), 7.98 (dd, J = 8.7, 2.3 Hz, 1H) , 7.54 (d, J = 8.9 Hz, 2H), 6.92 (tt, J = 9.4, 2.3 Hz, 1H) ppm; LC/MS (ESI) 319.4 m/z [M+H] + .
실시예 1-13. 2-((3,5-디클로로페닐)아미노)-7-니트로퀴나졸린-4(Example 1-13. 2-((3,5-dichlorophenyl)amino)-7-nitroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 노란색 고체의 2-((3,5-디클로로페닐)아미노)-7-니트로퀴나졸린-4(3H)-온(수율: 40%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-7-nitroquinazolin-4( 3H )-one (yield: 40%) was obtained as a yellow solid.
1H NMR (300 MHz, DMSO-d 6) δ11.51 (s, 1H), 9.23 (s, 1H), 8.19 (d, J = 8.7 Hz, 1H), 8.12 (d, J = 2.2 Hz, 1H), 7.99 (dd, J = 8.7, 2.3 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.28 (t, J = 1.9 Hz, 1H) ppm; LC/MS (ESI) 351.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.51 (s, 1H), 9.23 (s, 1H), 8.19 (d, J = 8.7 Hz , 1H), 8.12 (d, J = 2.2 Hz, 1H) ), 7.99 (dd, J = 8.7, 2.3 Hz, 1H), 7.87 - 7.80 (m, 2H), 7.28 (t, J = 1.9 Hz, 1H) ppm; LC/MS (ESI) 351.3 m/z [M+H] + .
실시예 1-14. 2-((3,5-디메틸페닐)아미노)-7-니트로퀴나졸린-4(Example 1-14. 2-((3,5-dimethylphenyl)amino)-7-nitroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 붉은색 고체의 2-((3,5-디메틸페닐)아미노)-7-니트로퀴나졸린-4(3H)-온(수율: 27%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dimethylphenyl)amino)-7-nitroquinazolin-4( 3H )-one (yield: 27%) was obtained as a red solid.
1H NMR (300 MHz, DMSO-d 6) δ11.15 (s, 1H), 8.71 (s, 1H), 8.24 - 8.08 (m, 2H), 7.92 (dd, J = 8.6, 2.3 Hz, 1H), 7.35 (s, 2H), 6.73 (s, 1H), 2.31 - 2.27 (m, 6H) ppm; LC/MS (ESI) 311.4 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ11.15 (s, 1H), 8.71 (s, 1H), 8.24 - 8.08 (m, 2H), 7.92 (dd, J = 8.6, 2.3 Hz, 1H) , 7.35 (s, 2H), 6.73 (s, 1H), 2.31 - 2.27 (m, 6H) ppm; LC/MS (ESI) 311.4 m/z [M+H] + .
실시예 1-15. 2-((3,5-디플로로페닐)아미노)-6,7-디메톡시퀴나졸린-4(Examples 1-15. 2-((3,5-difluorophenyl)amino)-6,7-dimethoxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 갈색 고체의 2-((3,5-디플로로페닐)아미노)-6,7-디메톡시퀴나졸린-4(3H)-온(수율: 56%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-6,7-dimethoxyquinazolin-4( 3H )-one (yield: 56%) was obtained as a brown solid. .
1H NMR (300 MHz, DMSO-d 6) δ10.84 (s, 1H), 8.98 (s, 1H), 7.56 - 7.44 (m, 2H), 7.33 (s, 1H), 6.97 (s, 1H), 6.83 (tt, J = 9.3, 2.3 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H) ppm; LC/MS (ESI) 334.4 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ10.84 (s, 1H), 8.98 (s, 1H), 7.56 - 7.44 (m, 2H), 7.33 (s, 1H), 6.97 (s, 1H) , 6.83 (tt, J = 9.3, 2.3 Hz, 1H), 3.90 (s, 3H), 3.82 (s, 3H) ppm; LC/MS (ESI) 334.4 m/z [M+H] + .
실시예 1-16. 2-((3,5-디클로로페닐)아미노)-6,7-디메톡시퀴나졸린-4(Example 1-16. 2-((3,5-dichlorophenyl)amino)-6,7-dimethoxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 회색 고체의 2-((3,5-디클로로페닐)아미노)-6,7-디메톡시퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-6,7-dimethoxyquinazolin-4( 3H )-one (yield: 99%) was obtained as a gray solid.
1H NMR (300 MHz, DMSO-d 6) δ11.44 (s, 1H), 10.80 (s, 1H), 7.87 (d, J = 1.9 Hz, 2H), 7.34 (s, 1H), 7.17 (t, J = 1.9 Hz, 1H), 6.91 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H) ppm; LC/MS (ESI) 366.3 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ11.44 (s, 1H), 10.80 (s, 1H), 7.87 (d, J = 1.9 Hz, 2H), 7.34 (s, 1H), 7.17 (t , J = 1.9 Hz, 1H), 6.91 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H) ppm; LC/MS (ESI) 366.3 m/z [M+H] + .
실시예 1-17. 2-((3,5-디메틸페닐)아미노)-6,7-디메톡시퀴나졸린-4(Example 1-17. 2-((3,5-dimethylphenyl)amino)-6,7-dimethoxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 암록색의 2-((3,5-디메틸페닐)아미노)-6,7-디메톡시퀴나졸린-4(3H)-온(수율: 84%)을 얻었다.According to the synthesis method of Comp 5, dark green 2-((3,5-dimethylphenyl)amino)-6,7-dimethoxyquinazolin-4( 3H )-one (yield: 84%) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ11.03 (s, 1H), 9.17 (s, 1H), 7.38 (s, 2H), 7.31 (s, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.28 (s, 6H) ppm; LC/MS (ESI) 326.5 m/z [M+H]+
.
1 H NMR (300 MHz, DMSO- d 6 ) δ11.03 (s, 1H), 9.17 (s, 1H), 7.38 (s, 2H), 7.31 (s, 1H), 6.89 (s, 1H), 6.65 (s, 1H), 3.89 (s, 3H), 3.81 (s, 3H), 2.28 (s, 6H) ppm; LC/MS (ESI) 326.5 m/z [M+H] + .
실시예 1-18. 6,8-디브로모-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-18. 6,8-dibromo-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 노란색 고체의 6,8-디브로모-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 32%)을 얻었다.According to the synthesis method of Comp 5, 6,8-dibromo-2-((3,5-difluorophenyl)amino)quinazoline-4( 3H )-one (yield: 32%) was obtained as a yellow solid. got it
1H NMR (300 MHz, DMSO-d 6) δ11.35 (s, 1H), 9.33 (s, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.82 - 7.62 (m, 2H), 6.90 (tt, J = 9.3, 2.4 Hz, 1H) ppm; LC/MS (ESI) 430.2 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.35 (s, 1H), 9.33 (s, 1H), 8.23 (d, J = 2.3 Hz , 1H), 8.04 (d, J = 2.3 Hz, 1H) ), 7.82 - 7.62 (m, 2H), 6.90 (tt, J = 9.3, 2.4 Hz, 1H) ppm; LC/MS (ESI) 430.2 m/z [M+H] + .
실시예 1-19. 6,8-디브로모-2-((3,5-디메틸페닐)아미노)퀴나졸린-4(Example 1-19. 6,8-dibromo-2-((3,5-dimethylphenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 베이지색 고체의 (수율: 41%)을 얻었다.According to the synthesis method of Comp 5, a beige solid (yield: 41%) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ11.15 (s, 1H), 8.89 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.62 - 7.55 (m, 2H), 6.71 (s, 1H), 2.29 (s, 6H) ppm; LC/MS (ESI) 422.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.15 (s, 1H), 8.89 (s, 1H), 8.19 (d, J = 2.3 Hz , 1H), 8.01 (d, J = 2.3 Hz, 1H) ), 7.62 - 7.55 (m, 2H), 6.71 (s, 1H), 2.29 (s, 6H) ppm; LC/MS (ESI) 422.3 m/z [M+H] + .
실시예 1-20. 2-((3,5-디메틸페닐)아미노)-6,7-디플로로퀴나졸린-4(Example 1-20. 2-((3,5-dimethylphenyl)amino)-6,7-difluoroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 회색 고체의 2-((3,5-디메틸페닐)아미노)-6,7-디플로로퀴나졸린-4(3H)-온(수율: 31%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dimethylphenyl)amino)-6,7-difluoroquinazolin-4( 3H )-one (yield: 31%) was obtained as a gray solid.
1H NMR (300 MHz, DMSO-d 6) δ10.01 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.80 - 6.70 (m, 2H), 2.23 - 2.22 (m, 6H) ppm; LC/MS (ESI) 302.4 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ10.01 (s, 1H), 8.22 ( d, J = 2.0 Hz, 1H), 7.23 - 7.15 (m, 2H), 6.80 - 6.70 (m, 2H) , 2.23 - 2.22 (m, 6H) ppm; LC/MS (ESI) 302.4 m/z [M+H] + .
실시예 1-21. 6,8-디브로모-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-21. 6,8-dibromo-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 노란색 고체의 6,8-디브로모-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 9%)을 얻었다.According to the synthesis method of Comp 5, 6,8-dibromo-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 9%) was obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ9.52 - 9.42 (m, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 2H), 8.05 (d, J = 2.3 Hz, 1H), 7.25 (t, J = 1.8 Hz, 1H) ppm; LC/MS (ESI) 462.2 m/z [M+H]+. 1H NMR (400 MHz, DMSO- d6 ) δ9.52 - 9.42 (m, 1H) , 8.23 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 1.9 Hz, 2H), 8.05 (d , J = 2.3 Hz, 1H), 7.25 (t, J = 1.8 Hz, 1H) ppm; LC/MS (ESI) 462.2 m/z [M+H] + .
실시예 1-22. 2-((3,5-디클로로페닐)아미노)-6,7-디플로로퀴나졸린-4(Example 1-22. 2-((3,5-dichlorophenyl)amino)-6,7-difluoroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 베이지색 고체의 2-((3,5-디클로로페닐)아미노)-6,7-디플로로퀴나졸린-4(3H)-온(수율: 10%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-6,7-difluoroquinazolin-4( 3H )-one (yield: 10%) was obtained as a beige solid. .
1H NMR (300 MHz, DMSO-d 6) δ10.55 (s, 1H), 8.89 (s, 1H), 8.33 (s, 1H), 7.65 (d, J = 1.9 Hz, 2H), 7.33 - 7.30 (m, 1H), 7.30 (s, 1H) ppm; LC/MS (ESI) 342.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ10.55 (s, 1H) , 8.89 (s, 1H), 8.33 (s, 1H), 7.65 (d, J = 1.9 Hz, 2H), 7.33 - 7.30 (m, 1H), 7.30 (s, 1H) ppm; LC/MS (ESI) 342.3 m/z [M+H] + .
실시예 1-23. 6,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-23. 6,8-dichloro-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 노란색 고체의 6,8-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 36%)을 얻었다.According to the synthesis method of Comp 5, 6,8-dichloro-2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 36%) was obtained as a yellow solid.
1H NMR (400 MHz, DMSO-d 6) δ11.36 (s, 1H), 9.32 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.75 - 7.64 (m, 2H), 6.91 (tt, J = 9.3, 2.4 Hz, 1H) ppm; HRMS (EI) calcd for [C14H7Cl2F2N3O]+([M]+):340.9934, found: 340.9936. 1H NMR (400 MHz, DMSO- d6 ) δ11.36 (s, 1H), 9.32 (s, 1H), 8.02 (d, J = 2.4 Hz , 1H), 7.89 (d, J = 2.4 Hz, 1H) ), 7.75 - 7.64 (m, 2H), 6.91 (tt, J = 9.3, 2.4 Hz, 1H) ppm; HRMS (EI) calcd for [C 14 H 7 Cl 2 F 2 N 3 O] + ([M] + ):340.9934, found: 340.9936.
실시예 1-24. 6,7-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-24. 6,7-dichloro-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 6,7-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 7.3%)을 얻었다.According to the synthesis method of Comp 5, 6,7-dichloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 7.3%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.38 (s, 1H), 9.21 (s, 1H), 8.05 (s, 1H), 7.79 (s, 2H), 7.69 (s, 1H), 7.25 (s, 1H) ppm; LC/MS (ESI) 374.4 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ11.38 (s, 1H), 9.21 (s, 1H), 8.05 (s, 1H), 7.79 (s, 2H), 7.69 (s, 1H), 7.25 (s, 1H) ppm; LC/MS (ESI) 374.4 m/z [M+H] + .
실시예 1-25. 6,7-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-25. 6,7-dichloro-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 6,7-디클로로-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 8.6%)을 얻었다.According to the synthesis method of Comp 5, 6,7-dichloro-2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 8.6%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.29 (s, 1H), 9.25 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.54 - 7.45 (m, 2H), 6.89 (tt, J = 9.3, 2.4 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO) δ163.74, 163.59, 161.33, 161.18, 160.16, 149.00, 148.19, 141.17, 137.09, 126.97, 125.70, 118.64, 102.54, 102.24, 97.99, 97.73, 97.47 ppm; HRMS (EI) calcd for [C14H7Cl2F2N3O]+([M]+):340.9934, found: 340.9935. 1 H NMR (300 MHz, DMSO- d 6 ) δ11.29 (s, 1H), 9.25 (s, 1H), 8.06 (s, 1H), 7.78 (s, 1H), 7.54 - 7.45 (m, 2H) , 6.89 (tt, J = 9.3, 2.4 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO) Δ163.74, 163.59, 161.33, 161.18, 160.16, 149.00, 148.19, 141.17, 137.09, 126.97, 125.70, 118.64, 102.54, 102.24, 97.99, 97.73, 97.47 ppm; HRMS (EI) calcd for [C 14 H 7 Cl 2 F 2 N 3 O] + ([M] + ):340.9934, found: 340.9935.
실시예 1-26. 5,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-26. 5,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 5,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 71%)을 얻었다.According to the synthesis method of Comp 5, 5,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 71%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.36 (s, 1H), 9.32 (s, 1H), 8.27 (d, J = 1.9 Hz, 1H), 8.07 (d, J = 1.9 Hz, 2H), 7.80 (d, J = 3.5 Hz, 1H), 7.26 (t, J = 1.8 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO) δ159.31, 148.19, 147.44, 140.82, 134.03, 133.84, 131.54, 127.91, 125.77, 121.68, 117.36, 116.69 ppm; HRMS (EI) calcd for [C14H7Cl4N3O]+([M]+):372.9343, found: 372.9343. 1H NMR (300 MHz, DMSO- d6 ) δ11.36 (s, 1H), 9.32 (s, 1H), 8.27 (d, J = 1.9 Hz , 1H), 8.07 (d, J = 1.9 Hz, 2H ), 7.80 (d, J = 3.5 Hz, 1H), 7.26 (t, J = 1.8 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO) δ 159.31, 148.19, 147.44, 140.82, 134.03, 133.84, 131.54, 127.91, 125.77, 121.68, 117.36, 116.69 ppm; HRMS (EI) calcd for [C 14 H 7 Cl 4 N 3 O] + ([M] + ):372.9343, found: 372.9343.
실시예 1-27. 6,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-27. 6,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 6,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 12.4%)을 얻었다.According to the synthesis method of Comp 5, 6,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 12.4%) was obtained as a white solid.
1H NMR (500 MHz, DMSO-d 6) δ11.48 (s, 1H), 9.39 (s, 1H), 8.04 (d, J = 1.9 Hz, 2H), 8.00 (t, J = 2.0 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO) δ160.64, 147.95, 145.48, 141.40, 134.49, 134.23, 130.41, 127.48, 124.52, 122.13, 121.19, 117.80 ppm; HRMS (EI) calcd for [C14H7Cl4N3O]+([M]+):372.9343, found: 372.9339. 1H NMR (500 MHz, DMSO- d6 ) δ11.48 (s, 1H), 9.39 (s, 1H), 8.04 (d, J = 1.9 Hz, 2H), 8.00 (t, J = 2.0 Hz, 1H ), 7.88 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 1.9 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO) δ 160.64, 147.95, 145.48, 141.40, 134.49, 134.23, 130.41, 127.48, 124.52, 122.13, 121.19, 117.80 ppm; HRMS (EI) calcd for [C 14 H 7 Cl 4 N 3 O] + ([M] + ):372.9343, found: 372.9339.
실시예 1-28. 2-((3,5-디플로로페닐)아미노)-6,7-디플로로퀴나졸린-4(Example 1-28. 2-((3,5-difluorophenyl)amino)-6,7-difluoroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)-6,7-디플로로퀴나졸린-4(3H)-온(수율: 4%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-6,7-difluoroquinazolin-4( 3H )-one (yield: 4%) was obtained as a white solid. got it
1H NMR (300 MHz, Acetone-d 6) δ7.66 (d, J = 11.1 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.68 (t, J = 9.1 Hz, 1H) ppm; LC/MS (ESI) 310.4 m/z [M+H]+. 1 H NMR (300 MHz, Acetone- d 6 ) δ7.66 (d, J = 11.1 Hz, 1H), 7.63 - 7.56 (m, 2H), 7.21 (d, J = 7.6 Hz, 1H), 6.68 (t , J = 9.1 Hz, 1 H) ppm; LC/MS (ESI) 310.4 m/z [M+H] + .
실시예 1-29. 7,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-29. 7,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7,8-디클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 10%)을 얻었다.According to the synthesis method of Comp 5, 7,8-dichloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 10%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.43 (s, 1H), 9.36 (s, 1H), 8.07 (d, J = 1.8 Hz, 2H), 7.93 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H) ppm; HRMS (EI) calcd for [C14H7Cl4N3O]+([M]+):372.9343, found: 372.9340. 1H NMR (300 MHz, DMSO- d6 ) δ11.43 (s, 1H), 9.36 (s, 1H), 8.07 (d, J = 1.8 Hz , 2H), 7.93 (d, J = 8.5 Hz, 1H ), 7.48 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H) ppm; HRMS (EI) calcd for [C 14 H 7 Cl 4 N 3 O] + ([M] + ):372.9343, found: 372.9340.
실시예 1-30. 2-((3,5-디클로로페닐)아미노)-7-(트리플로로메틸)퀴나졸린-4(Example 1-30. 2-((3,5-dichlorophenyl)amino)-7-(trifluoromethyl)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-7-(트리플로로메틸)퀴나졸린-4(3H)-온(수율: 33%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-7-(trifluoromethyl)quinazolin-4( 3H )-one (yield: 33%) was obtained as a white solid. .
1H NMR (300 MHz, Acetone-d 6) δ10.69 (s, 1H), 8.85 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.94 - 7.90 (m, 2H), 7.80 - 7.78 (m, 1H), 7.56 (dd, J = 8.3, 1.7 Hz, 1H), 7.18 (t, J = 1.8 Hz, 1H) ppm; 13C NMR (100 MHz, DMSO) δ160.84, 149.54, 148.05, 141.05, 134.05, 127.59, 125.01, 122.30, 121.91, 119.22, 117.77 ppm; HRMS (EI) calcd for [C15H8Cl2F3N3O]+([M]+):372.9997, found: 372.9996. 1 H NMR (300 MHz, Acetone- d 6 ) δ10.69 (s, 1H), 8.85 (s, 1H), 8.24 (d, J = 8.2 Hz, 1H), 7.94 - 7.90 (m, 2H), 7.80 - 7.78 (m, 1H), 7.56 (dd, J = 8.3, 1.7 Hz, 1H), 7.18 (t, J = 1.8 Hz, 1H) ppm; 13 C NMR (100 MHz, DMSO) δ 160.84, 149.54, 148.05, 141.05, 134.05, 127.59, 125.01, 122.30, 121.91, 119.22, 117.77 ppm; HRMS (EI) calcd for [C 15 H 8 Cl 2 F 3 N 3 O] + ([M] + ):372.9997, found: 372.9996.
실시예 1-31. 2-((3,5-디플로로페닐)아미노)-7-(트리플로로메틸)퀴나졸린-4(Example 1-31. 2-((3,5-difluorophenyl)amino)-7-(trifluoromethyl)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)-7-(트리플로로메틸)퀴나졸린-4(3H)-온(수율: 41%)을 얻었다.2-((3,5-difluorophenyl)amino)-7-(trifluoromethyl)quinazoline-4( 3H )-one as a white solid according to the synthesis method of Comp 5 (yield: 41%) got
1H NMR (300 MHz, Acetone-d 6) δ10.57 (s, 1H), 8.86 (s, 1H), 8.28 - 8.23 (m, 1H), 7.86 (dt, J = 1.7, 0.7 Hz, 1H), 7.63 - 7.54 (m, 3H), 6.73 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C15H8F5N3O]+([M]+):341.0588, found: 341.0591. 1 H NMR (300 MHz, Acetone- d 6 ) δ10.57 (s, 1H), 8.86 (s, 1H), 8.28 - 8.23 (m, 1H), 7.86 (dt, J = 1.7, 0.7 Hz, 1H) , 7.63 - 7.54 (m, 3H), 6.73 (tt, J = 9.2, 2.3 Hz, 1H) ppm; HRMS (EI) calcd for [C 15 H 8 F 5 N 3 O] + ([M] + ):341.0588, found: 341.0591.
실시예 1-32. 2-(페닐아미노)퀴나졸린-4(Example 1-32. 2-(phenylamino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-(페닐아미노)퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 2- (phenylamino)quinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ10.84 (s, 1H), 8.69 (s, 1H), 7.97 (dd, J = 7.9, 1.6 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.39 - 7.31 (m, 2H), 7.23 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.14 - 6.98 (m, 1H) ppm; LC/MS (ESI) 238.3 m/z [M+H]+
.
1H NMR (300 MHz, DMSO- d6 ) δ10.84 (s, 1H), 8.69 (s, 1H), 7.97 (dd, J = 7.9 , 1.6 Hz, 1H), 7.74 (d, J = 8.0 Hz , 2H), 7.65 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.39 - 7.31 (m, 2H), 7.23 (ddd, J = 8.1, 7.1, 1.1 Hz) , 1H), 7.14 - 6.98 (m, 1H) ppm; LC/MS (ESI) 238.3 m/z [M+H] + .
실시예 1-33. 2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-33. 2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 80%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 80%) was obtained as a white solid.
1H NMR (500 MHz, DMSO-d 6) δ11.11 (s, 1H), 9.04 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.84 (s, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H) ppm; LC/MS (ESI) 306.4 m/z [M+H]+. 1 H NMR (500 MHz, DMSO- d 6 ) δ11.11 (s, 1H), 9.04 (s, 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.84 (s, 2H), 7.69 (t , J = 7.7 Hz, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H) ppm; LC/MS (ESI) 306.4 m/z [M+H] + .
실시예 1-34. 2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-34. 2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.06 (s, 1H), 9.12 (s, 1H), 7.99 (dd, J = 7.9, 1.5 Hz, 1H), 7.69 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.29 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.86 (tt, J = 9.4, 2.4 Hz, 1H) ppm; LC/MS (ESI) 274.4 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.06 (s, 1H) , 9.12 (s, 1H), 7.99 (dd, J = 7.9, 1.5 Hz, 1H), 7.69 (ddd, J = 8.5, 7.1, 1.6 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.29 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.86 (tt, J = 9.4, 2.4 Hz, 1H) ppm; LC/MS (ESI) 274.4 m/z [M+H] + .
실시예 1-35. 7-아미노-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(Example 1-35. 7-amino-2-((3,5-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
2-((3,5-디플로로페닐)아미노)-7-니트로퀴나졸린-4(3H)-온(0.22 mmol)을 water/i-PrOH 용액(10/1, 1.21 mL)에 용해시켰다. Fe 분말(1.1 mmol) 및 NH4Cl (0.56 mmol)을 반응물에 첨가한 후 95℃에서 4시간 동안 가열하였다. 반응이 종결된 후 혼합물을 셀라이트로 여과하고 메탄올 및 에틸아세테이트로 세척하였다. 잔류 용매를 증발시킨 후 잔류물을 탄산수소나트륨 및 에틸아세테이트로 추출하였다. 유기층을 황산나트륨으로 여과하고 진공에서 농축시켰다. 잔류물을 prep-HPLC로 정제하여 노란색 고체의 7-아미노-2-((3,5-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 76%)을 얻었다.2-((3,5-difluorophenyl)amino)-7-nitroquinazolin-4( 3H )-one (0.22 mmol) was dissolved in water/ i -PrOH solution (10/1, 1.21 mL). . Fe powder (1.1 mmol) and NH 4 Cl (0.56 mmol) were added to the reaction mixture and heated at 95° C. for 4 hours. After the reaction was completed, the mixture was filtered through celite and washed with methanol and ethyl acetate. After evaporating the residual solvent, the residue was extracted with sodium bicarbonate and ethyl acetate. The organic layer was filtered over sodium sulfate and concentrated in vacuo. The residue was purified by prep-HPLC to obtain 7-amino-2-((3,5-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 76%) as a yellow solid.
1H NMR (500 MHz, DMSO-d 6) δ10.47 (s, 1H), 9.03 (s, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H), 6.81 (t, J = 9.4 Hz, 1H), 6.51 (d, J = 9.6 Hz, 2H), 5.95 (s, 2H) ppm; LC/MS (ESI) 289.1 m/z [M+H]+. 1H NMR (500 MHz, DMSO- d6 ) δ10.47 (s, 1H), 9.03 (s , 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 9.0 Hz, 2H) ), 6.81 (t, J = 9.4 Hz, 1H), 6.51 (d, J = 9.6 Hz, 2H), 5.95 (s, 2H) ppm; LC/MS (ESI) 289.1 m/z [M+H] + .
실시예 1-36. 7-아미노-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(Example 1-36. 7-amino-2-((3,5-dichlorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 베이지색 고체의 7-아미노-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 30%)을 얻었다.According to the synthesis method of Comp 5, 7-amino-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one (yield: 30%) was obtained as a beige solid.
1H NMR (500 MHz, DMSO-d 6) δ10.51 (s, 1H), 8.97 (s, 1H), 7.86 (s, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.18 (s, 1H), 6.52 - 6.46 (m, 2H), 5.98 (s, 2H) ppm; LC/MS (ESI) 321.4 m/z [M+H]+. 1 H NMR (500 MHz, DMSO- d 6 ) δ10.51 (s, 1H), 8.97 (s, 1H), 7.86 (s, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.18 (s , 1H), 6.52 - 6.46 (m, 2H), 5.98 (s, 2H) ppm; LC/MS (ESI) 321.4 m/z [M+H] + .
실시예 1-37. 2-((3,5-디플로로페닐)아미노)-6,8-디메틸퀴나졸린-4(Example 1-37. 2-((3,5-difluorophenyl)amino)-6,8-dimethylquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)-6,8-디메틸퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-6,8-dimethylquinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ8.18 (s, 1H), 7.64 (s, 2H), 7.59 (s, 1H), 7.56 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 2.54 (s, 3H), 2.45 (s, 3H) ppm; LC/MS (ESI) 302.4 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ8.18 (s, 1H), 7.64 (s, 2H), 7.59 (s, 1H), 7.56 (s, 1H), 7.09 (s, 1H), 6.86 (s, 1H), 2.54 (s, 3H), 2.45 (s, 3H) ppm; LC/MS (ESI) 302.4 m/z [M+H] + .
실시예 1-38. 2-((3,5-디클로로페닐)아미노)-6,8-디메틸퀴나졸린-4(Example 1-38. 2-((3,5-dichlorophenyl)amino)-6,8-dimethylquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-6,8-디메틸퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-6,8-dimethylquinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (500 MHz, DMSO-d 6) δ8.45 (s, 1H), 8.16 (s, 1H), 7.93 (s, 2H), 7.57 (s, 1H), 7.32 (d, J = 116.1 Hz, 2H), 2.54 (s, 3H), 2.44 (s, 3H) ppm; LC/MS (ESI) 334.4 m/z [M+H]+. 1 H NMR (500 MHz, DMSO- d 6 ) δ8.45 (s, 1H), 8.16 (s, 1H), 7.93 (s, 2H), 7.57 (s, 1H), 7.32 (d, J = 116.1 Hz , 2H), 2.54 (s, 3H), 2.44 (s, 3H) ppm; LC/MS (ESI) 334.4 m/z [M+H] + .
실시예 1-39. 2-((3,5-디플로로페닐)아미노)-8-히드록시퀴나졸린-4(Example 1-39. 2-((3,5-difluorophenyl)amino)-8-hydroxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)-8-히드록시퀴나졸린-4(3H)-온(수율: 66%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-8-hydroxyquinazolin-4( 3H )-one (yield: 66%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ10.92 (s, 1H), 9.50 (s, 1H), 9.08 (s, 1H), 7.68 - 7.54 (m, 2H), 7.44 (dd, J = 7.4, 2.0 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.84 (tt, J = 9.4, 2.4 Hz, 1H) ppm; LC/MS (ESI) 290.3 m/z [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 ) δ10.92 (s, 1H), 9.50 (s, 1H), 9.08 (s, 1H), 7.68 - 7.54 (m, 2H), 7.44 (dd, J = 7.4, 2.0 Hz, 1H), 7.16 - 7.07 (m, 2H), 6.84 (tt, J = 9.4, 2.4 Hz, 1H) ppm; LC/MS (ESI) 290.3 m/z [M+H] + .
실시예 1-40. 2-((3,5-디클로로페닐)아미노)-8-히드록시퀴나졸린-4(Example 1-40. 2-((3,5-dichlorophenyl)amino)-8-hydroxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-8-히드록시퀴나졸린-4(3H)-온(수율: 60%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-8-hydroxyquinazolin-4( 3H )-one (yield: 60%) was obtained as a white solid.
1H NMR (300 MHz, DMSO-d 6) δ11.02 (s, 1H), 9.44 (s, 1H), 8.99 (s, 1H), 7.95 (s, 2H), 7.44 (d, J = 7.4 Hz, 1H), 7.20 (s, 1H), 7.14 - 7.08 (m, 2H) ppm; LC/MS (ESI) 322.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ11.02 (s, 1H), 9.44 (s , 1H), 8.99 (s, 1H), 7.95 (s, 2H), 7.44 (d, J = 7.4 Hz , 1H), 7.20 (s, 1H), 7.14 - 7.08 (m, 2H) ppm; LC/MS (ESI) 322.3 m/z [M+H] + .
실시예 1-41. 2-((3,5-디플로로페닐)아미노)-5-메톡시퀴나졸린-4(Example 1-41. 2-((3,5-difluorophenyl)amino)-5-methoxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디플로로페닐)아미노)-5-메톡시퀴나졸린-4(3H)-온(수율: 55%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-difluorophenyl)amino)-5-methoxyquinazolin-4( 3H )-one (yield: 55%) was obtained as a white solid.
1H NMR (500 MHz, DMSO) δ10.68 (s, 1H), 8.97 (s, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.50 (d, J = 9.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.85 (tt, J = 9.2, 2.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H) ppm; LC/MS (ESI) 304.4 m/z [M+H]+. 1H NMR (500 MHz, DMSO) δ10.68 (s, 1H), 8.97 (s, 1H), 7.56 (t, J = 8.2 Hz, 1H), 7.50 (d, J = 9.1 Hz, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.85 (tt, J = 9.2, 2.2 Hz, 1H), 6.79 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H) ppm; LC/MS (ESI) 304.4 m/z [M+H] + .
실시예 1-42. 2-((3,5-디클로로페닐)아미노)-5-메톡시퀴나졸린-4(Example 1-42. 2-((3,5-dichlorophenyl)amino)-5-methoxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-5-메톡시퀴나졸린-4(3H)-온(수율: 55%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-5-methoxyquinazolin-4( 3H )-one (yield: 55%) was obtained as a white solid.
1H NMR (500 MHz, DMSO) δ10.74 (s, 1H), 8.91 (s, 1H), 7.82 (s, 2H), 7.56 (t, J = 8.2 Hz, 1H), 7.22 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H) ppm; LC/MS (ESI) 336.3 m/z [M+H]+. 1H NMR (500 MHz, DMSO) δ10.74 (s, 1H), 8.91 (s, 1H), 7.82 (s, 2H), 7.56 (t, J = 8.2 Hz, 1H), 7.22 (s, 1H) , 6.96 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H) ppm; LC/MS (ESI) 336.3 m/z [M+H] + .
실시예 1-43. 2-((3,5-디플로로페닐)아미노)-5-히드록시퀴나졸린-4(Example 1-43. 2-((3,5-difluorophenyl)amino)-5-hydroxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
2-((3,5-디플로로페닐)아미노)-5-메톡시퀴나졸린-4(3H)-온(0.5 mmol)을 DCM (5 mL)에 용해시켰다. BBr3 (1 M in MC, 0.6 mmol)를 -78℃에서 반응물에 천천히 적가한 후 반응물을 실온에서 3시간 동안 교반하였다. 반응이 종결된 후 반응물을 과량의 DCM으로 희석하고 물 및 염화암모늄으로 세척하였다. 유기층을 황산나트륨으로 건조시킨 후 여과 및 진공에서 농축하였다. 잔류물을 prep-HPLC로 정제하여 갈색 고체의 2-((3,5-디플로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.2-((3,5-difluorophenyl)amino)-5-methoxyquinazolin-4( 3H )-one (0.5 mmol) was dissolved in DCM (5 mL). BBr 3 (1 M in MC, 0.6 mmol) was slowly added dropwise to the reaction at -78 °C and then the reaction was stirred at room temperature for 3 hours. After the reaction was complete, the reaction was diluted with excess DCM and washed with water and ammonium chloride. The organic layer was dried over sodium sulfate, then filtered and concentrated in vacuo. The residue was purified by prep-HPLC to obtain 2-((3,5-difluorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (yield: 99%) as a brown solid.
1H NMR (500 MHz, DMSO) δ11.62 (s, 1H), 9.28 (s, 1H), 7.57 - 7.44 (m, 3H), 6.98 - 6.78 (m, 2H), 6.63 (d, J = 8.1 Hz, 1H) ppm; LC/MS (ESI) 290.4 m/z [M+H]+. 1 H NMR (500 MHz, DMSO) δ11.62 (s, 1H), 9.28 (s, 1H), 7.57 - 7.44 (m, 3H), 6.98 - 6.78 (m, 2H), 6.63 (d, J = 8.1 Hz, 1H) ppm; LC/MS (ESI) 290.4 m/z [M+H] + .
실시예 1-44. 2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(Example 1-44. 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온(수율: 62%)을 얻었다.According to the synthesis method of Comp 5, 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (yield: 62%) was obtained as a white solid.
1H NMR (500 MHz, DMSO) δ11.54 (s, 2H), 9.13 (s, 1H), 7.78 (s, 2H), 7.52 (t, J = 8.2 Hz, 1H), 7.28 (s, 1H), 6.84 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H) ppm; LC/MS (ESI) 322.3 m/z [M+H]+. 1 H NMR (500 MHz, DMSO) δ11.54 (s, 2H), 9.13 (s, 1H), 7.78 (s, 2H), 7.52 (t, J = 8.2 Hz, 1H), 7.28 (s, 1H) , 6.84 (d, J = 8.1 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H) ppm; LC/MS (ESI) 322.3 m/z [M+H] + .
실시예 1-45. 7-클로로-2-(페닐아미노)퀴나졸린-4(Example 1-45. 7-chloro-2-(phenylamino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-2-(페닐아미노)퀴나졸린-4(3H)-온(수율: 94%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-2-(phenylamino)quinazolin-4( 3H )-one (yield: 94%) was obtained as a white solid.
1H NMR (400 MHz, DMSO) δ10.91 (s, 1H), 8.76 (s, 1H), 7.97 - 7.92 (m, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.24 (dd, J = 8.6, 2.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H) ppm; LC/MS (ESI) 272.3 m/z [M+H]+. 1 H NMR (400 MHz, DMSO) δ10.91 (s, 1H), 8.76 (s, 1H), 7.97 - 7.92 (m, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 2.0 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.24 (dd, J = 8.6, 2.0 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H) ppm; LC/MS (ESI) 272.3 m/z [M+H] + .
실시예 1-46. 7-클로로-2-((3-플로로페닐)아미노)퀴나졸린-4(Example 1-46. 7-chloro-2-((3-fluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -one synthesis example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-2-((3-플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 93%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-2-((3-fluorophenyl)amino)quinazolin-4( 3H )-one (yield: 93%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ11.00 (s, 1H), 9.00 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 12.4, 2.6 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.5, 2.1 Hz, 1H), 6.91 - 6.84 (m, 1H) ppm; LC/MS (ESI) 290.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO) δ11.00 (s, 1H), 9.00 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.89 (dd, J = 12.4, 2.6 Hz, 1H) , 7.51 (d, J = 2.0 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.34 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.5, 2.1 Hz, 1H), 6.91 - 6.84 (m, 1H) ppm; LC/MS (ESI) 290.3 m/z [M+H] + .
실시예 1-47. 7-클로로-2-((2,4-디플로로페닐)아미노)퀴나졸린-4(Example 1-47. 7-chloro-2-((2,4-difluorophenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-2-((2,4-디플로로페닐)아미노)퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-2-((2,4-difluorophenyl)amino)quinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ11.24 (s, 1H), 8.62 (s, 1H), 8.44 (q, J = 9.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 7.15 - 7.08 (m, 1H) ppm; LC/MS (ESI) 308.3 m/z [M+H]+. 1 H NMR (300 MHz, DMSO) δ11.24 (s, 1H), 8.62 (s, 1H), 8.44 (q, J = 9.0 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 2.1 Hz, 1H), 7.41 - 7.33 (m, 1H), 7.26 (dd, J = 8.5, 2.1 Hz, 1H), 7.15 - 7.08 (m, 1H) ppm; LC/MS (ESI) 308.3 m/z [M+H] + .
실시예 1-48. 7-클로로-2-((3-메톡시페닐)아미노)퀴나졸린-4(Example 1-48. 7-chloro-2-((3-methoxyphenyl)amino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 7-클로로-2-((3-메톡시페닐)아미노)퀴나졸린-4(3H)-온(수율: 99%)을 얻었다.According to the synthesis method of Comp 5, 7-chloro-2-((3-methoxyphenyl)amino)quinazolin-4( 3H )-one (yield: 99%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ10.90 (s, 1H), 8.78 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 2.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.14 (dt, J = 8.2, 1.4 Hz, 1H), 6.66 - 6.62 (m, 1H), 3.78 (s, 3H) ppm; LC/MS (ESI) 302.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO) δ10.90 (s, 1H), 8.78 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.54 (t, J = 2.2 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.27 - 7.22 (m, 2H), 7.14 (dt, J = 8.2, 1.4 Hz, 1H), 6.66 - 6.62 (m, 1H), 3.78 (s, 3H) ppm ; LC/MS (ESI) 302.3 m/z [M+H] + .
실시예 1-49. 5,8-디클로로-2-(이소프로필아미노)퀴나졸린-4(Example 1-49. 5,8-dichloro-2-(isopropylamino)quinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 5,8-디클로로-2-(이소프로필아미노)퀴나졸린-4(3H)-온(수율: 26%)을 얻었다.According to the synthesis method of Comp 5, 5,8-dichloro-2-(isopropylamino)quinazolin-4( 3H )-one (yield: 26%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ11.09 (d, J = 144.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 6.5 Hz, 1H), 6.45 (s, 1H), 4.14 (d, J = 6.7 Hz, 1H), 1.21 (d, J = 6.5 Hz, 6H) ppm; LC/MS (ESI) 272.3 m/z [M+H]+. 1H NMR (300 MHz, DMSO) δ11.09 (d, J = 144.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.04 (dd, J = 8.4, 6.5 Hz, 1H), 6.45 (s, 1H), 4.14 (d, J = 6.7 Hz, 1H), 1.21 (d, J = 6.5 Hz, 6H) ppm; LC/MS (ESI) 272.3 m/z [M+H] + .
실시예 1-50. 2-(부틸아미노)-5,8-디클로로퀴나졸린-4(Example 1-50. 2-(butylamino)-5,8-dichloroquinazoline-4(
3H3H
)-온 합성예) -One Synthesis Example
상기 Comp 5의 합성방법에 따라 흰색 고체의 2-(부틸아미노)-5,8-디클로로퀴나졸린-4(3H)-온(수율: 70%)을 얻었다.According to the synthesis method of Comp 5, 2-(butylamino)-5,8-dichloroquinazolin-4( 3H )-one (yield: 70%) was obtained as a white solid.
1H NMR (300 MHz, DMSO) δ11.08 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 3.44 - 3.35 (m, 2H), 1.60 - 1.50 (m, 2H), 1.40 - 1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm; LC/MS (ESI) 286.3 m/z [M+H]+ . 1H NMR (300 MHz, DMSO) δ11.08 (s, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.55 (s, 1H), 3.44 - 3.35 (m, 2H), 1.60 - 1.50 (m, 2H), 1.40 - 1.29 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm; LC/MS (ESI) 286.3 m/z [M+H] + .
실시예 1-51. 3-아세틸-7-클로로-2-(3,5-디클로로페닐아미노)퀴나졸린-4(3H)-온Example 1-51. 3-acetyl-7-chloro-2-(3,5-dichlorophenylamino)quinazolin-4(3H)-one
1H NMR (300 MHz, Chloroform-d) δ 12.48 (s, 1H), 8.18 - 8.09 (m, 1H), 7.56 (t, J = 1.9 Hz, 1H), 7.34 (s, 1H), 7.28 (d, J = 2.0 Hz, 2H), 2.13 (s, 3H). 1 H NMR (300 MHz, Chloroform-d) δ 12.48 (s, 1H), 8.18 - 8.09 (m, 1H), 7.56 (t, J = 1.9 Hz, 1H), 7.34 (s, 1H), 7.28 (d , J = 2.0 Hz, 2H), 2.13 (s, 3H).
실시예 1-52. 7-클로로-2-(3,5-디플로로페닐아미노)퀴나졸린-4(3H)-온Example 1-52. 7-Chloro-2-(3,5-difluorophenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.14 (s, 1H), 7.96 (dt, J = 6.8, 3.3 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.29 (t, J = 5.9 Hz, 1H), 6.88 (q, J = 7.6, 5.9 Hz, 1H) ppm. 1H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 9.14 (s, 1H), 7.96 (dt, J = 6.8, 3.3 Hz, 1H), 7.58 - 7.44 (m, 3H), 7.29 (t , J = 5.9 Hz, 1H), 6.88 (q, J = 7.6, 5.9 Hz, 1H) ppm.
실시예 1-53. 7-클로로-2-(3-히드록시페닐아미노)퀴나졸린-4(3H)-온Example 1-53. 7-chloro-2-(3-hydroxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 9.43 (s, 1H), 8.69 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.46 (dd, J = 8.1, 2.4 Hz, 1H) ppm. 1H NMR (400 MHz, DMSO) δ 10.82 (s, 1H), 9.43 (s, 1H), 8.69 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.43 - 7.35 (m, 2H) ), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.03 (dd, J = 8.6, 2.1 Hz, 1H), 6.46 (dd, J = 8.1, 2.4 Hz, 1H) ppm.
실시예 1-54. 7-클로로-2-(3,5-디메톡시페닐아미노)퀴나졸린-4(3H)-온Example 1-54. 7-chloro-2-(3,5-dimethoxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.76 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.5, 2.0 Hz, 1H), 6.96 (d, J = 2.2 Hz, 2H), 6.23 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H) ppm. 1H NMR (400 MHz, DMSO) δ 10.86 (s, 1H), 8.76 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.25 ( dd, J = 8.5, 2.0 Hz, 1H), 6.96 (d, J = 2.2 Hz, 2H), 6.23 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H) ppm.
실시예 1-55. 5,8-디클로로-2-(3,5-디메톡시페닐아미노)퀴나졸린-4(3H)-온Example 1-55. 5,8-dichloro-2-(3,5-dimethoxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.90 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.14 (d, J = 2.2 Hz, 2H), 6.22 (t, J = 2.3 Hz, 1H), 3.77 (s, 6H) ppm. 1H NMR (400 MHz, DMSO) δ 10.93 (s, 1H), 8.90 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.14 ( d, J = 2.2 Hz, 2H), 6.22 (t, J = 2.3 Hz, 1H), 3.77 (s, 6H) ppm.
실시예 1-56. 5,8-디클로로-2-(3-메톡시페닐아미노)퀴나졸린-4(3H)-온Example 1-56. 5,8-dichloro-2-(3-methoxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.91 (s, 1H), 7.95 (t, J = 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.09 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 6.64 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.80 (s, 3H) ppm. 1H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.91 (s, 1H), 7.95 (t, J = 2.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.27 - 7.20 (m, 2H), 7.09 (ddd, J = 8.1, 2.1, 0.9 Hz, 1H), 6.64 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H), 3.80 (s, 3H) ppm.
실시예 1-57. 2-(3,5-디메톡시페닐아미노)-7-메톡시퀴나졸린-4(3H)-온Example 1-57. 2-(3,5-dimethoxyphenylamino)-7-methoxyquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.63 (s, 1H), 7.87 - 7.84 (m, 1H), 6.96 (d, J = 2.2 Hz, 2H), 6.83 - 6.81 (m, 2H), 6.22 (t, J = 2.2 Hz, 1H), 3.87 (s, 3H), 3.76 (s, 6H) ppm. 1 H NMR (400 MHz, DMSO) δ 10.57 (s, 1H), 8.63 (s, 1H), 7.87 - 7.84 (m, 1H), 6.96 (d, J = 2.2 Hz, 2H), 6.83 - 6.81 (m , 2H), 6.22 (t, J = 2.2 Hz, 1H), 3.87 (s, 3H), 3.76 (s, 6H) ppm.
실시예 1-58. 2-(3,5-디클로로페닐아미노)-7-메톡시퀴나졸린-4(3H)-온Example 1-58. 2-(3,5-dichlorophenylamino)-7-methoxyquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.98 (s, 1H), 7.90 - 7.86 (m, 1H), 7.84 - 7.79 (m, 2H), 7.23 (t, J = 1.9 Hz, 1H), 6.88 - 6.85 (m, 2H), 3.88 (s, 3H) ppm. 1H NMR (400 MHz, DMSO) δ 10.89 (s, 1H), 8.98 (s, 1H), 7.90 - 7.86 (m, 1H), 7.84 - 7.79 (m, 2H), 7.23 (t, J = 1.9 Hz , 1H), 6.88 - 6.85 (m, 2H), 3.88 (s, 3H) ppm.
실시예 1-59. 2-(3,5-디플로로페닐아미노)-7-메톡시퀴나졸린-4(3H)-온Examples 1-59. 2-(3,5-difluorophenylamino)-7-methoxyquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.55 - 7.48 (m, 2H), 6.93 (d, J = 2.5 Hz, 1H), 6.91 - 6.85 (m, 2H), 3.89 (s, 3H) ppm. 1H NMR (400 MHz, DMSO) δ 9.25 (s, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.55 - 7.48 (m, 2H), 6.93 (d, J = 2.5 Hz, 1H), 6.91 - 6.85 (m, 2H), 3.89 (s, 3H) ppm.
실시예 1-60. 7-클로로-2-(3,5-디히드록시페닐아미노)퀴나졸린-4(3H)-온Example 1-60. 7-chloro-2-(3,5-dihydroxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 9.25 (s, 2H), 8.63 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 6.68 (d, J = 2.1 Hz, 2H), 5.93 (t, J = 2.1 Hz, 1H) ppm. 1H NMR (400 MHz, DMSO) δ 10.78 (s, 1H), 9.25 (s, 2H), 8.63 (s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.24 (dd, J = 8.4, 2.1 Hz, 1H), 6.68 (d, J = 2.1 Hz, 2H), 5.93 (t, J = 2.1 Hz, 1H) ppm.
실시예 1-61. 5,8-디클로로-2-(3,5-디히드록시페닐아미노)퀴나졸린-4(3H)-온Example 1-61. 5,8-dichloro-2-(3,5-dihydroxyphenylamino)quinazolin-4(3H)-one
1H NMR (300 MHz, DMSO) δ 10.78 (s, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 2.1 Hz, 2H), 5.98 (t, J = 2.1 Hz, 1H)ppm. 1H NMR (300 MHz, DMSO) δ 10.78 (s, 1H), 8.66 (s, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.76 ( d, J = 2.1 Hz, 2H), 5.98 (t, J = 2.1 Hz, 1H) ppm.
실시예 1-62. 5,8-디클로로-2-(3-히드록시페닐아미노)퀴나졸린-4(3H)-온Example 1-62. 5,8-dichloro-2-(3-hydroxyphenylamino)quinazolin-4(3H)-one
1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 9.43 (s, 1H), 8.79 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.22 - 7.10 (m, 2H), 6.49 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H) ppm. 1H NMR (300 MHz, DMSO) δ 10.87 (s, 1H), 9.43 (s, 1H), 8.79 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.35 - 7.28 (m, 2H) ), 7.22 - 7.10 (m, 2H), 6.49 (ddd, J = 8.0, 2.3, 0.9 Hz, 1H) ppm.
실시예 1-63. 8-클로로-2-(3,5-디플로로페닐아미노)퀴나졸린-4(3H)-온Example 1-63. 8-Chloro-2-(3,5-difluorophenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.25 (s, 1H), 7.95 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 (dd, J = 7.8, 1.5 Hz, 1H), 7.76 - 7.65 (m, 2H), 7.26 (t, J = 7.9 Hz, 1H), 6.89 (tt, J = 9.3, 2.3 Hz, 1H) ppm. 1H NMR (400 MHz, DMSO) δ 11.17 (s, 1H), 9.25 (s, 1H), 7.95 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 (dd, J = 7.8, 1.5 Hz, 1H) ), 7.76 - 7.65 (m, 2H), 7.26 (t, J = 7.9 Hz, 1H), 6.89 (tt, J = 9.3, 2.3 Hz, 1H) ppm.
실시예 1-64. 8-클로로-2-(3,5-디클로로페닐아미노)퀴나졸린-4(3H)-온Example 1-64. 8-Chloro-2-(3,5-dichlorophenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 9.21 (s, 1H), 8.07 (d, J = 1.9 Hz, 2H), 7.95 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 (dd, J = 7.8, 1.5 Hz, 1H), 7.29 - 7.23 (m, 2H) ppm. 1H NMR (400 MHz, DMSO) δ 11.25 (s, 1H), 9.21 (s, 1H), 8.07 (d, J = 1.9 Hz, 2H), 7.95 (dd, J = 7.9, 1.5 Hz, 1H), 7.88 (dd, J = 7.8, 1.5 Hz, 1H), 7.29 - 7.23 (m, 2H) ppm.
실시예 1-65. 8-클로로-2-(3,5-디메톡시페닐아미노)퀴나졸린-4(3H)-온Example 1-65. 8-Chloro-2-(3,5-dimethoxyphenylamino)quinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.89 (s, 1H), 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (dd, J = 7.8, 1.5 Hz, 1H), 7.24 - 7.15 (m, 3H), 6.21 (t, J = 2.3 Hz, 1H), 3.78 (s, 6H) ppm. 1H NMR (400 MHz, DMSO) δ 10.91 (s, 1H), 8.89 (s, 1H), 7.93 (dd, J = 7.9, 1.5 Hz, 1H), 7.84 (dd, J = 7.8, 1.5 Hz, 1H) ), 7.24 - 7.15 (m, 3H), 6.21 (t, J = 2.3 Hz, 1H), 3.78 (s, 6H) ppm.
실시예 1-66. 2-(3,5-디플로로페닐아미노)-7-플로로퀴나졸린-4(3H)-온Example 1-66. 2-(3,5-difluorophenylamino)-7-fluoroquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.14 (s, 1H), 8.03 (dd, J = 8.8, 6.5 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.26 (dd, J = 10.6, 2.5 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.88 (ddd, J = 9.3, 7.0, 2.4 Hz, 1H) ppm. 1H NMR (400 MHz, DMSO) δ 11.06 (s, 1H), 9.14 (s, 1H), 8.03 (dd, J = 8.8, 6.5 Hz, 1H), 7.53 - 7.47 (m, 2H), 7.26 (dd , J = 10.6, 2.5 Hz, 1H), 7.15 - 7.09 (m, 1H), 6.88 (ddd, J = 9.3, 7.0, 2.4 Hz, 1H) ppm.
실시예 1-67. 2-(3,5-디클로로페닐아미노)-7-플로로퀴나졸린-4(3H)-온Example 1-67. 2-(3,5-dichlorophenylamino)-7-fluoroquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.08 (s, 1H), 8.03 (dd, J = 8.8, 6.5 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.27 - 7.06 (m, 3H) ppm. 1H NMR (400 MHz, DMSO) δ 11.14 (s, 1H), 9.08 (s, 1H), 8.03 (dd, J = 8.8, 6.5 Hz, 1H), 7.85 - 7.75 (m, 2H), 7.27 - 7.06 (m, 3H) ppm.
실시예 1-68. 2-(3,5-디메톡시페닐아미노)-7-플로로퀴나졸린-4(3H)-온Example 1-68. 2-(3,5-Dimethoxyphenylamino)-7-fluoroquinazolin-4(3H)-one
1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.74 (s, 1H), 8.01 (dd, J = 8.8, 6.6 Hz, 1H), 7.17 (dd, J = 10.7, 2.5 Hz, 1H), 7.08 (td, J = 8.7, 2.5 Hz, 1H), 6.96 (d, J = 2.3 Hz, 2H), 6.22 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H) ppm. 1H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 8.74 (s, 1H), 8.01 (dd, J = 8.8, 6.6 Hz, 1H), 7.17 (dd, J = 10.7, 2.5 Hz, 1H) ), 7.08 (td, J = 8.7, 2.5 Hz, 1H), 6.96 (d, J = 2.3 Hz, 2H), 6.22 (t, J = 2.2 Hz, 1H), 3.76 (s, 6H) ppm.
실시예 2-1 & 2-2.Example 2-1 & 2-2.
(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 피발레이트 / ((7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4-일)옥시)메틸 피발레이트(7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-yl)methyl pivalate / ((7-chloro-2-((3,5- dichlorophenyl)amino)quinazolin-4-yl)oxy)methyl pivalate
상기 Comp 6의 합성방법에 따라 (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 피발레이트 (실시예 2-1) 및 ((7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4-일)옥시)메틸 피발레이트 (실시예 2-2)을 얻었다. According to the synthesis method of Comp 6, (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl pivalate (Example 2-1) and ((7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4-yl)oxy)methyl pivalate (Example 2-2).
구체적으로, 테스트 튜브(test tube)에 (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (0.6 mmol, 200 mg)를 넣고 포타시움 카보네이트(potassium carbonate) (0.72 mmol, 99.5 mg)를 넣고, 디메틸아세트아미드(Dimethylacetamide) (6 mL)을 넣어 모두 녹여준 뒤, 아이오도 메틸피발레이트(Iodomethyl pivalate) (0.9 mmol, 140 μL)를 천천히 넣어주었다. rt에서 12시간 정도 교반한 뒤 반응이 끝나면 물과 EA로 워크업(work-up)을 해준 뒤 유기층을 MgSO4에 건조(drying) 후 필터한 뒤 증발(evaporation) 하여 미정제물(crude)를 얻었다. 미정제물(Crude)는 실리카(silica)로 정제(purify)하여 화합물(product)를 얻었다. (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 피발레이트 (실시예 2-1) (53 mg, 20%)와 ((7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4-일)옥시)메틸 피발레이트 (실시예 2-2) (94 mg, 35%)를 얻었다.Specifically, in a test tube (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (0.6 mmol, 200 mg), add potassium carbonate (0.72 mmol, 99.5 mg), add dimethylacetamide (6 mL) and dissolve them all, then iodomethyl pivalate (0.9 mmol, 140 μL) was added slowly. After stirring at rt for about 12 hours, after the reaction was completed, work-up was performed with water and EA, and the organic layer was dried in MgSO 4 , filtered, and evaporated to obtain a crude product. . The crude product was purified with silica to obtain a product. (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl pivalate (Example 2-1) (53 mg, 20%) ((7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4-yl)oxy)methyl pivalate (Example 2-2) (94 mg, 35%) was obtained.
2-1) 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.65 (s, 2H), 7.49 (s, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.12 (t, J = 1.8 Hz, 1H), 6.11 (s, 2H), 1.29 (s, 9H);2-1) 1 H NMR (300 MHz, CDCl 3 ) δ 9.30 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.65 (s, 2H), 7.49 (s, 1H), 7.22 ( d, J = 2.0 Hz, 1H), 7.12 (t, J = 1.8 Hz, 1H), 6.11 (s, 2H), 1.29 (s, 9H);
2-2) 1H NMR (300 MHz, CDCl3) δ 8.00 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.8 Hz, 2H), 7.40 (dd, J = 8.8, 1.9 Hz, 1H), 7.19 (t, J = 1.8 Hz, 1H), 6.26 (s, 2H), 1.24 (s, 9H); 2-2) 1 H NMR (300 MHz, CDCl 3 ) δ 8.00 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 1.9 Hz, 1H), 7.69 (d, J = 1.8 Hz, 2H) , 7.40 (dd, J = 8.8, 1.9 Hz, 1H), 7.19 (t, J = 1.8 Hz, 1H), 6.26 (s, 2H), 1.24 (s, 9H);
실시예 2-3. (2-((3,5-디플루오로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 피발레이트Example 2-3. (2-((3,5-difluorophenyl)amino)-5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate
상기 실시예 2-1의 과정과 동일하게 반응시키되, (2-((3,5-디플로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온) (실시예 1-43)을 사용하여, (2-((3,5-디플루오로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 피발레이트 (실시예 2-3)를 얻었다.The reaction was carried out in the same manner as in Example 2-1, but (2-((3,5-difluorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one) (Example 1- 43) using (2-((3,5-difluorophenyl)amino)-5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl pivalate (Example 2-3 ) was obtained.
1H NMR (500 MHz, CDCl3)δ11.15(s,1H),9.24(s,1H),7.54(t,J = 8.1 Hz, 1H), 7.41 - 7.28 (m, 2H), 6.95 (d, J = 8.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.55 (tt, J = 8.9, 2.3 Hz, 1H), 6.09 (s, 2H), 1.29 (s, 9H) ppm; 1 H NMR (500 MHz, CDCl 3 )δ 11.15(s, 1H), 9.24(s, 1H), 7.54(t, J = 8.1 Hz, 1H), 7.41 - 7.28 (m, 2H), 6.95 (d , J = 8.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 1H), 6.55 (tt, J = 8.9, 2.3 Hz, 1H), 6.09 (s, 2H), 1.29 (s, 9H) ppm;
실시예 2-4. ((2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4-일)옥시)메틸 피발레이트Example 2-4. ((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate
상기 실시예 2-1의 과정과 동일하게 반응시키되, 2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온 (실시예 1-44)을 사용하여, ((2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4-일)옥시)메틸 피발레이트 (실시예 2-4)를 얻었다.The reaction was carried out in the same manner as in Example 2-1, but using 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44). Thus, ((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-4) was obtained.
1H NMR (400 MHz, CDCl3) δ 11.15 (s, 1H), 9.20 (s, 1H), 7.64 (d, J = 1.9 Hz, 2H), 7.55 (t, J = 8.2 Hz, 1H), 7.10 (t, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.1, 1.0 Hz, 1H), 6.75 (dd, J = 8.3, 1.0 Hz, 1H), 6.08 (s, 2H), 1.30 (s, 9H) ppm; 436.5 m/z [M+H]+
1H NMR (400 MHz, CDCl 3 ) δ 11.15 (s, 1H), 9.20 (s, 1H), 7.64 (d, J = 1.9 Hz, 2H), 7.55 (t, J = 8.2 Hz, 1H), 7.10 (t, J = 1.8 Hz, 1H), 6.97 (dd, J = 8.1, 1.0 Hz, 1H), 6.75 (dd, J = 8.3, 1.0 Hz, 1H), 6.08 (s, 2H), 1.30 (s, 9H) ppm; 436.5 m/z [M+H] +
실시예 2-5 & 2-6 & 2-7.Examples 2-5 & 2-6 & 2-7.
디-tert-부틸((7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸) 포스페이트 / (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 / 소디움(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 포스페이트Di-tert-butyl((7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl) phosphate / (7-chloro-2-( (3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate / sodium (7-chloro-2-((3,5-dichlorophenyl)amino)- 4-oxoquinazolin-3(4H)-yl)methyl phosphate
상기 Comp 6의 합성방법에 따라 디-tert-부틸((7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸) 포스페이트 (실시예 2-5); (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 (실시예 2-6); 및 소디움(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 포스페이트 (실시예 2-7)을 얻었다. 구체적인 제조과정은 하기와 같다.Di-tert-butyl ((7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl) phosphate (according to the synthesis method of Comp 6 above) Example 2-5); (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate (Example 2-6); and sodium (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl phosphate (Example 2-7). The specific manufacturing process is as follows.
100 mL RBF에 실시예 1-1 화합물(7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (2.94 mmol, 1000 mg)을 넣고, 소디움 아이오다이드(sodium iodide) (1.76 mmol, 264 mg)와 세슘 카보네이트(cesium carbonate) (8.82 mmol, 2874 mg)를 넣고 실링(sealing) 후 질소 치환을 하였다. DMAc (29.4 mL)를 넣어 교반한 후, 디-tert-부틸 클로로메틸 포스페이트(Di-tert-butyl chloromethyl phosphate) (7.35 mmol, 1.73 mL)를 넣고 60 oC로 가열하였다. 반응이 끝나면 물과 EA로 워크업(work-up) 한 후 유기층을 모아 MgSO4에 건조(drying) 후 필터하고, 증발(evaporation) 하여 미정제물(crude)를 얻는다. 미정제물(Crude)의 정제(purification)는 실리카(silica)에서 EA/Hx 10% - 15%를 전개액(eluent)으로 컬럼 크로마토그래피(column chromatography)를 진행하여 ((2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4-일)옥시)메틸 피발레이트 (실시예 2-5) (380 mg, 23%)을 얻는다.Example 1-1 compound (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (2.94 mmol, 1000 mg) was added to 100 mL RBF, sodium eye Sodium iodide (1.76 mmol, 264 mg) and cesium carbonate (8.82 mmol, 2874 mg) were added, sealed, and nitrogen substitution was performed. After adding DMAc (29.4 mL) and stirring, di-tert-butyl chloromethyl phosphate (7.35 mmol, 1.73 mL) was added and heated to 60 ° C. After the reaction is completed, the organic layer is collected after work-up with water and EA, dried in MgSO 4 , filtered, and evaporated to obtain a crude product. Purification of the crude product was carried out by column chromatography using EA/Hx 10% - 15% as an eluent in silica ((2-((3,5 -Dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-5) (380 mg, 23%) is obtained.
2-5) 1H NMR (300 MHz, CDCl3) δ 10.01 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 1.8 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 7.08 (t, J = 1.8 Hz, 1H), 5.97 (d, J = 11.9 Hz, 2H), 1.49 (s, 18H) ppm;2-5) 1 H NMR (300 MHz, CDCl 3 ) δ 10.01 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 1.8 Hz, 2H), 7.48 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.5, 2.0 Hz, 1H), 7.08 (t, J = 1.8 Hz, 1H), 5.97 (d, J = 11.9 Hz, 2H), 1.49 (s, 18H) ppm;
50 mL RBF에 상기 수득한 ((2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4-일)옥시)메틸 피발레이트 (실시예 2-5) (380 mg, 0.675 mmol)를 넣고 DCM (13.5 mL)을 넣어 교반하였다. TFA (20.25 mmol, 1.6 mL)을 천천히 적가하였다. 반응이 끝나면 증발(evaporation) 하여 (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 (실시예 2-6) (304 mg, 99%)를 얻었다.((2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4-yl)oxy)methyl pivalate (Example 2-5) (380 mg, 0.675 mmol) was added and DCM (13.5 mL) was added and stirred. TFA (20.25 mmol, 1.6 mL) was added dropwise slowly. After the reaction was completed, it was evaporated to obtain (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate (Example 2- 6) (304 mg, 99%) was obtained.
2-6) 1H NMR (500 MHz, Acetone) δ 8.06 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1.9 Hz, 2H), 7.45 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.4, 2.1 Hz, 1H), 7.18 - 7.09 (m, 1H), 6.08 (d, J = 11.6 Hz, 2H) ppm;2-6) 1 H NMR (500 MHz, Acetone) δ 8.06 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 1.9 Hz, 2H), 7.45 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 8.4, 2.1 Hz, 1H), 7.18 - 7.09 (m, 1H), 6.08 (d, J = 11.6 Hz, 2H) ppm;
테스트 튜브(Test tube)에 상기 (7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 (실시예 2-6) (0.675 mmol, 300 mg)를 넣고 이소프로필 알코올(Isopropyl alcohol) (3 mL)을 넣었다. 2 N NaOH (0.8 mL)을 천천히 적가 한 뒤 60 oC로 가열하여 염 형태(salt form)를 얻었다. 증발(Evaporation) 하여 소디움(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)메틸 포스페이트 (실시예 2-7) (333 mg, 99%)을 얻었다.In a test tube, the above (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate (Example 2- 6) (0.675 mmol, 300 mg) was added and isopropyl alcohol (3 mL) was added. 2 N NaOH (0.8 mL) was slowly added dropwise and heated to 60 ° C to obtain a salt form. Evaporation to sodium (7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)methyl phosphate (Example 2-7) (333 mg , 99%) was obtained.
2-7) 1H NMR (500 MHz, DMSO) δ 7.96 (s, 3H), 7.33 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 5.63 (d, J = 10.3 Hz, 2H) ppm;2-7) 1 H NMR (500 MHz, DMSO) δ 7.96 (s, 3H), 7.33 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 5.63 (d, J = 10.3 Hz , 2H) ppm;
실시예 2-8 & 2-9. Examples 2-8 & 2-9.
메틸-7-클로로-2-((3,5-디클로로페닐)(메톡시카르보닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트 / 메틸-7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트Methyl-7-chloro-2-((3,5-dichlorophenyl)(methoxycarbonyl)amino)-4-oxoquinazoline-3(4H)-carboxylate / methyl-7-chloro-2-( (3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carboxylate
상기 Comp 6의 합성방법에 따라 메틸-7-클로로-2-((3,5-디클로로페닐)(메톡시카르보닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트 (실시예 2-8); 및 메틸-7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트 (실시예 2-9)을 얻었다. According to the synthesis method of Comp 6, methyl-7-chloro-2-((3,5-dichlorophenyl) (methoxycarbonyl) amino) -4-oxoquinazoline-3 (4H) -carboxylate (practice Examples 2-8); and methyl-7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carboxylate (Example 2-9).
구체적으로, 테스트튜브(Test tube)에 (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (0.15 mmol, 50 mg)을 넣고, 소디움 하이드라이드(sodium hydride) (0.45 mmol, 11 mg)을 넣고 DMF를 넣어 교반하였다. 온도를 0 oC로 낮춘 뒤 메틸 클로로포르메이트(Methyl chloroformate) (0.45 mmol, 35 μL)를 천천히 적가하였다. 그 뒤 rt에서 반응을 진행하였다. 반응이 끝나면 물과 EA로 워크업(work-up)을 하였다. 유기층을 모아 MgSO4에 건조(drying) 후 필터하고 증발(evaporation) 하여 미정제물(crude)를 얻는다. 미정제물(Crude)의 정제(purification)는 실리카(silica)에서 MeOH/MC 4% - 5%를 전개액(eluent)으로 컬럼 크로마토그래피(column chromatography)를 진행하여 메틸-7-클로로-2-((3,5-디클로로페닐)(메톡시카르보닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트 (실시예 2-8) (43 mg, 64%), 메틸-7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카르복실레이트 (실시예 2-9) (10 mg, 17%)를 얻었다.Specifically, in a test tube (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (0.15 mmol, 50 mg), sodium hydride (0.45 mmol, 11 mg) was added, DMF was added, and the mixture was stirred. After lowering the temperature to 0 ° C, methyl chloroformate (0.45 mmol, 35 μL) was slowly added dropwise. Then, the reaction proceeded at rt. After the reaction, work-up was performed with water and EA. The organic layer was collected, dried over MgSO 4 , filtered, and evaporated to obtain a crude product. Purification of the crude product was carried out by column chromatography using MeOH/MC 4% - 5% as an eluent in silica to obtain methyl-7-chloro-2-( (3,5-dichlorophenyl)(methoxycarbonyl)amino)-4-oxoquinazoline-3(4H)-carboxylate (Example 2-8) (43 mg, 64%), methyl-7- Chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carboxylate (Example 2-9) (10 mg, 17%) was obtained.
2-8) 1H NMR(400MHz, DMSO) δ 8.17 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.65 - 7.62 (m, 1H), 7.58 (t, J = 1.9 Hz, 1H), 3.80 (s, 3H), 3.47 (s, 3H) ppm;2-8) 1H NMR (400MHz, DMSO) δ 8.17 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 2H), 7.65 - 7.62 (m, 1H), 7.58 (t, J = 1.9 Hz, 1H), 3.80 (s, 3H), 3.47 (s, 3H) ppm;
2-9) 1H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.58 (s, 1H), 7.57 - 7.51 (m, 2H), 3.77 (s, 3H) ppm; LJY-21-018-2 LC/MS (ESI) 398.2 m/z [M+H]+
2-9) 1 H NMR (400 MHz, DMSO) δ 12.82 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.58 (s, 1H), 7.57 - 7.51 (m, 2H), 3.77 (s, 3H) ppm; LJY-21-018-2 LC/MS (ESI) 398.2 m/z [M+H] +
실시예 2-10. 3-아세틸-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온Example 2-10. 3-acetyl-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 6의 3-아세틸-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-10)을 얻었다. 3-acetyl-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one of Comp 6 (Example 2-10) was obtained.
구체적으로, 250 mL RBF에 (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (10 mmol, 3 g)을 넣고 아세틱 안하이드라이드(Acetic anhydride) (100 mL)를 넣고 교반한 뒤 TEA (30 mmoL, 4 mL)을 천천히 적가하였다. 반응물을 85 oC로 가열하여 반응을 진행하였다. 반응이 끝나면 브린(brine)과 EA로 워크업(Work-up)을 한 뒤 유기층을 MgSO4로 건조(drying) 한 후 필터한 뒤 증발(evaporation)하여 미정제물(crude)를 얻는다. 미정제물(Crude)의 정제(purification)는 실리카(silica)에서 EA/Hx 15%를 욜리액(Eluent)으로 컬럼 크로마토그래피(column chromatography)를 진행하여 3-아세틸-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-10) (2.9 g, 87%)를 분리해낸다.Specifically, (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (10 mmol, 3 g) was added to 250 mL RBF. After adding acetic anhydride (100 mL) and stirring, TEA (30 mmoL, 4 mL) was slowly added dropwise. The reaction proceeded by heating the reactant to 85 ° C. After the reaction is completed, work-up is performed with brine and EA, and the organic layer is dried with MgSO 4 , filtered, and evaporated to obtain a crude product. Purification of the crude product was performed by column chromatography using 15% EA/Hx as an eluent in silica to obtain 3-acetyl-7-chloro-2-(( Isolate 3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (Example 2-10) (2.9 g, 87%).
1H NMR (500 MHz, CDCl3) δ 12.45 (s, 1H), 8.12 (dd, J = 8.3, 0.6 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.24 (d, J = 1.8 Hz, 2H), 2.11 (s, 3H) ppm; LC/MS (ESI) 382.4 m/z [M+H]+
1H NMR (500 MHz, CDCl 3 ) δ 12.45 (s, 1H), 8.12 (dd, J = 8.3, 0.6 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.24 (d, J = 1.8 Hz, 2H), 2.11 (s, 3H) ppm; LC/MS (ESI) 382.4 m/z [M+H] +
실시예 2-11. 3-아세틸-7-클로로-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온Example 2-11. 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
상기 실시예 2-10의 과정과 동일하게 반응시키되, 7-클로로-2-(3,5-디플로로페닐아미노)퀴나졸린-4(3H)-온 (실시예 1-52)을 사용하여, 3-아세틸-7-클로로-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-11)을 얻었다.Reacted in the same manner as in Example 2-10, but using 7-chloro-2-(3,5-difluorophenylamino)quinazolin-4(3H)-one (Example 1-52) , 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one (Example 2-11) was obtained.
1H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.5, 2.1 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.28 (dd, J = 8.0, 2.3 Hz, 2H), 2.13 (s, 3H) ppm; LC/MS (ESI) 350.2 m/z [M+H]+
1H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.5, 2.1 Hz, 1H), 7.37 - 7.31 (m, 1H), 7.28 (dd, J = 8.0, 2.3 Hz, 2H), 2.13 (s, 3H) ppm; LC/MS (ESI) 350.2 m/z [M+H] +
실시예 2-12. 3-아세틸-2-((3,5-디플루오로페닐)아미노)-7-(트리플루오로메틸)퀴나졸린-4(3H)-온Example 2-12. 3-Acetyl-2-((3,5-difluorophenyl)amino)-7-(trifluoromethyl)quinazolin-4(3H)-one
상기 실시예 2-10의 과정과 동일하게 반응시키되, 2-((3,5-디플로로페닐)아미노)-7-(트리플로로메틸)퀴나졸린-4(3H)-온 (실시예 1-31)을 사용하여, 3-아세틸-2-((3,5-디플루오로페닐)아미노)-7-(트리플루오로메틸)퀴나졸린-4(3H)-온 (실시예 2-12)을 얻었다.The reaction was performed in the same manner as in Example 2-10, but 2-((3,5-difluorophenyl)amino)-7-(trifluoromethyl)quinazolin-4( 3H )-one (Example 1-31), 3-acetyl-2-((3,5-difluorophenyl)amino)-7-(trifluoromethyl)quinazolin-4(3H)-one (Example 2- 12) was obtained.
1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.82 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (dtd, J = 19.9, 8.1, 7.5, 2.4 Hz, 3H), 2.15 (s, 3H) ppm; LC/MS (ESI) 384.3 m/z [M+H]+
1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 7.87 (s, 1H), 7.82 (dd, J = 8.3, 1.8 Hz, 1H), 7.33 (dtd, J = 19.9, 8.1, 7.5, 2.4 Hz, 3H), 2.15 (s, 3H) ppm; LC/MS (ESI) 384.3 m/z [M+H] +
실시예 2-13. 7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카브알데히드Example 2-13. 7-Chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carbaldehyde
상기 Comp 6의 7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카브알데히드 (실시예 2-13)을 얻었다. 7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carbaldehyde of Comp 6 (Example 2-13) was obtained.
구체적으로, 테스트 튜브(Test tube)에 (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (0.15 mmol, 50 mg)를 넣고 포름산(formic acid) (100 μL)를 넣고 교반한다. 그 뒤 반응물에 아세틱 안하이드라이드(Acetic anhydride) (500 μL)를 천천히 적가하였다. 반응이 끝나면 소디움 바이카보네이트(sodium bicarbonate)와 EA를 사용하여 워크업(work-up)을 한다. 유기층을 MgSO4에 건조(drying)하고 필터한 뒤, 증발(evaporation) 하여 미정제물(crude)를 얻는다. 미정제물(Crude)의 정제(purification)은 실리카(silica)에서 EA/MC 50%를 전개액(eluent)으로 컬럼 크로마토그래피(column chromatography)를 진행하여 7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-카브알데히드 (실시예 2-13) (76 mg, 99%)를 얻는다.Specifically, in a test tube (7-chloro-2-((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (0.15 mmol, 50 mg) and formic acid (100 μL) was added and stirred. Then, acetic anhydride (500 μL) was slowly added dropwise to the reactant. After the reaction, work-up is performed using sodium bicarbonate and EA. The organic layer is dried over MgSO4, filtered, and evaporated to obtain a crude product. Purification of the crude product was performed by column chromatography using 50% EA/MC as an eluent in silica to obtain 7-chloro-2-((3,5- Dichlorophenyl)amino)-4-oxoquinazoline-3(4H)-carbaldehyde (Examples 2-13) (76 mg, 99%) is obtained.
1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 9.19 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.56 (d, J = 1.9 Hz, 2H), 7.50 (dd, J = 8.5, 2.0 Hz, 1H) ppm; LC/MS (ESI) 368.2 m/z [M+H]+
1H NMR (400 MHz, DMSO) δ 12.66 (s, 1H), 9.19 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.62 ( d, J = 2.0 Hz, 1H), 7.56 (d, J = 1.9 Hz, 2H), 7.50 (dd, J = 8.5, 2.0 Hz, 1H) ppm; LC/MS (ESI) 368.2 m/z [M+H] +
실시예 2-14. 7-클로로-2-((3,4-디클로로페닐)아미노)-3-메틸퀴나졸린-4(3H)-온Example 2-14. 7-chloro-2-((3,4-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 7-클로로-2-((3,4-디클로로페닐)아미노)-3-메틸퀴나졸린-4(3H)-온 (실시예 2-14)을 얻었다.According to the synthesis method of Comp 6, 7-chloro-2-((3,4-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one (Example 2-14) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 13.33 (s, 1H), 7.89 (dp, J = 4.1, 1.5 Hz, 1H), 7.77 - 7.45 (m, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.51 (dd, J = 8.7, 2.6 Hz, 1H), 3.32 (s, 3H) ppm; 1H NMR (300 MHz, DMSO- d 6 ) δ 13.33 (s, 1H), 7.89 (dp, J = 4.1, 1.5 Hz, 1H), 7.77 - 7.45 (m, 1H), 7.18 (d, J = 8.7 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 6.51 (dd, J = 8.7, 2.6 Hz, 1H), 3.32 (s, 3H) ppm;
실시예 2-15. 2-(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)-2-옥소에틸 아세테이트Example 2-15. 2-(7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)-2-oxoethyl acetate
상기 Comp 6의 합성방법에 따라 2-(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)-2-옥소에틸 아세테이트 (실시예 2-15)을 얻었다.2-(7-chloro-2-((3,5-dichlorophenyl)amino)-4-oxoquinazolin-3(4H)-yl)-2-oxoethyl acetate according to the synthesis method of Comp 6 Example 2-15) was obtained.
구체적으로, (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (200 mg, 0.587 mmol)을 디클로로메탄 (3 mL)과 트리에틸아민 (164 mL. 1.174 mmL)을 사용하여 녹이고 아세톡시아세틸 클로라이드 (195 mL, 1.761 mmol)를 첨가하였다. 반응혼합물을 40 oC에서 2.5시간 동안 교반한 뒤 반응이 완료되면 디클로로메탄 (20 mL)을 사용하여 묽힌 뒤 물 (20 mL)로 씻었다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 7)로 2-(7-클로로-2-((3,5-디클로로페닐)아미노)-4-옥소퀴나졸린-3(4H)-일)-2-옥소에틸 아세테이트 (실시예 2-15) (162 mg, 63%)를 얻었다.Specifically, (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (200 mg, 0.587 mmol) was mixed with dichloromethane (3 mL) and triethylamine (164 mL. 1.174 mmL) and acetoxyacetyl chloride (195 mL, 1.761 mmol) was added. The reaction mixture was stirred at 40 ° C for 2.5 hours, and when the reaction was complete, it was diluted with dichloromethane (20 mL) and washed with water (20 mL). Magnesium sulfate was added to the organic layer, filtered, and the filtrate was concentrated to obtain 2-(7-chloro-2-((3,5-dichlorophenyl) by silica gel chromatography (eluent: ethyl acetate: hexane = 1: 7). This gave amino)-4-oxoquinazolin-3(4H)-yl)-2-oxoethyl acetate (Example 2-15) (162 mg, 63%).
1H NMR (400 MHz, DMSO-d 6) δ 12.78 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.58 (dd, J = 8.4, 2.1 Hz, 1H), 7.51 (d, J = 1.9 Hz, 2H), 4.92 (s, 2H), 2.05 (s, 3H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.78 (s, 1H) , 8.10 (d, J = 8.5 Hz, 1H), 7.77 - 7.66 (m, 2H), 7.58 (dd, J = 8.4, 2.1 Hz, 1H), 7.51 (d, J = 1.9 Hz, 2H), 4.92 (s, 2H), 2.05 (s, 3H).
실시예 2-16. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-프로피오닐퀴나졸린-4(3H)-온Example 2-16. 7-Chloro-2-((3,5-dichlorophenyl)amino)-3-propionylquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 7-클로로-2-((3,5-디클로로페닐)아미노)-3-프로피오닐퀴나졸린-4(3H)-온 (실시예 2-16)을 얻었다.According to the synthesis method of Comp 6, 7-chloro-2-((3,5-dichlorophenyl)amino)-3-propionylquinazolin-4(3H)-one (Example 2-16) was obtained.
1H NMR (300 MHz, DMSO-d 6)δ12.87(s,1H),8.10(d,J = 8.5 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.58 (qd, J = 9.2, 8.5, 2.0 Hz, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H). MS (ESI) 396.2 m/e [M+H]+. 1 H NMR (300 MHz, DMSO- d 6 )δ 12.87(s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.58 (qd, J = 9.2, 8.5, 2.0 Hz, 4H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.3 Hz, 3H). MS (ESI) 396.2 m/e [M+H] + .
실시예 2-17. 2-((3,5-디클로로페닐)아미노)-5-하이드록시-3-프로피오닐퀴나졸린-4(3H)-온Example 2-17. 2-((3,5-dichlorophenyl)amino)-5-hydroxy-3-propionylquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 2-((3,5-디클로로페닐)아미노)-5-하이드록시-3-프로피오닐퀴나졸린-4(3H)-온 (실시예 2-17)을 얻었다.According to the synthesis method of Comp 6, 2-((3,5-dichlorophenyl)amino)-5-hydroxy-3-propionylquinazolin-4(3H)-one (Example 2-17) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 13.08 (s, 1H), 11.64 (s, 1H), 7.76-7.50 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H). 1H NMR (300 MHz, DMSO- d6 ) δ 13.08 (s, 1H) , 11.64 (s, 1H), 7.76-7.50 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.85 ( d, J = 8.2 Hz, 1H), 2.38 (q, J = 7.2 Hz, 2H), 1.04 (t, J = 7.2 Hz, 3H).
실시예 2-18. 3-아세틸-2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4(3H)-온Example 2-18. 3-Acetyl-2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아세틸-2-((3,5-디클로로페닐)아미노)-5-하이드록시퀴나졸린-4(3H)-온 (실시예 2-18)을 얻었다.According to the synthesis method of Comp 6, 3-acetyl-2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4(3H)-one (Example 2-18) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 13.07 (s, 1H), 11.59 (s, 1H), 7.72-7.55 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 2.13 (s, 3H). MS (ESI) 364.3 m/e [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ 13.07 (s, 1H) , 11.59 (s, 1H), 7.72-7.55 (m, 4H), 7.03 (d, J = 8.1 Hz, 1H), 6.86 ( d, J = 8.2 Hz, 1H), 2.13 (s, 3H). MS (ESI) 364.3 m/e [M+H] + .
실시예 2-19. 3-아세틸-7-클로로-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온Example 2-19. 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아세틸-7-클로로-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-19)을 얻었다.According to the synthesis method of Comp 6, 3-acetyl-7-chloro-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one (Example 2-19) was obtained.
1H NMR (300 MHz, DMSO-d 6)δ12.89(s,1H),8.10(d,J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.5, 2.1 Hz, 1H), 7.36 (dt, J = 9.3, 2.4 Hz, 1H), 7.28 (dd, J = 8.0, 2.3 Hz, 2H), 2.13 (s, 3H). MS (ESI) 350.3 m/e [M+H]+. 1H NMR (300 MHz, DMSO- d 6 )δ 12.89(s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.5, 2.1 Hz, 1H), 7.36 (dt, J = 9.3, 2.4 Hz, 1H), 7.28 (dd, J = 8.0, 2.3 Hz, 2H), 2.13 (s, 3H). MS (ESI) 350.3 m/e [M+H] + .
실시예 2-20. 3-아세틸-6,8-디브로모-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온Example 2-20. 3-acetyl-6,8-dibromo-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아세틸-6,8-디브로모-2-((3,5-디플루오로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-20)을 얻었다.According to the synthesis method of Comp 6, 3-acetyl-6,8-dibromo-2-((3,5-difluorophenyl)amino)quinazolin-4(3H)-one (Example 2-20 ) was obtained.
1H NMR (500 MHz, DMSO-d 6) δ 12.99 (s, 1H), 8.32 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.36 (tt, J = 9.6, 2.5 Hz, 1H), 7.29 (dd, J = 7.9, 2.2 Hz, 2H), 2.18 (s, 3H). MS (ESI) 472.2 m/e [M+H]+. 1H NMR (500 MHz, DMSO- d6 ) δ 12.99 (s, 1H) , 8.32 (d, J = 2.2 Hz, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.36 (tt, J = 9.6, 2.5 Hz, 1H), 7.29 (dd, J = 7.9, 2.2 Hz, 2H), 2.18 (s, 3H). MS (ESI) 472.2 m/e [M+H] + .
실시예 2-21. 3-아세틸-2-((3,5-디클로로페닐)아미노)-8-(트리플루오로메틸)퀴나졸린-4(3H)-온Example 2-21. 3-Acetyl-2-((3,5-dichlorophenyl)amino)-8-(trifluoromethyl)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아세틸-2-((3,5-디클로로페닐)아미노)-8-(트리플루오로메틸)퀴나졸린-4(3H)-온 (실시예 2-21)을 얻었다.According to the synthesis method of Comp 6, 3-acetyl-2-((3,5-dichlorophenyl)amino)-8-(trifluoromethyl)quinazolin-4(3H)-one (Example 2-21) got
1H NMR (300 MHz, DMSO-d 6) δ 12.85 (s,1H), 8.34 (dd, J = 7.9, 1.5 Hz, 1H), 8.17 - 8.09 (m, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 3H), 2.17 (s, 3H). MS (ESI) 416.3 m/e [M+H]+. 1H NMR (300 MHz, DMSO- d 6 ) δ 12.85 (s, 1H), 8.34 (dd, J = 7.9, 1.5 Hz, 1H), 8.17 - 8.09 (m, 1H), 7.73 (t, J = 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 3H), 2.17 (s, 3H). MS (ESI) 416.3 m/e [M+H] + .
실시예 2-22. 7-클로로-3-(2-클로로아세틸)-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온Example 2-22. 7-chloro-3-(2-chloroacetyl)-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 7-클로로-3-(2-클로로아세틸)-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-22)을 얻었다.According to the synthesis method of Comp 6, 7-chloro-3-(2-chloroacetyl)-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (Example 2-22) got
1H NMR (400 MHz, DMSO-d 6) δ 12.82 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.59 (dd, J = 8.5, 2.0 Hz, 3H), 4.65 (s, 2H). 1H NMR (400 MHz, DMSO- d6 ) δ 12.82 (s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.59 (dd, J = 8.5, 2.0 Hz, 3H), 4.65 (s, 2H).
실시예 2-23. 3-아크릴로일-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온Example 2-23. 3-acryloyl-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아크릴로일-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-23)을 얻었다.According to the synthesis method of Comp 6, 3-acryloyl-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (Example 2-23) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 12.94 (s, 1H), 8.11 (d, J = 8.5 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.57 (dd, J = 8.5, 2.1 Hz, 1H), 7.52 (d, J = 1.9 Hz, 2H), 6.41 - 6.36 (m, 2H), 5.91 - 5.85 (m, 1H). MS (ESI) 394.2 m/e [M+H]+. 1H NMR (400 MHz, DMSO- d6 ) δ 12.94 (s, 1H) , 8.11 (d, J = 8.5 Hz, 1H), 7.71 - 7.65 (m, 2H), 7.57 (dd, J = 8.5, 2.1 Hz, 1H), 7.52 (d, J = 1.9 Hz, 2H), 6.41 - 6.36 (m, 2H), 5.91 - 5.85 (m, 1H). MS (ESI) 394.2 m/e [M+H] + .
실시예 2-24. 3-아세틸-2-((3,5-디클로로페닐)아미노)-7-플루오로퀴나졸린-4(3H)-온Example 2-24. 3-Acetyl-2-((3,5-dichlorophenyl)amino)-7-fluoroquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 3-아세틸-2-((3,5-디클로로페닐)아미노)-7-플루오로퀴나졸린-4(3H)-온 (실시예 2-24)을 얻었다.According to the synthesis method of Comp 6, 3-acetyl-2-((3,5-dichlorophenyl)amino)-7-fluoroquinazolin-4(3H)-one (Example 2-24) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 12.84 (s, 1H), 8.17 (dd, J = 9.6, 6.3 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 2H), 7.40 (ddd, J = 10.0, 6.4, 2.5 Hz, 2H), 2.13 (s, 3H). MS (ESI) 366.2 m/e [M+H]+. 1H NMR (300 MHz, DMSO- d6 ) δ 12.84 (s, 1H) , 8.17 (dd, J = 9.6, 6.3 Hz, 1H), 7.70 (t, J = 1.9 Hz, 1H), 7.60 (d, J = 1.9 Hz, 2H), 7.40 (ddd, J = 10.0, 6.4, 2.5 Hz, 2H), 2.13 (s, 3H). MS (ESI) 366.2 m/e [M+H] + .
실시예 2-25. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-토실퀴나졸린-4(3H)-온Example 2-25. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-tosylquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 7-클로로-2-((3,5-디클로로페닐)아미노)-3-토실퀴나졸린-4(3H)-온 (실시예 2-25)을 얻었다.According to the synthesis method of Comp 6, 7-chloro-2-((3,5-dichlorophenyl)amino)-3-tosylquinazolin-4(3H)-one (Example 2-25) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 10.30 (s, 1H), 8.18 - 8.10 (m, 2H), 8.01 (d, J = 1.9 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.23 (t, J = 1.9 Hz, 1H), 2.42 (s, 3H). 1H NMR (300 MHz, DMSO- d6 ) δ 10.30 (s, 1H) , 8.18 - 8.10 (m, 2H), 8.01 (d, J = 1.9 Hz, 2H), 7.84 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 1.9 Hz, 1H), 7.53 - 7.42 (m, 3H), 7.23 (t, J = 1.9 Hz, 1H), 2.42 (s, 3H).
실시예 2-26. 2-((3,5-디클로로페닐)아미노)-5-하이드록시-3-메틸퀴나졸린-4(3H)-온Example 2-26. 2-((3,5-dichlorophenyl)amino)-5-hydroxy-3-methylquinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 2-((3,5-디클로로페닐)아미노)-5-하이드록시-3-메틸퀴나졸린-4(3H)-온 (실시예 2-26)을 얻었다.According to the synthesis method of Comp 6, 2-((3,5-dichlorophenyl)amino)-5-hydroxy-3-methylquinazolin-4(3H)-one (Example 2-26) was obtained.
구체적으로, 2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온 (실시예 1-44) (200 mg, 0.621 mmol)을 DMF (4 mL)에 녹이고 소디움 하이드라이드 (60% dispersion oil, 37mg, 0.931 mmol)와 메틸 아이오다이드 (46 mL, 0.745 mmol)를 첨가했다. 반응 혼합물을 실온에서 2시간 교반한 뒤 반응이 완료되면 에틸 아세테이트 (20 mL)을 사용하여 묽힌 뒤 물 (10 mL x 5)로 씻어준다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 4)로 2-((3,5-디클로로페닐)아미노)-5-하이드록시-3-메틸퀴나졸린-4(3H)-온 (실시예 2-26) (34 mg, 16%)를 얻었다.Specifically, 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44) (200 mg, 0.621 mmol) was dissolved in DMF (4 mL). and sodium hydride (60% dispersion oil, 37mg, 0.931 mmol) and methyl iodide (46 mL, 0.745 mmol) were added. After stirring the reaction mixture at room temperature for 2 hours, when the reaction is complete, it is diluted with ethyl acetate (20 mL) and washed with water (10 mL x 5). Magnesium sulfate was added to the organic layer, filtered, and the filtrate was concentrated to obtain 2-((3,5-dichlorophenyl)amino)-5-hydroxy by silica gel chromatography (eluent: ethyl acetate: hexane = 1: 4). -3-methylquinazolin-4(3H)-one (Example 2-26) (34 mg, 16%) was obtained.
1H NMR (400 MHz, Chloroform-d) δ 11.64 (d, J = 53.3 Hz, 1H), 7.39 (s, 1H), 7.14 (s, 1H), 6.89 (t, J = 31.2 Hz, 2H), 6.64 (s, 1H), 6.28 (s, 1H), 3.54 (s, 3H). MS (ESI) 336.4 m/e [M+H]+. 1 H NMR (400 MHz, Chloroform- d ) δ 11.64 (d, J = 53.3 Hz, 1H), 7.39 (s, 1H), 7.14 (s, 1H), 6.89 (t, J = 31.2 Hz, 2H), 6.64 (s, 1H), 6.28 (s, 1H), 3.54 (s, 3H). MS (ESI) 336.4 m/e [M+H] + .
실시예 2-27. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-메틸퀴나졸린-4(3H)-온Example 2-27. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one
상기 실시예 2-26의 과정과 동일하게 반응시키되, (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1)을 사용하여, 7-클로로-2-((3,5-디클로로페닐)아미노)-3-메틸퀴나졸린-4(3H)-온 (실시예 2-27)을 얻었다.The reaction was carried out in the same manner as in Example 2-26, but (7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4( 3H )-one) (Example 1-1) was used to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)-3-methylquinazolin-4(3H)-one (Example 2-27).
1H NMR (300 MHz, DMSO-d 6) δ 9.10 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.74 (s, 2H), 7.37 (d, J = 2.0 Hz, 1H), 7.31 - 7.21 (m, 2H), 3.54 (s, 3H). 1H NMR (300 MHz, DMSO- d6 ) δ 9.10 (s, 1H) , 7.97 (d, J = 8.5 Hz, 1H), 7.74 (s, 2H), 7.37 (d, J = 2.0 Hz, 1H) , 7.31 - 7.21 (m, 2H), 3.54 (s, 3H).
실시예 2-28. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(메틸설포닐)퀴나졸린-4(3H)-온Example 2-28. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-(methylsulfonyl)quinazolin-4(3H)-one
상기 Comp 6의 합성방법에 따라 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(메틸설포닐)퀴나졸린-4(3H)-온 (실시예 2-28)을 얻었다.According to the synthesis method of Comp 6, 7-chloro-2-((3,5-dichlorophenyl)amino)-3-(methylsulfonyl)quinazolin-4(3H)-one (Example 2-28) was prepared. got it
구체적으로, (7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온) (실시예 1-1) (500 mg, 1.468 mmol)을 디클로로메탄 (12 mL)과 트리에틸아민 (307 mL, 2.20 mmol)에 녹이고 0 oC에서디메틸아미노피리딘 (18 mg, 0.147 mmol)과 메테인설포닐 클로라이드 (136 mL, 1.762 mmol)을 첨가하였다. 반응혼합물을 실온에서 2시간 동안 교반하였다. 반응이 완료되면 디클로로메탄 (30 mL)으로 묽힌 뒤 물 (20 mL)과 중탄산 나트륨 수용액 (20 mL)으로 씻었다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 4)로 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(메틸설포닐)퀴나졸린-4(3H)-온 (실시예 2-28) (76 mg, 13%)를 얻었다.Specifically, (7-chloro-2 - ((3,5-dichlorophenyl) amino) quinazolin-4 ( 3H ) -one) (Example 1-1) (500 mg, 1.468 mmol) was mixed with dichloromethane (12 mL) and triethylamine (307 mL, 2.20 mmol) and dimethylaminopyridine (18 mg, 0.147 mmol) and methanesulfonyl chloride (136 mL, 1.762 mmol) were added at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours. Upon completion of the reaction, the mixture was diluted with dichloromethane (30 mL) and washed with water (20 mL) and aqueous sodium bicarbonate solution (20 mL). Magnesium sulfate was added to the organic layer, filtered, and the filtrate was concentrated and purified by silica gel chromatography (eluent: ethyl acetate: hexane = 1: 4) to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)- 3-(methylsulfonyl)quinazolin-4(3H)-one (Example 2-28) (76 mg, 13%) was obtained.
1H NMR (300 MHz, DMSO-d 6) δ 10.42 (s, 1H), 8.05 - 7.96 (m, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (t, J = 1.9 Hz, 1H), 3.96 (s, 3H). 1H NMR (300 MHz, DMSO- d6 ) δ 10.42 (s, 1H) , 8.05 - 7.96 (m, 3H), 7.85 (d, J = 2.0 Hz, 1H), 7.51 (dd, J = 8.8, 2.0 Hz, 1H), 7.24 (t, J = 1.9 Hz, 1H), 3.96 (s, 3H).
실시예 2-29. 2-((3,5-디클로로페닐)아미노)-4-옥소-3,4-디하이드로퀴나졸린-5-일 2-하이드록시아세테이트Example 2-29. 2-((3,5-dichlorophenyl)amino)-4-oxo-3,4-dihydroquinazolin-5-yl 2-hydroxyacetate
(중간과정 물질 1: 
)(intermediate substance 1: )
2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온 (실시예 1-44) (1 g, 3.104 mmol)을 피리딘 (30 mL)에 녹인 후 벤질옥시아세틸 클로라이드 (980 mL, 6.2 mmol)를 첨가하였다. 반응혼합물을 12시간 동안 교반한 뒤 에틸아세테이트 (100 mL)로 묽힌 뒤 10% 카퍼 설페이트 수용액 (50 mL x 3)으로 씻어준 뒤 물 (50 mL)로 씻었다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 3)로 물질 1 (568 mg, 39%)를 얻었다.After dissolving 2-((3,5-dichlorophenyl)amino)-5-hydroxyquinazolin-4( 3H )-one (Example 1-44) (1 g, 3.104 mmol) in pyridine (30 mL) Benzyloxyacetyl chloride (980 mL, 6.2 mmol) was added. After stirring the reaction mixture for 12 hours, it was diluted with ethyl acetate (100 mL), washed with 10% copper sulfate aqueous solution (50 mL x 3), and washed with water (50 mL). Magnesium sulfate was added to the organic layer, filtered, and the filtrate was concentrated to obtain material 1 (568 mg, 39%) by silica gel chromatography (eluent ethyl acetate : hexane = 1 : 3).
물질 1 (365 mg, 0.123 mmol)을 N-메틸-2-피롤리돈 (7 mL)에 녹인 후 10% 활성화된 팔라듐/카본 (140 mg)을 첨가했다. 수소 풍선을 꽂아 반응혼합물을 1시간 동안 실온에서 교반했다. 반응이 완료되면 셀라이트를 사용하여 필터한 뒤 prep-HPLC를 통해서 2-((3,5-디클로로페닐)아미노)-4-옥소-3,4-디하이드로퀴나졸린-5-일 2-하이드록시아세테이트 (실시예 2-29)를 얻었다.After dissolving material 1 (365 mg, 0.123 mmol) in N-methyl-2-pyrrolidone (7 mL), 10% activated palladium/carbon (140 mg) was added. A hydrogen balloon was inserted and the reaction mixture was stirred at room temperature for 1 hour. After the reaction was completed, 2-((3,5-dichlorophenyl)amino)-4-oxo-3,4-dihydroquinazolin-5-yl 2-hydroxy was obtained through prep-HPLC after filtering using Celite. Roxyacetate (Examples 2-29) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 11.04 (s, 1H), 9.08 (s, 1H), 7.88 - 7.77 (m, 2H), 7.69 (t, J = 8.1 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H), 7.25 (t, J = 1.9 Hz, 1H), 6.95 (dd, J = 7.9, 1.1 Hz, 1H), 5.58 (t, J = 6.6 Hz, 1H), 4.36 (d, J = 6.5 Hz, 2H). MS (ESI) 380.2 m/e [M+H]+. 1 H NMR (400 MHz, DMSO- d 6 ) δ 11.04 (s, 1H), 9.08 (s, 1H), 7.88 - 7.77 (m, 2H), 7.69 (t, J = 8.1 Hz, 1H), 7.35 ( d, J = 8.2 Hz, 1H), 7.25 (t, J = 1.9 Hz, 1H), 6.95 (dd, J = 7.9, 1.1 Hz, 1H), 5.58 (t, J = 6.6 Hz, 1H), 4.36 ( d, J = 6.5 Hz, 2H). MS (ESI) 380.2 m/e [M+H] + .
실시예 2-30. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(2-하이드록시아세틸)퀴나졸린-4(3H)-온Example 2-30. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-(2-hydroxyacetyl)quinazolin-4(3H)-one
(중간과정 물질 2: 
)(intermediate substance 2: )
물질 2의 합성은 상기 실시예 2-10의 과정과 동일하게 반응시키되, 아세톡시아세틸 클로라이드 대신 벤질옥시아세틸 클로라이드를 사용했다.The synthesis of material 2 was reacted in the same manner as in Example 2-10, but benzyloxyacetyl chloride was used instead of acetoxyacetyl chloride.
물질 2 (3 g, 6.138 mmol)를 에틸아세테이트 (70 mL)에 녹인 후 10% 활성화된 팔라듐/카본 (1.2 g)을 첨가하였다. 수소 풍선을 꽂아 반응혼합물을 2시간 동안 실온에서 교반하였다. 반응이 완료되면 셀라이트를 사용하여 필터한 뒤 prep-HPLC를 통해서 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(2-하이드록시아세틸)퀴나졸린-4(3H)-온 (실시예 2-30) (194 mg, 8%)를 얻었다.After dissolving material 2 (3 g, 6.138 mmol) in ethyl acetate (70 mL), 10% activated palladium/carbon (1.2 g) was added. A hydrogen balloon was inserted and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, 7-chloro-2-((3,5-dichlorophenyl)amino)-3-(2-hydroxyacetyl)quinazoline-4(3H )-one (Example 2-30) (194 mg, 8%) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 12.73 (s, 1H), 10.59 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2.0 Hz, 2H), 7.45 - 7.31 (m, 3H), 5.06 (s, 2H). MS (ESI) 398.2 m/e [M+H]+. 1H NMR (400 MHz, DMSO- d6 ) δ 12.73 (s, 1H) , 10.59 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 2.0 Hz, 2H) , 7.45 - 7.31 (m, 3H), 5.06 (s, 2H). MS (ESI) 398.2 m/e [M+H] + .
실시예 2-31. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-글리실퀴나졸린-4(3H)-온Example 2-31. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-glycylquinazolin-4(3H)-one
(중간과정 물질 3: 
)(intermediate substance 3: )
물질 2의 합성은 상기 실시예 2-10의 과정과 동일하게 반응시키되, 아세톡시아세틸 클로라이드 대신 아지도 아세틸클로라이드를 사용했다.The synthesis of material 2 was reacted in the same manner as in Example 2-10, except that azido acetyl chloride was used instead of acetoxyacetyl chloride.
물질 3 (210 mg, 0.496 mmol)에 에탄올 (40 mL)과 36% HCl 수용액 (74 mL)을 넣고 10% 활성화된 팔라듐/카본 (1.2 g)을 첨가하였다. 수소 풍선을 꽂아 반응혼합물을 3시간 동안 실온에서 교반하였다. 반응이 완료되면 셀라이트를 사용하여 필터한 뒤 prep-HPLC를 통해서 7-클로로-2-((3,5-디클로로페닐)아미노)-3-글리실퀴나졸린-4(3H)-온 (실시예 2-31) (26 mg, 13%)를 얻었다.To substance 3 (210 mg, 0.496 mmol) was added ethanol (40 mL) and 36% HCl aqueous solution (74 mL) and 10% activated palladium/carbon (1.2 g) was added. A hydrogen balloon was inserted and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, 7-chloro-2-((3,5-dichlorophenyl)amino)-3-glycylquinazolin-4(3H)-one was obtained through prep-HPLC after filtering using Celite. Example 2-31) (26 mg, 13%) was obtained.
1H NMR (400 MHz, DMSO-d 6) δ 11.36 (s, 1H), 10.48 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 1.9 Hz, 2H), 7.30 (t, J = 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 (s, 1H), 4.21 (d, J = 5.3 Hz, 2H). MS (ESI) 397.2 m/e [M+H]+. 1H NMR (400 MHz, DMSO- d6 ) δ 11.36 (s, 1H), 10.48 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 1.9 Hz, 2H) , 7.30 (t, J = 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 7.15 (dd, J = 8.5, 2.1 Hz, 1H), 6.76 (s, 1H), 4.21 (d, J = 5.3 Hz, 2H). MS (ESI) 397.2 m/e [M+H] + .
실시예 2-32. (2-((3,5-디클로로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트Example 2-32. (2-((3,5-dichlorophenyl)amino)-5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate
2-((3,5-디클로로페닐)아미노)-5-히드록시퀴나졸린-4(3H)-온 (실시예 1-44) (1 g, 3.104 mmol)에 무수 다이메칠아세타마이드 (30 mL), 소디움 아이오다이드 (279 mg, 1.86 mmol)과 세슘 카보네이트 (3 g, 9.3 mmol)를 넣고 10분간 교반하였다. 디-t-부틸 클로로메틸 포스페이트(Di-t-butyl chloromethyl phosphate) (1.8 mL, 7.75 mmol)을 첨가하고 반응혼합물을 60 oC에서 1시간 교반하였다. 반응이 완료되면 에틸아세테이트 (100 mL)로 묽히고 물 (50 mL x 3)로 씻었다. 유기층에 마그네슘 설페이트를 첨가하여 필터한 뒤 여과액을 농축하여 실리카젤 크로마토그래피 (전개액 에틸아세테이트 : 헥산 = 1 : 5)로 (2-((3,5-디클로로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 (실시예 2-32) (365 mg, 22%)를 얻었다.Dimethylacetamide anhydrous ( 30 mL), sodium iodide (279 mg, 1.86 mmol) and cesium carbonate (3 g, 9.3 mmol) were added and stirred for 10 minutes. Di- t -butyl chloromethyl phosphate (1.8 mL, 7.75 mmol) was added and the reaction mixture was stirred at 60 ° C for 1 hour. Upon completion of the reaction, it was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 3). After adding magnesium sulfate to the organic layer and filtering, the filtrate was concentrated and purified by silica gel chromatography (eluent: ethyl acetate: hexane = 1: 5) (2-((3,5-dichlorophenyl) amino) -5-hydroxy Roxy-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate (Example 2-32) (365 mg, 22%) was obtained.
1H NMR (500 MHz, DMSO-d 6) δ 11.37 (s, 1H), 10.54 (s, 1H), 7.78 (s, 2H), 7.59 (t, J = 8.1 Hz, 1H), 7.27 (t, J = 1.9 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 11.3 Hz, 2H). MS (ESI) 432.4 m/e [M+H]+. 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.37 (s, 1H), 10.54 (s, 1H), 7.78 (s, 2H), 7.59 (t, J = 8.1 Hz, 1H), 7.27 (t, J = 1.9 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.87 (d, J = 11.3 Hz, 2H). MS (ESI) 432.4 m/e [M+H] + .
실시예 2-33. 소디움 (2-((3,5-디클로로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 포스페이트Example 2-33. sodium (2-((3,5-dichlorophenyl)amino)-5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl phosphate
(2-((3,5-디클로로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 디하이드로겐 포스페이트 (실시예 2-32) (490 mg, 1.134 mmol)에 THF (4 mL)를 녹이고 1N 소디움 하이드록사이드 (2.268 mL, 2.268 mmol)를 첨가하였다. 반응혼합물을 실온에서 4시간 교반한 뒤 THF (10 mL)로 묽힌 후 필터하여 소디움 (2-((3,5-디클로로페닐)아미노)-5-하이드록시-4-옥소퀴나졸린-3(4H)-일)메틸 포스페이트 (실시예 2-33) (338 mg, 72%)를 얻었다.(2-((3,5-dichlorophenyl)amino)-5-hydroxy-4-oxoquinazolin-3(4H)-yl)methyl dihydrogen phosphate (Example 2-32) (490 mg, 1.134 mmol) in THF (4 mL) and 1N sodium hydroxide (2.268 mL, 2.268 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, diluted with THF (10 mL), filtered, and sodium (2-((3,5-dichlorophenyl)amino)-5-hydroxy-4-oxoquinazoline-3(4H )-yl)methyl phosphate (Example 2-33) (338 mg, 72%) was obtained.
1H NMR (300 MHz, Methanol-d 4) δ 7.94 (d, J = 1.9 Hz, 2H), 7.51 (t, J = 8.2 Hz, 1H), 7.06 (t, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.2, 0.9 Hz, 1H), 6.62 (dd, J = 8.2, 0.9 Hz, 1H), 5.86 (d, J = 9.2 Hz, 2H). 1 H NMR (300 MHz, Methanol- d 4 ) δ 7.94 (d, J = 1.9 Hz, 2H), 7.51 (t, J = 8.2 Hz, 1H), 7.06 (t, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.2, 0.9 Hz, 1H), 6.62 (dd, J = 8.2, 0.9 Hz, 1H), 5.86 (d, J = 9.2 Hz, 2H).
실시예 2-34. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(2-(디메틸아미노)에틸)퀴나졸린-4(3H)-온Example 2-34. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-(2-(dimethylamino)ethyl)quinazolin-4(3H)-one
테트라하이드로퓨란 (100 mL)에 4-클로로안트라닐산 (3.42 g, 19.9 mmol) 및 트리포스겐 (2.4 g, 8.1 mmol) 용액을 50 oC에서 1시간 교반하였다. 상기 용매를 감압 건조하여 제거하고, 생성물을 n-헥산으로 수회 세척하였다. 진공건조 후, 7-클로로안타라닐산 무수화물 (3.8 g, 95%)을 얻었다.A solution of 4-chloroanthranilic acid (3.42 g, 19.9 mmol) and triphosgene (2.4 g, 8.1 mmol) in tetrahydrofuran (100 mL) was stirred at 50 oC for 1 hour. The solvent was removed by drying under reduced pressure, and the product was washed several times with n-hexane. After vacuum drying, 7-chloroantranilic acid anhydride (3.8 g, 95%) was obtained.
테트라하이드로퓨란 (100 mL)에 7-클로로안타라닐산 무수화물 (3.8 g, 19.2 mmol) 및 N,N-다이메틸에탄-1,2-다이아민 (2.5 mL, 23.2 mmol)의 혼합물을 1시간 동안 환류하였다. 출발물질인 무수화물이 사라진 후, 용매를 감압 건조하여 제거한 후, 플래시 컬럼 크로마토그래피 정제 (용출액: 디클로메틴 및 메탄올) 하여 2-아미노-4-클로로-N-(2-(다이메틸아미노)에틸)벤즈아미드 (3.2 g, 69%)을 얻었다.A mixture of 7-chloroantranilic acid anhydride (3.8 g, 19.2 mmol) and N,N-dimethylethane-1,2-diamine (2.5 mL, 23.2 mmol) was added to tetrahydrofuran (100 mL) for 1 hour. refluxed during After disappearance of the anhydride as the starting material, the solvent was removed by drying under reduced pressure, followed by flash column chromatography purification (eluent: diclomethine and methanol) to obtain 2-amino-4-chloro-N-(2-(dimethylamino) Ethyl)benzamide (3.2 g, 69%) was obtained.
DMF (6 mL)에 2-아미노-4-클로로-N-(2-(다이메틸아미노)에틸)벤즈아미드 (0.2 g, 0.7 mmol) 및 1,3-디클로로-5-이소싸이오씨아네이토벤젠 (0.143 g, 0.7 mmol) 및 CuBr (0.05 g, 0.35 mmol) 및 트리에틸아민 (0.05 mL, 0.36 mmol)의 혼합물을 80 oC에서 8시간 동안 환류하였다. 출발물질인 무수화물이 사라진 후, 용매를 감압 건조하여 제거한 후, 플래시 컬럼 크로마토그래피 정제 (용출액: 디클로메틴 및 메탄올) 하여 7-클로로-2-((3,5-디클로로페닐)아미노)-3-(2-(다이메틸아미노)에틸)퀴나졸린-4(3H)-온 (실시예 2-34) (0.16 g, 56%)을 얻었다.2-Amino-4-chloro-N-(2-(dimethylamino)ethyl)benzamide (0.2 g, 0.7 mmol) and 1,3-dichloro-5-isothiocyanatobenzene in DMF (6 mL) (0.143 g, 0.7 mmol) and a mixture of CuBr (0.05 g, 0.35 mmol) and triethylamine (0.05 mL, 0.36 mmol) was refluxed at 80 oC for 8 hours. After disappearance of the starting material anhydride, the solvent was removed by drying under reduced pressure, followed by flash column chromatography purification (eluent: diclomethine and methanol) to obtain 7-chloro-2-((3,5-dichlorophenyl)amino)- 3-(2-(dimethylamino)ethyl)quinazolin-4(3H)-one (Example 2-34) (0.16 g, 56%) was obtained.
1H NMR (300 MHz, DMSO-d6) δ 7.98 (d, J = 8.5 Hz, 1H), 7.72-7.45 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 1.9 Hz, 2H), 4.30 (s, 2H), 2.81 (s, 2H), 2.44 (s, 6H). MS (ESI) 411.3 m/e [M+H]+. 1 H NMR (300 MHz, DMSO-d 6 ) δ 7.98 (d, J = 8.5 Hz, 1H), 7.72-7.45 (m, 2H), 7.42 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 1.9 Hz, 2H), 4.30 (s, 2H), 2.81 (s, 2H), 2.44 (s, 6H). MS (ESI) 411.3 m/e [M+H]+.
실시예 2-35. 3-(벤조일옥시)-7-클로로-2-((3,5-디클로로페닐)아미노)퀴나졸린-4(3H)-온Example 2-35. 3-(benzoyloxy)-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one
테트라하이드로퓨란 (13 mL)에 7-클로로안타라닐산 무수화물 (0.5 g, 2.5 mmol) 및 O-벤질하이드록실아민 (0.35 mL, 3.0 mmol) 의 혼합물을 50 ℃에서 5시간 동안 교반하였다. 출발물질인 무수화물이 사라진 후, 용매를 감압 건조하여 제거한 후, 플래시 컬럼 크로마토그래피 정제 (용출액: 헥산 및 에틸아세테이트) 하여 2-아미노-N-(벤질옥시)-4-클로로벤즈아미드 (0.69 g, 99%)을 얻었다.A mixture of 7-chloroantharanilic anhydride (0.5 g, 2.5 mmol) and O-benzylhydroxylamine (0.35 mL, 3.0 mmol) in tetrahydrofuran (13 mL) was stirred at 50 °C for 5 hours. After disappearance of the anhydride as the starting material, the solvent was removed by drying under reduced pressure, followed by flash column chromatography purification (eluent: hexane and ethyl acetate) to obtain 2-amino-N-(benzyloxy)-4-chlorobenzamide (0.69 g , 99%) was obtained.
DMF (13 mL)에 2-아미노-N-(벤질옥시)-4-클로로벤즈아미드 (0.69 g, 2.49 mmol) 및 1,3-디클로로-5-이소싸이오씨아네이토벤젠 (0.51 g, 2.49 mmol) 및 트리에틸아민 (0.18 mL, 1.25 mmol) 및 CuBr (0.18 g, 1.25 mmol) 의 혼합물을 80 oC에서 8시간 동안 환류하였다. 출발물질인 무수화물이 사라진 후, 용매를 감압 건조하여 제거한 후, 플래시 컬럼 크로마토그래피 정제 (용출액: 헥산 및 에틸아세테이트) 하여 3-(벤질옥시)-7-클로로-2-((3,5-다이클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-35) (0.40 g, 36%)를 얻었다.2-Amino-N-(benzyloxy)-4-chlorobenzamide (0.69 g, 2.49 mmol) and 1,3-dichloro-5-isothiocyanatobenzene (0.51 g, 2.49 mmol) in DMF (13 mL) ) and a mixture of triethylamine (0.18 mL, 1.25 mmol) and CuBr (0.18 g, 1.25 mmol) was refluxed at 80 ° C for 8 h. After disappearance of the anhydride as the starting material, the solvent was removed by drying under reduced pressure, followed by flash column chromatography purification (eluent: hexane and ethyl acetate) to obtain 3-(benzyloxy)-7-chloro-2-((3,5- Dichlorophenyl)amino)quinazolin-4(3H)-one (Example 2-35) (0.40 g, 36%) was obtained.
1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 4.8 Hz, 3H), 7.43 (d, J = 1.8 Hz, 2H), 7.32 - 7.27 (m, 4H), 7.21 - 7.09 (m, 2H), 5.39 (s, 2H). 1H NMR (300 MHz, CDCl 3 ) δ 8.15 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 4.8 Hz, 3H), 7.43 (d , J = 1.8 Hz, 2H), 7.32 - 7.27 (m, 4H), 7.21 - 7.09 (m, 2H), 5.39 (s, 2H).
실시예 2-36. 7-클로로-2-((3,5-디클로로페닐)아미노)-3-하이드록시퀴나졸린-4(3H)-온Example 2-36. 7-chloro-2-((3,5-dichlorophenyl)amino)-3-hydroxyquinazolin-4(3H)-one
25mL RBF에 3-(벤질옥시)-7-클로로-2-((3,5-다이클로로페닐)아미노)퀴나졸린-4(3H)-온 (실시예 2-35) (0.35 g, 0.78 mmol) 과 10% Pd/C (50 mg)과 EtOH (20 mL)를 넣고 섞어준다. 수소화 반응을 시킨 뒤, 반응이 종결된 것을 확인하고 셀라이트(Celite)를 이용해 Pd/C을 걸러낸다. 증발(evaporation) 하여 미정제물(crude)을 얻고 prep-HPLC를 통해서 7-클로로-2-((3,5-디클로로페닐)아미노)-3-하이드록시퀴나졸린-4(3H)-온 (15 mg, 5%)를 얻었다.3-(benzyloxy)-7-chloro-2-((3,5-dichlorophenyl)amino)quinazolin-4(3H)-one (Example 2-35) in 25 mL RBF (0.35 g, 0.78 mmol ) and 10% Pd/C (50 mg) and EtOH (20 mL) were added and mixed. After the hydrogenation reaction, it is confirmed that the reaction is complete, and Pd/C is filtered out using Celite. Evaporation to obtain crude product and 7-chloro-2-((3,5-dichlorophenyl)amino)-3-hydroxyquinazolin-4(3H)-one (15 mg, 5%).
1H NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 9.86 (s, 1H), 8.18 - 7.94 (m, 3H), 7.49 (d, J = 2.1 Hz, 1H), 7.38 - 7.25 (m, 2H). 1H NMR (300 MHz, DMSO) δ 12.05 (s, 1H), 9.86 (s, 1H), 8.18 - 7.94 (m, 3H), 7.49 (d, J = 2.1 Hz, 1H), 7.38 - 7.25 (m , 2H).
실험예 1. 항COVID-19 활성평가Experimental Example 1. Evaluation of anti-COVID-19 activity
1-1. 세포주 및 바이러스 준비1-1. Cell line and virus preparation
본 발명에 사용한 베로 세포(vero cell)는 American Type Culture Collection (ATCC, CCL-81; Manassas, VA)으로부터 구매하여 사용하였으며, 10% 열 불활성화 소 태아 혈청 및 1× 항생제-항진균제(Antibiotic-Antimycotic, Gibco/Thermo Fisher Scientific, Waltham, MA)가 포함된 Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea)에 담아 37℃에서 5% 이산화탄소 하에서 배양하였다.Vero cells used in the present invention were purchased from the American Type Culture Collection (ATCC, CCL-81; Manassas, VA) and used, 10% heat inactivated fetal bovine serum and 1× antibiotic-antimycotic , Gibco/Thermo Fisher Scientific, Waltham, MA) containing Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and incubated at 37°C under 5% carbon dioxide.
SARS-CoV-2 한국 분리주(MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15])를 한국질병관리본부 국립보건원으로부터 제공받아, Kim et al., 2016 doi:10.1093/cid/ciw239에 제시된 방법에 따라 베로 세포에서 증식하였다. MERS-CoV를 사용한 모든 실험은 한국질병관리본부로부터 승인받은 국립보건원의 강화된 생물 안전 등급 3단계(Biosafety Level 3, BL-3) 봉쇄 절차를 준수한 한국 파스퇴르 연구소에서 수행하였다.SARS-CoV-2 Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was obtained from the Korea Centers for Disease Control and Prevention, National Institutes of Health , and proliferated in Vero cells according to the method presented in Kim et al., 2016 doi: 10.1093/cid/ciw239. All experiments using MERS-CoV were performed at the Pasteur Institute in Korea, which followed the enhanced Biosafety Level 3 (BL-3) containment procedures of the National Institutes of Health approved by the Korea Centers for Disease Control and Prevention.
1-2. 시약 준비1-2. reagent preparation
클로로퀸 이인산염(Chloroquine diphosphate (CQ; C6628))과 로피나비르(lopinavir (LPV; GP6351)), 렘데시비르(Remdesivir)를 각각 SelleckChem (Houston, TX)과 Glentham Life Science (UK)에서 구매하였다. 일차 항체로 사용된 항-SARS-CoV-2 spike 항체는 Sino Biological Inc. (Beijing, China)로부터 구매하였다. 이차항체인 Alexa Fluor 488 goat anti-rabbit IgG 및 세포핵 염색체인 Hoechst 33342는 MolecularProbes/Thermo Fisher Scientific (Waltham, MA)에서 구매하였다. 32% Paraformaldehyde (PFA) 수용액과 정상염소 혈청은 각각 Electron Microscopy Sciences (Hatfield, PA) 및 Vector Laboratories, Inc. (Burlingame, CA)에서 구매하였다.Chloroquine diphosphate (CQ; C6628), lopinavir (LPV; GP6351), and Remdesivir were purchased from SelleckChem (Houston, TX) and Glentham Life Science (UK), respectively. The anti-SARS-CoV-2 spike antibody used as the primary antibody was manufactured by Sino Biological Inc. (Beijing, China). Alexa Fluor 488 goat anti-rabbit IgG as a secondary antibody and Hoechst 33342 as a nuclear chromosome were purchased from Molecular Probes/Thermo Fisher Scientific (Waltham, MA). 32% Paraformaldehyde (PFA) aqueous solution and normal goat serum were obtained from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc, respectively. (Burlingame, CA).
1-3. 면역형광어세이를 이용한 이미지 기반 어세이1-3. Image-based assays using immunofluorescence assays
SARS-CoV-2에 감염된 세포는 바이러스 단백질을 발현하기 때문에 바이러스 단백질에 특이적으로 결합하는 항체를 사용하여 측정할 수 있다. 본 발명에서는 SARS-CoV-2의 스파이크(spike) 단백질에 결합하는 항체를 이용하여 세포를 염색하였고, 현미경을 통해 감염된 세포를 이미지화하였다. 감염률(SARS-CoV-2 spike 단백질을 발현하는 세포의 수/총 세포수)은 내부에서 개발된 Image Mining 3.0 (IM 3.0) 플러그인으로 측정되었다. 저분자 화합물의 항바이러스 효과를 비교하기 위해 음성대조군으로 디메틸설폭사이드(DMSO)가 처리된 감염세포를 사용하였고, SARS-CoV-2에 대한 항바이러스 활성이 알려진 3개의 화합물(CQ, LPV, Remdesivir)을 양성대조군으로 사용하여 이미지 기반 어세이를 최적화하였다.Since cells infected with SARS-CoV-2 express viral proteins, it can be measured using antibodies that specifically bind to viral proteins. In the present invention, cells were stained using an antibody that binds to the spike protein of SARS-CoV-2, and infected cells were imaged through a microscope. The infection rate (number of cells expressing SARS-CoV-2 spike protein/total number of cells) was measured with an internally developed Image Mining 3.0 (IM 3.0) plug-in. In order to compare the antiviral effects of small molecule compounds, infected cells treated with dimethyl sulfoxide (DMSO) were used as negative controls, and three compounds (CQ, LPV, Remdesivir) known to have antiviral activity against SARS-CoV-2 was used as a positive control to optimize the image-based assay.
1-4. 저분자 화합물 라이브러리1-4. Small molecule compound library
약 20만 개의 저분자 화합물들은 DMSO에 녹였으며, 분석 전까지 -80℃에서 보관하였다.About 200,000 small molecule compounds were dissolved in DMSO and stored at -80°C until analysis.
1-5. 이미지기반 저분자 화합물 스크리닝1-5. Image-based small molecule compound screening
베로 세포를 각 웰당 1.2×104 세포로 4 mM L-Glutamine 및 1× Antibiotic-Antimycotic가 포함된 Opti-PRO™ SFM에 담아 블랙, 384-웰, 마이크로클리어 플레이트(Clear plates, Greiner bio-one, Kremsmunster, Austria)에 분주하였다. 24시간 후, 저분자 화합물을 바이러스 감염 전에 자동화 액체 처리 시스템(automated liquid handling system (Apricot Designs, Covina, CA))을 사용하여 각 웰에 첨가하였다. 실험 화합물의 최종 농도는 2.5 내지 28.2 μM이었고, DMSO의 농도는 0.5%로 유지하였다. 화합물이 처리된 군은 BL-3 봉쇄실로 옮긴 후, 0.0625 MOI의 SARS-CoV-2에 감염되었다.Vero cells were plated at 1.2×10 4 cells per well in Opti-PRO™ SFM containing 4 mM L-Glutamine and 1× Antibiotic-Antimycotic in black, 384-well, microclear plates (Clear plates, Greiner bio-one, Kremsmunster, Austria). After 24 hours, small molecule compounds were added to each well using an automated liquid handling system (Apricot Designs, Covina, Calif.) prior to virus infection. The final concentration of the test compound was 2.5 to 28.2 μM, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was transferred to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625.
감염 후 24시간에 PFA를 사용(최종 PAF 농도= 4%)하여 감염을 고정하였다. 항-MERS-CoV spike 항체를 고정된 세포에 처리한 후 Alexa Fluor 488 goat anti-rabbit IgG 및 Hoechst 33342를 사용하여 염색하였다. 감염된 세포의 고정 및 염색 후 20× 배율의 형광 이미징 시스템(Perkin Elmer Operetta, 20×, Waltham, MA) 상에서 이미지화하였다. 저분자 화합물이 처리된 세포의 SARS-CoV-2에 대한 감염률은 각 플레이트 상에 있는 음성대조군(0% 감염억제율) 및 양성대조군(100% 감염억제율)으로 하여 환산되었고, 90% 이상의 억제효과를 야기하는 저분자 화합물이 동정되었다.Infection was fixed using PFA (final PAF concentration = 4%) 24 hours after infection. After treatment with anti-MERS-CoV spike antibody, the fixed cells were stained using Alexa Fluor 488 goat anti-rabbit IgG and Hoechst 33342. After fixation and staining of infected cells, they were imaged on a fluorescence imaging system (Perkin Elmer Operetta, 20×, Waltham, MA) at 20× magnification. The infection rate for SARS-CoV-2 of the cells treated with the small molecule compound was converted into the negative control group (0% infection inhibition rate) and the positive control group (100% infection inhibition rate) on each plate, resulting in an inhibitory effect of 90% or more A low-molecular-weight compound was identified.
1-6. 유효 화합물의 농도-반응곡선 실험1-6. Effective compound concentration-response curve experiment
화합물의 농도에 따른 바이러스 감염의 억제효과를 농도-반응곡선 실험을 통해 알 수 있다. 실험화합물의 최고농도를 5 mM로 하여 DMSO를 사용하여 2배 희석하여 10단계까지 연속적으로 희석한다. 이를 상기 1-5와 같은 방법으로 준비된 세포에 처리한다. 실험화합물의 최종농도의 최고농도는 25 μM가 되었고, DMSO의 농도는 0.5%로 유지하였다. 화합물 처리군은 BL-3 봉쇄실로 옮긴 후, 0.0625 MOI의 SARS-CoV-2에 감염되었다. 감염 24시간 후 상기 1-5와 동일한 방법으로 감염률을 이미지화하고 환산하였다. 농도반응곡선 실험으로 화합물의 50% 바이러스 억제농도 (Inhibitory concentration 50; IC50), 50% 세포독성농도 (Cytotoxicity concentration; CC50), 약물과 세포독성 사이의 비율(selectivity index; SI)을 산출하였다. 그 결과를 하기 표 1에 나타내었다.The inhibitory effect of viral infection according to the concentration of the compound can be seen through a concentration-response curve experiment. The highest concentration of the test compound is 5 mM, diluted 2 times with DMSO, and serially diluted up to 10 steps. This is treated with cells prepared in the same way as in 1-5 above. The highest concentration of the final concentration of the test compound was 25 μM, and the concentration of DMSO was maintained at 0.5%. The compound-treated group was moved to a BL-3 containment room and infected with SARS-CoV-2 at an MOI of 0.0625. 24 hours after infection, the infection rate was imaged and converted in the same manner as in 1-5 above. In the concentration response curve experiment, the compound's 50% viral inhibitory concentration (Inhibitory concentration 50; IC 50 ), 50% cytotoxicity concentration (CC 50 ), and the ratio between drug and cytotoxicity (selectivity index; SI) were calculated. . The results are shown in Table 1 below.
| 화합물compound | IC50 IC 50 | CC50 CC 50 | SISI |
| 실시예 1-1Example 1-1 | 0.2690.269 | >25>25 | 92.992.9 |
| 실시예 1-2Example 1-2 | 0.4030.403 | >25>25 | 62.08562.085 |
| 실시예 1-3Example 1-3 | 5.135.13 | >25>25 | 4.874.87 |
| 실시예 1-4Example 1-4 | 2.0642.064 | >25>25 | 12.11312.113 |
| 실시예 1-5Example 1-5 | 0.3280.328 | >25>25 | 76.376.3 |
| 실시예 1-6Example 1-6 | 0.2720.272 | >25>25 | 9292 |
| 실시예 1-7Examples 1-7 | 0.2540.254 | >25>25 | 98.24198.241 |
| 실시예 1-8Examples 1-8 | >25>25 | >25>25 | 1One |
| 실시예 1-9Examples 1-9 | >25>25 | >25>25 | 1One |
| 실시예 1-10Examples 1-10 | 4.8774.877 | 12.912.9 | 2.642.64 |
| 실시예 1-11Example 1-11 | >25>25 | >25>25 | 1One |
| 실시예 1-12Examples 1-12 | 0.410.41 | >25>25 | 60.9460.94 |
| 실시예 1-13Examples 1-13 | 0.5110.511 | >25>25 | 48.9348.93 |
| 실시예 1-14Examples 1-14 | 1.5131.513 | >25>25 | 16.5216.52 |
| 실시예 1-15Examples 1-15 | >25>25 | >25>25 | 1One |
| 실시예 1-16Examples 1-16 | >25>25 | >25>25 | 1One |
| 실시예 1-17Examples 1-17 | >25>25 | >25>25 | 1One |
| 실시예 1-18Examples 1-18 | 0.3620.362 | >25>25 | 7171 |
| 실시예 1-19Examples 1-19 | 0.9910.991 | >25>25 | 25.2225.22 |
| 실시예 1-20Examples 1-20 | >25>25 | >25>25 | 1One |
| 실시예 1-21Example 1-21 | 0.3710.371 | >25>25 | 68.6768.67 |
| 실시예 1-22Examples 1-22 | 0.890.89 | >25>25 | 28.128.1 |
| 실시예 1-23Examples 1-23 | 0.3330.333 | >25>25 | 7575 |
| 실시예 1-24Examples 1-24 | 0.3080.308 | 14.04614.046 | 45.5545.55 |
| 실시예 1-25Examples 1-25 | 0.3060.306 | >25>25 | 81.61781.617 |
| 실시예 1-26Examples 1-26 | 0.4710.471 | >25>25 | 53.05653.056 |
| 실시예 1-27Examples 1-27 | 0.3250.325 | >25>25 | 76.8476.84 |
| 실시예 1-28Example 1-28 | 2.72.7 | >25>25 | 9.39.3 |
| 실시예 1-29Examples 1-29 | 0.2440.244 | >25>25 | 102.52102.52 |
| 실시예 1-30Examples 1-30 | 0.2110.211 | 7.1127.112 | 33.77433.774 |
| 실시예 1-31Examples 1-31 | 0.2020.202 | 7.6167.616 | 37.67937.679 |
| 실시예 1-32Examples 1-32 | >25>25 | >25>25 | 1One |
| 실시예 1-33Example 1-33 | 2.0842.084 | >25>25 | 1212 |
| 실시예 1-34Example 1-34 | 1.5831.583 | >25>25 | 15.815.8 |
| 실시예 1-35Examples 1-35 | >25>25 | >25>25 | 1One |
| 실시예 1-36Examples 1-36 | >25>25 | >25>25 | 1One |
| 실시예 1-37Examples 1-37 | >25>25 | >25>25 | 1One |
| 실시예 1-38Examples 1-38 | >25>25 | >25>25 | 1One |
| 실시예 1-39Examples 1-39 | 1.6431.643 | >25>25 | 15.2215.22 |
| 실시예 1-40Examples 1-40 | 0.6190.619 | >25>25 | 40.36540.365 |
| 실시예 1-41Examples 1-41 | >25>25 | >25>25 | 1One |
| 실시예 1-42Examples 1-42 | >25>25 | >25>25 | 1One |
| 실시예 1-43Examples 1-43 | 0.4660.466 | >25>25 | 53.67853.678 |
| 실시예 1-44Examples 1-44 | 0.2360.236 | >25>25 | 105.982105.982 |
| 실시예 1-45Examples 1-45 | >25>25 | >25>25 | 1One |
| 실시예 1-46Examples 1-46 | 1.3751.375 | >25>25 | 18.218.2 |
| 실시예 1-47Example 1-47 | >25>25 | >25>25 | 1One |
| 실시예 1-48Example 1-48 | 10.810.8 | >25>25 | 2.322.32 |
| 실시예 1-49Examples 1-49 | >25>25 | >25>25 | 1One |
| 실시예 1-50Examples 1-50 | 8.9848.984 | >25>25 | 2.7832.783 |
| 실시예 1-51Examples 1-51 | 0.3750.375 | 9.7199.719 | 25.90525.905 |
| 구분division | |||
| 실시예 2-1Example 2-1 | 4.7524.752 | >25>25 | 6.6636.663 |
| 실시예 2-2Example 2-2 | 6.5386.538 | >25>25 | 3.8243.824 |
| 실시예 2-3Example 2-3 | 1.5471.547 | >25>25 | 16.15916.159 |
| 실시예 2-4Example 2-4 | 0.8490.849 | >25>25 | 29.4429.44 |
| 실시예 2-5Example 2-5 | >25>25 | >25>25 | 1One |
| 실시예 2-6Example 2-6 | 4.3624.362 | >25>25 | 5.7315.731 |
| 실시예 2-7Examples 2-7 | 3.7423.742 | >25>25 | 6.686.68 |
| 실시예 2-8Example 2-8 | >25>25 | >25>25 | 1One |
| 실시예 2-9Example 2-9 | 7.047.04 | >25>25 | 3.53.5 |
| 실시예 2-10Examples 2-10 | 0.3260.326 | 9.3889.388 | 25.90525.905 |
| 실시예 2-11Examples 2-11 | 0.2870.287 | >25>25 | 87.03787.037 |
| 실시예 2-12Example 2-12 | 0.450.45 | 14.814.8 | 33.933.9 |
| 실시예 2-13Example 2-13 | 0.230.23 | 11.211.2 | 52.652.6 |
| 실시예 2-14Example 2-14 | >25>25 | >25>25 | 1One |
| 실시예 2-15Example 2-15 | 0.370.37 | >25>25 | 71.371.3 |
| 실시예 2-16Example 2-16 | 0.2140.214 | >25>25 | 117117 |
| 실시예 2-17Examples 2-17 | 0.50.5 | >25>25 | 42.542.5 |
| 실시예 2-18Example 2-18 | 0.120.12 | >25>25 | 238238 |
| 실시예 2-19Examples 2-19 | 0.30.3 | >25>25 | 8787 |
| 실시예 2-20Example 2-20 | 0.7360.736 | 1212 | 1717 |
| 실시예 2-21Example 2-21 | 0.1680.168 | 14.70614.706 | 9090 |
| 실시예 2-22Example 2-22 | 9.869.86 | >25>25 | 2.42.4 |
| 실시예 2-23Example 2-23 | 0.630.63 | 11.511.5 | 18.618.6 |
| 실시예 2-24Example 2-24 | 0.1440.144 | >25>25 | 172172 |
| 실시예 2-25Examples 2-25 | 0.590.59 | >25>25 | 4444 |
| 실시예 2-26Examples 2-26 | >25>25 | >25>25 | 1One |
| 실시예 2-27Examples 2-27 | 5.6555.655 | >25>25 | 44 |
| 실시예 2-28Examples 2-28 | 0.50.5 | >25>25 | 51.851.8 |
| 실시예 2-29Examples 2-29 | 0.2650.265 | >25>25 | 9999 |
| 실시예 2-30Examples 2-30 | 2.432.43 | >25>25 | 9.79.7 |
| 실시예 2-31Examples 2-31 | >25>25 | >25>25 | 1One |
| 실시예 2-32Examples 2-32 | 0.9120.912 | >25>25 | 2828 |
| 실시예 2-33Examples 2-33 | 1.5061.506 | >25>25 | 1717 |
| 실시예 2-34Examples 2-34 | >25>25 | >25>25 | 1One |
| 실시예 2-35Examples 2-35 | 5.535.53 | >25>25 | 4.524.52 |
| 실시예 2-36Examples 2-36 | 1.691.69 | >25>25 | 14.814.8 |
| 구분division | |||
| 클로로퀸Chloroquine | 7.287.28 | >150>150 | 20.6120.61 |
| 로피나비르Lopinavir | 9.129.12 | >50>50 | 5.485.48 |
| 렘데시비르Remdesivir | 11.4111.41 | >25>25 | 2.192.19 |
상기 표 1에 나타난 바와 같이, 본 발명의 일 측면에 따른 화합물은 SARS-CoV-2에 대한 항바이러스 억제활성이 우수하므로, COVID-19(코로나바이러스감염증-19) 치료제로 사용될 수 있음을 알 수 있다.As shown in Table 1 above, since the compound according to one aspect of the present invention has excellent antiviral inhibitory activity against SARS-CoV-2, it can be seen that it can be used as a treatment for COVID-19 (coronavirus infection-19). there is.
이상, 본 발명을 예시적으로 설명하였으며, 본 발명이 속하는 기술분야에서 통상의 지식을 가지는 자라면 본 발명의 본질적인 특성에서 벗어나지 않는 범위에서 다양한 변형이 가능할 것이다. 따라서, 본 명세서에 개시된 실시예들은 본 발명을 한정하기 위한 것이 아니라 설명하기 위한 것이고, 이러한 실시예에 의하여 본 발명의 사상과 범위가 한정되는 것은 아니다. 본 발명의 보호범위는 아래의 청구범위에 의해서 해석되어야 하며, 그와 동등한 범위 내에 있는 모든 기술은 본 발명의 권리범위에 포함하는 것으로 해석되어야 할 것이다.In the above, the present invention has been described as an example, and those skilled in the art will be able to make various modifications without departing from the essential characteristics of the present invention. Accordingly, the embodiments disclosed in this specification are intended to explain, not limit, the present invention, and the spirit and scope of the present invention are not limited by these embodiments. The protection scope of the present invention should be construed by the following claims, and all techniques within the equivalent range should be construed as being included in the scope of the present invention.
본 발명은 2-아미노퀴나졸린 유도체 또는 이의 약학적으로 허용가능한 염의 새로운 약학 조성물을 통해 항바이러스 효과를 통해 제약, 의약 분야에서 유용하다.The present invention is useful in the field of medicine and medicine through antiviral effects through a novel pharmaceutical composition of a 2-aminoquinazoline derivative or a pharmaceutically acceptable salt thereof.
Claims (11)
- 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염:A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof:[화학식 1][Formula 1]
{상기 화학식 1에서,{In Formula 1,1) R1 및 R4는, 서로 독립적으로, 수소원자; C1~C3 알콕시기; C1~C6의 알킬기; -C(=O)R1a; -S(=O)2R1b; -(CH2)m-R1c; 또는 -(CH2)m-O-P(=O)(-OR1d)(-OR1e)이고, 1) R 1 and R 4 are, independently of each other, a hydrogen atom; C 1 ~ C 3 alkoxy group; C 1 ~ C 6 Alkyl group; -C(=0)R 1a ; -S(=0) 2 R 1b ; -(CH 2 ) m -R 1c ; or -(CH 2 ) m -OP(=0)(-OR 1d )(-OR 1e );R4는 부존재할 수 있으며,R 4 may be absent;상기 R1a는 치환되거나 비치환된 C1~C6의 알킬기; 또는 치환되거나 비치환된 C2~C6의 알켄일기이고, Wherein R 1a is a substituted or unsubstituted C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 2 ~ C 6 alkenyl group,여기에서 C1~C6의 알킬기가 치환되는 경우, C1~C3의 알콕시기; 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되며,Here, when the C 1 ~ C 6 alkyl group is substituted, a C 1 ~ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,여기에서, C2~C6의 알켄일기가 치환되는 경우, 히드록시기, 아미노기, 할로겐원자 또는 아세톡시기로 치환되고,Here, when the alkenyl group of C 2 ~ C 6 is substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,상기 R1b는 C1~C6의 알킬기; 또는 치환되거나 비치환된 C6~C10의 아릴기이며,R 1b is a C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 6 ~ C 10 aryl group,여기에서, C6~C10의 아릴기가 치환되는 경우, C1~C3의 알킬기로 치환되고,Here, when the C 6 ~ C 10 aryl group is substituted, it is substituted with a C 1 ~ C 3 alkyl group,상기 R1c는 히드록시기; C1~C6의 알카노일옥시기; 벤질옥시기; 또는 NRaRb 이고, Wherein R 1c is a hydroxyl group; C 1 ~ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;상기 R1d 및 R1e는 서로 독립적으로 수소; 소디움; 또는 C1~C6의 알킬기이며, R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ~ C 6 alkyl group,m은 0 내지 3의 정수이고,m is an integer from 0 to 3;2) R2는 수소, C3~C6의 시클로알킬기; -(X)n-C6~C10의 아릴기이며,2) R 2 is hydrogen, a C 3 ~ C 6 cycloalkyl group; -(X) n -C 6 ~ C 10 An aryl group,상기 X는 -CH2; 카보닐(C=O); 또는 -C(=O)-CH=CH-;이며, n은 0 또는 1이고,X is -CH 2 ; carbonyl (C=O); or -C(=0)-CH=CH-; and n is 0 or 1;3) 또는, R1 및 R2가 함께 고리를 형성할 수 있고3) or, R 1 and R 2 together may form a ring;4) R3은 =O; C1~C6의 알킬기; NRcRd; 또는 -O-(CH)o-R3a이며,4) R 3 is =0; C 1 ~ C 6 Alkyl group; NR c R d ; or -O-(CH) o -R 3a ;상기 R3a는 C1~C6의 알카노일옥시기이고, o는 1 또는 2이고,Wherein R 3a is a C 1 ~ C 6 alkanoyloxy group, o is 1 or 2;5) R5는 수소; 할로겐; 시아노기; 니트로기; 히드록시기; 아미노기; C1~C6의 알킬기; C2~C6의 알켄일기; C2~C6의 알킨일기; C1~C6의 알콕시기; C1~C6의 알카노일옥시기; C3~C6의 시클로알킬기; C6~C10의 아릴기; O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기; NReRf; 이며, a가 1이상일 때 복수의 R5는 서로 동일하거나 상이하고,5) R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ~ C 6 Alkyl group; C 2 ~ C 6 Alkenyl group; A C 2 ~C 6 alkynyl group; A C 1 ~ C 6 alkoxy group; C 1 ~ C 6 alkanoyloxy group; C 3 ~ C 6 Cycloalkyl group; C 6 ~ C 10 aryl group; A C 2 ~C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,6) a는 0 내지 4의 정수이며,6) a is an integer from 0 to 4;7) 상기 Ra, Rb, Rc, Rd, Re 및 Rf는 서로 독립적으로 수소; 또는 C1~C3의 알킬기;이고,7) R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ~ C 3 alkyl group;8)는 단일결합 또는 이중결합을 의미하며,
는 단일결합 또는 결합이 형성되지 않음을 의미하고,8)
Means a single bond or a double bond,Means that a single bond or no bond is formed,9) 여기서, 상기 알킬기, 알켄일기, 알킨일기, 시클로알킬기, 알카노일옥시기, 아릴기 및 헤테로고리기는 각각 중수소; 할로겐; 히드록시기; 시아노기; 니트로기; C1~C6 알킬기; -C(=O)-C1~C6의 알킬기; -C(=O)NH2; C1~C6 알콕시기; 및 O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기;로 이루어진 군에서 선택된 하나 이상의 치환기로 더욱 치환될 수 있으며, 이들 치환기들은 서로 결합하여 고리를 형성할 수도 있고, 여기서 '고리'란 탄소수 3 내지 20의 지방족고리 또는 탄소수 6 내지 20의 방향족고리 또는 탄소수 2 내지 20의 헤테로고리 또는 이들의 조합으로 이루어진 융합 고리를 말하며, 포화 또는 불포화 고리를 포함한다.}9) Here, the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the alkanoyloxy group, the aryl group, and the heterocyclic group are each deuterium; halogen; hydroxy group; cyano group; nitro group; C 1 ~ C 6 alkyl group; -C(=O)-C 1 ~ C 6 Alkyl group; -C(=O)NH 2 ; C 1 ~ C 6 alkoxy group; And a C 2 ~ C 10 heterocyclic group containing at least one heteroatom of O, N, and S; Alternatively, the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring. } - 제1항에 있어서, According to claim 1,상기 화학식 1은 하기 화학식 2로 표시되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:A compound or a pharmaceutically acceptable salt thereof, characterized in that Formula 1 is represented by Formula 2 below:[화학식 2][Formula 2]
{상기 화학식 2에서,{In Formula 2,1) R1, R3, R4, R5 및 a는 상기 청구항 1에서 정의한 바와 동일하며,1) R 1 , R 3 , R 4 , R 5 and a are the same as defined in claim 1,2) R6은 수소; 할로겐; 히드록시기; 시아노기; 니트로기; C1~C6의 알킬기; C2~C6의 알켄일기; C2~C6의 알킨일기; C1~C6의 알콕시기; 또는 -C(=O)NH2;이고, b가 1이상일 때 복수의 R6은 서로 동일하거나 상이하며,2) R 6 is hydrogen; halogen; hydroxy group; cyano group; nitro group; C 1 ~ C 6 Alkyl group; C 2 ~ C 6 Alkenyl group; A C 2 ~C 6 alkynyl group; A C 1 ~ C 6 alkoxy group; or -C(=0)NH 2 ; and, when b is 1 or more, a plurality of R 6 are the same as or different from each other;3) b는 0 내지 5의 정수이다.}3) b is an integer from 0 to 5.} - 제2항에 있어서, According to claim 2,상기 화학식 2는 하기 화학식 3 내지 화학식 5 중 어느 하나로 표시되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:A compound or a pharmaceutically acceptable salt thereof, characterized in that Formula 2 is represented by any one of Formulas 3 to 5 below:[화학식 3][Formula 3]
[화학식 4][Formula 4]
[화학식 5][Formula 5]
{상기 화학식 3 내지 5에서,{In Formulas 3 to 5,1) R1, R4, R5, R6, a 및 b는 상기 청구항 2에서 정의한 바와 동일하며,1) R 1 , R 4 , R 5 , R 6 , a and b are the same as defined in claim 2,2) R7은 C1~C6의 알킬기; 또는 tert-부타노일옥시메톡시기이다.}2) R 7 is a C 1 ~ C 6 alkyl group; or a tert-butanoyloxymethoxy group.} - 제1항 또는 제2항에 있어서,According to claim 1 or 2,상기 R1 및 R4 중 적어도 하나가 -C(=O)R1a이고, At least one of R 1 and R 4 is -C(=0)R 1a ,상기 R1a는 치환되거나 비치환된 C1~C6의 알킬기; 또는 치환되거나 비치환된 C2~C6의 알켄일기이며Wherein R 1a is a substituted or unsubstituted C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 2 ~ C 6 alkenyl group,여기에서, 여기에서 C1~C6의 알킬기가 치환되는 경우, C1~C3의 알콕시기; 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되며,Here, when a C 1 ~ C 6 alkyl group is substituted here, a C 1 ~ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,여기에서, C2~C6의 알켄일기가 치환되는 경우, 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되는 것인, 화합물 또는 이의 약학적으로 허용가능한 염.Here, when the C 2 ~ C 6 alkenyl group is substituted, it is substituted with a hydroxyl group, an amino group, a halogen or an acetoxy group, or a pharmaceutically acceptable salt thereof.
- 제1항 또는 제2항에 있어서, According to claim 1 or 2,상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염은 하기 화합물들 중 어느 하나로 표시되는 것을 특징으로 하는 화합물 또는 이의 약학적으로 허용가능한 염:The compound represented by Formula 1 or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof, characterized in that represented by any one of the following compounds:
.
. - 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 포함하는 항바이러스용 약학 조성물:An antiviral pharmaceutical composition comprising a compound represented by Formula 1 below or a pharmaceutically acceptable salt thereof as an active ingredient:[화학식 1][Formula 1]
{상기 화학식 1에서,{In Formula 1,1) R1 및 R4는, 서로 독립적으로, 수소원자; C1~C3 알콕시기; C1~C6의 알킬기; -C(=O)R1a; -S(=O)2R1b; -(CH2)m-R1c; 또는 -(CH2)m-O-P(=O)(-OR1d)(-OR1e)이고, 1) R 1 and R 4 are, independently of each other, a hydrogen atom; C 1 ~ C 3 alkoxy group; C 1 ~ C 6 Alkyl group; -C(=0)R 1a ; -S(=0) 2 R 1b ; -(CH 2 ) m -R 1c ; or -(CH 2 ) m -OP(=0)(-OR 1d )(-OR 1e );R4는 부존재할 수 있으며,R 4 may be absent;상기 R1a는 치환되거나 비치환된 C1~C6의 알킬기; 또는 치환되거나 비치환된 C2~C6의 알켄일기이고, Wherein R 1a is a substituted or unsubstituted C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 2 ~ C 6 alkenyl group,여기에서 C1~C6의 알킬기가 치환되는 경우, C1~C3의 알콕시기; 히드록시기, 아미노기, 할로겐 또는 아세톡시기로 치환되며,Here, when the C 1 ~ C 6 alkyl group is substituted, a C 1 ~ C 3 alkoxy group; substituted with a hydroxy group, an amino group, a halogen or an acetoxy group,여기에서, C2~C6의 알켄일기가 치환되는 경우, 히드록시기, 아미노기, 할로겐원자 또는 아세톡시기로 치환되고,Here, when the alkenyl group of C 2 ~ C 6 is substituted, it is substituted with a hydroxyl group, an amino group, a halogen atom or an acetoxy group,상기 R1b는 C1~C6의 알킬기; 또는 치환되거나 비치환된 C6~C10의 아릴기이며,R 1b is a C 1 ~ C 6 alkyl group; Or a substituted or unsubstituted C 6 ~ C 10 aryl group,여기에서, C6~C10의 아릴기가 치환되는 경우, C1~C3의 알킬기로 치환되고,Here, when the C 6 ~ C 10 aryl group is substituted, it is substituted with a C 1 ~ C 3 alkyl group,상기 R1c는 히드록시기; C1~C6의 알카노일옥시기; 벤질옥시기; 또는 NRaRb 이고, Wherein R 1c is a hydroxyl group; C 1 ~ C 6 alkanoyloxy group; benzyloxy group; or NR a R b ;상기 R1d 및 R1e는 서로 독립적으로 수소; 소디움; 또는 C1~C6의 알킬기이며, R 1d and R 1e are each independently hydrogen; sodium; Or a C 1 ~ C 6 alkyl group,m은 0 내지 3의 정수이고,m is an integer from 0 to 3;2) R2는 수소, C3~C6의 시클로알킬기; -(X)n-C6~C10의 아릴기이며,2) R 2 is hydrogen, a C 3 ~ C 6 cycloalkyl group; -(X) n -C 6 ~ C 10 An aryl group,상기 X는 -CH2; 카보닐(C=O); 또는 -C(=O)-CH=CH-;이며, n은 0 또는 1이고,X is -CH 2 ; carbonyl (C=O); or -C(=0)-CH=CH-; and n is 0 or 1;3) 또는, R1 및 R2가 함께 고리를 형성할 수 있고3) or, R 1 and R 2 together may form a ring;4) R3은 =O; C1~C6의 알킬기; NRcRd; 또는 -O-(CH)o-R3a이며,4) R 3 is =0; C 1 ~ C 6 Alkyl group; NR c R d ; or -O-(CH) o -R 3a ;상기 R3a는 C1~C6의 알카노일옥시기이고, o는 1 또는 2이고,Wherein R 3a is a C 1 ~ C 6 alkanoyloxy group, o is 1 or 2;5) R5는 수소; 할로겐; 시아노기; 니트로기; 히드록시기; 아미노기; C1~C6의 알킬기; C2~C6의 알켄일기; C2~C6의 알킨일기; C1~C6의 알콕시기; C1~C6의 알카노일옥시기; C3~C6의 시클로알킬기; C6~C10의 아릴기; O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기; NReRf; 이며, a가 1이상일 때 복수의 R5는 서로 동일하거나 상이하고,5) R 5 is hydrogen; halogen; cyano group; nitro group; hydroxy group; amino group; C 1 ~ C 6 Alkyl group; C 2 ~ C 6 Alkenyl group; A C 2 ~C 6 alkynyl group; A C 1 ~ C 6 alkoxy group; C 1 ~ C 6 alkanoyloxy group; C 3 ~ C 6 Cycloalkyl group; C 6 ~ C 10 aryl group; A C 2 ~C 10 heterocyclic group containing at least one heteroatom selected from O, N, and S; NR e R f ; And, when a is 1 or more, a plurality of R 5 are the same as or different from each other,6) a는 0 내지 4의 정수이며,6) a is an integer from 0 to 4;7) 상기 Ra, Rb, Rc, Rd, Re 및 Rf는 서로 독립적으로 수소; 또는 C1~C3의 알킬기;이고,7) R a , R b , R c , R d , R e and R f are each independently hydrogen; Or a C 1 ~ C 3 alkyl group;8)는 단일결합 또는 이중결합을 의미하며,
는 단일결합 또는 결합이 형성되지 않음을 의미하고,8)
Means a single bond or a double bond,Means that a single bond or no bond is formed,9) 여기서, 상기 알킬기, 알켄일기, 알킨일기, 시클로알킬기, 알카노일옥시기, 아릴기 및 헤테로고리기는 각각 중수소; 할로겐; 히드록시기; 시아노기; 니트로기; C1~C6 알킬기; -C(=O)-C1~C6의 알킬기; -C(=O)NH2; C1~C6 알콕시기; 및 O, N, S 중 적어도 하나 이상의 헤테로원자를 포함하는 C2~C10의 헤테로고리기;로 이루어진 군에서 선택된 하나 이상의 치환기로 더욱 치환될 수 있으며, 이들 치환기들은 서로 결합하여 고리를 형성할 수도 있고, 여기서 '고리'란 탄소수 3 내지 20의 지방족고리 또는 탄소수 6 내지 20의 방향족고리 또는 탄소수 2 내지 20의 헤테로고리 또는 이들의 조합으로 이루어진 융합 고리를 말하며, 포화 또는 불포화 고리를 포함한다.}9) Here, the alkyl group, the alkenyl group, the alkynyl group, the cycloalkyl group, the alkanoyloxy group, the aryl group, and the heterocyclic group are each deuterium; halogen; hydroxy group; cyano group; nitro group; C 1 ~ C 6 alkyl group; -C(=O)-C 1 ~ C 6 Alkyl group; -C(=O)NH 2 ; C 1 ~ C 6 alkoxy group; And a C 2 ~ C 10 heterocyclic group containing at least one heteroatom of O, N, and S; Alternatively, the term 'ring' herein refers to a fused ring composed of an aliphatic ring having 3 to 20 carbon atoms, an aromatic ring having 6 to 20 carbon atoms, a heterocyclic ring having 2 to 20 carbon atoms, or a combination thereof, and includes a saturated or unsaturated ring. } - 제6항에 있어서,According to claim 6,상기 바이러스는 코로나바이러스인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition, characterized in that the virus is a coronavirus.
- 제6항에 있어서,According to claim 6,상기 코로나바이러스는 코로나바이러스감염증-19인 것을 특징으로 하는 약학 조성물.The pharmaceutical composition, characterized in that the coronavirus is COVID-19.
- 제6항에 있어서,According to claim 6,약학적으로 허용가능한 담체 하나 이상을 더 포함하는 것을 특징으로 하는 약학 조성물.A pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers.
- 제6항에 있어서,According to claim 6,다른 항바이러스제 하나 이상을 더 포함하는 것을 특징으로 하는 약학적 조성물.A pharmaceutical composition, characterized in that it further comprises at least one other antiviral agent.
- 제1항에 따른 화합물 또는 이의 식품학적으로 허용가능한 염을 유효성분으로 포함하는 바이러스 감염증 예방 및 개선용 건강식품 조성물.A health food composition for preventing and improving viral infection, comprising the compound according to claim 1 or a food chemically acceptable salt thereof as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2021/013418 WO2023054759A1 (en) | 2021-09-30 | 2021-09-30 | 2-aminoquinazoline derivative and anti-viral composition comprising same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2021/013418 WO2023054759A1 (en) | 2021-09-30 | 2021-09-30 | 2-aminoquinazoline derivative and anti-viral composition comprising same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2023054759A1 true WO2023054759A1 (en) | 2023-04-06 |
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| PCT/KR2021/013418 WO2023054759A1 (en) | 2021-09-30 | 2021-09-30 | 2-aminoquinazoline derivative and anti-viral composition comprising same |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
| US12030904B2 (en) | 2023-04-14 | 2024-07-09 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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| KR20070027487A (en) * | 2003-09-16 | 2007-03-09 | 아스트라제네카 아베 | Quinazoline derivatives |
| WO2008009078A2 (en) * | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| US20140073642A1 (en) * | 2011-05-18 | 2014-03-13 | Janssen R&D Ireland | Quinazoline derivatives for the treatment of viral infections and further diseases |
| KR20210143131A (en) * | 2020-05-19 | 2021-11-26 | 한국화학연구원 | 2-Aminoquinazoline derivatives and antiviral composition comrising the same |
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| KR20070027487A (en) * | 2003-09-16 | 2007-03-09 | 아스트라제네카 아베 | Quinazoline derivatives |
| WO2008009078A2 (en) * | 2006-07-20 | 2008-01-24 | Gilead Sciences, Inc. | 4,6-dl- and 2,4,6-trisubstituted quinazoline derivatives useful for treating viral infections |
| US20140073642A1 (en) * | 2011-05-18 | 2014-03-13 | Janssen R&D Ireland | Quinazoline derivatives for the treatment of viral infections and further diseases |
| KR20210143131A (en) * | 2020-05-19 | 2021-11-26 | 한국화학연구원 | 2-Aminoquinazoline derivatives and antiviral composition comrising the same |
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| LEE JUN YOUNG, SHIN YOUNG SUP, JEON SANGEUN, LEE SE IN, NOH SOOJIN, CHO JUNG-EUN, JANG MIN SEONG, KIM SEUNGTAEK, SONG JONG HWAN, K: "Design, synthesis and biological evaluation of 2-aminoquinazolin-4(3H)-one derivatives as potential SARS-CoV-2 and MERS-CoV treatments", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 39, 1 May 2021 (2021-05-01), Amsterdam NL , pages 127885, XP055806252, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2021.127885 * |
| SHUM, DAVID; SMITH, JESSICA L.; HIRSCH, ALEC J.; BHINDER, BHAVNEET; RADU, CONSTANTIN; STEIN, DAVID A.; NELSON, JAY A.; FRUEH, KLAU: "High-Content Assay to Identify Inhibitors of Dengue Virus Infection", ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES, MARY ANN LIEBERT, INC. PUBLISHERS, US, vol. 8, no. 5, 1 October 2010 (2010-10-01), US , pages 553 - 570, XP009154193, ISSN: 1540-658X, DOI: 10.1089/adt.2010.0321 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11963967B2 (en) | 2020-10-16 | 2024-04-23 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
| US12030904B2 (en) | 2023-04-14 | 2024-07-09 | Gilead Sciences, Inc. | Phospholipid compounds and uses thereof |
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