WO2014113859A1 - Composés 2-chloro-4-anilino-quinazoliniques inhibiteurs de protéines tyrosine kinases, compositions pharmaceutiques les comprenant, procédé pour leur production et méthode d'inhibition de tyrosine kinases - Google Patents

Composés 2-chloro-4-anilino-quinazoliniques inhibiteurs de protéines tyrosine kinases, compositions pharmaceutiques les comprenant, procédé pour leur production et méthode d'inhibition de tyrosine kinases Download PDF

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WO2014113859A1
WO2014113859A1 PCT/BR2014/000034 BR2014000034W WO2014113859A1 WO 2014113859 A1 WO2014113859 A1 WO 2014113859A1 BR 2014000034 W BR2014000034 W BR 2014000034W WO 2014113859 A1 WO2014113859 A1 WO 2014113859A1
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chloro
ylamino
phenyl
quinazolin
amine
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PCT/BR2014/000034
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Portuguese (pt)
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Eliezer Jesus De Lacerda Barreiro
Maria Letícia DE CASTRO BARBOSA
Lidia Moreira Lima
Stefan Andreas LAUFER
Carlos Mauricio RABELLO DE SANT'ANNA
Roberta TESCH
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Universidade Federal Do Rio De Janeiro
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to 2-chloro-4-anilino-quinazoline derivatives which exhibit EGFR and / or VEGFR-2 protein tyrosine kinase inhibitory activity, anti-tumor pharmaceutical compositions comprising such compounds, and processes for their production.
  • the present invention further provides a method of treating solid tumors due to the tyrosine kinase inhibiting property.
  • Protein kinases play a prominent role in regulating various cellular processes, including cell proliferation, differentiation and survival. [Ishikawa, T. et al., J. Med. Chem., 2011, 54, 8030.
  • the epidermal growth factor receptor also known as ErbB1, HER1
  • EGFR epidermal growth factor receptor
  • HER1 is a transmembrane receptor tyrosine kinase belonging to the ErbB receptor family [Chilin, A. et al, J. Med. Chem., 2010, 53, 1862]; ie a four-member family of growth factor receptor kinase tyrosines that includes EGFR (HER1), ErbB2 (HER2 / neu), ErbB3 (HER3), and ErbB4 (HER4) [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642.
  • EGFR-mediated cell signaling pathways have been implicated in several human malignant tumors, promoting tumor growth, tissue and organ invasion, angiogenesis and metastasis.
  • EGFR overexpression and / or dysregulation are common clinical findings in solid tumors and are generally associated with an unfavorable prognosis.
  • Activation of EGFR also stimulates the release of vascular endothelial growth factor (VEGF), considered the primary inducer of the angiogenesis process.
  • VEGF vascular endothelial growth factor
  • VEGF vascular endothelial growth factor receptor 2
  • VEGFR-2 vascular endothelial growth factor receptor
  • EGFR and VEGFR-2 receptor tyrosine kinases are closely related, playing a relevant role in tumor growth and angiogenesis.
  • the relationship between these tyrosine kinases in cancer treatment is also known, i.e. inhibition of VEGFR-2 mediated signaling contributes to the antitumor effects of EGFR inhibitors; whereas EGFR receptor-independent pathway-mediated VEGF growth factor overexpression is considered to be one of the possible resistance-inducing mechanisms of anti-EGFR therapy.
  • EGFR and VEGFR-2 tyrosine kinases are validated therapeutic targets for cancer treatment and several inhibitors are already approved for clinical use in solid tumors where overexpression of these protein kinases is observed, such as the inhibitors shown in Figure 1.
  • Arora, A. & Scholar E., J. Pharmacol. Exp. Ther., 2005, 315, 971 [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642]
  • WO 2009/036066 also describes VEGFR inhibitors, but such inhibitors differ from those described in the present invention in that they have a pyrazole ring fused to a 6 membered ring.
  • the present invention relates to the identification of 2-chloro-4-anilino-quinazoline derivatives that exhibit EGFR and / or VEGFR-2 protein tyrosine kinase inhibitory activity.
  • objects of the invention are 2-chloro-4-anilino-quinazoline derivatives having a structure according to the general formula (I):
  • Y is SO 2 or CO
  • R 1 is C 1 -C 5 alkyl, OH, NR R 5 , morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC 5 alkyl) piperazinyl, 4-aryl piperazinyl;
  • R 2 and R 3 independently correspond to H, CC 5 alkyl, C 1 -C 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms independently from O, N, S;
  • R 4 and R 5 independently correspond to H, CC 3 alkyl
  • a further object of the present invention is a process for producing 2-chloro-4-anilino-quinazoline derivatives comprising the steps of: a) cyclization of a compound of formula (II):
  • Y is SO 2 or CO
  • R 1 is CC 5 alkyl, OH, NR 4 R 5 , morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC 5 alkyl) piperazinyl, 4-aryl piperazinyl;
  • R 2 and R 3 independently correspond to H, C 1 -C 5 alkyl, CC 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms independently from 0, N, S;
  • R and R 5 independently correspond to H, C r C 3 alkyl
  • R 6 corresponds to H or NH 2 .
  • the present invention provides alternatives for the treatment of solid tumors characterized by protein kinases dysregulation and / or overexpression, especially EGFR and VEGFR-2 tyrosine kinases.
  • composition comprising:
  • Y is SO 2 or CO
  • R 2 and R 3 independently correspond to H, C 1 -C 6 alkyl, CC 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5 or 6 membered heterocyclic ring containing 1 to 2 independently selected atoms from O, N, S;
  • R 4 and R 5 independently correspond to H, CC 3 alkyl
  • a further object of the present invention is a method of treating solid tumors comprising a step of administering to a patient a 2-chloro-4-anilino-quinazoline derivative of the structure according to formula
  • Y is SO 2 or CO
  • RT is C r C 5 alkyl, OH, NR 4 R 5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC 5 alkyl) piperazinyl, 4-aryl piperazinyl;
  • R 2 and R 3 independently correspond to H, CC 5 alkyl, CC 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 independently selected atoms. O, N, S;
  • R and R 5 independently correspond to H, C r C 3 alkyl
  • the derivatives are chosen from the group comprising:
  • Figure 1 EGFR and VEGFR receptor tyrosine kinase inhibitors.
  • Figure 2 Genesis of the new 2-chloro-4-anilino-quinazolinic derivatives (8, 9 and 10), drawn from prototypes PD153035 (4), Tivozanib (6) and 7.
  • Figure 3 (A) Overlap of 9c (yellow) with Gefitinib (2, purple) at the EGFR tyrosine kinase molecular recognition site; (B) Interaction of derivative 9c (yellow) with EGFR; (C) Interaction of derivative 9g (magenta) with EGFR; (D) Interaction of derivative 9a (green) with EGFR; (E) Interaction of derivative 9e (blue) with EGFR; (F) Interaction of derivative 9p (pink) with EGFR.
  • Semi-rigid molecular mooring studies were performed in the GOLD 5.1 program (CCDC; License Number: G / 414/2006).
  • Figure 4 (A) Overlap of 9c (yellow) with Tivozanibe (6, orange) at the VEGFR-2 tyrosine kinase molecular recognition site; (B) Interaction of derivative 9c (yellow) with VEGFR-2; (C) Interaction of derivative 9e (blue) with VEGFR-2; (D) Interaction of derivative 9p (pink) with VEGFR-2.
  • Semi-rigid molecular mooring studies were performed using the GOLD 5.1 program (CCDC; License Number: G / 414/2006).
  • the derivatives of the present invention are 2-chloro-4-anilino-quinazoline derivatives having a structure according to general formula (I):
  • Y is SO 2 or CO
  • R 1 is CC 5 alkyl, OH, NR 4 R s, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C 1 -C 5 alkyl) piperazinyl, 4-aryl piperazinyl;
  • R 2 and R 3 independently correspond to H, C r C 5 alkyl, CC 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms regardless of ON S;
  • R 4 and R 5 independently correspond to H, CC 3 alkyl
  • the heterocyclic ring formed by R2 and R3 together with the quinazoline ring forms the structure [1,3] Dioxolo [4,5-gjquinazoline.
  • LASSBio-1814 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide
  • LASSBio-1816 4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (hereinafter called LASSBio-1816)
  • composition of the present invention comprising:
  • Y is SO 2 or CO
  • R 1 is CC 5 alkyl, OH, NR 4 R 5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C r C5 alkyl) piperazinyl, 4-aryl-piperazinyl;
  • R 2 and R 3 independently correspond to H, CC 5 alkyl, CC 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 independently selected atoms. O, N, S;
  • R 4 and R 5 independently correspond to H, C 1 -C 3 alkyl
  • the pharmaceutical composition described herein preferably comprises an active ingredient selected from LASSBio-1807 (8g), LASSBio-1808 (9g), LASSBio-1814 (9c), LASSBio-1815 (8c), LASSBio-1816 (9e), LASSBio-1819 ( 9p) and their counterparts (8a-z, 9a-z, 10a-z, 11a-z), agents designed as dual inhibitors of EGFR and VEGFR-2 protein kinases ( Figure 2).
  • compositions containing the compounds of the invention are usually prepared following conventional methods and may be administered in a variety of dosage forms, for example, orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions; rectal route in the form of suppositories; parenterally, ie intramuscularly, or by intravenous and / or intrathecal and / or intraspinal infusion or injection.
  • solid oral forms may contain along with the active compound diluents, ie lactose, dextrose, sucrose, cellulose, cornstarch or potato starch; lubricants, ie silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixture; dyes; sugars; wetting agents such as lectin, polysorbates, lauryl sulfates; and, generally, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations can be manufactured in a manner known, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
  • Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions.
  • Syrups may contain as a carrier, for example, sucrose or sucrose with glycerine and / or manita and / or sorbitol.
  • Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, i.e. sterile water, olive oil, ethyl oleate, glycols, ie propylene glycol, and, if desired, appropriate amount of lidocaine hydrochloride.
  • a pharmaceutically acceptable carrier i.e. sterile water, olive oil, ethyl oleate, glycols, ie propylene glycol, and, if desired, appropriate amount of lidocaine hydrochloride.
  • Solutions for intravenous injections or infusions may contain as a carrier, for example sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline or they may contain as a propylene glycol carrier.
  • Suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier for example cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.
  • Reactors and conditions (a) (1) AcOH, H 2 O, 35 ° C, 15 '(2) KOCN, H 2 O, 35 ° C, 30' (3) NaOH (4) HCl aq 37%, rt, 85-87%; b) cone. HN0 3, cat. H 2 SO 4> 0 ° C, 2 h, 67%; c) (1) oxalyl chloride, CH 2 CI 2 , cat.
  • Reagents and conditions (g) DIPEA, dioxane, 80 ° C, 12 h, 60-66%; h) isopropanol, 82 ° C, 24 h, 67-72%; i) ethanol, 78 ° C, 24 h, 64-73%; j) Pd (AcO) 2 , XPhos, tBuONa, tBuOH, toluene, 90 ° C, 1h, 45-55%.
  • the process of producing derivatives of formula (I) then comprises the steps of:
  • Y is SO 2 or CO
  • R is C r C 5 alkyl, OH, NR 4 R 5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C r C 5 alkyl) piperazinyl, 4-aryl-piperazinyl;
  • R 2 and R 3 independently correspond to H, CC 5 alkyl, C r C 5 alkyl ether, aryl, aryl ether or R 2 and R 3 together form a 5 or 6 membered heterocyclic ring containing from 1 to 2 selected atoms independently from O, N, S;
  • R 4 and R 5 independently correspond to H, C r C 3 alkyl
  • R 6 corresponds to H or NH 2 .
  • the compounds (8a-z; 9a-z; 10a-z) of the present invention may be prepared by a key condensation step comprising the reaction between 2,4-dichloroquinazoline intermediates (18a-c) and the corresponding anilines by Regioselective Aromatic Nucleophilic Substitution and / or Regioselective Buchwald-Hartwig Amination (Scheme 2).
  • IR (ATR: cm -1 ): 3362, 3179, 2921, 1653, 1526, 1347.
  • Example 5 6-Aminobenzo [d] [1,3] dioxola-5-carboxamide
  • the reaction medium containing 14 (2.00 g, 9.52 mmol), metal iron (3.72 g, 66.62 mmol), ammonium chloride (1.02 g, 19.03 mmol) 100 mL ethanol and 20 mL distilled water, was stirred and heated at 78 ° C for 12 hours. The end of the reaction was verified by CCD. The product was isolated by filtration on Celite ® , followed by washing with ethanol.
  • IR (ATR: cm -1 ): 3380, 3284, 3189, 2910, 1644, 1618.
  • IR (ATR: cm -1 ): 3141, 3083, 3009, 2954, 1725, 1673, 1626, 1497, 1453.
  • reaction mixture containing the quinazolinediones (1.00 g) and POCI 3 (15 mL; 24.77 g; 161.53 mmol) was stirred and heated at 100 ° C for 24 hours. Isolation was performed by slowly and carefully pouring the reaction medium into a mixture of ice and water by vigorous stirring. The precipitate obtained was vacuum filtered and purified by filtration on silica gel using dichloromethane as eluent.
  • IR (ATR: cm -1 ): 3023, 2978, 2945, 1610, 1552, 1507, 1459, 747.
  • IR (ATR: cm -1 ): 3053, 2921, 1607, 1556, 1468, 1420, 715.
  • IR (ATR: cm -1 ): 3398, 2935, 2828, 1597, 1572, 1512, 1420, 1327, 1234, 1149, 838, 723.
  • Example 13 4- (2-chloro-6,7-methylenedioxyquinazolin-4-Mamino) -Î ”Î ⁇ -Dimethylbenzene sulfonamide (8g)
  • Compound 8g was synthesized as a yellow solid in 45% yield after precipitation from a mixture of dichloromethane and hexane, mp 245-247 ° C.
  • IR (ATR: cm -1 ): 3323, 2917, 2848, 1595, 1568, 1499, 1458, 1325, 1260, 1158,
  • Compound 10g was synthesized as a yellow solid in 55% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 245-246 ° C. HPLC: 230 nm: 100%; 254 nm: 97.3%.
  • Compound 9a was synthesized as a beige solid in 50% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 184- 186 ° C. HPLC: 230 nm: 96.4%; 254 nm: 97.2%.
  • IR (ATR: cm -1 ): 3369, 2916, 2835, 1597, 1572, 1505, 1423, 1338, 1283, 1134, 834, 738.
  • Example 17 2-Chloro-6,7-methylenedioxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8h)
  • Compound 8h was synthesized as a yellow solid in 55% yield after precipitation from a mixture of dichloromethane and hexane, mp 160-162 ° C.
  • Compound 8j was synthesized as a white solid in 54% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 266-268 ° C. HPLC: 230 nm: 100%; 254 nm: 100%.
  • Example 23 4- (2-Chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide hydrochloride (9c)
  • Compound 9c was synthesized as a white solid in 68% yield after recrystallization from methanol, mp> 300 ° C.
  • IR (ATR: cm -1 ): 3391, 3331, 2979, 2939, 1594, 1568, 1509, 1449, 1323, 1234, 1149, 834, 701.
  • Example 25 4- (2-Chloro-6,7-dimethoxyquinazolin-4-ylamino) -A-methylbenzene sulfonamide hydrochloride (9e)
  • Compound 9e was synthesized as a white solid in 68% yield after recrystallization from methanol, mp> 300 ° C.
  • IR (ATR: cm -1 ): 3398, 3008, 2974, 2932, 1599, 1565, 1508, 1463, 1315, 1285, 1145, 842, 694.
  • the 2-chloro-4-amino-quinazoline derivatives designed as dual inhibitors of EGFR and VEGFR-2 tyrosine kinases as candidates for antitumor drugs were evaluated for their ability to inhibit the enzymatic activity of the protein kinases in question, ie as to their ability to inhibit enzyme substrate phosphorylation by the previously activated enzyme.
  • the spectroscopically synthesized and synthesized 2-chloro-4-amino-quinazoline analogs showed inhibitory ability on both EGFR and VEGFR-2 receptor tyrosine kinases, such as derivatives 8c, 8g, 9c, 9e, 9g and 9p, as shown in Table 1 .
  • a direct correlation was observed between inhibitory potencies against the two tyrosine kinases evaluated.
  • Table 1 Inhibitory activity of prototype 7 and 2-chloro-4-anilino-quinazoline derivatives against EGFR and VEGFR-2 receptor tyrosine kinases
  • a Radiometric assay of protein kinase activity was employed to measure the inhibitory effect of EGFRwt and VEGFR-2 tyrosine kinases.
  • b Cl 50 values were calculated using Quattro Workflow V3.1.0 (Quattro Research GmbH, Kunststoff, Germany; www.quattroresearch.com) and are given in ⁇ .
  • a radiometric tyrosine kinase activity assay ( 33 PanQinase ® ) was employed to measure the inhibition ability of the enzymatic activity of the protein kinases in question by the synthesized derivatives, ie their ability to inhibit enzyme substrate phosphorylation by the previously activated enzyme. All assays were performed in a 96-well plate (Perkin Élmer, Boston, MA, USA) in a reaction volume of 50 ⁇ _.
  • the assay for all enzymes contained 70 mM HEPES-NaOH, pH 7.5, 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ sodium orthovanate, 1.2 mM DTT, 1 ⁇ ⁇ / [ ⁇ - 33 ⁇ ] - ⁇ (approx. 5 x 10 5 cpm / well).
  • the enzyme and substrate amounts per well employed were: EGF-Rwt / poly (Glu, Tyr) 4: i: 10 ng / 125 ng and VEGF-R2 / poly (Glu, Tyr) 4: i: 25 ng / 125 ng . Reaction mixtures were incubated at 30 ° C for 60 minutes.

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Abstract

La présente invention concerne des dérivés 2-chloro-4-anilino-quinazoliniques présentant une activité inhibitrice de protéine tyrosine kinase EGFR et/ou VEGFR-2, des compositions pharmaceutiques antitumorales comprenant ces composés et des procédés pour leur production. La présente invention concerne également une méthode de traitement de tumeurs solides faisant appel à la propriété d'inhibition des tyrosine kinases.
PCT/BR2014/000034 2013-01-24 2014-01-24 Composés 2-chloro-4-anilino-quinazoliniques inhibiteurs de protéines tyrosine kinases, compositions pharmaceutiques les comprenant, procédé pour leur production et méthode d'inhibition de tyrosine kinases WO2014113859A1 (fr)

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BR102013001809-0A BR102013001809B1 (pt) 2013-01-24 2013-01-24 Compostos 2-cloro-4-anilino-quinazolinicos inibidores de proteínas tirosina cinases, composições farmacêuticas compreendendo os mesmos, processo para sua produção e método para inibição de tirosina cinases

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CN105884699A (zh) * 2016-05-11 2016-08-24 中国药科大学 4-取代苯胺喹唑啉类衍生物及其制备方法和用途
JP2017537154A (ja) * 2015-01-13 2017-12-14 北京賽特明強医薬科技有限公司 キナゾリン複素環式化合物、その製造方法及び癌を治療する上皮成長因子受容体阻害剤としての応用
CN111138371A (zh) * 2019-12-30 2020-05-12 重庆威尔德浩瑞医药化工有限公司 2,4-二氯-6,7-二甲氧基喹唑啉溶剂合物及其制备方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017537154A (ja) * 2015-01-13 2017-12-14 北京賽特明強医薬科技有限公司 キナゾリン複素環式化合物、その製造方法及び癌を治療する上皮成長因子受容体阻害剤としての応用
CN105884699A (zh) * 2016-05-11 2016-08-24 中国药科大学 4-取代苯胺喹唑啉类衍生物及其制备方法和用途
CN105884699B (zh) * 2016-05-11 2019-05-07 中国药科大学 4-取代苯胺喹唑啉类衍生物及其制备方法和用途
CN111138371A (zh) * 2019-12-30 2020-05-12 重庆威尔德浩瑞医药化工有限公司 2,4-二氯-6,7-二甲氧基喹唑啉溶剂合物及其制备方法

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