Quinazoline derivatives and method of preparation

专利摘要:
The present invention relates to a quinazoline derivative shown in formula (i) and a preparation method thereof, a pharmaceutical composition comprising the compound indicated in formula (i) and an application of the compound in the preparation of drugs for cure and prevention of tumors. The compound of the present invention can irreversibly prevent egfr phosphorylation and effectively depress cancer cell signal transduction and, consequently, has greater antitumor activity in vitro and in vivo.
公开号:BR112016006692A2
申请号:R112016006692
申请日:2014-09-28
公开日:2020-05-12
发明作者:Xiao Dengming；Kong Fansheng；Luo Hong；Zhang Hui；Wang Huting；Li Jijun；Zhu Yan；Peng Yong；Han Yongxin；Hu Yuandong
申请人:Centaurus Biopharma Co Ltd；Chia Tai Tianqing Pharmaceutical Group Co Ltd；Lianyungang Runzhong Pharmaceutical Co Ltd；
IPC主号:

专利说明:

COMPOUND REPRESENTED BY FORMULA (I) OR A PHARMACEUTICALLY ACCEPTABLE SALT OF THE SAME, USE OF THE SAME AND PHARMACEUTICAL COMPOSITION
Technical field
[0001] The present disclosure relates to a quinazoline derivative and pharmaceutically acceptable salts thereof, its method of preparation, its pharmaceutical composition and its use in the prevention and treatment of the respective tumor.
Fundamentals of technique
[0002] Worldwide, lung cancer is currently a malignant tumor, with the highest incidence and mortality. Lung cancer can be divided into two main types: small cell lung cancer and non-small cell lung cancer, where non-small cell lung cancer represents 80% of the total number of lung cancer patients. Conventional chemotherapy and radiation therapy against non-small cell lung cancer lack specificity. Through these treatments, a certain therapeutic effect is achieved and the life expectancy of patients is prolonged to some degree, however, these treatments also have many side effects. Therefore target therapies, which can prevent excessive damage to normal cells, are most appreciated by the academy in the field of tumor and a wide variety of patients. Target therapies, epidermal growth factor receptor (EGFR) inhibitors play a significant role.
[0003] EGFR, a tyrosine kinase receptor, is a member of the HER / ErbB family. The HER / ErbB family includes EGFR, HER2, HER3 and HER4, which consist of three parts: an extracellular ligand binding domain, a transmembrane domain consisting of single chain or intracellular tyrosine kinase domain. EGFRs are widely distributed on the cell surface of mammalian epithelial cells,
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2/57 fibroblasts, glial cells, keratinocytes, etc. EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation, etc. The functional deficiency of protein tyrosine kinase as of the EGFR type, or abnormal activity or cellular localization of key factors in related signaling pathways, can lead to the occurrence of immune deficiency, tumor, diabetes and cardiovascular diseases.
[0004] So far the EGFR-related drugs available on the market include: Gefitinib (Iressa®), Erlotinib (Tarceva®), which are selective EGFR tyrosine kinase inhibitors (EGFR - TKI); and Lapatinib (Tykerb®), which is a double inhibitor of EGFR / HER2. They competitively bind the tyrosine kinase phosphorylation site in the intracellular segment to block the interaction between the phosphorylation site and ATP and inhibit tyrosine phosphorylation and a series of downstream signal transduction and then inhibit the growth of tumor cells. Among these drugs, the reversible EFGR inhibitor Gefitinib and Erlotinib show favorable therapeutic effects in patients with non-small cell lung cancer with an EGFR mutation; they can significantly prolong the progression-free survival (PFS) and overall survival (OS) of patients. However, recent clinical use indicates that the PFS of most patients who are positive for an EGFR mutation is no more than 12 - 14 months and soon after develop resistance to the EGFR-TKIs mentioned above.
[0005] Current research showing that approximately half of the drug resistance generated after treatment of EGFR-TKI is related to the secondary mutation (T790M) in exon 20 of EGFR. In this regard, several irreversible inhibitors, such as Afatinib (BIBW-2992), Canertinib (CI-1033), Neratinib (HKI-272), CO-1686, HM781-36B and the like are developed; they can solve the drug resistance problem of the EGFR-TKIs indicated above. These drug molecules
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3/57 share a common structural characteristic, that is, the existence of a functional acrylamide group. This functional group can form covalent bond with cysteine 773 (Cys733) in the ATP binding region of EGFR. Such a covalent bond can irreversibly block EGFR self-phosphorylation and effectively inhibit signal transduction of cancer cells. Therefore, these drugs show greater antitumor activity in vitro and in vivo.
resume
[0006] The present disclosure provides a series of new quinazoline derivatives or their pharmaceutically acceptable salts and pharmaceutical composition comprising these compounds and the method of using such compounds to prevent and treat the tumor.
[0007] In accordance with an aspect of the disclosure, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
(i)
Where the Ar ring is an aryl group or a heteroaryl group;
X is selected from -NR ⁸ -, --5--, -8 (= 0) - or -5 (-0) 2-:
nor are they each, independently, an integer from 0 to 6 and m, n and are not simultaneously 0;
p is an integer from 0 to 5;
q is an integer from 0 to 8;
R ¹ is independently selected from a C 3 alkyl group and a C ₃ cycloalkyl group. ₈ , a C ₂ alkenyl group. ₆ , a C ₂ alkynyl group. _6, a heterocycloalkyl group, a halogen atom, an amino group, a mono (alkyl Ci. ₆₎ alkylamino group, a di (CI_ ₆ alkyl) amino, a hydroxyl group,
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4/57 CI_ ₆ alkoxy group, a mercapto group, an alkylthio group C ^ · a ₆ CI_ aiquilcarbonil group, an aryl group, a heteroaryl group, a cyano group and a nitro group, wherein the alkyl group Cf. ₆ , alkoxy group 0) .6, C ₂ alkenyl group. ₆ , alkynyl group C ₂ -6 can be substituted by a halogen atom, a cyano group, a nitro group, an alkoxy group C). ₆ , an aryl group, a heteroaryl group or a heterocycloalkyl group; and the aryl group, heteroaryl group and heterocycloalkyl group can additionally be replaced by a halogen atom, a cyano group, a nitric group, a C alkyl group). ₆ , an alkoxy group C). ₆ , or an alkylcarbonyl group C). ₆ ;
R ² is selected from hydrogen, a hydroxyl group, an alkoxy group C). ₆ , a heterocyclylalkyloxy group or an alkoxy group C). ₆ replaced by alkoxy C). ₆ or heterocycloalkyl group;
R ³ is independently selected from a halogen atom, a cyano group, a mercapto group, a C ₁ - ₆ alkylthio group, a C ₃ alkyl group. G, a C ₃ cycloalkyl group. ₈ , a heterocycloalkyl group, an amino group, a mono (C alkyl) group. ₆ ) amino, a di (C-alkyl) group. ₆₎ amino, a hydroxy group, an alkoxy group CI_ _6, an alkoxycarbonyl group C). ₆ , a C) alkylamido group; ₆ , a mono (C alkyl) group. ₆ ) aminoacyl and a di (C-alkyl) group. ₆ ) aminoacyl;
R ⁴ , R ⁵ , and R ⁶ are independently selected, each, from a hydrogen atom, a halogen atom, a C ₆ alkyl group, a C ₃ cycloalkyl group. ₈ is a heterocycloalkyl group, an amino group, a mono (CI_ ₆ alkyl) amino group, a di (CI_ ₆ alkyl) amino, a C alkylamido group). _6, a mono (C alkyl) _ ₆₎ aminoacyl group and di (alkyl CI_ ₆₎ alkoxycarbonyl and aminoacyl group CI_ _6;
R ⁷ and R ⁸ are selected each independently from hydrogen or an alkyl group CI_ _6.
[0008] In some forms of the present disclosure, X is selected from -NR ⁸ -, -S-; in some forms of this disclosure, X is -NR ⁸ -.
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[0009] In some modalities of the present disclosure, neither are each an integer from 0 to 3 in, n, are not simultaneously 0. In some modalities of the present disclosure, neither are each an integer of 0 a 3 en + m = 2, 3 or 4.
[0010] In some modalities of the present disclosure, p is an integer from 0 to 3. In some modalities, p is 1 or 2.
[0011] In some modalities of the present disclosure, q is an integer from 0 to 3. In some modalities, q is 0.
[0012] In some embodiments of the present disclosure, R ⁷ , R ⁸ are hydrogen.
[0013] In some embodiments of the present disclosure, the Ar ring is a phenyl group.
[0014] In some embodiments of the present invention, R ¹ is independently selected from a C · ^alkyl group, a C2-6 alkenyl group, a C2-alkynyl group, a halogen atom, an amino group, a hydroxyl group, a C4 alkoxy group, an alkylcarbonyl group, a cyano group and a nitro group, where the C1-6 alkyl group, C1-6 alkoxy group, C2.6 alkenyl group θ C2.6 alkynyl group can be replaced by a halogen atom, a cyano group, a nitro group, a C- | 6 alkoxy group, an aryl group, a heteroaryl group or a heterocycloalkyl group; and the aryl group, heteroaryl group and heterocycloalkyl group plus can be replaced by a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C i_6 alkoxy group or a Cv6 alkylcarbonyl group [0015] In some embodiments of the present invention, R ¹ is independently selected from a C2 alkynyl group. ₆ , a halogen atom, a C 1-4 alkoxy group. ₆ and a C4 alkylcarbonyl group, wherein the 0 _μ6 alkoxy group can be replaced by an aryl group, a heteroaryl group, or a heterocycloalkyl group; and the aryl group, the heteroaryl group and the heterocycloalkyl group can additionally be replaced by a halogen atom, a cyano group or a nitro group.
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[0016] In some modalities of the present disclosure, R ¹ is independently selected from an alkynyl group Ο ₂ -6, a halogen atom, an alkoxy group substituted with heteroaryl and a C ₆ alkoxy group substituted with aryl, and one CI_ ₆ alkylcarbonyl group wherein the aryl group and the heteroaryl group may additionally be substituted by one haiogênio atom.
[0017] In some embodiments of the present disclosure, R ¹ is independently selected from a group of ethynyl, a halogen atom, a C- | alkoxy group. ₆ substituted pyridyl, an alkoxy group substituted by Cl - ₆ halofenik
[0018] In some embodiments of the present disclosure, R ⁴ , R ⁵ and R ⁶ are hydrogen.
[0019] In some embodiments of the present disclosure, R ² is selected from hydrogen, a methoxy group, a tetrahydrofuranyloxl group, a methoxy-substituted ethoxy group, a morpholinyl-substituted ethoxy group.
[0020] Some modalities of the present disclosure relate to the following compounds or their salts:

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[0021] For example, through the steps of scheme 1, 2 or other similar methods, the compound of formula (I) of the present disclosure can be prepared:
Scheme 1:
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PG is an amino protection group.
[0022] Under the reflux condition, the Formula 1 compound reacts with thionyl chloride to form the Formula 2 compound. The Formula 2 compound and the 2 'compound are refluxed in acetonitrile to obtain the Formula compound. 3. The Formula 3 compound reacts with R ² H in the presence of potassium tert-Butoxide and DMSO to form the formula 4 compound. The formula 4 compound is reduced with hydrogen in the presence of Raney Nickel to obtain the formula compound 5. In the presence of trifluoroacetic acid or acetic acid and sodium triacetoxyborohydride, the compound of formula 5 reacts with the compound of formula 5 'to form the compound of formula 6. The compound of formula 6, heated to 60 ° C in the presence of trifluoroacetic acid, or in the hydrochloric acid-methanol solution, forms the compound of formula 7. In the presence of diisopropylethylamine and tetrahydrofuran, the compound of formula 7 reacts with acryloyl chloride to form the compound of formula 8.
[0023] Scheme 2:
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™
In the presence of sodium nitrite, sulfuric acid, potassium thiocyanate, ferric chloride and H ₂ O, the compound of formula 5 reacts and forms the compound of formula 9. In the presence of sodium borohydride, potassium carbonate and ethanol, the compound of formula 9 reacts with the compound of formula 9 ^S to form the compound of formula 10. The compound of formula 10 is heated to 60 ° C in the presence of trifluoroacetic acid to form the compound of formula 11.0 compound of formula 11 reacts with chloride acryloyl to form the compound of formula 12.
[0024] The above schemes only list the methods for preparing part of the compounds of the present disclosure. According to the techniques known in this field, based on the schemes shown above, those skilled in the art can synthesize the compounds of the present disclosure with similar methods.
[0025] The compounds of the present disclosure can be asymmetric, for example, with one or more stereoisomers. Unless otherwise specified, all stereoisomers include, for example, enantiomers and diastereomers. The compounds with asymmetric carbon atoms of the disclosure can be isolated in pure optically active or racemic form. The pure optically active form can be resolved from the racemic mixture, or synthesized through chiral materials or chiral reagents.
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[0026] The pharmaceutically acceptable salts of the compound of formula (I) of the present disclosure, formed with inorganic acid or organic acid, can also be used. Said organic inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, lactic acid, malonic acid, succinic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric, ascorbic acid, palmitic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, methylbenzenesulfonic acid.
[0027] Another aspect of the present disclosure further relates to a pharmaceutical composition, which comprises the compound of formula I as defined by the present disclosure or its pharmaceutically acceptable salts and pharmaceutically acceptable carriers.
[0028] The pharmaceutical composition of the present disclosure can be prepared by combining the compounds of the present disclosure and pharmaceutically acceptable acceptable carriers. For example, it can be prepared as solid, semi-solid, liquid or gaseous formulations, such as tablets, pills, capsules, powder, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosol, etc.
[0029] Typical routes for administration of the compounds of the present disclosure or their pharmaceutically acceptable salts or pharmaceutical composition include, but are not limited to, oral, rectal, transmucosal, enteral or parenteral, topical, percutaneous, inhalation, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration. The preferred route of administration is oral administration.
[0030] The pharmaceutical composition of the present disclosure may be manufactured by methods well known in the art, such as
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[0031] In a preferred embodiment, the pharmaceutical composition is in the form for oral use. For oral administration, the active compounds can be mixed with pharmaceutically acceptable carriers, known in the art, to prepare the pharmaceutical composition. With these carriers, the compounds of the present disclosure can be formulated into tablets, pills, lozenges, sugar-coated tablets, capsules, liquid, gels, syrup, suspensions and the like, for oral administration to patients.
[0032] The composition of solids for oral use can be prepared through conventional mixing, filling or compression methods. For example, it can be obtained through the following method: the active compounds are mixed with the solid excipients; optionally, the resulting mixture is ground and other suitable adjuvants are added if necessary; then, the mixture is processed into granules, so that the core of the tablets or sugar-coated tablets is obtained. Suitable adjuvants include, but are not limited to, glues, thinners, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc., such as microcrystalline cellulose, glucose solution, starch mucilage, arabic gum, sucrose and gelatin solution; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or dicalcium phosphate; silica; sodium carboxymethylcellulose chitosan, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethylcellulose, polyvinylpyrrolidone chitosan, etc. Optionally, the tablet core can be coated with methods well known in general pharmaceutical practice and enteric coating is particularly used.
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[0033] The pharmaceutical composition is also suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in the form of an appropriate dose of the unit. Suitable excipients, such as fillers, buffers or surfactants, can also be used.
[0034] Another aspect of the present disclosure relates to the use of the Formula I compound of the present disclosure, or its pharmaceutically acceptable salts, or its pharmaceutical composition, for the manufacture of a medicament for the prevention or treatment of the tumor.
[0035] In all methods, to apply the compound of formula I, according to the disclosure, the daily dosage administered is preferably 0.01 ~ 200 mg / kg of body weight.
[0036] Unless otherwise defined, all technical and scientific terms in this document have the same meaning as commonly understood by a person skilled in the field who belongs to the subjects claimed. Unless otherwise specified, all patents, patent applications and publications are incorporated into this document in its entirety by reference.
[0037] It should also be noted that, unless otherwise specified, the expression either means and / or. In addition, the term include and other ways to understand, contain ”and have as used here are not restrictive.
[0038] Unless otherwise specified, the terms used in this document have the following meanings:
[0039] The term halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
[0040] The term hydroxy group refers to -OH.
[0041] The term mercapto group refers to ~ SH.
[0042] The term cyan group refers to -CN.
[0043] The term nitro group refers to - NO ₂ .
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[0044] The term alkyl group refers to a straight or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is attached to the rest of the molecule through a single bond. For example, the alkyl group can have 1-6 carbon atoms (represented by Cv ₆ alkyl group) and preferably have 1-4 carbon atoms. Non-limiting examples of the alkyl group include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2-methylbutyl, Neopentyl, n-hexyl.
[0045] The term alkoxy group refers to the group - O-alkyl, where the alkyl group is the same as defined above. The alkoxy group can have 1-6 carbon atoms, preferably 1-4 carbon atoms. Non-limiting examples of the alkoxy group include, but are not limited to, methoxy ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy, n-pentyloxy,
2-methylbutoxy, neopentyloxy, n-hexoxy.
[0046] The term "alkylthio group" refers to the group - S-alkyl, where the alkyl group is the same as defined above.
[0047] The term amino group refers to -NH ₂ .
[0048] The term mono (alkyl) group refers to -NH (alkyl group), where the alkyl group is the same as defined above.
[0049] The term di (alkyl) amino group refers to -N (alkyl group) ₂ , where the alkyl group is the same as defined above, and the two alkyl groups can be the same or different.
[0050] The term cycloalkyl group refers to the non-aromatic saturated or unsaturated cyclic hydrocarbon group. Non-limiting examples of the cycloalkyl group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohepty, etc.
[0051] The term alkenyl group refers to a straight or branched alkenyl group, preferably a straight or branched alkenyl group, which has 2-6 carbon atoms. Non-limiting examples of the alkenyl group
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14/57 include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.
[0052] The term alkynyl group refers to a linear or branched alkynyl group, preferably a linear or branched alkynyl group, which has
2-6 carbon atoms. Non-limiting examples of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.
[0053] The term aryl group refers to an all-carbon fused monocyclic or polycyclic aromatic ring group which has a conjugated π electron system. It preferably has 6-14 carbon atoms, more preferably it has 6 to 12 carbon atoms, more preferably it has 6 carbon atoms. Non-limiting examples of the aryl group include, but are not limited to, phenyl, naphthyl and anthracyl.
[0054] The term heteroaryl group refers to a monocyclic or fused ring which has 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, where the ring has 1, 2, 3 or 4 ring atoms selected from N, O, S, while the rest of the ring atoms are C, and the ring has a completely conjugated π electron system. The heteroaryl group preferably has a 5 or 6-membered ring, more preferably a 5-membered ring. Non-limiting examples of the heteroaryl group include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinoxyl, isoquinolyl, tetrazolyl, triazolyl, triazinyl.
[0055] The term heterocycloalkyl group refers to a monocyclic or fused ring which has 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, where 1, 2 or 3 atoms of the ring are heteroatoms selected from N, O, S (O) _n (where n is 0, 1 or 2), while the other ring atoms are C. Such a ring can be saturated or unsaturated (for example with one or more double bonds), but it lacks a completely conjugated π electron system. Examples of a 3-membered heterocycloalkyl group include, but are not limited to, oxiranyl, tiiranyl, aziridinyl. Examples of 4-membered heterocycloalkyl group, but are not
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15/57 limited to azetidinyl, oxetanil, tietanil. Examples of a 5-membered heterocycloalkyl group, but are not limited to tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinyl, diazolidinyl, imidazolidinyl, dihydrofuranilyl, dihydroturazolyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyrrolidinyl, pyridine. Examples of the 6-membered heterocycloalkyl group include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydropyranyl, morpholinyl, piperazinyl, 1,4thionyl, 1,4-dioxanoyl, thiomorpholinyl, 1,2- or 1,4- dithianyl, dihydropyridyl, tetrahydropyridyl, dihydropyranyl, tetrahydropyranyl, dihydropypyranyl. Examples of a 7-membered heterocycloalkyl group include but are not limited to azepanyl, oxepanyl, tiepanyl. A monocyclic heterocycloalkyl group which has 5 or 6 ring atoms is preferred.
[0056] The term therapeutically effective amount means that, when administered to mammals, preferably humans, the compound of the present disclosure may be sufficient to effectively treat mammalian diseases (preferably humans). The amount of the compound of the present disclosure, which constitutes the therapeutically effective amount, varies according to the nature of the compound, the condition and severity of the disease, the route of administration and the age of the mammal to be treated. However, the quantity can be determined routinely by a person skilled in the art, based on his knowledge and the content of the present disclosure.
[0057] The term treatment means that the compound or formulation of the present disclosure is administered, to prevent, alleviate or eliminate the disease, or one or more symptoms related to said disease. And it comprises:
(i) prevent the occurrence of the disease or morbid condition in mammals, especially when such mammals are susceptible to the morbid condition, but have not yet been diagnosed as suffering from that morbid condition;
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(Ii) inhibit the disease or morbid condition, that is, suppress the development of the disease or morbid condition;
(iii) relieving the disease or morbid condition, that is, promoting the regression of the disease or morbid condition.
[0058] The term pharmaceutical composition refers to a formulation, which comprises one or more compounds of the present disclosure, or their salts, together with carriers, excipients and / or means generally accepted in the field for delivering the biologically active compounds for organisms (such as humans). The purpose of the pharmaceutical composition is to facilitate the administration of the compound of the present disclosure to the organisms.
[0059] The term pharmaceutically acceptable carrier refers to carriers and diluents which have no significant irritating effect on organisms and do not impair the biological activity and the performance of the active compounds. Pharmaceutically acceptable carriers include, but are not limited to, any carriers, excipients, media, glidants, sweeteners, diluents, preservatives, coloring / coloring agents, flavor enhancers, surfactants, wetting agents, dispersants, disintegrants, suspending agents , stabilizers, isotonic agents, solvents or emulsifying agents, permitted by the Food and Drug Administration as acceptable to be applied to humans or livestock.
Experiences
[0060] All moisture manipulations and / or oxygen-sensitive experiments were performed under a nitrogen atmosphere in pre-dried glass products. Unless otherwise specified, all raw materials were commercially available materials, and they were not further purified before use.
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[0061] For column chromatography, silica gel (200-300 mesh), manufactured by the Qingdao Marine Chemical Research Institute, was used. For thin layer chromatography (TLC), a pre-coated chromatography plate (silica gel 60PF254, 0.25 mm) manufactured by E. Merck Corp.
[0062] The instrument used in the spectral analysis of nuclear magnetic resonance (NMR) was Varian resonance spectrometer VNMRS-400. Chemical displacement was referenced against the internal standard, Tetramethylsilane (TMS = õ 0.00). The H-NMR spectrum data were recorded as the following format: number of protons, peak pattern (s, singlet; d, doublet t, triplet; q, quartet; m, multiplet), coupling constant (in terms of Hz ).
[0063] For liquid chromatography / mass spectrometry, an Agilent LC 1200 series instrument (5 pm, chromatography column C18) was used.
Example 1 Synthesis of N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4fluorophenyl) -7-methoxyquinazoline-4,6-diamine (E1 compounds)
[0064] step 1: 4-chloro-7-fluor-6-nitroquinazoline
7-fluor-6-nitroquinazoline-4 (3H) -one (2.0 g, 9.6 mmol) and a drop of N, N-dimethylformamide were refluxed overnight in thionyl chloride (6 mL) and concentrated / non-vacuum. After adding toluene, the solution was again concentrated in vacuo so that the excess thionyl chloride was removed, and the title compound (2 g, 92%) was obtained.
¹ H NMR (CDCI ₃ ): δ 9.18 (1H, s), 9.05 (1H, d, J - 7.6 Hz), 7.95 (1H, d, J = 10.4).
[0065] Step 2: 3-chloro-N- (3,4-dimethoxybenzyl) -4-fluoraniline
3-chloro-4-fluoraniline (2.9 g, 20 mmol) and 3,4-dimethoxybenzaldehyde (3.3 g, 20 mmol) were added in 1,2-dichloroethane (30 mL), stirred at room temperature for 1 H. Then, sodium triacetoborohydride (10 g, 50 mmol) was added, and the reaction mixture was stirred at
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¹ H NMR (CDCI ₃ ): δ 6.94-6.82 (4H, m), 6.63-6.61 (1H, m), 6.45-6.41 (1H, m), 4.18 (2H, s), 3.98 (1H, br), 3.87 (3H, s), 3.86 (3H, s).
[0066] Step 3: N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxy-benzyl) -7fluoro-6-nitro-quinazolin-4-amine
4-chloro-7-fluoro-6-nitroquinazoline (2.1 g, 9.2 mmol) and 3-chloro-N ~ (3,4dimethoxybenzyl) -4 “fluoraniline (2.7 g, 9.2 mmol) were added in acetonitrile ( 20 mL), refluxed for 3 hours. After cooling, the sodium carbonate solution was added for neutralization. The mixture was extracted with ethyl acetate and the organic phase was separated and washed with saturated brine, dried, concentrated in vacuo, and the title compound (3.6 g, 80%) was obtained.
[0067] Step 4: N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxy-benzyl) -7methoxy-6-nitroquinazoline-4-amine
Metallic sodium (113 mg, õ.Ommol) was added in anhydrous methanol (20 mL), stirred at room temperature for 10 min. Then N- (3-chloro-4fluorfenyl) -N- (3,4-dimethoxybenzyl) -7-fluor-6-nitroquinazoline-4-amine (2.4 g, 5.0 mmol) was added. The reaction mixture was stirred at 40 ° C for 6 h. After cooling, the reaction mixture was poured into 100 ml of H ₂ O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo, and the title compound (2.35 g, 94%) was obtained.
¹ H NMR (CDCI3): δ 8.85 (1H, s), 7.57 (1H, s), 7.35 (1H, s), 7.23-7.19 (2H, m), 7.00-6.96 (1H, m), 6.84-6.78 (2H, m), 5.35 (2H, s), 4.05 (3H, s),
3.88 (3H, s), 3.83 (3H, s).
[0068] Step 5: N ⁴ - (3 ~ chloro-4-fluorophenyl) ~ N ⁴ - (3,4-dimethoxybenzyl) -7methoxyquinazoline-4,6-diamine
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N- (3-doro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7-methoxy-6-nitroquinazoline-4-amine (2.35 g, 4.7 mmol) and about 0.5 g of Raney Nickel were added in tetrahydrofuran (100 mL), replaced with hydrogen gas, stirred under a hydrogen gas atmosphere (1 atm) overnight at room temperature. The mixture was filtered; the filtrate was concentrated in vacuo, and the title compound (2 g, 90%) was obtained.
¹ H NMR (CDCI ₃ ): õ 8.72 (1H, s), 7.17 (1H, s), 7.09-7.06 (1H, m), 7.00-
6.95 (2H, m), 6.86-6.83 (1H, m), 6.79-6.74 (2H, m), 6.33 (1H, s), 5.30 (2H, s), 3.98-3.97 (5H, m), 3.83 ( 3H, s), 3.78 (3H, s).
[0069] Step 6: Benzyl 3 - {{4 - [(3 "ChlorO" 4 "fluorophenyl) (3,4-dimethoxybenzyl) amino] -7-methoxyquinazoline-6-yl} amino} -azetidine-1-carboxylate
The solution of N ⁴ - (3-chloro-4-fluorophenyl) -N ⁴ - (3,4dimethoxybenzyl) -7-methoxyquinazoline “4,6-diamine (1.10 g, 2.35 mmol) and benzyl 3 -oxoazetidine-1-carboxylate (0.58 g, 2.83 mmol) in trifluoroacetic acid (7 mL) was stirred at room temperature for 10 minutes and then sodium triacetoborohydride (0.52 g, 2.45 mmol) was added at the same time. After 0.5 h of reaction, benzyl 3-oxoazetidine-
Additional 1-carboxylate (0.24 g, 1.17 mmol) and sodium triacetoborohydride (0.25 g, 1.17 mmol) were added, and the reaction was allowed to proceed for another 0.5 h. Once the reaction was complete, H ₂ O was added slowly to quench the reaction, and the solution was extracted with ethyl acetate. The resulting organic phase was sequentially washed with H ₂ O, 5% NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was made into a paste with ethyl ether, filtered, and the compound indicated in the title (1.3 g, 84%) was obtained.
¹ H NMR (CDCI3): δ 8.79 (1H, s), 7.68 (1H, br), 7.31-7.37 (5H, m), 7.05-7.11 (2H, m), 6.86-6.88 (2H, m), 6.79 -6.82 (1H, m), 6.73-6.75 (1H, m), 5.77 (1H, s), 5.32 (2H, s), 5.10 (2H, s), 4.83 (1H, d, J = 5.6 Hz), 3.83-3.97 (5H, m), 3.83 (3H, s), 3.77 (3H, s), 3.55-3.62 (3H, m).
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[0070] Step 7: N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7methoxyquinazoline-4,6-diamine
A solution of benzyl 3 ~ {{4 - [(3-chloro-4-fluorophenyl) (3,4-dimethoxybenzyl) amino] -7-methoxyquinazolin-6-yl} amino} azetidine-1-carboxylate (1.2 g , 1.82 mmol) in trifluoroacetic acid (8 mL) was stirred at 70 ° C for 6 h. Once the reaction was complete, the reaction solution was cooled and concentrated in vacuo. The residue was made into a paste with ethyl acetate, filtered, and a trifluoroacetate salt of the compound shown in the title (0.74 g, 84%) was obtained.
¹ H NMR (DMSO-όβ): δ 10.50 (1H, s), 9.04 (1H, s), 8.80 (1H, s), 8.70 (1H, s), 7.95-7.98 (1H, m), 7.65-7.68 (1H, m), 7.52-7.57 (1H, m), 7.24 (1H, s), 7.14 (1H, s), 6.86-6.89 (1H, m), 4.50-4.56 (1H, m), 4.41-4.44 (2H, m), 4.04-4.11 (5H, m).
[0071] Step 8: N ⁶ - (1-acryloylazetidin-3-H) -N ⁴ - (3-chloro-4-fluorophenyl) -7methoxyquinazoHna-4,6-diamine
The N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4 ~ fluorophenyl) ~ 7 ~ methoxyquinolineHna-4,6 ~ diamine trifluoroacetate salt (0.89 g, 1.82 mmol) and triethylamine (1 ml) in tetrahydrofuran (20 ml) was stirred at room temperature for 30 min, cooled to -40 ° C, and a solution of acryloyl chloride (166 mg, 1.82 mmol) in tetrahydrofuran (2 ml) was added slowly drop by drop. The reaction was allowed to continue for another 30 minutes. Once the reaction was complete, 5% NaHCO ₃ solution was slowly added to quench the reaction, and the solution was extracted with ethyl acetate. The resulting organic phase was sequentially washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was made into paste with ethyl acetate, and the title compound (0.32 g, 41%) was obtained.
¹ H NMR (CDCI ₃ ): δ 8.59 (1H, s), 7.92 (1H, s), 7.83-7.85 (1H, m), 7.57-
7.59 (1H, m), 7.19 (1H, s), 7.10-7.15 (1H, m), 6.68 (1H, s), 6.35-6.38 (1H,
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m), 6.17-6.31 (1H, m), 5.68-5.71 (1H, m), 5.05 (1H, d, J- 6.4 Hz), 4.58-4.63 (2H, m), 4.42-4.48 (1H, m) , 4.10-4.14 (1H, m), 4.01-4.03 (4H, m).
Example 2 Synthesis of N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4fluorophenyl) -7-methoxyquinazoline-4,6-diamine (compound E2)
[0072] Step 1: tert-butyl 4 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7 ~ methoxyquinazolin-6-yl} amino} piperidine-1-carboxylate formate
A solution of N ⁴ - (3-chloro-4-fluorophenyl) -N ⁴ - (3,4-dimethoxybenzyl) -7methoxyquinazoline-4,6-diamine (469 g, 1.0 mmol) and tert-butyl 4oxopiperidine-1 -carboxylate (239 g, 1.2 mmol) in acetic acid (10 mL) was stirred at room temperature for 2 hours and then sodium triacetoxyborohydride (254 g, 1.2 mmol) was added at the same time. After 0.5 h of reaction, H ₂ O was added slowly to quench the reaction. The solution was extracted with ethyl acetate. The resulting organic phase was sequentially washed with H ₂ O, 5% NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was separated by column chromatography on silica, and the title compound (404 mg, 62%) was obtained.
¹ H NMR (DMSO-Ó6): δ 8.57 (1H, s), 7.33-7.27 (2H, m), 7.09 (1H, s),
6.99 (1H, m), 6.84-6.80 (1H, m), 6.81-6.80 (1H, m), 6.79-6.78 (1H, m), 5.99 (1H, m), 5.29 (2H, s), 3.91 ( 3H, m), 3.85-3.82 (2H, m), 3.64 (3H, m), 3.61 (3H, m), 2.80-2.75 (1H, m), 2.59-2.53 (2H, m), 1.42-1.37 ( 11H, m), 1.20-
1.17 (2H, m).
[0073] Step 2: N ⁶ - (piperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7methoxyquinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, the compound shown in the title was synthesized from the product of step 1.
¹ HNMR (DMSO-Ó6): õ 10.62 (1H, s), 8.75 (1H, s), 8.68-8.60 (1H, br),
8.50-8.41 (1H, br), 7.96-7.94 (1H, m), 7.66-7.64 (1H, m), 7.58-7.56 (1H, m),
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7.39 (1H, s), 7.20 (1 Η, s), 6.19-6.17 (1 Η, m), 4.05 (3H, s), 3.80-3.60 (2H, m), 3.05-2.96 (2H, m), 2.16-2.12 (2H, m), 1.78-1.74 (2H, m).
[0074] Step 3: N ⁶ - (1 ~ acryloylpiperidin ~ 4 ~ yl) -N ⁴ ~ (3-chloro-4-fluorophenyl) 7-methoxyquinazoline-4,6-diamine
A solution of N ^s mono trifluoracetate salt - (piperidin-4-yl) -N ⁴ (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4,6-diamine (258 mg, 0.5 mmol) and triethylamine ( 202 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. After cooling to 0 ° C, a solution of acryloyl chloride (54 mg, 0.6 mmol) in tetrahydrofuran (2 ml) was added dropwise, then the reaction was allowed to proceed for an additional 30 minutes. Once the reaction was complete, 5% NaHCO ₃ solution was slowly added to quench the reaction. The solution was extracted with ethyl acetate. The resulting organic phase was sequentially washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was separated by silica column chromatography, and the target product was obtained (150 mg, 66%).
¹ H NMR (DMSO-Ó6): δ 9.24 (1H, s), 8.33 (1H, s), 8.09-8.08 (1H, m),
7.77-7.74 (1H, m), 7.42-7.40 (1H, m), 7.23 (1H, s), 7.06 (1H, s), 6.85-6.81 (1H, m), 6.10-6.06 (1H, m), 5.66-5.64 (1H, m), 5.32-5.29 (1H, m), 4.41-4.38 (1H, m), 4.09-4.06 (1H, m), 3.93 (3H, s), 3.79-3.78 (1H, m ), 3.35-3.34 (1H, m), 2.87-2.84 (1H, m), 2.03-2.01 (2H, m), 1.44-1.41 (2H, m).
Example 3 Synthesis of (S) -N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) ~ 7 ~ (tetrahydrofuran-3-yloxy) quinazoline ~ 4,6-diamine (compound E3)
[0075] step 1: N- (3-chloro-4-fluorophenyl) -7-fluor-6-nitroquinazoline-4Amine
4-chloro-7-fluor-6 ~ nitroquinazoline (2.28 g, 10 mmol) and 3-chloro-4 fluoraniline (1.46 g, 10 mmol) were dissolved in acetonitrile (50 mL), refluxed under heating by 1h. The solution was concentrated in vacuo and the solvent was removed. Saturated sodium carbonate and ethyl acetate were added to the residue. The solution was stirred for 10 min.
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Then separated. The aqueous phase was extracted with ethyl acetate. The organic phases were combined and dried over anhydrous sodium sulfate. The solution was concentrated in vacuo and the solvent was removed. The residue was made into a paste with diethyl ether, filtered, and the title compound (3.01 g, 90%) was obtained.
¹ H NMR (DMSO ~ d6): õ 10.51 (1H, s), 9.58 (1H, d, J - 8.0 Hz), 8.73 (1H, s), 8.13 (1H, dd, J = 6.8 Hz, 2.8 Hz) , 7.85 (1H, d, J = 12.4 Hz), 7.77-
7.61 (1H, m), 7.49 (1H, t, 9.2 Hz).
[0076] Step 2: (S) ~ N- (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran ~ 3 ~ yloxy) ~
6-nitroquinazoline-4-amine
N- (3-chloro-4-fluorophenyl) -7-fluor-6-nitroquinazoline-4-amine (37.1 g, 0.11 mol) and (S) -3-hydroxytetrahydrofuran (13.6 g, 0.154 mol ) were dissolved in dry DMSO (200 ml). Potassium tert-Butoxide (30.9 g, 0.275 mol) was added in batches; meanwhile the internal temperature was maintained at 30 ° C or below by a water bath. The solution was stirred at room temperature for 4 h. The reaction mixture was poured into 1.2 L of H ₂ O, filtered with suction, washed with H ₂ O and dried to obtain the crude product. The crude product was then made in slurry with ethanol, filtered with suction, to obtain the compound indicated in the title (33.4 g, 75%).
¹ H NMR (DMSO-όβ): õ 10.08 (1H, s), 9.15 (1H, s), 8.61 (1H, s), 8.118.09 (1H, m), 7.77-7.74 (1H, m), 7.43 -7.39 (2H, m), 5.41-5.38 (1H, m), 3.96-
3.92 (1H, m), 3.87-3.73 (3H, m), 2.33-2.28 (1H, m), 2.06-2.01 (1H, m).
[0077] Step 3: (S) -N ⁴ - (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3yloxy) quinazoline-4,6-diamine
With a method similar to that described in step 5, example 1, the compound shown in the title was synthesized from (S) -N- (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) - 6-nitroquinazoline-4amine.
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24/57 ¹ H NMR (DMS0-d6): δ 8.55 (1H, s), 7.96-7.93 (1H, m), 7.56-7.51 (1H, m), 7.18-7.13 (3H, m), 6.97 (1H , s), 5.13-5.10 (1H, m), 4.30 (1H, br), 4.134.03 (3H, m), 3.96-3.91 (1H, m), 2.39-2.34 (1H, m), 2.26-2.22 (1H, m).
[0078] Step 4: benzyl (S) -3 - {{4 - [(3-chloro-4-fluorophenyl) amino] -7 (tetrahydrofuran-3-yloxy) quinazolin-6-yl} amino} azetidine-1- carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from (S) -N ⁴ (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) - 6-nitroquinazoline-4,6-amine.
¹ H NMR (CDCI ₃ ): δ 10.63 (1H, br), 8.08-8.10 (1H, m), 8.02 (1H, s), 7.69-7.73 (1H, m), 7.31-7.37 (5H, m), 7.15-7.19 (1H, m), 7.00 (1H, s),
6.76 (1H, s), 5.12 (2H, s), 5.03-5.05 (1H, m), 4.52-4.60 (3H, m), 4.30-4.35 (1H, m), 3.91-4.00 (2H, m), 3.74-3.85 (4H, m), 2.14-2.20 (1H, m), 1.95-2.00 (1H, m).
[0079] Step S: (S) -N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzyl (S) -3 - {{4 - [(3-chloro-4-fluorophenyl) amino ] -7 (tetrahydrofuran-3-yloxy) quinazolin-6-yl} amino} azetidine-1-carboxylate.
¹ H NMR (DMSCM6): δ 10.80 (1H, s), 9.10 (1H, br), 8.90 (1H, br), 8.69 (1H, s), 7.90-7.93 (1H, m), 7.60-7.63 (1H , m), 7.50-7.574 (1H, m), 7.23 (1H, s), 7.11 (1H, s), 6.68 (1H, d, J = 5.6 Hz), 5.22-2.24 (1H, m), 4.40- 4.5 (3H, m), 3.90-4.09 (5H, m), 3.76-3.81 (1H, m), 2.43-2.48 (1H, m), 2.14-2.18 (1H, m).
[0080] Step 6: (S) -N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-chloro-4fluorfenyl) ~ 7 ~ (tetrahydrofuran-3-yloxy) quinazoline ~ 4,6-diamine
With a method similar to that described in step 8, example 1, the compound shown in the title was synthesized from the (S) -N ⁶ - (azetidin-3-yl) ~ N ⁴ - (3-chlorine trifluoracetate salt) -4fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4 _i 6-diamine.
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25/57 ¹ H NMR (CDCI ₃ ): δ 8.59 (1H, s), 7.97 (1H, s), 7.85-7.87 (1 H, m), 7.56-
7.59 (1H, m), 7.10-7.15 (2H, m), 6.70 (1H, s), 6.30-6.35 (1H, m), 6.19-6.26 (1H, m), 5.68-5.71 (1H, m), 5.13 (1H, s), 5.01 (1H, d, J = 6.4 Hz), 4.60-4.63 (2H, m), 4.42-4.46 (1H, m), 4.01-4.19 (5H, m), 3.91-3.94 ( 1H, m), 2.35-2.41 (1H, m), 2.22-2.29 (1H, m).
Example 4 Synthesis of (S) -N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine (compound E4)
[0081] Step 1: tert-butyl (S) -4- (4- (3-chloro-4-fluorophenylamino) -7 (tetrahydrofuran ~ 3 ~ yloxy) quinazolin-6-ylamino) piperidine ~ 1 ~ carboxylate
With a method similar to that described in step 1, example 2, the compound shown in the title was synthesized from (S) -N ⁴ (3-chloro-4-fluorophenyl) -7 ~ (tetrahydrofuran-3-yloxy) - 6-nitroquinazoline-4,6-amine.
¹ H NMR (CDCI ₃ ): δ 8.53 (1H, s), 7.84-7.82 (1H, m), 7.54-7.50 (1H, m),
7.18-7.10 (3H, m), 6.62 (1H, s), 5.10-5.09 (1H, m), 4.62 (1H, d, J- 8.0 Hz), 4.10-3.88 (6H, m), 3.61-3.57 ( 1H, m), 3.05-2.98 (2H, m), 2.38-2.07 (4H, m), 1.53-1.43 (11H, m).
[0082] Step 2: (S) -N ⁶ ~ (azetidin-3-yl) -N ⁴ ~ (3-chloro-4-fluorophenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine
Terc butyl (S) -4- (4- (3-chloro-4-fluorophenylamine) -7- (tetrahydrofuran-3yloxy) quinazolin ~ 6-ylamine) piperidin-1-carboxylate (1.0 g, 1.79 mmol) was added to 1 mol / L of HCI solution in methanol (10 mL), stirred at room temperature overnight. The solution was concentrated in vacuo, and sodium bicarbonate solution was added, then stirred for 1h. The solution was extracted with a mixed solution of ethyl acetate and methanol. The organic phase was dried and concentrated in vacuo, and the title compound (500 g, 61%) was obtained.
[0083] Step 3: (S) -N ⁶ - (1-acryloylpiperidin-4-H) -N ⁴ - (3-chloro-4fluorfenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from (S) -N ⁶
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26/57 (piperidin-4-yl) -N ⁴ - (3-doro-4-fluorophenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.40 (1H, s), 7.74-7.71 (1H, m), 7.49-7.45 (1H, m), 7.07-7.03 (2H, m), 6.76 (1H, s), 6.56-6.49 (1H, m), 6.25-6.20 (1H, m), 5.66-
5.63 (1H, m), 5.01-4.98 (1H, m), 4.55-4.41 (2H, m), 4.00-3.65 (6H, m), 3.28-
3.21 (1H, m), 3.00-2.89 (1H, m), 1.53-1.43 (2H, m).
ExamplesS Synthesis of (S) -N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-doro-4fluorfenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine (compound E5 )
[0084] Step 1: tert-butyl (S) -3- (4- (3-chloro-4-fluorophenylamino) -7 (tetrahydrofuran-3-yloxy) quinazolin-6-ylamino) piperidine-1-carboxylate
Using a method similar to that described in step 1, example 2, the compound shown in the title was synthesized from (S) -N ⁴ (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline -4 _i 6-diamine and tert-butyl 3-oxopiperidine-1-carboxylate.
¹ H NMR (CDCh): δ 8.56 (1H, s), 8.26-8.37 (1H, brs), 8.03-8.05 (1H, m), 7.90-7.94 (1H, m), 7.41 (1H, s), 7.12 (1H, t, J = 8.8 Hz), 6.98 (1H, s),
5.14 (1H, s), 5.02 (1H, s), 4.56-4.60 (1H, m), 3.93-4.06 (4H, m), 3.80-3.90 (2H, m), 3.26-3.33 (1H, m), 2.87-2.94 (1H, m), 2.37-2.47 (1H, m), 2.27-2.32 (1H, m), 2.17-2.22 (2H, m), 1.65-1.75 (2H, m), 1.43 (9H, s ).
[0085] Step 2: (S) -N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine
With a method similar to that described in step 2, example 4, the compound shown in the title was synthesized from tert-butyl (S) -3- (4- (3-chloro-4-fluorophenylamine) -7- ( tetrahydrofuran-
3-yloxy) quinazolin-6-ylamine) piperidine-1-carboxylate.
[0086] Step 3: (S) -N ⁶ ~ (1-acryloylpiperidin-3-yl) ~ N ⁴ - (3-chloro-4 ~ fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6 -diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from (S) -N ⁶ Petition 870160032686, of 06/30/2016, p. 34/65
27/57 (piperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-
4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.89-9.07 (1H, brs), 8.64 (1H, s), 8.35-8.39 (1H, m), 8.21-8.27 (1H, m), 7.76-7.86 (1H, m ), 7.16-7.22 (2H, m), 6.71 (1H, dd, J = 17.2 Hz, 10.4 Hz), 6.54 (1H, dd, J = 47.2 Hz, 1.2 Hz), 5.89 (1H, dd, J =
10.8 Hz, 1.2 Hz), 5.23-5.29 (2H, m), 4.66-4.74 (1H, m), 4.05-4.19 (4H, m),
3.87-3.97 (1H, m), 3.26-3.43 (3H, m), 2.46-2.60 (1H, m), 2.21-2.35 (1H, m), 2.01-2.10 (2H, m), 1.64-1.78 (2H , m).
Example 6 Synthesis of (S) -N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine (compound E6)
[0087] Step 1: tert-butyl (S) -3- (4- (3-chloro-4-fluorophenylamino) -7 (tetrahydrofuran ~ 3-yloxy) quinazolin-6-ylamino) pyrrolidine ~ 1 ~ carboxylate
Using a method similar to that described in step 1, example 2, the compound shown in the title was synthesized from (S) -N ⁴ - (3-chloro-4-fluorophenyl) -7- (tetrahydrofuran-3- iloxy) quinazoline-4,6diamine and tert-butyl 3-oxopyrrolidine-1-carboxylate.
[0088] Step 2: (S) -N ⁶ - (pyrrolidin-3-yl) -N ⁴ ~ (3-chloro ~ 4-fluorophenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine
Using a method similar to that described in step 2, example 4, the compound shown in the title was synthesized from tert-butyl (S) -3- (4- (3-chloro-4-fluorophenylamine) -7- (tetrahydrofuran- 3yloxy) quinazolin-6-ylamine) pyrrolidine-1-carboxylate.
[0089] Step 3: (S) -N ⁶ ~ (1-acryloylpyrrolidin-3-yl) ~ N ⁴ - (3-chloro-4 ~ fluorophenyl) -7- (tetrahydrofuran-3-yloxy) quinazoline-4,6 -diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from (S) -N ⁶ (pyrrolidin-3-yl) -N ⁴ - (3-chloro-4-fluorphenyl) -7 (tetrahydrofuran-3-yloxy) quinazoline-4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.97-8.57 (1H, m), 8.54-8.48 (1H, m), 7.84-7.76 (1H, m), 7.66-7.62 (1H, m), 7.40-7.20 (1H , m), 7.11-6.98 (2H, m), 6.49-6.32
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28/57 (2H, s), 5.74-5.67 (1H, s), 5.10-5.09 (1H, s), 4.66-4.63 (1H, m), 4.30-3.20 (8H, m), 2.42-1.91 (3H , m), 1.43-1.42 (1H, m).
Example 7 Synthesis of 1- (4 ~ (4 ~ (3-chloro-4- (3-fluorbenzyloxy) phenylamino) -
7-methoxyquinazoline-6-ylamine) piperidin-1-yl) prop-2-ene-1-one (Compound E7)
[0090] Step 1: 2-chloro-1- (3-fluorobenzyloxy) -4-nitrobenzene
2-chloro-4-nitrophenol (3.4 g, 20 mmol), 3-fluorobenzyl chloride (2.8 g, 20 mmol) and potassium carbonate (3.3 g, 24 mmol) were refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 ml of H ₂ O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated in vacuo to obtain the crude product. The crude product was washed with petroleum ether, filtered and dried, and the title compound (3.2 g, 57%) was obtained.
¹ H NMR (CDCI ₃ ): δ 8.35 (1H, d, J = 2.8 Hz), 8.17-8.14 (1H, m), 7.44-
7.38 (1H, m), 7.25-7.19 (2H, m), 7.10-7.06 (1H, m), 7.03 (1H, d, J-9.2 Hz),
5.26 (2H, s).
[0091] Step 2: 3-chloro-4- (3-fluorobenzyloxy) -aniline
2-chloro-1- (3-fluorbenzyloxy) -4-nitrobenzene (3.2 g, 11.4 mmol), zinc powder (4.5 g, 68.4 mmol) and ammonium chloride (1.52 g, 28.5 mmol) were added in a mixed solution of ethanol (60 mL) and H ₂ O (10 mL). The mixture was stirred at 60 ° C overnight. Then, the reaction mixture was poured into 200 mL of H ₂ O, extracted with ethyl acetate. The organic phase was separated, washed with saturated brine and dried. The solvent was removed in vacuo. The title compound (2.8 g, 98%) was obtained.
¹ H NMR (CDCI3): δ 7.36-7.30 (1H, m), 7.22-7.18 (2H, m), 7.02-6.97 (1H, m), 6.79-6.76 (2H, m), 6.52-6.49 (1H, m), 5.03 (2H, s), 3.49 (2H, br).
[0092] Step 3: N- (3-chloro-4- (3-fluorobenzyloxy) phenyl) -7-methoxy-6nitroquinazoline-4-amine
3-chloro-4- (3-fluorobenzyloxy) -aniline (2.82 g, 11.1 mmol), 4-chloro-7-methoxy-6 Petition 870160032686, 06/30/2016, p. 36/65
29/57 nitroquinazoline (2.68 g, 11.2 mmol) was added in isopropanol (30 mL), stirred at 60 ° C for 3 h. The solution was filtered, washed with isopropanol and dried, and the title compound (4.8 g, 95%) was obtained.
¹ H NMR (DMSO-d6): δ 10.94 (1H, br), 9.33 (1H, s), 8.79 (1H, s), 7.91 (1H, d, J 2.4 Hz), 7.64-7.61 (1H, m) , 7.47-7.40 (2H, m), 7.31-7.27 (3H, m),
7.18-7.13 (1H, m), 5.25 (2H, s), 4.06 (3H, s).
[0093] Step 4: N ⁴ - (3-chloro-4- (3-fluorbenzyloxy) phenii) -7-methoxyquinazoline-4,6-diamine
A mixture of N ~ (3 ~ chlorine ~ 4 ~ (3-fluorbenzyloxy) phenyl) ~ 7 ~ methoxy-6-nitroquinazoline-4-amine (4.8 g, 10.5 mmol), iron powder (3.54 g, 63 mmol), acetic acid (6 ml) and ethanol (60 ml), was stirred at 85 ° C overnight. Then, the reaction mixture was poured into 300 ml of H ₂ O, filtered to obtain the crude product. The crude product was washed with ethyl acetate, filtered and dried, and the title compound (3.8 g, 85%) was obtained.
¹ H NMR (DMSO-c / 6): δ 10.70 (1H, br), 8.68 (1H, s), 7.84 (1H, d, J =
2.4 Hz), 7.59-7.45 (3H, m), 7.32-7.30 (3H, m), 7.19-7.16 (2H, m), 5.93 (2H, br), 5.29 (2H, s), 4.02 (3H, s ).
[0094] Step 5: tert-butyl 4 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7-methoxyquinazolin-6-ll} amino} piperidine formate ~ 1-carboxylate
Using a method similar to that described in step 1, example 2, the compound shown in the title was synthesized from N ⁴ - (3-chloro-4- (3-fluorbenzyloxy) phenyl) -7-methoxy-quinazoline ~ 4,6- diamine.
¹ H NMR (CDCI ₃ ): õ 8.47 (1H, s), 7.78 (1H, d, J = 2.4 Hz), 7.58-7.55 (1H, m), 7.40-7.35 (1H, m), 7.26-7.22 ( 2H, m), 7.17 (1H, s), 7.06-7.01 (1H,
m), 6.97 (1H, d, J 8.8 Hz), 6.71 (1H, br), 5.16 (2H, s), 4.68 (1H, d, J 8.0
Hz), 4.10-4.05 (2H, m), 3.96 (3H, s), 3.68 (1H, br), 3.11-3.04 (2H, m), 2.15-
2.11 (2H, m), 1.52-1.43 (11H, m).
[0095] Step 6: N ⁴ - (3-chloro-4- (3-fluorobenzyloxy) phenyl) ~ 7 ~ methoxy ~ N ⁶ ~ (piperldin-4-yl) quinazoline-4,6-diamlna
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Using a similar method to that described in step 1, example 4, the compound shown in the title was synthesized from tert-butyl 4- (4 ~ (3-doro-4- (3-fluorbenzyloxy) phenylamino) -7methoxyquinazHna-6- ylamine) piperidine-1-carboxylate ¹ H NMR (DMSO-c / 6): δ 9.62 (1H, s), 8.29 (1H, s), 8.07 (1H, s), 7.82 (1H, d, j- 9.2 Hz ), 7.55 (1H, s), 7.49-7.43 (1H, m), 7.33-7.29 (2H, m), 7.23-
7.14 (2H, m), 7.05 (1H, s), 5.23 (2H, s), 5.14 (1H, d, J = 8.4 Hz), 4.04-4.00 (1H, m), 3.95 (3H, s), 3.12 -3.09 (2H, m), 2.92-2.86 (2H, m), 2.05-2.01 (2H, m), 1.53-1.50 (2H, m).
[0096] Step 7: 1- (4- (4- (3-doro-4- (3-fluorbenzyloxy) phenylamino) -7methoxyquinazoline-6-ylamine) piperidin-1-yl) prop-2-ene-1-one
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - (3doro-4 ”(3-fluorbenzyloxy) phenyl) -7-methoxy-N ⁶ (piperidin-4 -yl) quinazoline-4,6-diamine.
¹ H NMR (DMSO-c / 6): δ 9.14 (1H, s), 8.30 (1H, s), 7.90 (1H, d, J = 2.8 Hz), 7.67-7.64 (1H, m), 7.32-7.23 (4H, m), 7.19-7.14 (1H, m), 7.06 (1H, s),
6.87-6.80 (1H, m), 6.12-6.07 (1H, m), 5.68-5.65 (1H, m), 5.27 (1H, d, J =
8.4 Hz), 5.24 (1H, s), 4.44-4.38 (1H, m), 4.12-4.07 (1H, m), 3.94 (3H, s), 3.81-3.77 (1H, m), 2.92-2.83 (1H , m), 2.07-2.02 (2H, m), 1.46-1.40 (2H, m).
Example 8 Synthesis of 1 ~ (4 ~ (4- (3-chloro-4- (pyridin ~ 2ylmethoxy) phenylamino) -7-methoxyquinazolineHna-6-ylamine) piperidin-1-yl) prop-2-ene1 ~ one (Compound E8)
[0097] Step 1: 2 - ((2-doro-4-nitrophenoxy) methyl) pyridine
2-chloro-4-nitrophenol (3.4 g, 20 mmol), hydrochloride of 2 (chloromethyl) pyridine (3.4 g, 21 mmol), potassium carbonate (3.3 g, 24 mmol) and sodium iodide (3.0 g, 20 mmol) were refluxed in acetonitrile (30 mL) overnight. The reaction mixture was poured into 100 ml of H ₂ O, extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, evaporated with a rotary evaporator, to obtain the
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31/57 crude product. The crude product was washed with petroleum ether, filtered and dried, and the title compound (3.9 g, 74%) was obtained.
¹ H NMR (CDCI ₃ ): δ 8.63 (1H, d, J = 4.8 Hz), 8.34 (1H, d, J = 2.8 Hz), 8.16-8.14 (1H, m), 7.79-7.76 (1H, m) , 7.62-7.60 (1H, m), 7.31-7.27 (1H, m),
7.11 (1H, d, J = 9.2 Hz), 5.49 (2H, s).
[0098] Step 2: 3-chloro-4- (pyridin ~ 2 ~ ylmethoxy) aniline
The 2 - ((2-chloro-4-nitrophenoxy) methyl) pyridine (3.9 g, 15 mmol), zinc powder (5.8 g, 88 mmol) and ammonium chloride (2.4 g, 44 mmol) were added in a mixed solution of ethanol (60 ml) and H ₂ O (10 ml). The mixture was stirred at 60 ° C overnight. Then, the reaction mixture was poured into 200 ml of H ₂ O, extracted with ethyl acetate. The organic phase was separated, washed with saturated brine and dried. The solvent was removed in vacuo, and the title compound (3.4 g, 98%) was obtained.
¹ H NMR (CDCI3): δ 8.57 (1H, d, J = 4.8 Hz), 7.75-7.70 (1H, m), 7.65-
7.63 (1H, m), 7.23-7.20 (1H, m), 6.81 (1H, d, J = 9.2 Hz), 6.77 (1H, d, J =
2.8 Hz), 5.18 (2H, s), 3.48 (2H, br).
[0099] Step 3: N ~ (3-chloro ~ 4 ~ (pyridin ~ 2 ~ ylmeioxy) phenyl) ~ 7 ~ methoxy ~ 6 ~ nitroquinazoline-4-amine
3-chloro-4- (3-pyridin-2-ylmethoxy) -aniline (3.5 g, 14 mmol), 4-chloro-7-methoxy-6-nitroquinazoline (3.4 g, 14 mmol) were added in isopropanol (40 mL), stirred at 60 ° C for 3 h. The solution was filtered; The filter cake was washed with isopropanol and dried, and the title compound (5.6 g, 92%) was obtained.
¹ H NMR (DMSO-d6): õ 10.91 (1H, br), 9.34 (1H, s), 8.80 (1H, s), 8.63 (1H, d, J- 4.4 Hz), 7.97-7.91 (2H, m ), 7.68-7.61 (2H, m), 7.50 (1H, s), 7.44-
7.40 (1H, m), 7.34 (1H, d, J-9.2 Hz), 5.34 (2H, s), 4.09 (3H, s).
[00100] Step 4: N ⁴ - (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7methoxyquinazoline-4,6 ~ diamine
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A mixture of N- (3-doro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxy-6-nitroquinazoline-4-amine (5.6 g, 13 mmol), iron powder (4.5 g, 81 mmol), acetic acid (8 ml) and ethanol (60 ml), was stirred at 85 ° C overnight. The mixture was poured into 300 ml of H ₂ O, filtered to obtain the crude product. The crude product was washed with ethyl acetate, filtered and dried, and the title compound (4.5 g, 86%) was obtained.
¹ H NMR (DMSO-c / 6): δ 10.66 (1H, br), 8.67 (1H, s), 8.59 (1H, d, J =
4.4 Hz), 7.90-7.84 (2H, m), 7.58-7.54 (2H, m), 7.51 (1H, s), 7.38-7.35 (1H, m), 7.30 (1H, d, J = 9.2 Hz), 7.15 (1H, s), 5.92 (2H, br), 5.31 (2H, s), 4.00 (3H, s).
[00101] Step 5: tert-butyl 4- (4- (3-chloro-4- (pyridin-2ylmethoxy) phenylamino-7 ~ methoxyquinazoline ~ 6-ylamino) piperidine-1-carboxylate
With a method similar to that described in step 1, example 2, the compound shown in the title was synthesized from N ⁴ - (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7methoxyquinazoline-4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.60 (1H, d, J = 4.8 Hz), 8.50 (1H, s), 7.77-7.73 (2H, m), 7.66 (1H, d, 7.6 Hz), 7.49-7.46 (1H, m), 7.26-7.23 (1H, m), 7.16 (1H, s), 7.00 (1H, d, J = 8.8 Hz), 6.61 (1H, br), 5.28 (2H, s), 4.64 ( 1H, d, J = 8.0 Hz), 4.08-3.98 (5H, m), 3.62-3.59 (1H, m), 3.06-3.00 (2H, m), 2.11-2.07 (2H, m), 1.49-1.46 ( 11H, m).
[00102] Step 6: N ⁴ - (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7-methoxy-N ⁶ (piperidin-4-H) quinazoline-4,6 ~ diamine
With a method similar to that described in step 2, example 4, the compound shown in the title was synthesized from 4- (4 ~ (3 ~ chloro ~ 4 ~ (pyridin-2-iimethoxy) phenylamino) -7methoxyquinazoline tert-butyl -6-ylamine) piperidine-1-carboxylate
[00103] Step 7: 1- (4- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7methoxyquinazoHna-6-ylamine) piperidin ~ 1-yl) prop ~ 2 ~ ene-1 -one
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Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - (3 chloro ~ 4 ~ (pyridin ~ 2 ~ ylmethoxy) phenyl) -7-methoxy ~ N ⁶ (piperidine -4-yl) quinazoline-4,6-diamine.
¹ H NMR (DMSO-c / 6): õ 8.60 (1H, d, J = 4.8 Hz), 8.47 (1H, s), 7.78-
7.74 (2H, m), 7.66-7.64 (1H, m), 7.49-7.47 (1H, m), 7.26-7.24 (1H, m), 7.16 (1H, s), 6.97 (1H, d, J = 8.8 Hz), 6.79 (1H, br), 6.63-6.56 (1H, m), 6.32-6.27 (1H, m), 5.72-5.69 (1H, m), 5.26 (2H, s), 4.65 (1H, d, J- 8.0 Hz), 4.55-4.50 (1H, m), 4.01-3.95 (4H, m), 3.76-3.74 (1H, m), 3.36-3.29 (1H, s), 3.08-3.00 (1H, m) , 2.22-2.14 (2H, m), 1.52-1.46 (2H, m).
Example 9 Synthesis of 1- (3- (4- (3-chloro-4- (pyridin-2ylmethoxy) phenylamine) -7-methoxyquinazoline-6-ylamine) azetidin-1-yl) prop-2-eno-
1-one (Compound E9)
[00104] Step 1: benzyl 4- (4- (3-chlorO ”4- (pyridin-2-ylmethoxy) phenylamino7-methoxyquinazoline-6-ylamino) azetidine-1-carboxylate
With a method similar to that described in step 6, example 2, the compound shown in the title was synthesized from N ⁴ - (3-chloro-4- (pyridin-2-ylmethoxy) phenyl) -7methoxyquinazoline-4,6-diamine.
[00105] Step 2: N ^ S-chloro ^ pyridin ^ -nmethoxyOphenylO-methoxy-N ⁶ (azetidin-3-yl) quinazoline-4,6diamine
Using a method similar to that described in step 7, example 1, the compound shown in the title was synthesized from benzyl of 3- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7methoxyquinazoline ~ 6 ~ ylamine) azetidine ~ 1 ~ carboxylate
[00106] Step 3: 1- (4- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) -7methoxyquinazoline-6-ylamine) azetidin-1-yl) prop-2-ene-1 -one
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - (3
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34/57 chlorine ~ -4 ~ - (pindin ~ 2 ~ Hethoxy) fenn) - 7 - methoxyHN ⁶ "(piperidin-4-yl) quinazollna-4,6-diamine.
¹ H NMR (DMSO-cfô): δ 8.58 (1H, d, J = 4.8 Hz), 8.45 (1H, s), 8.30 (1H, br), 7.77-7.75 (2H, m), 7.64-7.62 (1H , m), 7.51-7.48 (1H, m), 7.26-7.24 (1H, m), 7.18 (1H, s), 6.92 (1H, d, J - 9.2 Hz), 6.79 (1H, s), 6.35- 6.30 (1H, m), 6.22-6.15 (1H, m), 5.69-5.66 (1H, m), 5.23 (2H, s), 5.05 (1H, d, J - 6.8 Hz), 4.69-4.53 (3H, m), 4.08-4.04 (1H, m), 3.99-3.95 (4H, m).
Example 10 Synthesis of N ⁶ - (1-acryloylpiperidin-3-yl) -N ⁴ - (3-ethynylphenyl) -7 ~ methoxyquinazoline-4,6 ~ diamine (compound E10)
[00107] Step 1: N- (3-ethynylphenyl) -7-methoxy-6-nitroquinazoline-4-amine
4-chloro-7-methoxy-6-nitroquinazoline (1.00 g, 4.17 mmol) was added in a solution of 3-ethinHaniline (0.49 g, 4.17 mmol) in isopropanol (15 mL), refluxed with heating for 1h. Once the reaction was complete, the solution was cooled and filtered, and the title compound (1.12 g, 84%) was obtained.
¹ H NMR (DMSO-c / 6): õ 11.08 (1H, br), 9.47 (1H, s), 8.89 (1H, s), 7.95 (1H, s), 7.79-7.82 (1H, m), 7.56 (1H, s), 7.47-7.52 (1H, m), 7.37-7.40 (1H, m), 4.27 (1H, s), 4.10 (3H, s).
[00108] Step 2: N ⁴ - (3-ethynylphenyl) -7-methoxyquinoline-4,6-diamine
At room temperature, a saturated solution of ammonium chloride (10 mL) was slowly added dropwise in a suspension of iron powder (1.00 g, 17.9 mmol) and N- (3-ethynylphenyl) -7- methoxy-6-nitroquinazoline-4amine (1.12 g, 3.5 mmol) in ethanol (30 ml). When the addition was complete, the temperature was slowly increased, and the mixture was refluxed with heating for 4 hours. Once the reaction was complete, the mixture was cooled and concentrated in vacuo. The residue was added in N, N-dimethylformamide (40 ml), then stirred for 30 min, filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to dry. The residue was made into a paste with H ₂ O, filtered, washed with H ₂ O and dried, then solid yellow (0.78 g, 86%) was obtained.
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35/57 ¹ H NMR (DMS0-Ó6): δ 9.77 (1H, br), 8.49 (1H, s), 7.99 (1H, s), 7.81-
7.84 (1H, m), 7.46 (1H, s), 7.37-7.41 (1H, m), 7.20-7.23 (1H, m), 7.12 (1H, s),
5.56 (2H, br), 4.19 (1H, s), 3.99 (3H, s).
[00109] Step 3: benzyl 4 - {[4- (3-ethinylphenylamino) -7-methoxyquinazolin-
6- yl] amino} piperidine-1-carboxylate
Using a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - (3-ethynylphenyl) -7-methoxyquinazoline-4,6-diamine formylate and benzyl 4oxopiperidine ~ 1 - carboxylate.
[00110] Step 4: N ⁴ - (3-ethynylphenyl) -7-methoxy-N ⁶ - (piperidin-4yl) quinazoline-4,6 ~ diamine
The 40% aqueous potassium hydroxide solution (4 mL) was added to a benzyl formate solution 4 - {[4- (3-ethynylphenylamino) -
7-methoxyquinazoline-6-yl] amino} piperidine-1-carboxylate (200 mg, 0.39 mmol) in ethanol (5 mL), heated to 100 ° C and stirred for 3 h. Once the reaction was complete, H ₂ O was added slowly then extracted with ethyl acetate. The resulting organic phase was sequentially washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was made into a paste with ethyl ether, filtered, and the title compound (116 g, 79%) was obtained.
¹ H NMR (DMSO-d6): δ 9.17 (1H, s), 8.36 (1H, s), 7.98 (1H, s), 7,897.91 (1H, m), 7.36-7.40 (1H, m), 7.28 (1H, s), 7.16-7.19 (1H, m), 7.09 (1H, s), 5.10 (1H, d, J = 8.8 Hz), 4.19 (1H, s), 3.98 (3H, s), 3.62- 3.72 (1H, m), 2.97-3.02 (2H, m), 2.64-2.71 (2H, m), 1.96-2.01 (2H, m), 1.30-1.40 (2H, m).
[00111] Step S: N ⁶ - (1-acryloylpiperidin-4-yl) -N ⁴ - (3-ethynylphenyl) -7methoxyquinazoline-4,6 ~ diamine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - ( ³ -ethynylphenyl) ~ 7 ~ methoxy ~ N ⁶ - (piperidin-4-yl) quinazoline-4,6 -diamine.
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36/57 ¹ H NMR (DMS0-d6): δ 9.13 (1H, s), 8.38 (1H, s), 7.97 (1H, s), 7.90-
7.93 (1H, m), 7.37-7.41 (1H, m) 7.31 (1H, s), 7.18-7.21 (1H, m), 7.10 (1H, s), 6.81-6.89 (1H, m), 6.09-6.13 (1H, m), 5.66-5.70 (1H, m), 5.34 (1H, d, J =
8.8 Hz), 4.40-4.44 (1H, m), 4.19 (1H, s), 4.08-4.13 (1H, m), 3.97 (3H, s), 3.81-3.88 (1H, m), 2.82-2.91 (2H , m), 2.02-2.11 (2H, m), 1.40-1.48 (2H, m).
Example 11 Synthesis of N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - ( ³ -ethynylphenyl) -7-methoxyquinazoline-4,6-diamine (compound E11)
[00112] Step 1: benxyl 3 - {[4- (3-ethynylphenylamino) -7-methoxyquinazolin-6yl] amino} azetidine ~ 1 ~ carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - ( ³ -ethynylphenyl)) - 7-methoxyquinazoline-4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.54 (1H, s), 7.81 (1H, s), 7.71-7.73 (1H, m), 7.22-
7.38 (8H, m) 7.14 (1H, s), 6.44 (1H, s), 5.10 (2H, s), 5.01-5.04 (1H, m), 4.43-4.49 (2H, m), 4.32-4.40 (1H , m), 3.99 (1H, s), 3.96 (3H, s), 3.89-3.94 (2H, m).
[00113] Step 2: N ⁶ - (azetidin-3-yl) -N ⁴ - (3-ethynylphenyl) -7methoxyquinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, the compound shown in the title was synthesized from benzyl
3 - {[4- (3-ethynylphenylamino) -7-methoxyquinazoline-6-yl] amino} azetidine-1-carboxylate
[00114] Step 3: N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-ethynylphenyl) -7methoxyquinazoline-4,6-diamine
With a method similar to that described in step 3, example 1, the compound shown in the title was synthesized from N ⁶ (azetidin-3-yl) -N ⁴ - (3-ethinylphenyl) -7-methoxyquinazoline-
4,6-diamine.
¹ H NMR (CD3OD): Õ8.40 (1H, s), 7.83 (1H, s), 7.70-7.72 (1H, m), 7.31-
7.38 (2H, m), 7.24-7.27 (1H, m), 7.04 (1H, s), 6.34-6.38 (1H, m), 6.22-6.27
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Example 12 Synthesis of N ⁴ - (3 ~ acetylphenyl) ~ N ⁶ - (1acryloylpiperidin-4-yl) -7-methoxyquinazoline-4,6-diamine (compounds E12)
[00115] step 1: N ⁴ - (3-acetylphenyl) -7-methoxy-N ⁶ - (piperidin-4yl) quinazoline-4,6-diamine
With reference to the method in step 1, example 10, N- (3acetylphenyl) -7-methoxy-6nitroqiiinazoline-4-Amine was prepared from 4-chloro-7-methoxy-6nitroquinazoline and 3-acetylaniline. Then, sequentially, with reference to the methods in step 2-4, example 10, the title compound was prepared.
[00116] Step 2: N ⁴ - (3-acetylphenyl) -N ⁶ ~ (1 ~ acryloylpiperidin-4-yl) -7methoxyquinazoline-4,6-diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - (3acetylphenyl ^ -methoxy-N ^ piperidin ^ -iOquinazoline-
4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.58 (1H, s), 8.20-8.22 (1H, m), 8.10 (1H, s), 7.697.72 (1H, m), 7.50-7.54 (1H, m), 7.18-7.21 (2H, m), 6.59-6..62 (2H, m), 6,286,333 (1H, m), 5.70-5.75 (1H, m), 4.69 (1H, d, J = 7.2 Hz) , 4.50-4.57 (1H, m), 4.00-4.03 (4H, m), 3.73-3.80 (1H, m), 3.34-3.42 (1H, m), 3.07-3.14 (1H, m), 2.65 (3H, s), 2.17-2.24 (2H, m), 1.40-1.48 (2H, m).
Example 13 Synthesis of N ⁴ - (3-acetylphenyl) -N ⁶ - (1acryloylazetidin-3-yl) -7-methoxyquinazoline-4,6-diamine (compounds E13)
[00117] Step 1: N ⁴ - (3-acetylphenyl) -N ⁶ - (azetidin-3-yl) -7methoxyquinazoline-4,6 ~ diamine
With a similar method as described in step 2, example 10, N- (3 ”acetylphenyl) -7-methoxy-quinazoline-4,6-diamine was prepared from N ~ (3-acetylphenyl) ~ 7 ~ methoxy-6 -nitroquinazoline ~ 4 ~ amine. Then,
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3Q / 57 sequentially, with a similar method to those in steps 6 and 7, example 1, the compound shown in the title was synthesized.
¹ H NMR (DMSO-d6): õ 10.85 (1H, s), 9.24 (1H, br), 8.98 (1H, br), 8.75 (1H, s), 8.17 (1H, s), 7.96-8.00 (1H , m), 7.90-7.94 (1H, m), 7.33 (1H, s),
7.25 (1H, s), 6.95-6.98 (1H, m), 4.50-4.56 (1H, m), 4.41-4.44 (2H, m), 4.04-
4.11 (5H, m).
[00118] Step 2: N ⁴ - (3-acetylphenyl) -N ⁶ - (1-acryloylazetidin-3-yl) -7methoxyquinazoline-4,6-diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁴ - (3acetylphenyl) -N ⁶ - (azetidin-3-yl) -7methoxyquinazoline-4,6-diamine.
¹ H NMR (CDCI ₃ ): õ 8.60 (1H, s), 8.14-8.20 (2H, m), 7.68-7.72 (1H, m), 7.47-7.52 (1H, m), 6.64 (1H, s), 6.31-6.36 (1H, m), 6.17-6.25 (1H, m), 5.66-5.70 (1H, m), 5.13 (1H, d, J = 6.8 Hz), 4.50-4.73 (3H, m), 3.90- 4.12 (4H, m), 2.62 (3H, s).
Example 14 Synthesis of N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-bromophenyl) -7-methoxyquinazoline-4,6-diamine (compounds E14)
[00119] Step 1: N- (3-bromophenyl) -7-methoxy-6-nitroquinazoline-4amine
With a method similar to that described in step 1, example 3, the compound shown in the title was synthesized from 4-chloro-7-methoxy-6-nitroquinazoline and 3-bromoaniline.
¹ H NMR (DMSO-Ó6): õ 11.10 (1H, br), 9.43 (1H, s), 8.87 (1H, s), 8.048.05 (1H, m), 7.74-7.78 (1H, m), 7.52 (1H, s), 7.38-7.44 (2H, m), 4.07 (3H, s).
[00120] Step 2: N ⁴ - (3-bromophenyl) -7-methoxyquinazoline-4,6-diamine
With a method similar to that described in step 4, example 7.0, the compound shown in the title was synthesized from N- (3bromophenyl) -7-methoxy-6-nitroquinazoline-4-amine.
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39/57 ¹ H NMR (DMS0-d6): δ 10.09 (1H, br), 8.57 (1H, s), 8.05 (1H, s), 7.72-
7.75 (1H, m), 7.47 (1H, s), 7.30-7.38 (2H, m), 7.13 (1H, s), 5.62 (2H, br),
3.97 (3H, s).
[00121] Step 3: benzyl 3 - {[4- (3-bromophenylamino) -7-methoxyquinazolin6-yl] amino} azetidine-1-carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - (3bromophenyl)) ”7-methoxyquinazoline-4,6” diamine.
[00122] Step 4: N ⁶ - (azetidin-3-yl) -N ⁴ - (3-bromophenyl) -7methoxyquinazoline-4,6-diamine
Using a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzyl 3 - {[4- (3-bromophenylamino) -7methoxyquinazoline ”6-yl] amino} azetidine -1 ” ¹ H NMR carboxylate (DMSO-d6): õ 10.40 (1H, br), 8.97 (1H, br), 8.72 (1H, br),
8.66 (1H, s), 7.95 (1H, s), 7.68-7.71 (1H, m), 7.38-7.45 (2H, m), 7.16-7.19 (2H, m), 6.80-6.82 (1H, m), 4.44-4.56 (1H, m), 4.38-4.43 (2H, m), 3.99-4.08 (5H, m).
[00123] Step 5: N ⁶ - (1-acryloylazetidin-3-ll) -N ⁴ - (3-bromophenyl) -7methoxyquinazoline ”4,6-diamine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the N ⁶ - (azetidin ~ 3 ~ yl) -N ⁴ ~ (3-bromophenyl) trifluoracetate salt
-7-methoxyquinazoline-4,6-diamine.
¹ H NMR (DMSO-c / 6): δ 9.23 (1H, s), 8.38 (1H, s), 8.08 (1H, s), 7.82-
7.85 (1H, m), 7.29-7.34 (1H, m), 7.22-7.25 (1H, m), 7.10 (1H, s), 7.03 (1H, s), 6.30-6.38 (2H, m), 6.07- 6.12 (1H, m), 5.62-5.67 (1H, m), 4.65-4.68 (1H, m), 4.38-4.51 (2H, m), 4.09-4.13 (1H, m), 3.90-3.96 (4H, m ).
Example 15 Synthesis of N ⁶ - (1 ~ acryloylazetidin ~ 3-yl) -N ⁴ ~ ( ³ -bromophenyl) -7-methoxyquinazoline-4,6-diamine (compounds E15)
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[00124] step 1: benzyl 4 - {[4- (3-bromophenHamino) -7-methoxyquinazoHna6-yl] amino} piperidine-1-carboxylate
With a method similar to that described in step 3, example 10, the compound shown in the title was synthesized from N ⁴ - (3bromophenyl)) ”7-methoxyquinazoline4,6” diamine.
1H NMR (DMSO-d6): õ 9.42 (1H, br), 8.44 (1H, s), 8.10 (1H, s), 7.84 (1H, d, J = 8.0), 7.29-7.39 (8H, m), 7.11 (1H, s), 5.40-5.42 (1H, m), 5.10 (2H, s), 4.04-4.08 (2H, m), 3.99 (3H, s), 3.75-3.81 (1H, m), 3.00- 3.15 (2H, m), 1.982.05 (2H, m), 4.42-1.48 (2H, m).
[00125] Step 2: N ⁴ - (3-bromophenyl) -7-methoxy-N ⁶ - (piperidin-4yl) quinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzyl 4 - {[4- (3-bromophenylamino) -7methoxyquinazoline-6-yl] amino} piperidine -1-carboxylate ¹ H NMR (DMSO-c / 6): d 10:40 (1H, br), 8.70 (1H, s), 8.61 (1H, br), 8:44 (1H, br), 7.97 (1H, s) , 7.72-7.74 (1H, m), 7.42-7.498 (2H, m), 7.38 (1H, s),
7.19 (1H, s), 6.02-6.05 (1H, m), 4.04 (3H, s), 3.75-3.80 (1H, m), 3.32-3.38 (2H, m), 2.98-3.04 (2H, m), 2.12-2.18 (2H, m), 1.70-1.81 (2H, m).
[00126] Step 3: N ^s - (1-acryloylpiperidin-4-yl) -N ⁴ - (3-bromophenyl) -7methoxyquinazoline-4,6-diamine
Using a similar method to that described in step 3, example 2, the compound shown in the title was synthesized from the N ⁴ - (3-bromophenyl) -7-methoxyN ⁶ - (piperidin-4-yl) quinazoline trifluoracetate salt -4,6-diamine.
¹ H NMR (DMSO-c / 6): õ 9.26 (1H, s), 8.39 (1H, s), 8.13 (1H, s), 7.86-
7.90 (1H, m), 7.25-7.37 (3H, m), 7.10 (1H, s), 6.82-6.89 (1H, m), 6.09-6.14 (1H, m), 5.66-5.70 (1H, m), 5.37 (1H, d, J = 8.8 Hz), 4.39-4.45 (1H, m), 4.09-4.13 (1H, m), 3.97 (3H, s), 3.79-3.88 (1H, m), 3.21-3.27 2.83 -
2.92 (1H, m), 2.02-2.09 (2H, m), 1.41-1.50 (2H, m).
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Example 16 Synthesis of N ^s ~ (1 ~ acrylazetidin ~ 3 ~ ily) -N ⁴ ~ (3-chloro-4fluorophenyl) -7-methoxyquinazoline-4,6-diamine (compound E16)
[00127] step 1: N- (3-chloro-4-fluorophrenyl) -7- (2 ~ methoxyethoxy) -6nitroquinazoline-4-amine
With a method similar to that described in step 2, example 3, the compound shown in the title was synthesized from N- (3-chloro-4-fluorophenyl) -7-fluor-6-nitroquinazoline-4amine and 2-methoxyethanol.
¹ H NMR (DMSO-de): δ 10.13 (1H, s), 9.18 (1H, s), 8.65 (1H, s), 8.14 (1H, dd, J- 6.8 Hz, 2.4 Hz), 7.75-7.79 ( 1H, m), 7.49 (1H, s), 7.45 (1H, t, J =
9.2 Hz), 4.42 (2H, t, J = 4.8 Hz), 3.72 (2H, t, J = 4.8 Hz), 3.32 (3H, s).
[00128] Step 2: N ⁴ - (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazoline-4,6-diamine
With a method similar to that described in step 5, example 1, the compound shown in the title was synthesized from N- (3-chloro-4-fluorophenyl) -7-fluor-6-nitroquinazoline-4amine and 2-methoxyethanol.
¹ H NMR (DMSO-d6): δ 9.38 (1H, s), 8.36 (1H, s), 8.17 (1H, dd, J- 6.8 Hz, 2.4 Hz), 7.77-7.81 (1H, m), 7.39 ( 1H, s), 7.37 (1H, t, J = 9.2 Hz), 7.10 (1H, s), 5.29 (2H, s), 4.28 (2H, t, J = 4.4 Hz), 3.77 (2H, t, J = 4.4 Hz), 3.34 (3H, s).
[00129] Step 3: Benzyl 3 - {[4- (3-chloro-4-fluorophenyl) -7- (2methoxyethoxy) quinazolin-6-yl] amino} azetidine-1-carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazoline-
4,6-diamine.
¹ H NMR (CDCI ₃ ): δ 8.54 (1H, s), 7.84 (1H, dd, J = 6.8 Hz, 2.4 Hz), 7.48-7.52 (1H, m), 7.29-7.37 (5H, m), 7.18 (1H, s), 7.15 (1H, t, J 8.8 Hz), 6.37 (1H, s), 5.09-5.13 (3H, m), 4.47 (2H, dd, J = 9.2 Hz, 7.2 Hz), 4.25- 4.38
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[00130] Step 4: N ⁶ - (azetidin ~ 3-yl) -N ⁴ ~ (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzii 3 - {[4- (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazolin- 6-yl] amino} azetidine-1-carboxylate
[00131] Step 5: N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4-fluorophenyl) -7 (2-methoxyethoxy) quinazoline-4,6-diamine
With a method similar to that described in step 8, example 1, the compound shown in the title was synthesized from N ⁶ (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorfenii) -7 (2 -methoxyethoxy) quinazoline-4,6 “diamine.
¹ H NMR (DMSO): õ 9.27 (1H, s), 8.37 (1H, s), 8.08 (1H, dd, J = 6.8 Hz, 2.4 Hz), 7.75-7.79 (1H, m), 7.42 (1H, t, J = 9.2 Hz), 7.14 (1H, s), 7.04 (1H, s), 6.36 (1H, dd, J = 17.2 Hz, 10.4 Hz), 6.16 (1H, d, J = 6.8 Hz), 6.11 (1H, dd, J-16.4 Hz, 2.4 Hz), 5.66 (1H, dd, J = 10.4 Hz, 2.4 Hz), 4.71 (1H, t, J = 8.0 Hz), 4.41-4.53 (2H, m), 4.31 (2H, t, J = 4.8 Hz), 4.13-4.16 (1H, m),
3.93-3.97 (1H, m), 3.79 (2H, t, J = 4.8 Hz), 3.34 (3H, s).
Example 17 Synthesis of N ⁶ - (1-acryloylpiperidin-4-yl) ~ N ⁴ - (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4,6-diamine (compounds E17)
[00132] step 1: tert-butyl 4 - {[4- (3 ”Chloro-4” fluorophenyl) -7 ”(2 methoxyethoxy) quinazolin-6-ii] amino} piperidine-1carboxylate
A solution of N ⁴ - (3 ~ chloro-4 ~ fluorophenyl) ~ 7 ~ (2-methoxyethoxy) quinazoline ~
4,6-diamine (100 g, 0.28 mmol) and tert-butyl 4-oxoazetidine-1-carboxylate (167 g, 0.84 mmol) in acetic acid (4 mL) was stirred at room temperature for 2 hours. Then, sodium triacetoxyborohydride (178 mg, 0.84 mmol) was added. After 1 h of reaction, H ₂ O was slowly
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43/57 added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The resulting organic phase was sequentially washed with H ₂ O, 5% NaHCO ₃ solution and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was separated by silica column chromatography, and the title compound (85 mg, 56%) was obtained.
¹ H NMR (CDCI ₃ ): δ 8.52 (1H, s), 7.83 (1H, dd, J = 6.8 Hz, 2.4 Hz),
7.51-7.55 (1H, m), 7.17 (1H, s), 7.16 (1H, t, J = 8.8 Hz), 6.57 (1H, s), 4.72-
4.76 (1H, brs), 4.29 (2H, t, J = 4.4 Hz), 4.02-4.11 (2H, m), 3.82 (2H, t, J =
4.4 Hz), 3.57-3.64 (1H, m), 3.46 (3H, s), 3.01-3.08 (2H, m), 2.08-2.03 (2H, m), 1.45-1.53 (11H, m).
[00133] Step 2: N ⁶ ~ (piperidin ~ 4 ~ yl) -N ⁴ ~ (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazoline-4,6diamine
Using a method similar to that described in step 2, example 4, the compound shown in the title was synthesized from tert-butyl 4 ~ {[4 ~ (3-chloro-4-fluorophenyl) -7- (2-methoxyethoxy) quinazolin -6-yl] amino} piperidine-1-carboxylate.
[00134] Step 3: N®- (1-acryloylpiperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7 (2-methoxyethoxy) quinazoline
-4,6-diamine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from N ⁶ (piperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7- ( 2 methoxyethoxy) quinazoline-4,6-diamine.
¹ H NMR (DMSO): δ 9.68-9.75 (1H, brs), 8.40 (1H, s), 8.08 (1H, dd, J = 6.8 Hz, 2.4 Hz), 7.75-7.79 (1H, m), 7.42 ( 1H, t, J = 8.8 Hz), 7.40 (1H, s),
7.11 (1H, s), 6.82 (1H, dd, J = 16.8 Hz, 10.8 Hz), 6.08 (1H, dd, 16.8 Hz,
2.4 Hz), 5.65 (1H, dd, J = 10.8 Hz, 2.4 Hz), 5.21 (1H, d, J - 8.8 Hz), 4.374.42 (1H, m), 4.28 (2H, t, J - 4.4 Hz ), 4.05-4.10 (1H, m), 3.82-3.91 (1H, m),
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3.76 (2H, t, J = 4.4 Hz), 3.31 (3H, s), 3.20-3.26 (1H, m), 2.85-2.92 (1H, m), 2.00-2.06 (2H, m), 1.35-1.46 ( 2H, m).
Example 18 Synthesis of N ⁶ - (1-acryloylazetidin-3-yl) ~ N ⁴ - (3-chloro-4-fluorophenyl) -7- (2-morpholinylethoxy) quinazoline-4,6-diamine (compounds E18)
[00135] step 1: N- (3-chloro-4-fluorophenyl) -7- (2-morpholinylethoxy) -6nitroquinazoline-4-amine
With a method similar to that described in step 2, example 3, the compound shown in the title was synthesized from N- (3-chloro-4-fluorophenyl) -7-fluor-6-nitroquinazoline-4amine and 2-morphethanol.
¹ H NMR (DMSO): δ 10.17 (1H, s), 9.19 (1H, s), 8.65 (1H, s), 8.14 (1H, dd, J - 6.8 Hz, 2.4 Hz), 7.76-7.80 (1H, m), 7.51 (1H, s), 7.45 (1H, t, J = 9.2 Hz), 4.41 (2H, t, J = 5.6 Hz), 3.54-3.56 (4H, m), 2.76 (2H, t, J = 5.6 Hz), 2.49-2.52 (4H, m).
[00136] Step 2: N ⁴ - (3-chloro-4-fluorophenyl) -7- (2morpholinylethoxy) quinazoline-4,6-diamine
With a method similar to that described in step 5, example 1, the compound shown in the title was synthesized from N- (3-chloro-4-fluorophenyl) -7- (2-morpholinylethoxy) -6-nitroquinazoline-4-amine.
¹ H NMR (DMSO-c / 6): õ 9.36 (1H, s), 8.34 (1H, s), 8.15 (1H, dd, J- 7.2 Hz, 2.8 Hz), 7.75-7.79 (1H, m), 7.37 (1H, s), 7.36 (1H, t, J = 9.2 Hz), 7.09 (1H, s), 5.29 (2H, s), 4.25 (2H, t, J = 5.6 Hz), 3.55-3.57 (4H , m), 2.79 (2H, t,
5.6 Hz), 2.48-2.50 (4H, m).
[00137] Step 3: benzyl 3 - {[4- (3 ~ chloro ~ 4 ~ fluorophenyl) ~ 7 ~ (2 ~ morpholinylethoxy) quinazolin-6-yl] amino} azetidine-1carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - (3
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¹ H NMR (DMS0 ~ d6): δ 9.36-9.39 (1H, brs), 8.38 (1H, s), 8.11-8.13 (1H, m), 7.79-7.84 (1H, m), 7.43 (1H, t, J - 9.2 Hz), 7.30-7.39 (5H, m), 7.16 (1H, s), 7.13 (1H, s), 6.06-6.14 (1H, brs), 5.07 (2H, s), 4.41-4.48 (3H , m),
4.31 (2H, t, J ™ 5.6 Hz), 3.90-4.01 (2H, m), 3.56-3.64 (4H, m), 2.86 (2H, t, J = 5.6 Hz), 2.50-2.54 (4H, m) .
[00138] Step 4: N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7- (2morfohnylethoxy) quinazoline-4,6diamine
Using a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzyl 3 - {[4- (3-chloro-4 “fluorophenyl) -7- (2morpholinylethoxy) quinazolin-6-yl] amino} azetidine-1-carboxylate ¹ H NMR (DMSO-d6): δ 10.32-10.47 (1H, brs), 9.14-9.24 (1H, brs), 9.03-9.12 (1H, brs), 8.63 (1H, s), 7.97 (1H, dd, J = 6.8 Hz, 2.4 Hz), 7.65-
7.70 (1H, m), 7.49 (1H, t, J == 9.2 Hz), 7.31 (1H, s), 7.17 (1H, s), 6.91-6.95 (1H, brs), 4.51-4.64 (3H, m ), 4.39-4.48 (2H, m), 4.08-4.16 (2H, m), 3.40-
3.97 (10H, m).
[00139] Step 5: N ⁶ - (1-acryloylazetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -7 (2-morpholinylethoxy) quinazoline-4,6-diamine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the N ⁶ - (azetidin-3-yl) -N ⁴ - (3-chloro-4-fluorophenyl trifloracetate salt ) -7- (2morpholinylethoxy) quinazoline-4,6-diamine.
¹ H NMR (DMSO-c / 6): δ 9.47 (1H, s), 8.37 (1H, s), 8.14 (1H, dd, J- 6.8 Hz, 2.4 Hz), 7.82-7.86 (1H, m), 7.41 (1H, t, J = 9.2 Hz), 7.18 (1H, S), 7.14 (1 H, s), 6.35 (1H, dd, J = 13.2 Hz, 9.2 Hz), 6.11 (1H, dd, J = 13.2 Hz, 2.4 Hz), 5.66 (1H, dd, J = 10.0 Hz, 2.4 Hz), 4.72 (1H, t, J = 7.6 Hz), 4.52-4.59
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3.99 (1H, m), 3.53-3.68 (4H, m), 2.77-2.90 (2H, m), 2.50-2.58 (4H, m).
Example 19 synthesis of 6- (1-acryloylazetidin-3-yl):
thio-N- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4-amine (compound E19)
[00140] Step 1: N- (3-chloro-4-fluorophenyl) -N ~ (3,4 ~ dimethoxybenzyl) ~ 7methoxy-6-thiocyanatoquinazoline-4-amine
At 0 ° C, N ⁴ - (3-chloro-4-fluorophenyl) -N ⁴ - (3,4-dimethoxybenzyl) -7methoxyquinazoline-
4,6-diamine (0.25g, O.õmmol) was slowly added in 30% sulfuric acid (3g), stirred for 30 min to make it completely dissolved. Sodium nitrite (0.072 g, 1 mmol) was added slowly. The system was stirred at 0 ° C for a further 30 minutes, then warmed to room temperature and stirred for 30 min. At room temperature, the solution indicated above was slowly added dropwise in aqueous solution of 30 ml of potassium thiocyanate (0.5 g, 5 mmol) and ferric chloride (0.25 g, 1.5 mmol) with stirring vigorous. After the addition, the solution was further stirred overnight, filtered with suction, washed with H ₂ O and dried. A compound was obtained, as shown in the title (0.25 g, 92%) yellow.
¹ H NMR (DMSO-όβ): Õ9.03 (1H, s), 7.83 (1H, s), 7.44 (1H, t,> 8.0Hz), 7.29-7.38 (2H, m), 7.24 (1H, s ), 6.92 (1H, s), 6.81 (1H, s), 5.48 (3H, s), 4.05 (3H, s), 3.69 (3H, s), 3.66 (3H, s).
[00141] Step 2: tert-butyl 3 - {{4 - [(3-chloro-4-fluorophenyl) (3,4 ~ dimethoxybenzyl) amino] -7-methoxyquinazoline-6-yl} thio) azetidine-1-carboxylate
Sodium borohydride (16 mg, 0.43 mmol) was added in a solution of N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7-methoxy-6thiocyanatoquinazoline-4-amine ( 44mg, 0.086mmol) in ethanol (2 mL), stirred at room temperature for 1 h, then additional sodium borohydride (5 mg) was added, and the solution was further stirred
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47/57 for 30 min. When the raw material disappeared, as confirmed with TLC, anhydrous potassium carbonate (120 mg) and tert-butyl 3-iodoazetidine ~ 1 ~ carboxylate (30 mg, 0.106 mmol) were added sequentially. Then, the mixture was heated to 50 ° C, and the reaction was allowed to proceed for 5 hours. Once the reaction was complete, the solution was cooled and H ₂ O was added slowly to quench the reaction, then the solution was extracted with ethyl acetate. The resulting organic phase was sequentially washed with H ₂ O, and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with preparative thin layer chromatography (dichloromethane: ethyl acetate (v / v) = 1: 2) and the title compound (15 g, 27%) was obtained.
¹ H NMR (CDCI ₃ ): δ 8.82 (1H, s), 7.38 (1H, br), 7.10-7.20 (2H, m), 6.80-6.93 (2H, m), 6.72-6.77 (3H, m), 5.33 (2H, s), 4.10-4.15 (2H, m), 3.98 (3H, s), 3.84 (3H, s), 3.79 (3H, s), 3.60-6.68 (2H, m), 3.30-3.35 ( 1H, m),
1.45 (9H, s).
[00142] Step 3: 6- (azetidin-3-yl) thio-N- (3-chloro-4-fluorophenyl) -7methoxyquinazoline-4-amine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from tert-butyl 3 - {{4 - [(3-chloro-4-fluorphenyl) (3,4dimethoxybenzyl ) amino] -7-methoxyquinazoline-6-yl} thio} azetidine-1-carboxylate ¹ H NMR (DMSO-c / 6): δ 10.30 (1H, s), 8.97-9.03 (2H, m), 8.64 (1 H, s), 8.16 (1H, s), 8.02-8.04 (1H, m), 7.70-7.72 (1H, m), 7.46-7.49 (1H, m), 7.27 (1H, s), 4.42-4.47 ( 3H, m), 3.99 (3H, s), 3.82-3.88 (3H, m).
[00143] Step 4: 6- (1-acnloylazetidyl-3-yl) thio-N- (3-chloro-4-fluorphenyl) -7methoxyquinazoline-
4-amine
With a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the salt of
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48/57 6- (azetidin-3-yl) thio-N- (3chloro-4-fluorophenyl) -7-methoxyquinazoline-4-amine triofluorophosphate.
¹ H NMR (CD ₃ OD): δ 8.39 (1H, s), 8.03 (1H, s), 7.88-7.90 (1 H, m), 7.54-7.56 (1H, m), 7.16-7.20 (1H, m ), 7.11 (1H, s), 6.17-6.24 (2H, m), 5.64-
5.67 (1H, m), 4.71-4.73 (1H, m), 4.45-4.48 (1H, m), 4.26-4.29 (1H, m), 4.114.13 (1H, m), 3.95 (3H, s), 3.86-3.89 (1H, m).
example 20 synthesis of 6- (1-acryloylpyrrolidin-3-yl) thio-N- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4amine (compound E20)
[00144] Step 1: tert-butyl 3 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7-methoxyquinazoline-6-yl} thio} pyrrolidine-1-carboxylate
Using a method similar to that described in step 2, example 19, the compound shown in the title was synthesized from tert-butyl N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7methoxy- 6-thioclanatoquinazoline-4-amine and 3-iodopyrrolidine-1-carboxylate.
¹ H NMR (CDCI3): δ 8.81 (1H, s), 7.15-7.26 (2H, m), 7.05-7.12 (1H, m), 7.04 (1H, s), 6.95 (1H, s), 6.90-6.94 (1H, m), 6.78-6.82 (1H, m), 6.74-6.77 (1H, m), 5.30-5.35 (2H, m), 3.98 (3H, s), 3.84 (3H, s), 3.79 (3H , s), 3.35-
3.60 (3H, m), 3.12-3.21 (2H, m), 1.92-2.05 (1H, m), 1.60-1.70 (1H, m), 1.45 (9H, s).
[00145] Step 2: N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (pyrrolidin-1thio) quinazoline ~ 4 ~ amine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from tert-butyl 3 - {{4 ~ [(3 ~ chloro ~ 4 ~ fluorophenyl) (3,4dimethoxybenzyl ) amino] -7-methoxyquinazoline-6-yl} thio} pyrrolidine-1-carboxylate.
¹ H NMR (DMSO-c / 6): δ 10.50 (1H, br), 9.03-9.09 (2H, br), 8.73 (1H, s), 8.40 (1H, s), 8.02-8.04 (1H, m) , 7.70-7.75 (1H, m), 7.49-7.55 (1H, m), 7.32
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[00146] Step 3: 6- (1-acryloylpyrrolidin-3-yl) thio-N- (3-chloro-4-fluorophenyl) -7methoxyquinazoline-4-amine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the N- (3-chloro-4-fluorophenyl) -7methoxy · 6- (pyrrolidin-1 ”) triofluorphosphate salt ) quinazoline-4-amine.
¹ H NMR (CD ₃ OD): δ 8.46 (1H, s), 8.31-8.34 (1H, m), 7.94-7.98 (1H, m), 7.61-7.65 (1H, m), 7.21-7.26 (1H, m), 7.15 (1H, s), 6.45-6.61 (1H, m), 6.20-6.28 (1H, m), 5.65-5.75 (1H, m), 4.17-4.25 (1H, m), 3.99 (3H, s), 3.79-
3.88 (1H, m), 3.65-3.78 (1H, m), 3.35-3.42 (2H, m), 2.30-2.48 (1H, m), 1,902.08 (1H, m).
example 21 synthesis of 6- (1-acryloylpiperidin-4-yl) thio-N- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4-amine (compound E21)
[00147] Step 1: tert-butyl 4 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7-methoxyquinazolin ~ 6 ~ yl} amino thio) piperidine-1-carboxylate
Using a method similar to that described in step 2, example 19, the compound shown in the title was synthesized from N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7methoxy- -6-thiocyanatoquinazoNna-4-amine and 4-iodopiperidine-1-tert-butik ¹ H NMR (CDCh): δ 8.82 (1H, s), 7.10-7.18 (4H, m), 6.88-6.93 (2H, m) ,
6.78-6.82 (1H, m), 6.74-6.77 (1H, m), 5.33 (2H, s), 3.98 (3H, s), 3.84 (3H, s), 3.79 (3H, s), 2.86-2.96 ( 3H, m), 1.50-1.70 (4H, m), 1.45 (9H, s), 1.30-
1.40 (2H, m).
[00148] Step 2: N- (3-chloro-4-fluorophenyl) -6- (piperidin-4-ylthio) -7methoxyquinazoline-4-amine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was
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50/57 synthesized from tert-butyl 4 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7-methoxyquinazoline-6-yl} thio} piperidine-1-carboxylate.
¹ H NMR (DMSO-Ó6): δ 10.54 (1H, br), 8.74 (1H, s), 8.63 (1 H, br), 8.56 (1H, s), 8.48 (1H, br), 8.05-8.09 ( 1H, m), 7.72-7.78 (1H, m), 7.48-7.55 (1H, m), 7.30 (1H, s), 4.03 (3H, s), 3.72-3.80 (1H, m), 3.26-3.35 ( 2H, m), 2.983.05 (2H, m), 2.06-2.15 (2H, m), 1.65-1.78 (2H, m).
[00149] Step 3: 6- (1-acryloylpiperidin-4-yl) thio-N- (3-chloro-4-fluorophenyl) -7methoxyquinazoline-4amine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the N- (3-chloro-4-fluorophenyl) -6 (piperidin-4-yl) triofluorphosphate salt -7 -methoxyquinazoline-4-amine.
¹ H NMR (CD ₃ OD): õ 8.46 (1H, s), 8.38 (1H, s), 7.94-7.98 (1H, m),
7.61-7.65 (1H, m), 7.21-7.26 (1H, m), 7.15 (1H, s), 6.69-6.74 (1H, m), 6.14-
6.19 (1H, m), 5.68-5.72 (1H, m), 4.24-4.29 (1H, m), 3.98-4.06 (4H, m), 3.68-
3.75 (1H, m), 3.30-3.40 (1H, m), 3.12-3.20 (1H, m), 1.97-2.03 (2H, m), 1.50-
1.60 (2H, m).
Example 22 synthesis of (R) -6- (1-acryloylpiperidin-3-yl) thio-N (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4-amine (compound E22)
[00150] Step 1: tert-butyl (R) -3 - {{4 - [(3-chloro-4-fluorophenyl) (3,4dimethoxybenzyl) amino] -7-methoxyquinazoline-6-yl} thio} piperidine-1- carboxylate
With a method similar to that described in step 2, example 19, the compound shown in the title was synthesized from tert-butyl N- (3-chloro-4-fluorophenyl) -N- (3,4-dimethoxybenzyl) -7methoxy- e-thiocyanatoquinazoline ^ -amine and (S) -3-iodopiperidine-1-carboxylate.
¹ H NMR (CDCI3): δ 8.83 (1H, s), 7.08-7.18 (1H, m), 7.07 (1H, s), 6.8595 (3H, m), 6.78-6.85 (1H, m), 6.74-6.78 (2H, m), 5.33 (2H, s), 3.97 (3H, s), 3.84 (3H, s), 3.75-3.80 (4H, m), 2.45-3.00 (2H, m), 1.65-1.92 (4H , m), 1.30-
1.50 (11H, m).
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[00151] Step 2: (R) -N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (piperidin-3thio) quinazoline-4-amine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from tert-butyl (R) -3 - {{4 - [(3-chloro-4-fluorophenyl) (3,4-dimethoxybenzyl) amino] ~ 7 ~ methoxyquinazoline-6-yl} thio} piperidine ~ 1 ~ carboxylate.
¹ H NMR (CD ₃ OD): õ 8.65 (1H, s), 8.61 (1H, s), 7.92-7.95 (1H, m),
7.61-7.65 (1H, m), 7.27-7.33 (1H, m), 7.25 (1H, s), 4.09 (3H, s), 3.74-3.80 (1H, m), 3.51-3.58 (2H, m), 2.99-3.06 (2H, m), 2.16-2.22 (1H, m), 2.00-2.06 (1H, m), 1.80-1.92 (2H, m), 1.62-1.73 (1H, m).
[00152] Step 3: (R) ~ 6 ~ (1 ~ acryloylpiperidin-3-yl) thio ~ N ~ (3-chloro-4fluorfenyl) -7-methoxyquinazoline-4-amine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the (R) -N- (3-chloro-4-fluorophenyl) -7methoxy · 6- (piperidine) triofluorphosphate salt -3-ylthio) quinazoHna ~ 4 ~ amine.
¹ H NMR (CD3OD): 58.44 (1H, s), 8.22 (1H, s), 8.14-8.17 (1H, m), 7.95-8.00 (1H, m), 7.16-7.20 (1H, m), 7.06 ( 1H, s), 6.77-6.85 (1H, m), 6.26-
6.31 (1H, m), 5.78-5.81 (1H, m), 4.78-4.82 (1H, m), 4.04-4.12 (1H, m), 3.98 (3H, s), 3.38-3.45 (2H, m), 2.73-2.79 (1H, m), 2.12-2.18 (1H, m), 1.93-1.97 (1H, m), 1.62-1.80 (2H, m).
Example 23 Synthesis of N ⁶ - (1-acnloylpiperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) -quinazoHna-4,6-diamine (compounds E23)
[00153] Stage 1: 6-nitroquinazoline-4 (3H) ”Ona
In an ice bath, quinazoline-4 (3H) -one (1.46 g, 10 mmol) was added slowly in batches in a mixture of acid (concentrated sulfuric acid: concentrated nitric acid = 4: 1) (8 mL). When the addition was complete, the system temperature slowly increased to 95 ° C. After 1 h of reaction, the reaction mixture was poured into ice water (100 mL),
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52/57 stirred until solid has precipitated. The mixture was filtered and the resulting solid was separated by column chromatography on silica and then the title compound (1.45 g, 76%) was obtained.
¹ H NMR (DMSO-c / 6): δ 12.90 (1H, br), 8.78 (1H, d, J = 2.4 Hz), 8.52 (1H, dd, J-2.4 Hz, 8.8 Hz), 8.28 (1H, s), 7.83 (1H, d, J-8.8 Hz).
[00154] Step 2: N ⁴ - (3 ~ chloro ~ 4 ~ (3-fluorbenzyloxy) phenyl) ~ 7 ~ methoxyquinazoline-4,6-diamine
A solution of 6-nitroquinazoline-4 (3H) -one (1.34 g, 7.0 mmol) and phosphorus pentachloride (1.46 g, 7.0 mmol) in phosphorus trichloride (5 mL) was stirred for 6 h at 160 ° C, then cooled to room temperature. The reaction mixture was poured into chilled n-hexane, stirred until a solid had precipitated. The mixture was filtered, and the filter cake was washed with ethyl ether, dried in vacuo to obtain the white solid. Acetonitrile (20 mL) was added to the resulting solid white and 3-chloro-4-fluoraniline (1.02 g, 7.0 mmol) mixture, and then the system temperature slowly increased to 80 ° C. After 2 h of reaction, the mixture was cooled to room temperature, while the solvent was evaporated under reduced pressure. After adding saturated NaHCO ₃ solution (50 mL), the mixture was extracted with ethyl acetate. The resulting organic phase was sequentially washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo until completely dry. The residue was dissolved in a liquid mixture of DMF: methanol = 1: 1 (20 mL), then Raney Nickel (70 mg) was added to the resulting mixture. The system was replaced with hydrogen gas and stirred under an atmosphere of hydrogen gas (1atm) at 40 ° C for 4 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting oily product was separated by silica column chromatography, and the target product was obtained (303 mg, 15%).
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53/57 ¹ H NMR (DMSO-c / 6): δ 9.90 (1H, br), 8.45 (1H, s), 8.11-8.09 (1H, m), 7.75-7.73 (1H, m), 7.55-7.53 (1H, m), 7.42-7.39 (1H, m), 7.28-7.27 (1H, m),
5.17 (2H, br).
[00155] Step 3: benzyl 4 - {{4-amino [(3-chloro-4-fluorophenyl)] quinazolin - 6-yl} amino} -piperidine-1-carboxylate
With a method similar to that described in step 6, example 1, the compound shown in the title was synthesized from N ⁴ - (3 chloro-4 ”fluorophenyl) -quinazoline-4,6-diamine and benzyl 4-oxopiperidine-1 carboxylate.
¹ H NMR (d6-DMSO): δ 10.63 (1H, br), 8.63 (1H, s), 7.96-7.94 (1H, m), 7.65-7.61 (2H, m), 7.56-7.52 (1H, m) , 7.24-7.21 (1H, m), 7.38-7.34 (5H, m),
6.64 (1H, s), 5.07 (2H, s), 3.98-3.95 (2H, m), 3.65-3.62 (1H, m), 3.18-3.14 (2H, m), 1.99-1.95 (2H, m), 1.36-1.34 (2H, m).
[00156] Step 4: N ⁶ - (piperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) quinazoline-4,6-diamine
With a method similar to that described in step 7, example 1, a trifluoracetate salt of the compound shown in the title was synthesized from benzyl 4 - {{4 - [(3-chloro-4-fluorophenyl) amino] -quinazolin- 6-yl} amino} piperidine-1-carboxylate.
¹ H NMR (DMSO-άβ): δ 10.79 (1H, s), 8.67-8.52 (3H, m), 7.96-7.93 (1H, m), 7.64-7.61 (2H, m), 7.54-7.51 (1H, m), 7.48-7.45 (1H, m), 7.34-7.31 (1H, m), 6.84 (1H, s), 3.70-3.68 (2H, m), 3.04-2.98 (3H, m), 2.14-2.11 ( 2H, m), 1.66-1.64 (2H, m).
[00157] Step 5: N ⁶ - (1-acryloylpiperidin-4-yl) -N ⁴ - (3-chloro-4-fluorophenyl) quinazoline-4,6-diamine
Using a method similar to that described in step 3, example 2, the compound shown in the title was synthesized from the N ⁶ - (piperidin-4 ”yl) -N ⁴ - (3-chloro-4fluorophenyl) trifloracetate salt - quinazoline-4,6 ~ diamine.
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54/57 ¹ H NMR (DMSO-άβ): δ 9.55 (1H, s), 8.30 (1H, s), 8.16-8.14 (1H, m),
7.84-7.83 (1H, m), 7.46-7.43 (1H, m), 7.42-7.39 (1H, m), 7.31-7.29 (1H, m),
7.24-7.22 (1H, m), 6.85-6.81 (1H, m), 6.15-6.05 (2H, m), 5.66-5.63 (1H, m),
4.29-4.26 (1H, m), 4.02-3.98 (1H, m), 3.84-3.79 (2H, m), 3.01-2.97 (1H, m),
2.02-1.98 (2H, m), 1.20-1.18 (2H, m).
In vitro activity test
1. The method for in vitro enzyme testing
[00158] EGFR, EGFR (T790IVL L858R), HER2 kinase were expressed and purified through an insect cell expression system by the department of biology, Centaurus Biopharma, Beijing, or purchased from commercially available products.
[00159] The platform to test the kinase activity of EGFR, EGFR (T790M, L858R) and HER2 was created based on the homogeneous time resolved fluorescence method (HTRF) provided by Cisbio Bioassays and the activity of the compounds was determined with the platform. Starting from 100nM (for EGFR and HER2) or 1 μΜ (for EGFRT790M / L858R), the compounds were diluted in a 3-fold gradient with 100% DMSO. For each concentration, 4 pL of solution was taken and added in 96 pL of reaction buffer (50mm 4 hydroxyethylpiperazine ethanesulfonic acid (HEPES) (pH 7.0) 0.02% NaN ₃ , 0.01% bovine serum albumin (BSA) 0.1 mM orthovanadate sodium, 5 mM MgCl ₂ , 50 nM SEB (Cisbio, Cat n. ⁰ 61SEBALB), 1 mm DTT). And 2.5pL of the mixture was taken, added to 384-well plates (OptiPlate-384, PerkinElmer) and then 2.5 pL of kinase was added, mixed thoroughly by centrifugation. Then, 5 pL of ATP and TKbiotin substrate were added to initiate the reaction. The 384-well plates were incubated at 23 ° C in the incubator for a period of time, then 5 µl of Eu3 ⁺ - Cryptate labeled TK-antibody and 5 µl of streptavidin-XL665 were added to stop the reaction. After 1 hour incubation in the incubator, the fluorescence value was read on Envision
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55/57 (PerkinElmer). The IC ₅₀ value of the compound was calculated with the GraphPad Prism 5.0 software.
2. Proliferation test of independent anchoring cells
[00160] NCI-H1975, a non-small cell lung cancer cell and BT474, a human breast cancer cell line, were incubated with RPIM-1640 or DMEM supplemented with 10% fetal bovine serum (FBS) in a cell incubator (37 ° C, 5% CO ₂ ). In the test of the compounds, the coated substrate with a concentration of 0.6% was used. The cells were selected with 0.3% low melting point agarose and then coated in 96-well plates, with a density of 10,000 cells per well (100 pL). From 10 mM on, the compounds were diluted in a 3-fold gradient. For each concentration, 2 pL of the solution was taken and added to 98 pL of the medium, then 5.3 pL of the mixture was added to the cell culture medium (where the final concentration of DMSO was 0.1%, v / v). After a week (7 days) of treatment, 20pL of CeliTiter-Biue® reagent (Promega) was added, incubated at 37 ° C for 4 h. The fluorescent signal was read on envision (Perkin Elmer). Velor IC ₅₀ , which showed the inhibitory effect of compounds on cell proliferation, was calculated with GraphPad Prism 5.0.
Table: biological activity
Compound Enzyme activity (IC ₅₀ nM) Cellular activity (IC ₅₀ nM) EGFR EGFR-L858R / T790M HER2 HI 975 BT474 Example 1 0 3 0.8 0.5 21.8 4.2 Example 2 0.2 2.0 0.2 14.0 2.1 Example 3 0.2 0.6 0.3 31.4 5.1 Example 4 0.4 2.1 0.4 25.6 1.6 Example 6 NT 52.1 NT NT NT Example 7 NT 36.7 NT NT NT Example 8 0.6 3.7 1.2 244.2 62.1 Example 10 NT 8.6 NT NT NT Example 11 NT 1.1 NT NT NT
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Example 12 NT 21.2 NT NT NT Example 13 0.1 5.3 0.5 NT NT Example 14 NT 2.2 0.2 59.3 4.6 Example 15 0 3 2.9 0.2 56.0 4.2 Example 16 NT 1.2 0.3 32.4 8.7 Example 17 0.2 1.2 0.4 71.5 4.7 Example 18 NT 11.1 NT NT NT Example 19 0.4 11.7 NT 274.2 97.1 Example 20 NT 251.2 NT NT NT Example 21 NT 134.4 NT NT NT Example 23 NT 19.5 NT NT NT
Note: NT indicates not determined ”.
Pharmacokinetic testing in rats
[00161] In this study, 6 healthy adult male rats (from Beijing Vital River Laboratory Animal Technology Co., Ltd.) were used. The animals were fast during the night before the experiment. The fasting period was 12 h before administration, up to 4 h after administration. Drug administration was performed through gavage in a single dose of 5mg / kg. The compounds to be tested were dissolved in a 20% aqueous solution of sulfobutyl-p-cyclodextrin (SBE). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after drug administration. During the blood sampling, the animals were lightly anesthetized with isoflurane, and approximately 0.5 mL of whole blood collected from the retro-orbital venous sinus, placed in the tubes that contain heparin as an anticoagulant. The samples were centrifuged at 4 ° C, 4000 rpm for 5 min. The plasma was transferred to centrifuge tubes and stored at -80 ° C until being analyzed. The drug concentration in plasma was analyzed quantitatively with liquid tandem chromatography mass spectrometry (LC-MS / MS). From the result of the analysis of the samples, the pharmacokinetic parameter of the compounds was calculated with WinNonlin (WinNonlin Professional, version.6.3).
Compound Ti _{; 2} (hr) Max (hr) C, _riax (ng / mL) AUCo .. »(iir * ng / mL) Example 1 1.30 0.50 588 1346
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Example 2 2.39 1.00 1972 11040
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权利要求:
Claims (16)
[1]
1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[2]
2/6
R ³ is independently selected from a halogen atom, a cyano group, a mercapto group, a C1-6 alkylthio group, an ι-e alkyl group, a C3-8 cycloalkyl group, a heterocycloalkyl group, an amino group, a mono (C1-6 alkyl) amino group, a di (C1-3 alkyl) amino group, a hydroxy group, a C1-6 alkoxy group, a C1-6 alkoxycarbonyl group, a C1-6 alkylamido group, a mono group (C 1 -C) alkyl aminoacyl and a group of di (C 1 -C) alkyl aminoacyl;
R ⁴ , R ⁵ , and R ⁶ are independently selected, each, from a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a heterocycloalkyl group, an amino group , a mono (C 1 -alkyl) amino group, a di (C 1 -alkyl) amino group, a C 1-6 alkylamido group, a mono (C 1-6 alkyl) aminoacyl group and a di (C 1 -alkyl alkyl group) ) aminoacyl and a C1-8 alkoxycarbonyl group;
R ⁷ and R ⁸ are each independently selected from hydrogen and a C1-6 alkyl group.
2. Compound or pharmaceutically acceptable salt thereof, according to claim 1, characterized in that X is selected from -NR ⁸ - and -S-.
[3]
A compound or pharmaceutically acceptable salt thereof, according to claim 1 or 2, characterized by the fact that they are not each an integer from 0 to 3 and are not simultaneously 0.
[4]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-3, characterized by the fact that R ⁷ and R ⁸ are hydrogen.
[5]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-4, characterized in that the Ar ring is a phenyl group.
[6]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, characterized by the fact that p is an integer from 0 to 3.
Petition 870160010811, of 03/28/2016, p. 72/77
3/6
[7]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, characterized by the fact that q is an integer from 0 to 3.
[8]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-7, characterized in that R ¹ is independently selected from a C 1 -6 alkyl group, a C2-6 alkenyl group, an alkynyl group c 2-6, a halogen atom, an amino group, a hydroxyl group, a C1-6 alkoxy group, a C1-6 alkylcarbonyl group, a cyano group and a nitro group, where 0 C1-6 alkyl group, alkoxy group C1-6, C2-6 alkenyl group θ C2-6 alkynyl group can be replaced by a halogen atom, a cyano group, a nitro group, a C1-6 alkoxy group, an aryl group, a heteroaryl group or a heterocycloalkyl group ; and the aryl group, heteroaryl group and heterocycloalkyl group plus can be replaced by a halogen atom, a cyano group, a nitro group, a C1-6 alkyl group, a C 1-6 alkoxy group or a C1-6 alkylcarbonyl group .
[9]
A compound or pharmaceutically acceptable salt thereof, according to claim 8, characterized by the fact that R ¹ is independently selected from a C2-6 alkynyl group, a halogen atom, a C1-6 alkoxy group and a C 1-6 alkylcarbonyl group, wherein the C 1-6 alkoxy group can be replaced by an aryl group, a heteroaryl group, or a heterocycloalkyl group; and the aryl group, the heteroaryl group and the heterocycloalkyl group can additionally be replaced by a halogen atom, a cyano group or a nitro group.
[10]
A compound or pharmaceutically acceptable salt thereof, according to claim 9, characterized by the fact that R ¹ is independently selected from a C2-6 alkynyl group, a halogen atom, a C1-6 alkoxy group substituted with heteroaryl and a C1-6 alkoxy group substituted with aryl, and a C1-6 alkylcarbonyl group in which the aryl group
Petition 870160010811, of 03/28/2016, p. 73/77
4/6 and the heteroaryl group can additionally be replaced by a halogen atom.
[11]
A compound or pharmaceutically acceptable salt thereof, according to claim 10, characterized in that R ¹ is independently selected from a group of ethynyl, a halogen atom, a C1-6 alkoxy group substituted with pyridyl and a Ci-β alkoxy group substituted with halophenyl.
[12]
A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-11, characterized by the fact that R ⁴ , R ⁵ , and R ⁶ are hydrogen.
[13]
13. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-12, characterized in that R ² is selected from hydrogen, a methoxy group, a tetrahydrofuranyloxy group, an ethoxy group substituted with methoxy and an ethoxy group substituted with morpholinyl.
[14]
14. Compound, characterized by the fact that it is represented by any of the following formulas or a pharmaceutically acceptable salt thereof:

[15]
15. Pharmaceutical composition, characterized in that it comprises the compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-14 and an acceptable pharmaceutical carrier.
[16]
16. Use of the compound or pharmaceutically acceptable salt thereof, characterized by the fact that it complies with any of the
Petition 870160010811, of 03/28/2016, p. 75/77
6/6 claims 1-14 or the composition according to claim 15 for the preparation of a tumor prevention or treatment medicament.

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法律状态:
2018-03-06| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2021-09-08| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|Free format text: NOTIFICACAO DE DEVOLUCAO DO PEDIDO EM FUNCAO DA REVOGACAO DO ART. 229-C DA LEI NO 9.279, DE 1996, POR FORCA DA LEI NO 14.195, DE 2021 |

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2021-09-21| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-10-19| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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CN201310452885.4A|CN104513229A|2013-09-28|2013-09-28|Quinazoline derivatives and preparation method thereof|

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PCT/CN2014/087633|WO2015043515A1|2013-09-28|2014-09-28|Quinazoline derivative and preparation method therefor|

---