WO2009094831A1 - Composés hétéroaromatiques, leur procédé de préparation et leur utilisation - Google Patents

Composés hétéroaromatiques, leur procédé de préparation et leur utilisation Download PDF

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Publication number
WO2009094831A1
WO2009094831A1 PCT/CN2008/002046 CN2008002046W WO2009094831A1 WO 2009094831 A1 WO2009094831 A1 WO 2009094831A1 CN 2008002046 W CN2008002046 W CN 2008002046W WO 2009094831 A1 WO2009094831 A1 WO 2009094831A1
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Prior art keywords
methylsulfonyl
amino
amine
compound
group
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PCT/CN2008/002046
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English (en)
Chinese (zh)
Inventor
Gangsheng Chen
Sheng Liu
Long Xiong
Baohai Yang
Ruimao Feng
Lei He
Aifeng LÜ
Original Assignee
Sun, Piaoyang
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Priority to CN2008800125739A priority Critical patent/CN101663303B/zh
Publication of WO2009094831A1 publication Critical patent/WO2009094831A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • Heteroaromatic compound preparation method thereof and use thereof
  • the present invention relates to a series of heteroaromatic compounds, processes for their preparation, pharmaceutical compositions containing them and uses thereof; the invention also relates to intermediates useful in the synthesis of heteroaromatic compounds.
  • Protein tyrosine kinases catalyze the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation.
  • Protein tyrosine kinases can be broadly classified into receptors (eg, EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptors (eg, c-si'c, lck, zap70) kinases. . It has been shown that many such kinases are inappropriate or uncontrolled to activate, i.e., abnormal protein tyrosine kinase activity, e.g., caused by overexpression or mutation, can cause uncontrolled cell production.
  • protein tyrosine kinases such as c-erbB-2, c-src, c-met, EGFr, and PDGFr are associated with human malignancies.
  • elevated EGFr activity is associated with non-small cell lung cancer, bladder cancer, and head and neck cancer
  • elevated c-erbB-2 activity is associated with cancers of the breast, ovary, stomach, and pancreas. Therefore, inhibition of protein tyrosine kinases should provide treatment for the above tumors.
  • Abnormal protein tyrosine kinase activity is also associated with a variety of other diseases: psoriasis, fibrosis, atherosclerosis, restenosis, autoimmune diseases, allergies, asthma, etc., have been shown to pass some receptor tyrosine kinases. The role is to control these diseases.
  • Patent WO 99/35146 discloses a series of bicyclic heteroaromatic compounds which have protein tyrosine kinase inhibitory activity, but these compounds may also have disadvantages such as low activity and high toxicity, so that the hair activity is higher and the toxicity is more Low and more useful new compounds of this type are still necessary. Summary of the invention
  • the present invention discloses a compound of the formula (I) -
  • A is CR 1 and D is N;
  • A is CR 1 and D is CR 2 :
  • 1 represents CH 3 S0 2 [CH 2 ] N CH(NH 2 )[CH 2 ] m -Ar-, wherein Ar is selected from phenyl, furan, thiophene, pyrrole and thiazole substituted or unsubstituted by a substituent, The substituent is selected from a halogen atom, a CM fluorenyl group or a CM methoxy group, and the number of substituents is 1 or 2; m, n are independently 0, 1 or 2;
  • R 2 is selected from the group consisting of hydrogen, C, _4 decyloxy or a halogen atom:
  • Y is selected from phenyl, pyridyl, 3H-imidazolyl, fluorenyl, 1H-carbazolyl, 2,3-dihydro-1H-carbazolyl optionally substituted by R 3 , R 4 ;
  • R 3 is selected from benzyl, halo-, dihalo- or trihalobenzyl, halo-, dihalo- or trihalobenzyloxy, pyridylmethyl, pyridylmethoxy, 2 -methylpyridinyloxy or benzyloxy: and
  • R 4 is selected from hydrogen, a hydroxyl group, a halogen atom, a CM thiol group, a CM methoxy group, an amino group, a cyano group or a trifluoromethyl group.
  • R 2 is selected from hydrogen or methoxy, more preferably hydrogen.
  • Ar is selected from the group consisting of a substituted or unsubstituted furan, thiophene or thiazole, and the substituent is selected from a halogen atom, a CM thiol group or a CM alkoxy group, and the number of substituents is 1, preferably unsubstituted furan, thiophene or thiazole.
  • n 1 or 2.
  • Y is selected from the group consisting of phenyl, pyridyl, 1H-carbazolyl, 2,3-dihydro-1H-carbazolyl optionally substituted by R 3 , R 4 ; more preferred scheme Yes, Y is selected from phenyl or 1H-carbazolyl optionally substituted by R 3 , R 4 ;
  • R 3 is selected from benzyl, halo-benzyl, halo-benzyloxy, pyridylmethyl, pyridylmethoxy, 2-methylpyridinyloxy or benzyloxy, preferably halo-benzyl, Halo-benzyloxy or 2-methylpyridyloxy; and
  • R 4 is selected from hydrogen, a halogen atom, or alkyl with the CM. 4 embankment group.
  • CM thiol includes, but is not limited to, the following species: methyl, ethyl, propyl, isopropyl, butyl, etc.;
  • the compounds of the invention contain one or more asymmetric centers and may therefore exist as racemates, racemic mixtures, single enantiomers, mixtures of non-enantiomers, and single non-enantiomers.
  • the present invention encompasses all such isomeric forms of these compounds.
  • the compound of the formula (I) of the present invention is preferably the following compound -
  • Another object of the present invention is to provide a process for the preparation of a compound of the formula (I), Method One:
  • A, D, Ar, m, n, Y are as defined above;
  • A' is CR 1 ',
  • R 1 ' represents CH 3 S0 2 [CH 2 ] n CH(NH-R 5 )[C3 ⁇ 4] m -Ai'-,
  • R 5 is selected from hydrogen or an amino protecting group;
  • the group " is various groups well known to those skilled in the art including, but not limited to, the following groups: tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, formyl, acetyl, trifluoroacetyl, 4 -Methoxybenzyl or trityl; a preferred embodiment is selected from hydrogen or tert-butoxycarbonyl-.
  • the method of using the deprotecting group is also different.
  • the deprotecting group is reacted under acidic conditions such as trifluoroacetic acid or hydrochloric acid.
  • R 5 is a group such as a benzyloxycarbonyl group, a benzyl group or a 4-methoxybenzyl group
  • the deprotection group reaction is completed by hydrogenation in the presence of a catalyst
  • R 5 is a formyl group, acetyl group
  • the group or the trifluoroacetyl group or the like the deprotection group reaction can be carried out under acidic or basic conditions.
  • the condensation reaction of the compound of the formula (II) with (111), (V) and (VI) is carried out in the presence of a catalyst, and the catalyst used is a composite palladium catalyst selected from the group consisting of: di(triphenylphosphine) dichloride Palladium, tetrakis(triphenylphosphine)palladium or bis(cyanobenzene)palladium dichloride, preferably bis(triphenylphosphine)palladium dichloride.
  • Another object of the present invention is to provide compounds of the formula ( ⁇ ) and (V) which are useful intermediates for the preparation of compounds of the general formula (I):
  • Ar, m, n, R 5 , R 6 , X are as defined above.
  • Preferred compounds of the general formula (II) or (V) include:
  • the compounds of the formula (II) and (V) can be prepared by various methods to
  • a further object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier therefor.
  • a further object of the present invention is to provide a compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a medicament for the treatment of a disease associated with the regulation of c-erbB-2 and/or EGF-R protein tyrosine kinase activity Use in.
  • a further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the preparation of a therapeutically modulated c-erbB-2 and/or EGF-R protein tyrosine kinase Use in drugs for activity-related diseases.
  • a further object of the present invention is to provide a use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of cancer and malignancy.
  • a further object of the present invention is to provide a use of a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of psoriasis.
  • a further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for the treatment of cancer and malignancy.
  • a further object of the present invention is to provide a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for the treatment of psoriasis.
  • the pharmaceutical preparations of the present invention may be present in unit dosage form containing a predetermined amount of active ingredient per unit dose.
  • Such units may contain, for example, 0.5 mg- lg, depending on the condition being treated, the route of administration, and the age, weight, condition, and the like of the patient.
  • the pharmaceutical preparations can be administered by any suitable route, such as oral, rectal, nasal, topical or parenteral (including subcutaneous, intramuscular, intravenous or transdermal) routes.
  • suitable route such as oral, rectal, nasal, topical or parenteral (including subcutaneous, intramuscular, intravenous or transdermal) routes.
  • the above various preparations can be prepared by any method known in the pharmaceutical art, for example, by mixing the active ingredient with a carrier or excipient.
  • the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can be administered alone or in combination with other therapeutic agents for treating the above diseases.
  • other therapeutic agents for treating the above diseases.
  • it should be considered in combination with other chemotherapeutic agents, hormones or antibody drugs.
  • Embodiment 1 In order to explain the present invention in more detail, the following examples are given. However, the scope of the invention is not limited thereto. Embodiment 1
  • n-butyl lithium / n-hexane solution (2.5 M, 3.95 ml) was added, and the reaction was kept for 15 min.
  • boron triisopropylboride (3.73 ml) was quickly added, and the reaction was completed.
  • N-methoxy-N-methyl-2-(methylthio)acetamide 28 g
  • 2, 5-dibromofuran or 2-bromo-5-iodo-furan 53 g or 64 g
  • Dissolve in THF 200 ml
  • cool to -10 ⁇ -20 °C under nitrogen protection add t-butylmagnesium chloride/THF solution (2 M, 200 nil) to the solution, control the drop acceleration to make the internal temperature ⁇ -10 ° C.
  • the temperature was naturally raised to room temperature overnight.
  • the prepared Grignard reagent was cooled to -20 ° C to 15 ° C, and triisopropoxy boron (2.53 ml) was slowly added dropwise, and the dropwise addition was completed, and the reaction was kept for 0.5 h.
  • Water (5 ml) was added, and the pH was adjusted to 3 to 4 with dilute hydrochloric acid, and stirred for 0.5 h.
  • the filtrate was added with water (50 ml), ethyl acetate (25 mlx2), and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure.
  • 6-boronic acid-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine (4.2 g) and 1-(4-bromothiazole-2-yl) -2-(Methanesulfonyl)ethylamine (2.7 g) was added to 200 ml of methanol, followed by triethylamine (3 ml), bistriphenylphosphinepalladium dichloride (0.2 g). Heat to reflux for 4 hours. The residue was added to EtOAc (EtOAc m.).
  • 6-iodo-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine (4.5 g) and 1-(4-boronic acid thiazole-2-S 2-(Methanesulfonyl)ethylcarbamic acid tert-butyl ester (3.0 g) was added to 200 ml of methanol, and then 3 ml of triethylamine and 0.2 g of bistriphenylphosphine palladium dichloride were added. Heat to reflux for 4 hours. Concentration, the residue was added to water, ethyl acetate was evaporated, and the organic layer was evaporated and evaporated.
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is 6-boronic acid-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl group.
  • Quinazoline-4-amine (4.2 g) and 1-(2-bromothiazol-4-yl)-3-(methylsulfonyl)propyl-2-amine (2.8 g);
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is 6-boronic acid-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl Quinazoline-4-amine (4.2 g) and 1-(5-bromofuran-2-yl)-2-(methylsulfonyl)ethylamine (2.5 g); when using Method B, the starting material is 6 -iodo-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine (4.5 g) and N-(tert-butoxycarbonyl-(5-boronic acid furan) -2-yl)-2-(methylsulfonyl)ethylamine (2.8 g),
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is 6-boronic acid-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl group.
  • Quinazoline-4-amine (4.2 g) and 1-(5-bromofuran-2-yl)-2-(methylsulfonyl)ethylamine (2.5 g); when using Method B, the starting material is 6 -iodo-N-(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)quinazolin-4-amine (4.5 g) and N-(tert-butoxycarbonyl)-1-(5) -furan-2-yl)borate-2-(methylsulfonyl)ethylamine (2.8 g),
  • the preparation method is the same as the method ⁇ or hydrazine in the seventh embodiment, except that when the method is used, the starting material is N-(l-(3-fluorobenzyl)-1H-indol-5-yl)-6-boronic acid.
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(l-(3-fluoro)-1 ⁇ -indol-5-yl)-6-boronic acid quinazolin-4-amine (4.3 g) and di(2-bromothiazol-4-yl)-3- ( Methanesulfonyl)propyl-2-amine (2.8 g);
  • the starting material is N-(l-(3-fluorobenzyl)-1H-indazol-5yl)-6-iodoquine Oxazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(2-thiazolyl-4-yl)-3-(methylsulfonyl)propyl-2-amine (3.1 g) ,
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(l-(3-fluorobenzyl)-1H- ⁇ II--5-based)-6- Quinazoline-4-amine borate (4.3 g) and N-(tert-butoxycarbonyl)-1-(5-bromofuran-2-yl)-2-(methylsulfonyl)ethylamine (3.5 g); In the case of Method B, the starting material is N-(l-(3-fluorobenzyl)-1H-indazol-5yl)-6-iodoquinazolin-4-amine (4.6 g) and N- (tert-butyl) Oxycarbonyl)-1-(5-boronic acid furan-2-yl)-2-(methylsulfonyl)ethylamine (2.8 g),
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(l-(3-fluorobenzyl)-1 ⁇ -oxazol-5yl)-6-boronic acid.
  • Quinazoline-4-amine 4.3 g
  • 1-(5-bromofuran-2-yl)-3-(methylsulfonyl)propyl-2-amine 2.7 g
  • Method B starting The starting material is N-(l-(3-fluorobenzyl)-1H--5 base)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(5) -furan-2-yl borate)-3-(methylsulfonyl)propyl-2-amine (3.0 g)
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is -N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6- Quinazoline-4-amine borate (4.4 g) and 1-(5-bromofuran-2-yl)-2-(methylsulfonyl)ethylamine (2.5 g) ; when using Method B, the starting material is N -(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(5-boronic acid Furan-2-yl)-2-(methylsulfonyl)ethylamine (2.8 g), which is compound 11 of the invention, m/z (M+1) + : 567.
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is 6-boric acid-N-(3-chloro-4-(6-methylpyridin-3-yloxy).
  • Phenyl)quinazolin-4-amine (4.2 g) and 1-(5-bromofuran-2-yl)-2-(methylsulfonyl)ethylamine (2.5 g) ; starting material using Method B Is N-(3-chloro-4-(6-methylpyridin-3-yloxy)phenyl)-6-iodoquinazolin-4-amine (4.5 g) and N-(tert-butoxycarbonyl)- 1-(5-boronic acid furan-2-yl)-2-(methylsulfonyl)ethylamine (2.8 g),
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-boronic acid quinquin.
  • the preparation method is the same as the method or the method in the seventh embodiment, except that when the method is used, the starting material is 6-boric acid-N-(3-chloro-4-(6-methylpyridin-3-yloxy). Phenyl)quinazolin-4-amine (4.2 g) and 1-(5-bromofuran-2-yl)-3-(methylsulfonyl)propyl-2-amine (2.7 g); The starting material is N-(3-chloro-4-(6-methylpyridin-3-yloxy)phenyl)-6-iodoquinazolin-4-amine (4.5 g) and N- (tert-butyl) Oxycarbonyl)-1 -(5-boronic acid furan-2-yl)-3-(methylsulfonyl)propyl-2-amine (3.0 g),
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(4-(3-fluorobenzyloxy)-3-chloro Phenyl)-6-boronic acid quinazolin-4-amine (4.4 g) and 1-(4-bromothiazol-2-yl)-2-(methylsulfonyl)ethylamine (2.7 g);
  • the starting material is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-borate quinolate.
  • Oxazolin-4-amine 4.4 g
  • 1-(4-bromothiazol-2-yl)-3-(methylsulfonyl)propan-2-amine 2.8 g
  • the starting material is N-(4-(3-Fluorobenzyloxy)-3-chlorobenzene ffi)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(4- Thiazol-2-yl) -3-(methylsulfonyl)propyl-2-month 3 ⁇ 4 (3.4 g)
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-borate quinolate.
  • the starting material is N-( 4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(2-boric acid thiazole- 4-yl)- 2-(methylsulfonyl)ethylamine (3.0 g), which is compound 17 of the invention, m/z (M+1) +: 584.
  • the preparation method is the same as the method A or B in the seventh embodiment, except that when the method A is used, the starting material is N-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-6-borate quinolate.
  • Oxazolin-4-amine (4.4 g) and 1-(2-bromothiazol-4-yl)-3-(methylsulfonyl)propyl-2-amine (2.8 g); starting material using Method B N-(4-(3-Fluorobenzyloxy)-3-chlorophenyl)-6-iodoquinazolin-4-amine (4.6 g) and N-(tert-butoxycarbonyl)-1-(2) -thiazol-4-yl)-3-(methylsulfonyl)propyl-2-amine (3.1 g),
  • Inhibition rate (%) (control group OD value - medication OD value) / control group OD value ⁇ 100%
  • Inventive compound 11 100 5/5 1.56 ⁇ 1.26 37.0*
  • Inventive compound 17 100 5/5 2.44 ⁇ 0.47 57.8*
  • Inventive compound 18 100 5/5 3.04 ⁇ 0.68 72.0
  • Lapatinib 100 5/5 2.12 ⁇ 0.82 50.2*
  • d0 First dosing time; dn: 19 days after the first dose; TV: tumor volume; RTV: relative tumor volume; *P ⁇ 0.01 vs control

Abstract

La présente invention concerne un composé hétéroaromatique de formule générale (I), ainsi que son procédé de préparation et son utilisation. Dans la formule, A, D et Y sont tels que définis dans le descriptif.
PCT/CN2008/002046 2008-01-22 2008-12-23 Composés hétéroaromatiques, leur procédé de préparation et leur utilisation WO2009094831A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2390251A1 (fr) * 2009-01-23 2011-11-30 Cen, Junda Composés de quinazoline optiquement purs

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101735200B (zh) * 2008-11-17 2013-01-02 岑均达 喹唑啉类化合物
CN102344445B (zh) * 2010-07-23 2015-11-25 岑均达 光学纯喹唑啉类化合物

Citations (2)

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Publication number Priority date Publication date Assignee Title
CN1139383A (zh) * 1994-01-25 1997-01-01 沃尼尔朗伯公司 能够抑制表皮生长因子受体族酪氨酸激酶的双环化合物
CN1292788A (zh) * 1998-01-12 2001-04-25 葛兰素集团有限公司 作为蛋白酪氨酸激酶抑制剂的二环杂芳族化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1139383A (zh) * 1994-01-25 1997-01-01 沃尼尔朗伯公司 能够抑制表皮生长因子受体族酪氨酸激酶的双环化合物
CN1292788A (zh) * 1998-01-12 2001-04-25 葛兰素集团有限公司 作为蛋白酪氨酸激酶抑制剂的二环杂芳族化合物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2390251A1 (fr) * 2009-01-23 2011-11-30 Cen, Junda Composés de quinazoline optiquement purs
EP2390251A4 (fr) * 2009-01-23 2012-08-01 Cen Junda Composés de quinazoline optiquement purs

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