WO2008020711A1 - Quinazoline derivative as phosphodiesterase inhibitor and a process for preparing the same - Google Patents

Quinazoline derivative as phosphodiesterase inhibitor and a process for preparing the same Download PDF

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Publication number
WO2008020711A1
WO2008020711A1 PCT/KR2007/003908 KR2007003908W WO2008020711A1 WO 2008020711 A1 WO2008020711 A1 WO 2008020711A1 KR 2007003908 W KR2007003908 W KR 2007003908W WO 2008020711 A1 WO2008020711 A1 WO 2008020711A1
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Prior art keywords
methoxy
chloro
quinazolin
benzylamino
compound
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PCT/KR2007/003908
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French (fr)
Inventor
Soon Kil Ahn
Sungsook Lee
Nam Song Choi
Jae Kwang Lee
Seung Kee Moon
Hojin Choi
Su Jin Kim
Young Hoon Kim
Sung Kwon Kang
Hong Woo Lee
Jaesoo Shin
Sang Woong Kim
Eun Ju Lee
Eon Kyeom Kim
Jung Gyu Lee
Chung Youl Yoo
Dae Yon Lee
Dai Sig Im
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Chong Kun Dang Pharmaceutical Corp.
Leadgenex Inc.
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Publication of WO2008020711A1 publication Critical patent/WO2008020711A1/en

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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
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention relates to a quinazoline derivative, a preparation method thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a pharmaceutical composition comprising the same and use thereof as a therapeutic agent.
  • the present inveniont relates to a quinazoline derivative exhibiting inhibitory activity against phosphodiesterase V (PDE5).
  • the present invention relates to a pharmaceutical composition to treat male sexual dysfunction, in particular, male erectile dysfunction (ED).
  • Erectile dysfunction refers to a condition of the inability to achieve and maintain penile erection sufficient to complete satisfactory sexual intercourse. It was thought that there are two major causes for the erectile dysfunction: organic and psychogenic causes. In these days, however, it is believed that most of erectile dysfunction comes from organic causes resulting from various adult diseases. In particular, patients suffering from diabetes, hypertention and cardiac diseases are liable to have ED.
  • Penile erection occurs through the following complicated physiological processes.
  • nitric oxide (NO) is released and activates guanylate cyclase located in the corpus cavernosum of the penis, leading to an elevation in intracellular cyclic guanosine monophosphate (cGMP) levels.
  • cGMP cyclic guanosine monophosphate
  • Phosphodiesterase 5 PDE5 is an enzyme which induces the hydrolysis of cGMP to 5'GMP.
  • PDE5 inhibitors are known.
  • ViagraTM also known as Sildenafil; WO94/28902
  • CialisTM also known as Tadalafil; WO95/19978
  • LevitraTM also known as Vardenafil; Bioorganic & Medicinal Chemistry Letters, 2002, 12, 865-868
  • These drugs are efficacious for male erectile dysfunction and improve sexual function of about 70% of patients.
  • the afore-mentioned drugs are reported to cause side effects e.g. flushing, headache, achromatopsia (color blindness) and myalgia (muscle pain) due to nonselectivity with other phosphodiesterases.
  • It is another object of the present invention to provide a pharmaceutical composition comprising: a quinazoline derivative, or an isomer or pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient.
  • R 1 is NO 2 , NH 2 , CN, CON(K), CON(K) 2 , COO(K), COO(K) 2 ,
  • K is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • R 4 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, CF 3 , substituted or unsubstituted C 6 -Ci 2 arylalkyl, C 1 -C 3 alkoxy or heterocyclyl-(C 1 -C 6 )alkyl;
  • R 5 is substituted or unsubstituted C 1 -C 6 alkyl, or substituted or unsubstituted phenyl, n is 0, 1 or 2;
  • R d is hydrogen, or substituted or unsubstituted C 1 -C 3 alkyl
  • R 2 is fluoro, chloro, hydroxy, C 1 -C 6 alkoxy or -0-Z,
  • Z is a compound represented by R Ir or ⁇ o ,
  • R 6 and R 7 are each independently hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl, p is an integer of 1 to 5, and R 8 is hydroxy, alkoxy or amino; R 1 and R 2 may be bonded to form a ring compound represented
  • A is -C-R 9 or -C(O), and B is oxygen or N-Ri 0 , wherein R 9 is substituted or unsubstituted Ci-C 6 alkyl; and Ri 0 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl; R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -
  • Ri 1 and Ri 2 are each independently hydrogen, or substituted or unsubstituted
  • Ci-C 6 alkyl, and Rn and Rj 2 may be bonded to form a ring, R 13 is hydrogen, or substituted or unsubstituted Ci-C 6 alkyl, and Ri 4 is hydroxy, amino, Ci-C 3 alkylamino or Ci-C 3 dialkylamino;
  • R 2 and R 3 may be bonded to form a ring which is a compound represented
  • R a and R b are each independently halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted Ci-C 6 alkoxy, hydroxy or methylenedioxy, and said R a and R b are same or different;
  • R c is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
  • D represented by K 16, wherein Ri 6 is hydroxy, CO 2 H, or Ci-C 6 ester, E is C, O, S or Ci-C 6 alkylamine, s is 0 or 1, Ri 7 is hydrogen or hydroxy, and r is an integer of 2 to 5.
  • heterocyclic compound may include imidazole, triazole and pyrazole.
  • the isomers of the compound of Formula (I) may include enantiomer, stereoisomer and tautomer.
  • the compound of Formula (I) may be a compound wherein R 1 is
  • R 2 , R 3 , R 4 , R a , R b , R c and R d are as defined above.
  • the compound of Formula (I) may be a compound wherein R 1 O
  • R 4 is Rd ;
  • R a is 3-chloro;
  • R b is 4-methoxy; and
  • R 2 , R 3 , R 4 , R c and Ra are as defined above.
  • the compound of Formula (I) may be a compound
  • the compound of Formula (I) may be a compound
  • R b is 3-chloro;
  • R b is 4-methoxy;
  • R c is hydrogen;
  • R 3 is propyl, allyl, 2-methylallyl, 2-methylpropyl, hydroxyethyl, dimethylaminoethyl, dimethylaminomethyl, 2,3-dihydroxypropyl, acetaldehyde, methylene carboxylic acid, ethylene carboxylic acid, methylene pyrrolidine or methylene piperidine; and
  • R 2 , R 4 and R d are as defined above.
  • the compound of Formula (I) may be a compound wherein R 1 is
  • K is hydrogen or substituted or unsubstituted C 1 -C 3 alkyl
  • R 4 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, C 1 -C 3 dialkylamino, CF 3 , substituted or unsubstituted C 6 -C 12 arylalkyl or heterocyclyl-(C 1 -C 6 )alkyl;
  • R 5 is substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted phenyl, n is 0, 1 or 2;
  • R d is hydrogen, or substituted or unsubstituted C 1 -C 3 alkyl
  • R 2 is fluoro, chloro, hydroxy, C 1 -C 6 alkoxy or -O-Z,
  • whrerin Z is a compound represented by R 7 or O 5 wherein m is an integer of 2 to 5, R 6 and R 7 are each independently hydrogen or substituted or unsubstituted C 1 -C 6 alkyl, p is an integer of 1 to 5, and R 8 is hydroxy, alkoxy or amino; R 1 and R 2 may be bonded to form a ring compound represented by wherein A is -C-R 9 or -C(O), and B is oxygen or N-R 1O , wherein R 9 is substituted or unsubstituted C 1 -C 6 alkyl; and R 10 is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl;
  • R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -
  • C 6 alkenyl 0H or Q , wherein q is 0, 1, 2 or 3, Q is C(O)H, -N(R 11 )(R 12 ), -0(R 13 ) or -C(O)R 14 , wherein R 11 and R 12 are each independently hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl and R 11 and R 12 may be bonded to form a ring, R 13 is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl, R 14 is hydroxy, amino, C 1 -C 3 alkylamino or C 1 - C 3 dialkylamino;
  • R 2 and R 3 may be bonded to form a ring compound represented by wherein X is oxygen; and Y is N-R 15 , wherein R 15 is C 1 -C 3 alkyl;
  • R a and R b are each independently halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, hydroxy or methylenedioxy, and said R 3 and R b are same or different;
  • R 0 is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
  • R 16 is hydroxy, CO 2 H, or C 1 -C 6 ester
  • E is C, O, S or C 1 -C 6 alkylamine
  • s is 0 or 1
  • R 17 is hydrogen or hydroxy
  • r is an integer of 2 to 5.
  • the heterocyclic compound may include amidazole, triazole and pyrazole.
  • the compound of Formula (I) may be a compound wherein R 1
  • Il ft is NO 2 , NH 2 , CN, CON(K), CON(K) 2 , COO(K), COO(K) 2 , Rd , Rd ⁇ O r
  • K is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl
  • R 4 is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, CF 3 or C 1 -C 3 alkoxy;
  • R 5 is C 1 -C 3 alkyl, or substituted or unsubstituted phenyl, n is O;
  • Rd is hydrogen, or substituted or unsubstituted C 1 -C 3 alkyl;
  • R 2 is hydroxy, C 1 -C 6 alkoxy or -O-Z,
  • Z is a compound represented by R ? or o , wherein m is an integer of 2 to 5, R 6 and R 7 are each independently hydrogen, or C 1 -C 6 alkyl, p is an integer of 1 to 3, and R 8 is hydroxy or alkoxy; R 1 and R 2 may be bonded to form a ring compound represented by wherein A is -C-R 9 or -C(O), and B is oxygen or N-R 1O , wherein R 9 is C 1 -C 3 alkyl; and R 10 is hydrogen or C 1 -C 6 alkyl;
  • R 3 is substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -
  • C 6 alkenyl or a compound represented by 0H or Q , wherein q is 1, 2 or 3, and Q is C(O)H, -N(R 11 )(R 12 ), -0(R 13 ) or -C(O)R 14 , wherein R 11 and R are each independently substituted or unsubstituted C 1 -C 6 alkyl, and R 11 and R 12 may be bonded to form a ring, R 13 is hydrogen or C 1 -C 6 alkyl, and R 14 is hydroxy;
  • R 2 and R 3 may be bonded to form a ring compound represented wherein X is oxygen; and Y is N-R 15 , wherein R 15 is C 1 -C 3 alkyl; Ra and R b are each independently halogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 alkoxy, or methyl enedioxy, and said Ra and R b are same or different;
  • R c is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
  • R 16 is CO 2 H, or C 1 -C 6 ester
  • E is C or C 1 -C 6 alkylamine
  • s is 0 or 1
  • R 17 is hydrogen or hydroxy
  • r is an integer of 2 to 5.
  • heterocyclic compound may include imidazole, triazole and pyrazole.
  • the compound of Formula (I) may include at least one chiral carbon atom and it may thus exist as two or more enantiomers. Such an enantiomer may be separated from racemic mixtures of the compound of Formula (I), or a desired salt or derivative thereof in accordance with a conventional resolution method e.g. fractional crystallization, column chromatography or high-performance liquid chromatography (HPLC).
  • a conventional resolution method e.g. fractional crystallization, column chromatography or high-performance liquid chromatography (HPLC).
  • each enantiomer of the compound (I) can be separated by resolving the corresponding racemate with the use of a chiral auxiliary via HPLC, or subjecting a mixture, which is obtained by reaction of the corresponding racemate with an optically active acid or base, to fractional crystallization or column chromatography. All isomers may be incorporated into the scope of the present invention.
  • the pharmaceutically acceptable salt include inorganic salts (e.g. sulfate, hydrochloride, phosphate and hydrobromide), organic salts (e.g.
  • specific examples of the present invention may include one selected from the group consisting of compounds as set forth in Table 1, and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof.
  • specific examples of the present invention may include one selected from the group consisting of the following compounds; and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof.
  • specific examples of the present invention may include one selected from the group consisting of the following compounds, and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof.
  • the compound of Formula (I) can be prepared in accordance with various methods disclosed in documents [Tobe, M. et al, Bioorganic. Medicinal Chemistry, 2003, 11, 383-391; Takase, Y. et al, Journal of Medicinal Chemistry, 1994, 37, 2106- 2111].
  • Reaction scheme 1 Reaction scheme 1
  • R 1 , R 2 , R 3 , R a , R b and Rc are as defined above; and R 16 is a leaving group and suitable examples thereof include halogen (e.g. chloro).
  • the compound of Formula (II) as a starting material may be preferably reacted with an amine derivative of Formula (III) in the presence of a base.
  • bases that can be used in the reaction include tertiary amine such as triethylamin, diisopropyl ethylamine, pyridine and dimethylaminopyridine.
  • preferred solvents that can be used in the reaction include organic solvents such as alcohol including ethanol, isopropanol, tetrahydrofuran and propanol. Preferred are ethanol and isopropanol.
  • reaction scheme 2 the compound of Formula (II) can be prepared in accordance with the following Reaction scheme 2: Reaction scheme 2
  • R 1 , R 2 , R 3 and Rc are as defined above; and R 16 is a leaving group and suitable examples thereof include halogen (e.g. chloro).
  • reaction of Reaction scheme 2 is carried out by mixing a material of
  • halogenating reagent e.g. thionylchloride (SOCl 2 ), oxallylchloride
  • Examples of preferred solvents that can be used herein include dimethylformamide (DMF), ethanol and tatrahydrofuran.
  • the reaction may be carried out at -20 ° C to 150 ° C , preferably at 20 ° C to 100 ° C .
  • 2- amino-4-chloro benzoic acid of the compound 1 or 2-amino-4-fluoro benzoic acid of the compound 1-1 is heated together with formamide, preferably, at 80 to 15O 0 C, to obtain a compound 2 or 2-1.
  • nitric acid in the presence of sulfuric acid at -20 to 80 0 C, preferably at O to 50 0 C and the temperature is then elevated up to 80 to 100 0 C to obtain a compound 3 and 3-1.
  • the compound 3 and 3-1 is chlorinated with POCl 3 or SOCl 2 and is thus reacted with benzyl amine of the compound 4 substituted at -20 to 80 0 C, preferably at 0 to 5O 0 C to obtain a compound 5 or 5-1.
  • the compound 5-1 is reacted with allyl alcohol and sodium hydride (NaH) in the presence of a dimethylamide (DMF) solvent at O 0 C to obtain a compound 8.
  • a base preferably, NaH or NaOMe
  • alcohol are added to the compound 5 and the temperature is elevated to 50 to 12O 0 C to obtain a compound 6.
  • Methoxy of the compound 6 is reacted with lithium chloride in the presence of DMF to selectively remove a methyl group from the compound 6 ⁇ Synthesis, 1989, 287) to obtain a compound 7.
  • the compound 7 is reacted with allyl bromide in the presence of a base, preferably K 2 CO 3 , Na 2 CO 3 or NaH to obtain a compound 8.
  • the compound 7 may be obtained by a Mitsunobu reaction employing PPh 3 , DEAD and DIAD (Synthesis, 1981, 1-28).
  • the compound 8 is heated in xylene or DMF at 100 to 200 0 C, preferably 80 to 150 0 C to obtain the compound of Example 1.
  • the compound 7 may be reacted with formaldehyde, p-formaldehyde, secondary and tertiary amines and acetic acid to obtain a compound 10 or 12.
  • the reaction temperature is 0-150 0 C, and preferably 20 to 120 0 C
  • the solvent is alcohol, preferably ethanol, isopropanol and propanol.
  • Reaction scheme 4 Specific Reactions in Reaction scheme 4 are given to illustrate a general method for preparing the compounds of Examples 49-52, 61-64 and 70 and compounds of other Examples can be prepared in accordance with the Reaction scheme.
  • the nitro group of the compound 9 is reduced with a reducing agent to obtain a compound 10.
  • the compound 10 is converted into a compound 11 through a coupling reaction.
  • Examples of the coupling agent that can be used for the coupling reaction include, but are not limited to dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC), 1-hydroxybenzothriazole (HOBT), thionylchloride (SOCl 2 ), triethylamine (Et 3 N) and pyridine.
  • the compound 11 is reacted with osmium tetroxide (OsO 4 ) and N-methylmorpholine to obtain a compound 12.
  • the compound 12 is oxidized with sodium periodate to obtain an aldehyde compound 13.
  • the compound 13 is reduced with sodium borohydride to obtain an alcohol compound 14.
  • reagent a) KOCN, AcOH, NaOH, H 2 O; b) KNO 3 , H 2 SO 4 , 0 0 C; c) POCI 3 , (Hunig's base ) , tolun ⁇ .reflux; d) benzylamine, Et 3 N 1 IPA; ⁇ )allyl alcohol, NaH 1 DMF; f) isonipecotio acid, EtOH, reflux; g) DMFjeflux; h) OMF ⁇ -eflux; i) K 2 CO 3 , CH 3 l,acetone, reflux.
  • Reaction scheme 5 Specific reactions depicted in Reaction scheme 5 are given to illustrate a general synthesis process for preparing the compounds of Examples 70 to 74 and the compounds of other Examples can be prepared as depicted in the Reaction scheme. Synthesis of the compound 15 is carried out according to the document (J. Med. Chem., 1995, 38, 2763) and the remaining reactions are carried out in the same manner as in Reaction scheme 3. Reaction scheme 6 example 64 compound 23
  • a pharmaceutical composition for treating a cardiovascular disease comprising: the compound of Formula (I), an enantiomer, a stereoisomer, rotomer thereof or a pharmaceutically acceptable salt thereof; a solvate or hydrate thereof; and a pharmaceutically acceptable carrier.
  • the cardiovascular disease includes male erectile dysfunction (ED), angina pectoris, hypertension and pulmonary hypertension or artery atherosclerosis.
  • ED male erectile dysfunction
  • angina pectoris hypertension
  • pulmonary hypertension or artery atherosclerosis there is provided a method for treating a cardiovascular disease comprising: administering a therapeutically effective amount of the composition to patients, wherein the cardiovascular disease includes male erectile dysfunction, angina pectoris, hypertension, pulmonary hypertension or artery atherosclerosis.
  • acute toxicity tests were conducted using mice to evaluate general toxicity of the compound (I).
  • the compound (I) of the present invention may be administered in the form of a formulation into a pharmaceutical preparation, which has a solid, semi-solid or liquid phase suitable for oral or non-oral administration and is prepared by mixing the compound with a pharmaceutically acceptable inert carrier.
  • the compound (I) of the present invention is administered in a daily dosage of
  • a dosage depends on the required level and the condition of patients and the compound to be used.
  • Example 2 The compound of Example 1 (11.6 mg, 0.029 mmol) and K 2 CO 3 (12 mg) were dissolved in acetone (3 ml) and CH 3 I (5.4 ⁇ L) was added at room temperature thereto. The resulting mixture was stirred at reflux for 5 hours. After completion of the reaction, the reaction mixture was filtered. The solvent was removed by distillation under reduced pressure, to yield the compound of Example 2 (9.6 mg, 80 %) as a deep yellow solid.
  • 1 H NMR (acetone -d 6 ) ⁇ 8.681 (s, IH) 1 8.576 (s, IH), 7.428 (d, J 2.09
  • Example 2 The compound of Example 2 (4.27 mg, 0.04 mmol) and K 2 CO 3 (0.5 mg, 10 mole %) were dissolved in MeOH (1 ml) and PtO 2 (0.5 mg, 10 mole%) was added thereto at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure, to obtain an amine compound (4.27 mg, 0.01 mmol). The amine compound was dissolved in dichloromethane (2 ml), and pyridine (1.16 ⁇ l) and anhydrous trifluoroacetic acid (TFAA, 1.86 ⁇ l) were added thereto. The resulting mixture was stirred at room temperature for 12 hours.
  • TFAA trifluoroacetic acid
  • the amine compound (40 mg, 0.104 mmol) was dissolved in CH 2 Cl 2 (5 ml) and anhydrous trifluoroacetic acid (TFAA, 22.03 ⁇ l) and pyridine (11.8 ⁇ l) were added thereto at room temperature. The resulting mixture was stirred at room temperature for 18 hours.
  • the reaction mixture was extracted with CH 2 Cl 2 .
  • the organic layer was washed with saturated saline, dried over anhydrous MgSO 4 and distilled under reduced pressure.
  • the compound was dissolved in CH 2 Cl 2 (2 ml), and TFAA (5.93 ⁇ l) and pyridine (3.64 ⁇ L) were added thereto at room temperature. The resulting mixture was stirred at the temperature for 18 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure.
  • Example 13 In the same manner as in Example 5, the compound of Example 13 as a white solid (52.1 mg, 52.7 %) was prepared from the compound of Example 12.
  • Example 14 The compound of Example 14 (175.1 mg, 75.6 %) as a red solid was prepared in the same manner as in Example 12 except that 4-(3-chloro-4-methoxy-benzylamino)- 6-nitro-quinazolin-7-ol (200 mg, 0.554 mmol) and paraformaldehyde (85.6 mg, 2.77 mmol) were dissolved in isopropyl alcohol (7 ml) and dimethyl amine (2.77 ml, 5.54 mmol) was added thereto.
  • Example 15 In the same manner as in Example 13, the compound of Example 15 as a white solid (52.1 mg, 86.5%) was prepared from the compound of Example 14. 1 H NMR (acetone -d 6 ) ⁇ 8.420 (s, IH), 8.249 (s, IH), 7.785 (m, IH),
  • Example 17 The compound of Example 17 as a yellow solid was prepared in the same manner as in Example 16.
  • N 4 -(3-chloro-4-methoxy-benzyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine 151 mg, 0.04 mmol
  • K 2 CO 3 1.5 mg, 10 mole%
  • PtO 2 1.5 mg, 10 mole%
  • Example 20 The compound of Example 20 as a light-yellow solid was prepared in the same manner as in Example 8.
  • Example 21 The compound of Example 21 as a light-yellow solid was prepared in the same manner as in Example 15.
  • Example 22 The compound of Example 22 (32.4 mg, 0.07 mmol) was dissolved in MeOH (3 mL) and PtO 2 (3.12 mg, 20 mole %) was added at room temperature thereto. The resulting mixture was stirred under a hydrogen atmosphere for one hour. After completion of the reaction, the reaction solution was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in CH 2 Cl 2 (4 ml), and TFAA (14.6 ⁇ L) and pyridine (10.1 ⁇ L) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 ;
  • Example 24 The compound (71 %) of Example 24 as a yellow solid was prepared from the compound of Example 1 in the same manner as in Example 22.
  • 1 H-NMR (CD 3 OD) ⁇ 8.795 (s, IH), 8.550 (s, IH), 7.403 (d, J 2.05
  • Example 26 synthesis of the compound: ⁇ - [4-(3-chloro-4-methoxy-benzylammo)-7-(2-dimethylaminoethoxy)- quinazolin-6-yl]-2, 2, 2-trifluoroacetamide
  • the compound of Example 26 (10 mg, 9 %) as a yellow solid was prepared in the same manner as in Example 23.
  • Example 31 The compound of Example 31 (5.2 mg, 17.7%) was prepared from 4-(3-chloro- 4-methoxy-benzylamino)-6-nitro-8-allyl-quinazolin-7-ol (42 mg, 0.11 mmol) in the same manner as in Examples 24 and 25.
  • 6-amino-4-(3-chloro-4-methoxy-benzylamino)-8-propyl-quinazolin-7-ol (100 mg, 0.2682 mmol) was dissolved in DMF (20 ml) and K 2 CO 3 (111 mg, 0.8046 mmol), oxalyl chloride (0.035 ml, 0.4023 mmol) was slowly added thereto. The resulting mixture was stirred at 80 ° C for 15 hours. After the reaction solution was poured into a cold saturated aqueous ammonium chloride solution (100 ml), the resulting mixture was extracted with EtOAc (150 ml) and washed with brine until DMF was removed.
  • Example 33 synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -methanes ulf onamide
  • N 4 -(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (36.1 mg, 0.09 mmol) was dissolved in CH 2 Cl 2 (5 ml) and pyridine (10.1 ⁇ L) and MsCl (9.8 ⁇ L) were added thereto at 0 ° C .
  • the resulting solution was stirred at room temperature for two hours.
  • the reaction solution was extracted with EtOAc (30 mL). The organic layer was washed with saturated saline, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure.
  • Example 35 synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazoUn-6- yl] -2-oxo-propionamide N 4 -(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (28 mg, 0.072 mmol) was dissolved in CH 2 Cl 2 (2 ml), pyruvic acid (7.5 ⁇ L, 0.11 mmol) and DCC (222.4 ⁇ L, 0.11 mmol) were added thereto and the resulting mixture was stirred at room temperature for 4 hours.
  • Example 36 synthesis of the compound: 4-(3-chloro-4-methoxy-benzylamino)-7-ethyI-9-propyl-5H-8-oxa-l,3,5- triaza-anthracene-6-one
  • 6-amino-4-(3-chloro-4-methoxy-benzylamino)-8-propyl-quinazolin-7-ol 50 mg, 0.1341 mmol
  • 2-bromobutylic acid ethyl ester (0.03 ml, 0.2011 mmol)
  • KF 23 mg, 0.4023 mmol
  • the reaction solution was poured into ice water (100 mL) and the resulting solution was extracted with EtOAc/MeOH (5/1, 150 mL).
  • Example 40 The compound of Example 40 (25 mg, 0.0651 mmol) was suspended in acetone (20 mL), and ethyl iodide (0.02 mL, 0.12 mmol) and K 2 CO 3 (27 mg, 0.1953 mmol) were added thereto. The resulting mixture was stirred at reflux for 15 hours. After allowed to cool to room temperature, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO 2 ; CH 2 Cl 2 ZMeOH ⁇ (Vl) to yield the compound of Example 41 (15 mg, 56 %) as a yellow solid .
  • Example 46 The compound of Example 46 (15.3 mg, 67 %) as a light-yellow solid was prepared from N 4 -(3 -chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6- diamine (20 mg, 0.052 mmol) and propionyl chloride (5.86 ⁇ L, 0.067 mmol) in the same manner as in Example 34.
  • Example 2 The compound of Example 2 (260 mg, 0.627 mmol) was dissolved in EtOH (15 mL), SnCl 2 (1.41 g, 6.27 mmol) was added thereto and the resulting mixture was stirred at reflux for 12 hours. After the reaction solution was poured into a cold saturated aqueous NaHCO 3 solution (200 ml), the resulting mixture was extracted with EA (200 ml). The organic layer was washed three times with a saturated aqueous NaHCO 3 solution (150 mL X 3) and once with brine (150 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was dried under reduced pressure to obtain a compound (240 mg, 0.624 mmol) as a yellow solid.
  • the compound was dissolved in pyridine (5 mL) and Ac 2 O (0.065 mL, 0.686 mmol) and DMAP (cat.) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into a cold saturated aqueous NaHCO 3 solution (100 mL) and the resulting mixture was extracted with EtOAc (100 ml). The organic layer was washed twice with a saturated aqueous ammonium chloride solution (100 mL X 2), once with a saturated aqueous NaHCO 3 solution (100 mL) and once with brine (100 mL). The collected organic layer was dried over anhydrous magnesium sulfate and filtered.
  • Example 50 synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl]-acetamide
  • the extracted organic layer was washed twice with a saturated aqueous ammonium chloride solution (100 mL X 2), once with an aqueous solution of saturated NaHCO 3 (100 mL) and once with brine (100 mL).
  • the organic layer was dried over anhydrous magnesium sulfate and filtered.
  • the filtrate was distilled under reduced pressure to remove the solvents.
  • Example 49 The compound of Example 49 (24.0 mg, 0.052 mmol) was dissolved in acetone/H 2 O (3 mL/1 mL) and NaIO 4 (23.8 mg, 0.11 mmol) was added thereto at 0 ° C .
  • Example 53 The compound of Example 53 as a yellow solid was prepared in the same manner as in Example 34.
  • N 4 -(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine 50 mg, 0.1292 mmol
  • acetone 30 mL
  • pivaloyl chloride 0.032 ml, 0.2584 mmol
  • K 2 CO 3 150 mg, 1.0856 mmol
  • the resulting solution was stirred at reflux for 18 hours. After being allowed to cool to room temperature, the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure.
  • N 4 -(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (17.2 mg, 0.045 mmol) was dissolved in CH 2 Cl 2 (3 mL), and propionyl chloride (5.07 ⁇ L, 0.058 mmol) and pyridine (4.34 ⁇ L, 0.054 mmol) were added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with CH 2 Cl 2 (2x10 mL). The organic layer was washed with a saturated NaHCO 3 solution and saturated saline, dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Example 57 The compound of Example 57 as a colorless oil was prepared from the compound of Example 55 in the same manner as in Example 48.
  • Example 58 The compound of Example 58 as a yellow solid was prepared in the same manner as in Example 56.
  • Example 59 The compound of Example 59 as a yellow oil was prepared in the same manner as in Example 56.
  • Example 60 The compound of Example 60 as a colorless oil was prepared from the compound of Example 55 in the same manner as in Example 46.
  • Example 56 The compound of Example 56 (95.6 mg, 0.22 mmol) was dissolved in acetone/H 2 O (5 ml, v/v 4:1) and NMMO (50.8 mg) and OsO 4 (3.26 ml, 20 mol%) were added thereto at 0 ° C . The resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, sodium sulfite was added to the reaction mixture and stirred for about one hour. The reaction solution was extracted with EtOAc (100 mL) and washed three times with saturated saline (100 niL X 3). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure.
  • Example 62 The compound of Example 62 as a yellow oil was prepared in the same manner as in Example 50.
  • Example 63 The compound of Example 63 as a yellow solid was prepared in the same manner as in Example 51.
  • Example 64 synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -propionamide
  • Example 66 The compound of Example 66 as a yellow solid was prepared with methylenedioxybenzylamine in the same manner as in Example 2.
  • 1 H-NMR (acetone) ⁇ 8.64 Cs, IH), 8.56 (s, IH), 7.01-6.68 (m, 3H),
  • Example 67 The compound of Example 67 as a yellow solid was prepared with dimethoxybenzylamine in the same manner as in Example 2.
  • Example 68 The compound of Example 68 as a yellow solid was prepared with methylbenzylamine in the same manner as in Example 2.
  • Example 69 The compound of Example 69 as a yellow solid was prepared with 3-chloro-4- ethoxy benzylamine in the same manner as in Example 2.
  • Example 70 synthesis of the compound: [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- acetic acid
  • Example 70 as a yellow solid was prepared from the compound of Example 2 in the same manner as in Examples 49 and 51.
  • the compound 15 (4.29 g, 23.8 mmol) was added to H 2 SO 4 (60 mL) and the mixture was cooled to 0 ° C with stirring. KNO 3 was added to the reaction mixture, followed by stirring at 0 ° C for one hour. After completion of the reaction, the reaction mixture was poured into ice water with stirring and the resulting mixture was filtered under reduced pressure. The filtrate as a brown solid was added to MeOH. The resulting mixture was stirred for one hour and filtered to yield the compound 16 (3.55 g, 66%) as a brown solid.
  • the compound 19 (846 mg, 1.94 mmol) was dissolved in DMF (100 mL) and the solution was stirred at reflux at 140 ° C for 6 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous NaHCO 3 solution (3 x 50 mL). The organic layer was dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to obtain a compound (675.2 mg, 78.3 %) as a red solid. The compound was dissolved in acetone (10 niL) and K 2 CO 3 (643 mg, 4.65 mmol) and CH 3 I (289.7 ⁇ L, 4.65 mmol) were added thereto at room temperature.
  • the compound was dissolved in acetone (5 mL) and K 2 CO 3 (95.3 mg, 0.69 mmol) and CH 3 I (42.9 ⁇ L, 0.69 mmol) were added thereto at room temperature. The resulting mixture was stirred at reflux for 3 hours. After completion of the reaction, the methanol was removed by concentration under reduced pressure. The resulting mixture was diluted with EtOAc (2 x 20 mL), washed with saturated NaHCO 3 (40 mL) and saturated saline, dried over anhydrous MgSO 4 and filtered. The solvent was removed by distillation under reduced pressure.
  • Example 46 The compound of Example 46 (80 mg, 0.18 mmol) was dissolved in THF (2 niL), NaH (8 mg, 0.36 mmol) was slowly added thereto at 0°C and the resulting mixture was stirred at 0 ° C for 30 min. To the reaction mixture was added CH 3 I (36 ⁇ L, 0.6 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated NH 4 Cl solution and extracted with CH 2 Cl 2 (2 x 10 mL). The collected organic layer was dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Example 76 The compound of Example 76 (48 mg, light-yellow) was prepared from the compound of Example 39 (68 mg, 1.5 mmol) in the same manner as in Example 75.
  • Example 64 The compound of Example 64 (2.225 g, 5.0 mmol) was dissolved in CH 2 Cl 2 (50 mL) and imidazole (0.408 g, 6.0 mmol) was added thereto. TBSCl (0.904g, 6.0 mmol) was added to the resulting mixture in an ice bath, followed by stirring at room temperature for 2 hours. After completion of the reaction, a saturated NaHCO 3 solution (20 mL) was added to the reaction mixture. The organic layer was washed with a saturated aqueous NH 4 Cl solution (60 mL) and saturated saline (60 mL), dried over anhydrous MgSO 4 and filtered. The solvent was removed by distillation under reduced pressure to yield a compound (2.6 g, 93 %) as a colorless oil.
  • the compound 23 (4 g, 10.3 mmol) was dissolved in CH 2 Cl 2 (40 mL) and imidazole (735 mg, 10.8 mmol) and TBSCl (1.58 mg, 10.5 mmol) were added thereto at 0 ° C .
  • the resulting mixture was stirred at room temperature for 3 hours.
  • the reaction mixture was washed with a saturated NH 4 Cl solution and extracted with EtOAc.
  • the collected organic layer was dried over anhydrous MgSO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the resulting residue was purified by column chromatography (n-Hex/ EA) to yield the compound 24 (4.4 g, 84.3 %) as a white solid.
  • the compound 25 (2.74 g, 4.88 mmol) was dissolved in THF (10 mL) and NaH (426 mg, 9.77 mmol) was slowly added thereto at 0 ° C . After stirring at 0 ° C for 30 min, CH 3 I (912 ⁇ L, 14.7 mmol) was added thereto and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, CH 2 Cl 2 (2 x 10 ml) was added to the reaction mixture. The organic layer was washed with a saturated NH 4 Cl solution, dried over MgSO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • the compound 26 (67.8 mg, 0.12 mmol) was dissolved in 1,4-dioxane (2 niL) and IM HCl (3 drops) was added thereto. The resulting mixture was stirred at room temperature for one hour. After completion of the reaction, CH 2 Cl 2 (20 ml) was added to the reaction mixture. The organic layer was washed with saturated NaHCO 3 , dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Example 81 (light-yellow).
  • Example 82 The compound of Example 82 (100 mg, 0.22 mmol) was dissolved in MeOH/H 2 O (10 mL, v/v 2:1) and NaIO 4 (71.5 mg, 0.33 mmol) was added thereto at O 0 C and the resulting mixture was stirred for 3 hours.
  • EtOAc (30 ml) was added to the reaction solution. The organic layer was washed with saturated saline (50 mL), dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. After MeOH (3 ml) was added to the resulting residue, NaBH 4 (12.6 mg, 0.33 mmol) was added thereto at O 0 C, followed by stirring for one hour.
  • EtOAc (30 ml) was added to the reaction solution. The organic layer was washed with a saturated NH 4 Cl solution, dried over anhydrous MgSO 4 and filtered.
  • Example 85 The compound of Example 85 (54.4 %) as a white solid was prepared from cyclopropanecarbonyl chloride in the same manner as in Example 84.
  • Example 64 The compound of Example 64 (2.225 g, 5.0 mmol) was dissolved in CH 2 Cl 2 (50 mL) and imidazole (0.408 g, 6.0 mmol) was added thereto. TBSCl (0.904g, 6.0 mmol) was added to the resulting mixture at 0 ° C, followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO 3 solution (20 mL) and CH 2 Cl 2 (30 mL) were added to the reaction mixture. The organic layer was washed with a saturated aqueous NH 4 Cl solution (60 mL) and saturated saline (60 mL), dried over anhydrous MgSO 4 and filtered.
  • the compound (1.15 g, 2.596 mmol) thus obtained was dissolved in acetone (12 ml) and a solution Of NMO-H 2 O (0.7 g, 5.19 mmol) in distilled water (20 mL) was added thereto.
  • a 4 wt% aqueous OsO 4 solution (0.165 ml, 0.026 mmol, 1.0 % mol) was slowly added dropwise to the resulting solution and stirred for 12 hours.
  • a Na 2 SO 3 (3.2g, 25 mmol) solution in distilled water (50 ml) was added to the reaction solution, the resulting mixture was stirred for 20 min and a saturated aqueous NaHCO 3 solution (100 ml) was added thereto.
  • Example 88 The compound of Example 88 (50 mg, 0.13 mmol) was added to EtOH, NaOH (32% aqueous, 1 ml) was added thereto and the resulting mixture was stirred at reflux for 6 hours.
  • the EtOH was removed by distillion under reduced pressure.
  • HCl was added to the resulting residue such that the acidity is adjusted to pH 7.
  • the reation solution was extracted with CH 2 Cl 2 .
  • the organic layer was dried over anhydrous MgSO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • MS(ESI) m/z 414 (M+l).
  • Example 90 synthesis of the compound: 8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid tert-butylamide
  • Example 88 The compound of Example 88 (100 mg, 0.25 mmol) was dissolved in acetone (5 ml), NMNO (119 mg, 0.51 mmol; 50% w/w H 2 O) and OsO 4 (154 ⁇ L, 0.025 mmol; 4 wt%) were added thereto at O 0 C and the resulting mixture was stirred at 0 ° C for 4 hours.
  • Example 91 (68 mg, 63 %) as a yellow solid.
  • Example 91 The compound of Example 91 (40 mg, 0.093 mmol) was dissolved in MeOH/H 2 O (6 ml, v/v 2:1) and NaIO 4 (29.9 mg, 0.14 mmol) was then added at 0 ° C thereto. The resulting mixture was stirred at O 0 C for one hour and at room temperature for one hour. EtOAc (30 mL) and saturated saline (20 mL) were added to the reaction solution. The organic layer was dried over anhydrous MgSO 4 and filtered. The solvent was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (2 ml), NaBH 4 (5.3 mg, 0.14 mmol) was added thereto at 0 ° C and the resulting mixture was stirred for one hour.
  • Phosphodiesterase V (hereinafter, referred to as "PDE-5") was known to exist in bovine platelets (Thrombosis Research, 1991, 62, 31, Journal of Biological Chemistry, 1990, 265, 14964, Molecular Pharmacology, 1999, 56, 124). Herein, PDE-5 was extracted from bovine platelets according to this reference.
  • the PRP was centrifuged (Sorvall RC-5C, 3,000 x g, 20 min, 20 °C) again to obtain a white platelet precipitate.
  • the supernatant, platelet- poor-plasma (PPP) was separated from the platelet precipitate.
  • the centrifugation of the PPP was conducted in the same manner as above to make the amount of red blood cells incorporated into the platelet precipitate as low as possible.
  • a red blood cell (RBC) lysis buffer was each fed into seven tubes containing the platelet precipitate thus obtained and thus resuspended for about 5 minutes.
  • the suspensions in the tubes were put together into one tube and centrifuged (Sorvall RC-5C, 3,000 x g, 20 min, 4 "C). The centrifugation was once repeated in the same manner as above.
  • the resulting platelet precipitate was washed with a cold 10 mM sodium phosphate buffer (about 40 ml, pH 7.2) and centrifuged in the same manner as above. The mass of the resulting platelet precipitate was measured.
  • the platelet precipitate was freezed in a freezer at -20 ° C for about 20 minutes and then defrosted at room temperature.
  • the resulting platelet precipitate was mixed with a storage buffer solution (10 mM sodium phosphate buffer containing 20% glycerol, pH 7.2) to prepare a platelet solution (concentration: ca. 20 mg/m£, based on the platelet mass).
  • the platelet solution was temporarily stored at -70 "C .
  • the platelet solution was sonicated in an ice bath (Ulsso Hitech Sonosmasher ® , Power: 25%, On: 15 sec, Off: 10 sec, Cycle: five times, Frequency: 19970).
  • the platelet solution was diluted with a storage buffer solution (10 mM sodium phosphate buffer containing 20% glycerol, pH 7.2) according to a Bradford method to adjust the concentration of the solution to about 2 mg/iM.
  • the dilution was aliquoted and stored at -70 ° C for use in phosphodiesterase V tests.
  • the PDE-5 enzyme solution stored at -70 ° C was defrosted in an ice bath and diluted with a buffer solution for PDE-5 enzyme activity test (40 mM MOPS, pH 7.5, 0.5 mM Na-EDTA, 15 mM Mg-acetate) at a dilution of 1/50 to prepare a PDE-5 enzyme solution.
  • a buffer solution for PDE-5 enzyme activity test 40 mM MOPS, pH 7.5, 0.5 mM Na-EDTA, 15 mM Mg-acetate
  • 96-well plates available from AB gene, 0.8 ml deep- well
  • the total volume of the reaction solution was 200 ⁇ i.
  • the well plates in which the lysis enzyme solution, and the substrate and enzyme buffer solutions are included, were thoroughly mixed with shaking for about 2 min and allowed to react in a water bath at 35 ° C for 30 min.
  • RI sample plate 20 ⁇ i of the collected filtrate was transferred to 96-well plates for radioactivity measurement (RI sample plate, Wallac; MicroBeta 1450). 100 ⁇ i of a cocktail for radioactivity measurement (RI cocktail; Wallac) was fed into each well and sealed with a sealing film (TopSeal-A ® ; Packard). The plates were slowly stirred for about one hour, or allowed to stand for about 18 hours, to allow the cocktail to be homogeneously mixed with the filtrate for measurement. Then, radioactivity (CPM; count per minute) of the the mixture was measured with ⁇ -counter (Wallac).
  • CPM radioactivity
  • PDE-5 enzyme activity test 60 ⁇ i of the substrate solution of the enzyme; and 50 ⁇ i of an enzyme solution diluted with a buffer such that the final concentration of protein is adjusted to 10 ⁇ g/vd.
  • the inhibitory activity of drugs against PDE-5 was evaluated in the same manner as above.
  • the drug inhibition (%) against PDE-5 was calculated by the following equation:
  • Drug inhibition(%) Jl Test ⁇ Blank I x j 00 (o /o )
  • PDE-6 phosphodiesterase VI
  • Sildenafil (sold under the name "Viagra”), a drug to treat male erectile dysfunction, causes cyanosis as a side effect. Such cyanosis is known to be caused by nonselective inhibition against PDE-6. Accordingly, to prevent the side effect, there is a need to develop a PDE-5-selective inhibitor that hardly exhibits inhibitory activity against PDE-6. To measure the selective inhibitory activities, PDE-6 enzyme was separated according to the afore-mentioned report and evaluated for inhibitory activity in the same manner as the case in PDE-5.
  • Phosphodiesterase XIAl (hereinafter, referred to as "PDE XIAl") is known to be in human prostate and muscle tissues. It is not easy to obtain such a tissue for PDE XIAl separation, or separate PDE XIAl from the tissue and purify the enzyme. Accordingly, expression vectors containing genes in the catalytic domain of human phosphodiesterase XIAl were prepared according to genetic methods known in the art (PNAS, 2000, 97, 3702-3707) and insect cells were allowed to express the target genes (Bac-To-Bac Baculovirus expression system; Invitrogen). The human PDE XIAl activity was tested in the same manner as the cases of PDE-5 and PDE-6.
  • the compounds thus prepared are useful in inhibiting PDE-5 enzyme. Inhibitory activity against enzyme was represented by an IC 50 value (50% inhibition of enzyme activity).
  • the IC 50 values of the compounds according to the present invention are set forth below.
  • a ratio of PDE VI IC 50 /PDE V IC 50 is shown. As the ratio increases, the compounds show more selective inhibition for PDE V IC 50 , as compared to PDE VI IC 50 , thus enabling a reduction in side effects.
  • all activity values mean approximate values.
  • the compounds of the present invention and salts thereof efficiently inhibit PDE V and have selevtivity for PDE VI.
  • the compound of Formula (I) can be effectively used to treat cardiovascular diseases such as male erectile dysfunction, angina pectoris, hypertension and artery atherosclerosis.

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Abstract

The present invention relates to a quinazoline derivative, a preparation method thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a pharmaceutical composition comprising the same and use thereof as a therapeutic agent. The present inveniont relates to a quinazoline derivative exhibiting inhibitory activity against C

Description

QUINAZOLINE DERIVATIVE AS PHOSPHODIESTERASE INHIBITOR AND A PROCESS FOR PREPARING THE SAME
Technical Field
The present invention relates to a quinazoline derivative, a preparation method thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, a hydrate thereof, a pharmaceutical composition comprising the same and use thereof as a therapeutic agent.
More specifically, the present inveniont relates to a quinazoline derivative exhibiting inhibitory activity against phosphodiesterase V (PDE5).
Background Art
The present invention relates to a pharmaceutical composition to treat male sexual dysfunction, in particular, male erectile dysfunction (ED). Erectile dysfunction refers to a condition of the inability to achieve and maintain penile erection sufficient to complete satisfactory sexual intercourse. It was thought that there are two major causes for the erectile dysfunction: organic and psychogenic causes. In these days, however, it is believed that most of erectile dysfunction comes from organic causes resulting from various adult diseases. In particular, patients suffering from diabetes, hypertention and cardiac diseases are liable to have ED.
Penile erection occurs through the following complicated physiological processes. During sexual arousal, nitric oxide (NO) is released and activates guanylate cyclase located in the corpus cavernosum of the penis, leading to an elevation in intracellular cyclic guanosine monophosphate (cGMP) levels. This rise in cGMP leads to a reduction in the intracellular calcium concentration and a relaxation of vascular endothelial cells, resulting in inflow of blood and an erection. Phosphodiesterase 5 (PDE5) is an enzyme which induces the hydrolysis of cGMP to 5'GMP. Thus, inhibition of PDE5 enables cGMP concentrations to maintain, thereby maintaining penile erection [Boolel, M. et al, Br. J. of Urology, 1996, 78, 257-261; Jeremy, J. Y. et al, Br. J. of Urology, 1997, 79, 958-963].
A variety of PDE5 inhibitors are known. For example, as a therapeutic agent for Male Erectile Dysfunction (MED), Viagra™ (also known as Sildenafil; WO94/28902) was firstly approved by USA FDA (Food and drag administration). In addition, Cialis™ (also known as Tadalafil; WO95/19978) and Levitra™ (also known as Vardenafil; Bioorganic & Medicinal Chemistry Letters, 2002, 12, 865-868) have USA FDA approval. These drugs are efficacious for male erectile dysfunction and improve sexual function of about 70% of patients. Furthermore, various PDE5 inhibitors are disclosed in WO 03/035653 Al, US 02/132818Al, WO 02/20489 A2, WO 01/12608 Al and WO 00/20033 Al. Quinazoline derivatives assosicated with the present invention are reported by WO 94/22855, US 6,046,206 and the documents [Journal of Medicinal Chemistry, 1995, 38, 3547-3557; Journal of Medicinal Chemistry, 1993, 36, 3765-3770; Journal of Medicinal Chemistry, 1994, 37, 2106-2111; J. Pharmacol. Exp. Ther., 1995, 272, 825-831]. Meanwhile, 11 types of phosphodiesterase are known to date [Nature, 2002,
674-682]. The afore-mentioned drugs are reported to cause side effects e.g. flushing, headache, achromatopsia (color blindness) and myalgia (muscle pain) due to nonselectivity with other phosphodiesterases.
Accodringly, there is a need for continuous development of a novel-structural drug that has neither toxicity nor side effect and exhibits exellent effects due to improved selectivity between several phosphodiesterases.
Disclosure of the Invention
Technical Problem
As a result of a great deal of research and efforts to solve the afore-mentiond problems, the present inventors have developed a quinazoline derivative siginificantly different from conventional quinazoline compounds, thus accomplishing the present invention.
Thus, it is one object of the present invention to provide a novel quinazoline derivative as a superior-selective phosphodiesterase V inhibitor, an isomer or pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof.
It is another object of the present invention to provide a method for producing a quinazoline derivative.
It is another object of the present invention to provide a pharmaceutical composition comprising: a quinazoline derivative, or an isomer or pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient. Technical Solution
In accordance with an aspect of the present invention for achieving the above object, there is provided a novel quinazoline derivative represented by Formula (I) below, an isomer or pharmaceutically acceptable salt thereof; or a solvate or hydrate thereof:
Figure imgf000004_0001
wherein R1 is NO2, NH2, CN, CON(K), CON(K)2, COO(K), COO(K)2,
Figure imgf000004_0002
wherein K is hydrogen, or substituted or unsubstituted C1-C6 alkyl;
R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, CF3, substituted or unsubstituted C6-Ci2 arylalkyl, C1-C3 alkoxy or heterocyclyl-(C1-C6)alkyl;
R5 is substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted phenyl, n is 0, 1 or 2;
Rd is hydrogen, or substituted or unsubstituted C1-C3 alkyl;
R2 is fluoro, chloro, hydroxy, C1-C6 alkoxy or -0-Z,
wherein Z is a compound represented by R Ir or ¥ o ,
wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl, p is an integer of 1 to 5, and R8 is hydroxy, alkoxy or amino; R1 and R2 may be bonded to form a ring compound represented
Figure imgf000005_0001
wherein A is -C-R9 or -C(O), and B is oxygen or N-Ri0, wherein R9 is substituted or unsubstituted Ci-C6 alkyl; and Ri0 is hydrogen or substituted or unsubstituted C1-C6 alkyl; R3 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-
Q alkenyl, 0H or Q ,
wherein q is 0, 1, 2 or 3, and Q is C(O)H, -N(R1O(Ri2), -0(Ri3) or -C(O)Ri4, wherein Ri 1 and Ri2 are each independently hydrogen, or substituted or unsubstituted
Ci-C6 alkyl, and Rn and Rj2 may be bonded to form a ring, R13 is hydrogen, or substituted or unsubstituted Ci-C6 alkyl, and Ri4 is hydroxy, amino, Ci-C3 alkylamino or Ci-C3 dialkylamino;
R2 and R3 may be bonded to form a ring which is a compound represented
Figure imgf000005_0002
wherein X is oxygen; and Y is N-R15, wherein Rj5 is Ci-C3 alkyl; Ra and Rb are each independently halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted Ci-C6 alkoxy, hydroxy or methylenedioxy, and said Ra and Rb are same or different;
Rc is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
D represented by K16,
Figure imgf000005_0003
wherein Ri6 is hydroxy, CO2H, or Ci-C6 ester, E is C, O, S or Ci-C6 alkylamine, s is 0 or 1, Ri7 is hydrogen or hydroxy, and r is an integer of 2 to 5.
Examples of the heterocyclic compound may include imidazole, triazole and pyrazole.
The isomers of the compound of Formula (I) may include enantiomer, stereoisomer and tautomer. Preferably, the compound of Formula (I) may be a compound wherein R1 is
Figure imgf000006_0001
and R2, R3, R4, Ra, Rb, Rc and Rd are as defined above.
More preferably, the compound of Formula (I) may be a compound wherein R1 O
-NΛR4 is Rd ; Ra is 3-chloro; Rb is 4-methoxy; and R2, R3, R4, Rc and Ra are as defined above.
Even more preferably, the compound of Formula (I) may be a compound
wherein R1
Figure imgf000006_0002
Ra is 3-chloro; Rb is 4-methoxy; R3 is propyl, allyl, 2- methylallyl, 2-methylpropyl, hydroxyethyl, dimethylaminoethyl, dimethylaminomethyl, 2,3-dihydroxypropyl, acetaldehyde, methylene carboxylic acid, ethylene carboxylic acid, methylene pyrrolidine or methylene piperidine; and R2, R4, R0 and Ra are as defined above.
Particuraly preferably, the compound of Formula (I) may be a compound
Figure imgf000006_0003
is 3-chloro; Rb is 4-methoxy; Rc is hydrogen; R3 is propyl, allyl, 2-methylallyl, 2-methylpropyl, hydroxyethyl, dimethylaminoethyl, dimethylaminomethyl, 2,3-dihydroxypropyl, acetaldehyde, methylene carboxylic acid, ethylene carboxylic acid, methylene pyrrolidine or methylene piperidine; and R2, R4 and Rd are as defined above.
Preferably, the compound of Formula (I) may be a compound wherein R1 is
-NAR4 -N^R5
NO2, NH2, CN, CON(K), CON(K)2, COO(K), COO(K)2, Rd , Rdυ Or
Figure imgf000006_0004
wherein K is hydrogen or substituted or unsubstituted C1-C3 alkyl;
R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C1-C3 alkoxy, C1-C3 alkylamino, C1-C3 dialkylamino, CF3, substituted or unsubstituted C6-C12 arylalkyl or heterocyclyl-(C1-C6)alkyl; R5 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted phenyl, n is 0, 1 or 2;
Rd is hydrogen, or substituted or unsubstituted C1-C3 alkyl;
R2 is fluoro, chloro, hydroxy, C1-C6 alkoxy or -O-Z,
whrerin Z is a compound represented by R7 or O 5 wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl, p is an integer of 1 to 5, and R8 is hydroxy, alkoxy or amino;
Figure imgf000007_0001
R1 and R2 may be bonded to form a ring compound represented by wherein A is -C-R9 or -C(O), and B is oxygen or N-R1O, wherein R9 is substituted or unsubstituted C1-C6 alkyl; and R10 is hydrogen or substituted or unsubstituted C1-C6 alkyl;
R3 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-
C6 alkenyl, 0H or Q , wherein q is 0, 1, 2 or 3, Q is C(O)H, -N(R11)(R12), -0(R13) or -C(O)R14, wherein R11 and R12 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl and R11 and R12 may be bonded to form a ring, R13 is hydrogen, or substituted or unsubstituted C1-C6 alkyl, R14 is hydroxy, amino, C1-C3 alkylamino or C1- C3 dialkylamino;
R2 and R3 may be bonded to form a ring compound represented by
Figure imgf000007_0002
wherein X is oxygen; and Y is N-R15, wherein R15 is C1-C3 alkyl;
Ra and Rb are each independently halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxy or methylenedioxy, and said R3 and Rb are same or different; R0 is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
represented by
Figure imgf000007_0003
wherein R16 is hydroxy, CO2H, or C1-C6 ester, E is C, O, S or C1-C6 alkylamine, s is 0 or 1, R17 is hydrogen or hydroxy; and r is an integer of 2 to 5. Examples of the heterocyclic compound may include amidazole, triazole and pyrazole.
More preferably, the compound of Formula (I) may be a compound wherein R1
0 Il ft is NO2, NH2, CN, CON(K), CON(K)2, COO(K), COO(K)2, Rd , Rdυ Or
Figure imgf000008_0001
wherein K is hydrogen, or substituted or unsubstituted C1-C6 alkyl; R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, CF3 or C1-C3 alkoxy;
R5 is C1-C3 alkyl, or substituted or unsubstituted phenyl, n is O;
Rd is hydrogen, or substituted or unsubstituted C1-C3 alkyl; R2 is hydroxy, C1-C6 alkoxy or -O-Z,
wherein Z is a compound represented by R? or o , wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen, or C1-C6 alkyl, p is an integer of 1 to 3, and R8 is hydroxy or alkoxy;
Figure imgf000008_0002
R1 and R2 may be bonded to form a ring compound represented by wherein A is -C-R9 or -C(O), and B is oxygen or N-R1O, wherein R9 is C1-C3 alkyl; and R10 is hydrogen or C1-C6 alkyl;
R3 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-
C6 alkenyl, or a compound represented by 0H or Q , wherein q is 1, 2 or 3, and Q is C(O)H, -N(R11)(R12), -0(R13) or -C(O)R14, wherein R11 and R are each independently substituted or unsubstituted C1-C6 alkyl, and R11 and R12 may be bonded to form a ring, R13 is hydrogen or C1-C6 alkyl, and R14 is hydroxy;
R2 and R3 may be bonded to form a ring compound represented
Figure imgf000008_0003
wherein X is oxygen; and Y is N-R15, wherein R15 is C1-C3 alkyl; Ra and Rb are each independently halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, or methyl enedioxy, and said Ra and Rb are same or different;
Rc is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
represented by
Figure imgf000009_0001
wherein R16 is CO2H, or C1-C6 ester, E is C or C1-C6 alkylamine, s is 0 or 1, R17 is hydrogen or hydroxy, and r is an integer of 2 to 5.
Examples of the heterocyclic compound may include imidazole, triazole and pyrazole. The compound of Formula (I) may include at least one chiral carbon atom and it may thus exist as two or more enantiomers. Such an enantiomer may be separated from racemic mixtures of the compound of Formula (I), or a desired salt or derivative thereof in accordance with a conventional resolution method e.g. fractional crystallization, column chromatography or high-performance liquid chromatography (HPLC). More specifically, each enantiomer of the compound (I) can be separated by resolving the corresponding racemate with the use of a chiral auxiliary via HPLC, or subjecting a mixture, which is obtained by reaction of the corresponding racemate with an optically active acid or base, to fractional crystallization or column chromatography. All isomers may be incorporated into the scope of the present invention. Examples of the pharmaceutically acceptable salt include inorganic salts (e.g. sulfate, hydrochloride, phosphate and hydrobromide), organic salts (e.g. maleates, succinates, acetates, toluenesulfonates, mesylates, benzenesulfonates, tartrates and citrates), salts of an alkali metal such as lithium, sodium and potassium and salts of an alkaline earth metal such as calcium and magnesium. Preferably, specific examples of the present invention may include one selected from the group consisting of compounds as set forth in Table 1, and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof.
Table 1
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
Figure imgf000014_0001
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Example Compound Name
No. Structure
4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-
91 dihydroxy-propyl)-7-methoxy-quinazolin-6- carbonitryl
4-(3-chloro-4-methoxy-benzylamino)-8-(2-
92 hydroxy-ethyl)-7-methoxy-quinazolin-6- carbonitryl
Figure imgf000019_0001
More preferably, specific examples of the present invention may include one selected from the group consisting of the following compounds; and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof. 8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol(The compound of Example 1)
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy-benzyl)- amine (The compound of Example 2)
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2,2,2-trifluoroacetamide (The compound of Example 3)
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]-
2, 2, 2-trifluoroacetamide (The compound of Example 5)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxypropyl)-7-methoxy- quinazolin-6-yl]-2,2,2-trifiuoroacetamide (The compound of Example 6) 5 (3-chloro-4-methoxy-benzyl)-(3-methyl-10-nitro-3,4-dihydro-2H-l-oxa-3,5,7- triaza-penanthren-8-yl)-amine (The compound of Example 12)
N-[8-(3-chloro-4-methoxy-benzylamino)-3-methyl-3,4-dihydro-2H-l-oxa- 3,5,7-triaza-penanthren-10-yl]-2,2,2-trifluoroacetamide (The compound of Example 13)
N.[4_(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-7-hydroxy- O quinazolin-6-yl]-2, 2, 2-trifluoroacetamide (The compound of Example 15)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-dimethylaminoemyl)-7- methoxy-quinazolin-6-yl]-2,2,2-trifluoroacetamide (The compound of Example 20
)
N-[4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-8-pyrrolidine-l-yl- 5 methyl-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide (The compound of Example 21) N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-acetamide (The compound of Example 34)
Cyclopropanecarboxylic acid [4-(3 -chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide (The compound of Example 38) [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl] - carbamic acid methyl ester (The compound of Example 39)
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-propionamide (The compound of Example 46)
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- acetamide (The compound of Example 48)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide (The compound of Example 49)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -acetamide (The compound of Example 52) N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide (The compound of Example 61)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-propionamide (The compound of Example 64)
N-[4-(3-chloro-4-methoxy-benzylammo)-7-methoxy-8-propyl-quinazolin-6- yl]-N-methyl-propionamide (The compound of Example 75)
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl]- methyl-carbamic acid methyl ester (The compound of Example 76)
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -carbamic acid methyl ester (The compound of Example 77) N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide (The compound of Example 78)
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methyl-carbamic acid methyl ester (The compound of Example 79)
3-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- propane- 1 ,2-diol (The compound of Example 82)
2-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- ethanol (The compound of Example 83)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide (The compound of Example 84) Cyclopropanecarboxylic acid-[4-(3-chloro-4-methoxy-benzylamino)-8-(2- hydroxy-ethyl)-7-methoxy-quinazolin-6-yl]-methylamide (The compound of Example 85)
N-[4-(3-chloro-4-memoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-ethyl-propionamide (The compound of Example 86)
[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester (The compound of Example 87)
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carbonitryl (The compound of Example 88) 8-allyl-4-(3 -chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid (The compound of Example 89)
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid tert-butylamide (The compound of Example 90)
4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl (The compound of Example 92)
Particularly preferably, specific examples of the present invention may include one selected from the group consisting of the following compounds, and an isomer, pharmaceutically acceptable salt, hydrate and solvate thereof.
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide (The compound of Example 49)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-acetamide (The compound of Example 52)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide (The compound of Example 61) N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-propionamide (The compound of Example 64)
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester (The compound of Example 77)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-emyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide (The compound of Example 78)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methyl-carbamic acid methyl ester (The compound of Example 79)
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide (The compound of Example 84) [4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester (The compound of Example 87) 4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl (The compound of Example 92)
Preparation of compound (I)
The compound of Formula (I) can be prepared in accordance with various methods disclosed in documents [Tobe, M. et al, Bioorganic. Medicinal Chemistry, 2003, 11, 383-391; Takase, Y. et al, Journal of Medicinal Chemistry, 1994, 37, 2106- 2111]. A detail for the preparation of the compound (I) with reference to Reaction schemes will be given as follows: Reaction scheme 1
Figure imgf000022_0001
In Reaction scheme 1, R1, R2, R3, Ra, Rb and Rc are as defined above; and R16 is a leaving group and suitable examples thereof include halogen (e.g. chloro).
In the reaction depicted in Reaction scheme 1 , the compound of Formula (II) as a starting material may be preferably reacted with an amine derivative of Formula (III) in the presence of a base. Examples of preferred bases that can be used in the reaction include tertiary amine such as triethylamin, diisopropyl ethylamine, pyridine and dimethylaminopyridine. Examples of preferred solvents that can be used in the reaction include organic solvents such as alcohol including ethanol, isopropanol, tetrahydrofuran and propanol. Preferred are ethanol and isopropanol. The reaction may be carried out at -20 °C to 150°C, preferably at 20 °C to 100°C . As the starting material in Reaction scheme 1, the compound of Formula (II) can be prepared in accordance with the following Reaction scheme 2: Reaction scheme 2
Figure imgf000022_0002
(IV) CMJ In Reaction scheme 2, R1, R2, R3 and Rc are as defined above; and R16 is a leaving group and suitable examples thereof include halogen (e.g. chloro).
The reaction of Reaction scheme 2 is carried out by mixing a material of
Formula (IV) as a starting material disclosed in the documents [Rewcastle, G. W. et al, J. Med. Chem., 1996, 39, 918-928; Fujino, K. et al, Organic Process Research &
Development, 2001, 5, 426-433; Tobe, M. et al, Bioorganic Medicinal Chemistry, 2003,
11, 383-391] with a halogenating reagent e.g. thionylchloride (SOCl2), oxallylchloride
(COCl2), phosphorus oxychloride (POCl3) or phosphorus pentachloride (PCl5).
Examples of preferred solvents that can be used herein include dimethylformamide (DMF), ethanol and tatrahydrofuran. The reaction may be carried out at -20 °C to 150 °C , preferably at 20 °C to 100 °C .
General methods for preparing the compound of Formula (I) of the present invention are the same as depicted in Reaction schemes 1 and 2, and the compounds of specific examples can be prepared in accordance with the following Reaction schemes 3 to 6.
Reaction scheme 3
Figure imgf000024_0001
Specific reactions depicted in Reaction scheme 3 are given to illustrate general synthesis processes for preparing the compounds of Examples 1 to 13. Other compounds of the present invention can be prepared, as depicted in the Reaction scheme. The compounds 3, 3-1 and 4 are disclosed in the documents [compound 3: Journal of Medicinal Chemistry, 1996, 39, 267-276; compound 3-1: Journal of Medicinal Chemistry, 1996, 39, 918-928; compound 4: Journal of Medicinal Chemistry, 1998, 41, 3367-3372; Journal of Medicinal Chemistry, 2001, 44, 1025-1027]. 2- amino-4-chloro benzoic acid of the compound 1 or 2-amino-4-fluoro benzoic acid of the compound 1-1 is heated together with formamide, preferably, at 80 to 15O0C, to obtain a compound 2 or 2-1. To the compound 2 or 2-1 is added nitric acid in the presence of sulfuric acid at -20 to 80 0C, preferably at O to 50 0C and the temperature is then elevated up to 80 to 100 0C to obtain a compound 3 and 3-1. The compound 3 and 3-1 is chlorinated with POCl3 or SOCl2 and is thus reacted with benzyl amine of the compound 4 substituted at -20 to 80 0C, preferably at 0 to 5O0C to obtain a compound 5 or 5-1. The compound 5-1 is reacted with allyl alcohol and sodium hydride (NaH) in the presence of a dimethylamide (DMF) solvent at O0C to obtain a compound 8. Alternatively, a base (preferably, NaH or NaOMe) and alcohol are added to the compound 5 and the temperature is elevated to 50 to 12O0C to obtain a compound 6. Methoxy of the compound 6 is reacted with lithium chloride in the presence of DMF to selectively remove a methyl group from the compound 6 {Synthesis, 1989, 287) to obtain a compound 7. The compound 7 is reacted with allyl bromide in the presence of a base, preferably K2CO3, Na2CO3 or NaH to obtain a compound 8. Alternatively, the compound 7 may be obtained by a Mitsunobu reaction employing PPh3, DEAD and DIAD (Synthesis, 1981, 1-28). The compound 8 is heated in xylene or DMF at 100 to 200 0C, preferably 80 to 150 0C to obtain the compound of Example 1. The compound 7 may be reacted with formaldehyde, p-formaldehyde, secondary and tertiary amines and acetic acid to obtain a compound 10 or 12. At this time, the reaction temperature is 0-150 0C, and preferably 20 to 120 0C, and the solvent is alcohol, preferably ethanol, isopropanol and propanol. Reaction scheme 4
0C
Figure imgf000026_0001
Figure imgf000026_0002
Specific Reactions in Reaction scheme 4 are given to illustrate a general method for preparing the compounds of Examples 49-52, 61-64 and 70 and compounds of other Examples can be prepared in accordance with the Reaction scheme. The nitro group of the compound 9 is reduced with a reducing agent to obtain a compound 10. The compound 10 is converted into a compound 11 through a coupling reaction. Examples of the coupling agent that can be used for the coupling reaction include, but are not limited to dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDC), 1-hydroxybenzothriazole (HOBT), thionylchloride (SOCl2), triethylamine (Et3N) and pyridine. The compound 11 is reacted with osmium tetroxide (OsO4) and N-methylmorpholine to obtain a compound 12. The compound 12 is oxidized with sodium periodate to obtain an aldehyde compound 13. The compound 13 is reduced with sodium borohydride to obtain an alcohol compound 14. Reaction scheme 5
Figure imgf000027_0001
1-1 15 16
Figure imgf000027_0002
reagent a) KOCN, AcOH, NaOH, H2O; b) KNO3, H2SO4, 00C; c) POCI3, (Hunig's base ) , tolunβ .reflux; d) benzylamine, Et3N1 IPA; θ)allyl alcohol, NaH1 DMF; f) isonipecotio acid, EtOH, reflux; g) DMFjeflux; h) OMF^-eflux; i) K2CO3, CH3l,acetone, reflux.
Specific reactions depicted in Reaction scheme 5 are given to illustrate a general synthesis process for preparing the compounds of Examples 70 to 74 and the compounds of other Examples can be prepared as depicted in the Reaction scheme. Synthesis of the compound 15 is carried out according to the document (J. Med. Chem., 1995, 38, 2763) and the remaining reactions are carried out in the same manner as in Reaction scheme 3. Reaction scheme 6
Figure imgf000028_0001
example 64 compound 23
Figure imgf000028_0002
26 example 79 compound a) 2N HCI, MeOH, b) imidazole, TBSCI1 CH2CI2, c) methylchloroformate .pyridine, CH2CI2; d) CH3I, NaH, THF; β) 1M HCI. 1,4-dioxane
Specific reactions depicted in Reaction scheme 6 are given to illustrate a general synthesis process for preparing the compounds of Examples 77 to 87 and the compounds of other Examples can be prepared as depicted in the Reaction scheme. The compound of Example 64 is hydrolyzed under acidic or alkaline conditions to obtain an amine compound 23. After the alcohol group of the compound 23 is protected, a substituent may be introduced into an amine group in the same manner as in Reaction scheme 4 to obtain a compound 25. An alkyl group may be introduced into the compound 25 in the presence of a base. As the base, there may be used sodium hydride (NaH), KO1Bu or NaOMe. Examples of solvents that can be used herein include dimethylformamide (DMF), tetrahysrofuran (THF) and dioxane.
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition for treating a cardiovascular disease comprising: the compound of Formula (I), an enantiomer, a stereoisomer, rotomer thereof or a pharmaceutically acceptable salt thereof; a solvate or hydrate thereof; and a pharmaceutically acceptable carrier.
The cardiovascular disease includes male erectile dysfunction (ED), angina pectoris, hypertension and pulmonary hypertension or artery atherosclerosis. In accordance with another aspect of the present invention, there is provided a method for treating a cardiovascular disease comprising: administering a therapeutically effective amount of the composition to patients, wherein the cardiovascular disease includes male erectile dysfunction, angina pectoris, hypertension, pulmonary hypertension or artery atherosclerosis. In the present invention, acute toxicity tests were conducted using mice to evaluate general toxicity of the compound (I). In the acute toxicity tests, toxic symptoms were not detected until the compound was orally administrated to mice in an amount lower than 200 mg/kg and the LD50 (50% lethal dosage) after oral administration of a single dose of the compound was 2 g/kg or higher. These results demonstrate that the compound (I) is considerably safe.
The compound (I) of the present invention may be administered in the form of a formulation into a pharmaceutical preparation, which has a solid, semi-solid or liquid phase suitable for oral or non-oral administration and is prepared by mixing the compound with a pharmaceutically acceptable inert carrier. The compound (I) of the present invention is administered in a daily dosage of
0.2 to 10.0 mg/kg (weight), based on the weight of the active compound. However, a dosage depends on the required level and the condition of patients and the compound to be used.
Mode for Invention
The present invention will be better understood from the following examples. These examples are not to be construed as limiting the scope of the invention.
Examples
Example 1, synthesis of the compound:
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol
1) Synthesis of compound 5 A starting material 3 (5.7 g, 25.3 mmol) was dissolved in thionyl chloride
(110.3 ml) and dimethylformamide (three drops) was added thereto at room temperature. The mixture was stirred at reflux for 17 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature. The solvent was removed by distillation under reduced pressure. The resulting mixture was diluted with ethyl acetate and washed with a saturated NaHCO3 solution and brine. The organic layer was dried over anhydrous sodium sulfate, distilled under reduced pressure to remove the solvents and dried under vacuum to obtain a compound. The compound and 3-chloro-4-methoxy-benzylamine (5.61 g, 27 mmol) were dissolved in isopropyl alcohol (50 ml) and triethylamine (7.56 ml, 54 mmol) was then added thereto. The resulting mixture was stirred at room temperature for 17 hours. After completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with 5% citric acid, 1 N sodium hydroxide, water and brine. The mixture was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was eluted with dichloromethane/hexane (4 :
1) to yield a compound 5 (7.8 g, 81%, 2 steps) as a yellow solid. 5 1H NMR (CD3OD, 400 MHz) δ 8.413 (s, IH), 7.907 (d, J = 2.21 Hz,
IH), 7.709 (d, J = 8.92 Hz, IH), 7.637 (dd, J = 8.91, 2.28 Hz, IH), 7.408 (d,
J = 2.10 Hz, IH), 7.306 (dd, J = 8.54, 2.21 Hz, IH), 7.006 (d, J = 8.44 Hz,0
IH), 4.780 (s, 2H), 3.846 (s, 3H), 3.051 (s, 3H). MS (ESI) m/z 393 (M+ + 1)
2) Synthesis of compound 6
A starting material 5 (93 mg, 0.245 mmol) was dissolved in methanol (3 ml) and sodium methoxide (40 mg) was added thereto. The resulting mixture was heated5 in a sealed tube for 16 hours. After completion of the reaction, the mixture was allowed to cool to room temperature and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (silica gel; dichloromethane/methanol = 15/1 ~ 10/1) to yield the compound 6 (62 mg, 67.5%) as a yellow solid.
1H-NMR (DMSO-de) δ 9.094 (t, J = 5.56 Hz, IH), 9.017 (s, IH), 8.516
(s, IH), 7.438 (d, J = 2.06 Hz, IH), 7.374 (s, IH), 7.317 (dd, J = 8.46, 2.08
Hz, IH), 7.102 (d, J = 8.52 Hz, IH), 4.685 (d, J = 5.59 Hz, 2H), 4.022 (s, Q 3H), 3.818 (s, 3H). MS (ESI) m/z 413 (M+ + Na) 3) Synthesis of compound 7
A starting material 6 (106 mg, 0.283 mmol) was dissolved in dimethylformamide (3 ml) and lithium chloride (36 mg) was added thereto. The resulting mixture was stirred at 15O0C for 5 hours. After completion of the reaction, the mixture was allowed to cool to room temperature and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (silica gel; dichloromethane/methanol = 12/1 ~ 10/1) to yield a compound 7 (42 mg, 41.2%) as a yellow solid.
1H-NMR (DMSOd6) 6 9.061 (s, IH), 8.906 (s, IH), 8.353 (s, IH),
7.357 (d, J = 1.90 Hz, IH), 7.237 (dd, J = 8.44, 1.96 Hz, IH), 7.030 (d, J =
8.46 Hz, IH), 7.018 (s, IH), 4.609 (m, IH), 3.753 (s, IH). 4) Synthesis of compound 8
Method i) A starting material 7 (6.18 mg, 0.0171 mmol) and potassium carbonate (7 mg) were dissolved in acetone (4 mL) and allyl bromide (10 μJt) was added thereto. The resulting mixture was stirred at 8O0C for 6 hours. After completion of the reaction, the mixture was allowed to cool to room temperature and filtered. The solvent was removed by distillation under reduced pressure. The resulting residue was neutralized with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 150 ml) as a solvent. The collected organic layer was washed with saturated saline, dried over anhydrous MgSO4 and filtered. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; n-Hex/EtOAc=l/l) to yield the compound 8 (6.12 mg, 89 %) as a brown solid.
Method ii) Allyl alcohol (5.64 mL, 83.8 mmol) was dissolved in DMF, the solution was cooled to 0°C and NaH (4.42 g, 110.5 mmol) was slowly added thereto. The resulting mixture was stirred at 0°C for 20 min. The compound 5-1 (10 g, 27.6 mmol) was slowly added to the mixture, followed by stirring for 18 hours. After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 150 ml) as a solvent. The collected organic layer was washed with brine, dried over anhydrous MgSO4 and filtered. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2; n-Hex/EtOAc=l/l) to yield a compound 8 (5.75 g, 52 %) as a brown solid. 1H-NMR (acetone -de) 6 8.739 (s, IH), 8.482 (s, IH), 7.423 (d, J = 2.10
Hz, IH), 7.331 (m ,2H), 7.004 (d, J = 8.44 Hz, IH), 6.064 (m, IH), 4.490 (m,
IH), 5.281 (m, IH), 4.845 (m, 2H), 4.807 (m, 2H), 3.811 (s, 3H).
5) Synthesis of the titled compound
A starting material 8 (6.0 mg, 0.0149 mmol) was added to xylene (2 ml) and the resulting mixture was heated in a sealed tube at 150 "C for 2 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by scintillation chromatography (silica gel; dichloromethane/methanol = 10/1) to yield the compound of Example 1 (4.5 mg, 75 %) as a red oil.
1H-NMR (acetone -d6) δ 9.077 (s, IH), 8.585 (s, IH), 7.493 (d, J = 2.08
Hz, IH), 7.395 (dd, J = 8.41, 2.06 Hz, IH), 7.074 (d, J = 8.46 Hz, IH),
6.050-5.982 (m, IH), 5.075-5.023 (m, IH), 4.954-4.917 (m, IH), 4.856 (m,
2H), 3.943-3.920 (m, 2H), 3.878 (s, 3H). MS (ESI) m/z 423 (M+ + Na)
Example 2, synthesis of the compound:
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy-benzyl)- amine
The compound of Example 1 (11.6 mg, 0.029 mmol) and K2CO3 (12 mg) were dissolved in acetone (3 ml) and CH3I (5.4 μL) was added at room temperature thereto. The resulting mixture was stirred at reflux for 5 hours. After completion of the reaction, the reaction mixture was filtered. The solvent was removed by distillation under reduced pressure, to yield the compound of Example 2 (9.6 mg, 80 %) as a deep yellow solid. 1H NMR (acetone -d6) δ 8.681 (s, IH)1 8.576 (s, IH), 7.428 (d, J = 2.09
Hz, IH), 7.329 (dd, J = 8.39, 2.08 Hz, IH), 7.009 (d, J = 8.45 Hz, IH),
6.072-6.004 (m, IH), 5.015-4.964 (m, IH), 4.936-4.907 (m, IH), 4.788 (m,
2H), 3.905 (s, 3H), 3.894-3.871 (m. 2H), 3.871 (s, 3H). MS (ESI) m/z 415
(M+ + 1)
Example 3, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyI-quinazolin-6- yl]-2,2,2-trifluoroacetamide
The compound of Example 2 (4.27 mg, 0.04 mmol) and K2CO3 (0.5 mg, 10 mole %) were dissolved in MeOH (1 ml) and PtO2 (0.5 mg, 10 mole%) was added thereto at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 2 hours. After completion of the reaction, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure, to obtain an amine compound (4.27 mg, 0.01 mmol). The amine compound was dissolved in dichloromethane (2 ml), and pyridine (1.16 μl) and anhydrous trifluoroacetic acid (TFAA, 1.86 μl) were added thereto. The resulting mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/Me0H = 10/1) to yield the compound of Example 3 (1.8 mg, 35%) as a white solid.
1H NMR (DMSO, 400 MHz) δ 8.532 (s, IH), 8.467 (s, IH), 8.170 (m,
IH), 7.476 (d, J = 2.12 Hz, IH), 7.373 (dd, J = 8.45, 2.13 Hz, IH), 7.047 (d,
J = 8.48 Hz, IH), 4.828 (m, 2H), 3.901 (s, 3H), 3.862 (s, 3H), 3.102 (m,
2H), 1.682 (m, 2H), 0.979 (t, J = 3.84 Hz, 3H). MS (ESI) m/z 483 (M+ + 1)
Example 4, synthesis of the compound: (3-chloro-4-methoxy-benzyl)-[7-methoxy-6-nitro-8-(2-piperidin-l-yl- ethyl)-quinazolin-4-yl] -amine
The compound of Example 2 (17.4 mg, 0.042 mmol) and N-methylmorphine- TV-oxide (9.84 mg) were dissolved in acetone/H2O (4:1, 3 ml) and OsO4 (420 μl, 0.2 eq) was added thereto at room temperature. The resulting mixture was stirred at the temperature for 6 hours. After completion of the reaction, a saturated aqueous Na2SO3 solution was added to the reaction mixture. The resulting mixture was stirred for 30 minutes at room temperature. Saturated saline was added to the reaction mixture and the mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/Me0H = 10/1) to obtain a compound (19 mg) as a yellow solid.
The compound (18 mg, 0.04 mmol) thus obtained was dissolved in MeOH (2 ml) and a solution Of NaIO4 (12.8 mg) in H2O (1 ml) was added thereto at O0C. The mixed solution was stirred at O0C for one hour. After completion of the reaction, saturated saline was added to the solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/Me0H = 10/1) to obtain a compound (6.92 mg, 40%, 2 steps) as a white solid.
The compound thus obtained (6.92 mg, 0.017 mmol) was dissolved in MeOH (2 ml) and AcOH (2.4 μl), NaBH3CN (2.6 mg) and piperidine (2.14 μl) were added thereto. The mixture was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/Me0H =10:1 --> 7:1) to yield a compound (6.02 mg, 74.6 %) as a white solid.
1H-NMR (acetone -d6) δ 8.804 (s, IH), 8.709 (s, IH), 7.488 (d, J = 2.13 Hz, IH), 7.397 (dd, J = 8.51, 2.12 Hz, IH), 7.078 (d, J = 8.48 Hz, IH),
4.860 (m, 2H), 4.010 (s, 3H), 3.874 (s, 3H), 3.582 (t, J = 6.99 Hz1 2H),
3.340-3.30 (m, 6H), 1.921-1.864 (m, 4H), 1.678 (m, 2H).MS (ESI) m/z 486
(M+ + 1) Example 5, synthesis of the compound:
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazoIin-6- yl]-2, 2, 2-trifluoroacetamide
As depicted in Reaction scheme 4, the compound of Example 2 (65 mg, 0.157 mmol) and SnC12 • 2H2O (176.8 mg) were dissolved in EtOH (4 ml), and c-HCl (1 drop) was added thereto at room temperature. The resulting mixture was heated at 9O0C for 4 hours. After completion of the reaction, the mixture was allowed to cool to room temperature. 10% NaHCO3 was added to the reaction mixture, followed by extraction with CH2Cl2. The organic layer was washed with saturated saline and dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/MeOH = 10:1) to yield an amine compound (40 mg, 66.2 %) as a white solid. The amine compound (40 mg, 0.104 mmol) was dissolved in CH2Cl2 (5 ml) and anhydrous trifluoroacetic acid (TFAA, 22.03 μl) and pyridine (11.8 μl) were added thereto at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was extracted with CH2Cl2. The organic layer was washed with saturated saline, dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2MeOH = 15:1) to yield the compound of Example 5 (32 mg, 64 %) as a white solid.
Example 6, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxypropyl)-7- methoxy-quinazolin-6-yl]-2,2,2-trifluoroacetamide
The compound of Example 5 (32 mg, 0.0672 mmol) and N-methylmorphine-N- oxide (15.7 mg) were dissolved in acetone/H2O (4:1, 3 ml) and OsO4 (670 μL, 0.2 eq) was added thereto at room temperature. The resulting mixture was stirred at the temperature for 6 hours. After completion of the reaction, a saturated aqueous Na2SO3 solution (5 mL) was added to the reaction mixture. The resulting mixture was stirred at the temperature for 30 minutes. Saturated saline was added to the reaction mixture and the resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2ZMeOH = 10:1) to yield the compound of Example 6 (30 mg) as a yellow solid.
Example 7, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl]-2,2,2-trifluoroacetamide
The compound of Example 6 (40 mg, 0.078 mmol) was dissolved in MeOH (2 ml), a solution Of NaIO4 (19.9 mg) in H2O (1 ml) was added thereto at O0C and the mixed solution was stirred at O0C for one hour. After completion of the reaction, saturated saline was added to the solution. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/Me0H = 10:1) to obtain the compound of Example 7 (16 mg) as a white solid.
Example 8, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylaπύno)-7-methoxy-8-(2-piperidine-l-yl- ethyl)-quinazolin-6-yl]-2,2,2-trifluoroacetamide
The compound of Example 7 (16 mg, 0.033 mmol) was dissolved in MeOH (2 ml). To the solution were added piperidine (4.3 μL), AcOH (5.7 μl), and NaBH3CN (6.6 mg) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2CVMeOH = 10:1 -> 7:1) to yield the compound of Example 8 (13.2 mg, 72.1 %) as a white solid.
1H-NMR (acetone -d6) δ 8.69 (s, IH), 8.57 (s, IH), 7.51 (d, IH), 7.40
(dd, IH), 7.08 (d, IH), 4.87 (m, 2H), 3.90-3.85 (m, 8H), 3.30-2.95 (m, 6H)1
1.96 (m, 4H), 1.75 (m, 2H)
Example 9, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-8-(2-methyl-allyl)-6-nitro-quinazolin- 7-ol 4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol (53 mg, 0.147 mmol) was dissolved in CH2C12/THF (4:1, 5 ml) and PPh3 (84.8 mg) was added thereto. The mixture was allowed to cool to O0C and diisopropyl azodicarboxylate (DIAD, 72.4 μl) was added thereto. The resulting mixture was stirred at room temperature for 10 min and methyl-2-propen-l-ol (27.4 μL) was added thereto. The reaction mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield (3- chloro-4-methoxy-benzyl)-[7-(2-methyl-allyloxy)-6-nitro-quinazolin-4-yl]-amine (56.2 mg, 92%) as a yellow solid.
The amine compound (50.9 mg, 0.123 mmol) thus obtained was dissolved in xylene (3 ml) and the resulting solution was heated in a sealed tube at 150 0C. After completion of the reaction, the reaction solution was allowed to cool to room temperature and saturated saline was added thereto. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; EA:n-Hex = 1 :1) to yield the compound of Example 9 (32 mg, dark green).
1H-NMR ( acetone -d6) δ 9.03 (s, IH), 8.53 (s, IH), 7.47 (d, IH), 7.43
(dd, IH), 7.01 (d, IH), 4.79 (m, 2H), 4.59 (m, IH), 4.36 (m, IH), 3.83 (m,
5H), 1.74 (d, 2H)
Example 10, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-methyl-8-(2- methyl-allyl)-quinazolin-6-yl)-2,2,2-trifluoroacetamide
The compound of Example 9 (25.5 mg, 0.062 mmol) and K2CO3 (25.5 mg) were dissolved in acetone (4 ml) and CH3I (11.5 μl) was added thereto at room temperature. The mixture was stirred at 8O0C for 5 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and saturated saline was added thereto. The resulting mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield a dark green compound (24.3 mg, 92 %).
1H NMR (acetone , 400 MHz) δ 8.75 (s, IH), 8.61 (s, IH), 7.49 (d, IH),
7.39 (dd, IH), 7.06 (d, IH), 4.84 (m, 2H), 4.70 (m, IH), 4.29 (m, IH),
3.93-3.87 (m, 8H), 1.89 (d, 2H)
(3-chloro-4-methoxy-benzyl)-[7-methoxy-8-(2-methyl-allyl)-6-nitro- quinazolin-4-ylamine] (24 mg, 0.06 mmol) thus obtained and SnCl2 • 2H2O (17.8 mg) were dissolved in EtOH (4 ml) and c-HCl (1 drop) was added at room temperature thereto. The mixture was stirred at 9O0C for 4 hours. After completion of the reaction, the reaction mixture was allowed to cool to room temperature and 10% NaHCO3 was added thereto. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with saturated saline, dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/ MeOH = 10 / 1) to yield a compound (12.1 mg, 0.03 mmol) as a white solid. The compound was dissolved in CH2Cl2 (2 ml), and TFAA (5.93 μl) and pyridine (3.64 μL) were added thereto at room temperature. The resulting mixture was stirred at the temperature for 18 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/ MeOH = 15 / 1) to yield the compound of Example 10 (10.6 mg, 85 %) as a white solid.
1H-NMR (acetone -d6) δ 8.52 (s, IH), 8.51 (s, IH), 7.48 (d, IH), 7.38
(dd, IH), 7.04 (d, IH), 4.83 (m, 2H), 4.67 (m, IH), 4.30 (m, IH), 3.86 (m,
8H), 1.80 (s, 2H) MS (ESI) m/z 495 (M+ + 1)
Example 11, synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-8-isobutyl-7-methoxy-quinazolin-
6-yl]-2, 2, 2-trifluoroacetamide The compound of Example 10 (6.8 mg, 0.17 mmol) was dissolved in MeOH (1.5 ml) and PtO2 (1.36 mg, 10 mole %) was added thereto at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 4 hours. After completion of the reaction, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by scintillation chromatography (SiO2; CH2Cl2/ MeOH = 15 / 1) to yield the compound of Example 11 (4.8 mg, 71%) as a white solid.
1H-NMR (acetone -d6) δ 8.36 (s, IH), 8.25 (s, IH), 7.42 (d, IH), 7.28
(dd, IH), 6.93 (d, IH), 4.70 (m, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 2.92 (d, 2H), 2.06 (m, IH), 0.82 (d, 6H)
Example 12, synthesis of the compound:
(3-chloro-4-methoxy-benzyl)-(3-methyl-10-nitro-3,4-dihydro-2H-l-oxa- 3,5,7-triaza-penanthren-8-yl)-amine
4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol (250 mg, 0.694 mmol) and paraformaldehyde (125.5 mg, 3.47 mmol) were dissolved in isopropyl alcohol (5 ml) and methyl amine (3.47 ml, 6.94 mmol) was added thereto. The resulting mixture was stirred at 80 °C for 18 hours. After completion of the reaction, the mixture was allowed to cool to room temperature. Saturated saline was added to the reaction solution and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/ MeOH = 15 / 1) to yield the compound of Example 12 (170 mg) as a yellow solid.
1H-NMR (acetone /CD3OD) δ 8.516 (s, IH), 8.463 (s, IH), 7.447 (d, J =
2.11 Hz, IH), 7.347 (dd, J = 8.42, 2.09 Hz, IH), 7.062 (d, J = 8.46 Hz, IH),
5.043 (s, 2H), 4.878 (s, 2H), 3.904 (s, 2H), 3.857 (s, 3H).
Example 13, synthesis of the compound: N-[8-(3-chloro-4-methoxy-benzylamino)-3-methyl-3,4-dihydro-2H-l-oxa- 3,5,7-triaza-penanthren- 10-yl] -2,2,2-trifluoroacetamide
In the same manner as in Example 5, the compound of Example 13 as a white solid (52.1 mg, 52.7 %) was prepared from the compound of Example 12.
1H NMR (acetone -de) 6 8.827 (m, IH), 8.464 (s, IH), 8.385 (s, IH),
7.459 (d, J = 2.07 Hz1 IH), 7.359 (dd, J = 8.42, 2.04 Hz, IH), 7.061 (d, / =
8.44 Hz, IH), 5.062 (s, 2H), 4.870 (m, 2H), 3.905 (s, 2H), 3.854 (s, 3H),
2.463 (s, 3H). MS (ESI) m/z 482 (M+ + 1)
Example 14, synthesis of the compound: 4-(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-6-nitro- quinazolin-7-ol)
The compound of Example 14 (175.1 mg, 75.6 %) as a red solid was prepared in the same manner as in Example 12 except that 4-(3-chloro-4-methoxy-benzylamino)- 6-nitro-quinazolin-7-ol (200 mg, 0.554 mmol) and paraformaldehyde (85.6 mg, 2.77 mmol) were dissolved in isopropyl alcohol (7 ml) and dimethyl amine (2.77 ml, 5.54 mmol) was added thereto.
1H-NMR (DMSO-de) δ 8.66 (s, IH), 8.22 (s, IH), 7.36 (d. IH), 7.25
(dd, IH), 7.03 (d, IH), 4.61 (s, 2H), 4.48 (s, 2H), 3.79 (s, 3H), 2.70 (s, 6H).
MS (ESI) m/z 418 (M+ + 1)
Example 15, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-7- hydroxy-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide
In the same manner as in Example 13, the compound of Example 15 as a white solid (52.1 mg, 86.5%) was prepared from the compound of Example 14. 1H NMR (acetone -d6) δ 8.420 (s, IH), 8.249 (s, IH), 7.785 (m, IH),
7.413 (d, J = 2.16 Hz, IH), 7.301 (dd, J = 8.40, 2.12 Hz, IH), 6.976 (d, J =
8.48 Hz, IH), 4.738 (m, 2H), 4.533(s, 2H), 3.810 (s, 3H), 2.732 (s, 3H). MS
(ESI) m/z 484 (M+ + 1)
Example 16, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -4-methoxy-benzenesulf onamide
4-(3-chloro-4-methoxy-benzylamino)-6-amino-7-methoxy-8-propyl- quinazoline (22 mg, 0.056 mmol) as a starting material was dissolved in dichloromethane (3 mL) and pyridine (5.7 μL) and 4-methoxy sulfuryl chloride (14.5 mg) were added thereto at room temperature. The resulting mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was diluted with dichloromethane and washed with water. The resulting solution was dried over anhydrous sodium sulfate and the solvents were then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/ MeOH = 10 / 1) to yield the compound of Example 16 (15.1 mg, 44.5%) as a yellow solid.
1H NMR (CD3OD-d4) δ 8.362 (s, IH), 7.798 (d, J = 2.20 Hz, IH),
7.683 (dd, J = 7.01, 1.94 Hz, 2H), 7.554 (d, J = 8.94 Hz, IH), 7.428 (dd, J =
8.91, 2.18 Hz, IH), 7.375 (d, J = 2.06 Hz, IH), 7.254 (dd, J = 10.5, 8.42 Hz,
IH), 6.986 (d, J = 8.45 Hz, IH), 6.932 (dd, J = 7.11, 1.91 Hz, 2H), 4.730 (s,
2H), 3.901 (s, 3H), 3.836 (s, 3H), 3.766 (s, 3H), 3.102 (m, 2H), 1.682 (m,
2H), 0.979 (t, J = 3.84 Hz, 3H).
MS (ESI) m/z 558 (M+ + 1)
Example 17, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -benzenesulf onaniide
The compound of Example 17 as a yellow solid was prepared in the same manner as in Example 16.
MS (ESI) m/z 528 (M+ + 1)
Example 18, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide
N4-(3-chloro-4-methoxy-benzyl)-(7-methoxy-6-nitro-quinazolin-4-yl)-amine (151 mg, 0.04 mmol) and K2CO3 (1.5 mg, 10 mole%) were dissolved in MeOH (2 ml) and PtO2 (1.5 mg, 10 mole%) was added thereto at room temperature. The resulting mixture was stirred under a hydrogen atmosphere for 3 hours. After completion of the reaction, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 1 1 1) to yield N4-(3-chloro-4-methoxy- benzyl)-(7-methoxy-6-amino-quinazolin-4-yl)-amine (6 mg, 45.3 %) as a white solid.
1H NMR (MeOH) δ 8.22 (s, IH), 7.37 (d, IH), 7.27 (dd, IH), 7.16 (s,
IH), 7.02-6.99 (m, 2H), 4.72 (s, 2H), 4.00 (s, 3H), 3.84 (s, 3H)
The amine compound (6 mg, 0.0174 mmol) thus obtained was dissolved in dichloromethane (2 ml) and TFAA (2.95 μL) and pyridine (1.83 μL) were added thereto at room temperature. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 18 (6.98 mg, 91%) as a yellow solid.
1H NMR (acetone -d6) δ 8.42 (s, IH), 8.36 (s, IH), 7.35 (d, IH), 7.25
(dd, IH), 7.15 (s, IH), 6.95 (d, IH), 3.98 (s, 3H), 3.79 (s, 3H), MS (ESI) m/z
462 (M+ + Na) Example 19, synthesis of the compound:
4-(3-chloro-4-methoxy-benzyIamino)-8-ethoxymethyl-6-nitro- quinazolin- 7-ol
The compound of Example 14 (30.3 mg, 0.073 mmol) and K2CO3 (30.3 mg) were dissolved in ethanol (3 ml) and methyl sulfate (10.4 μL) was added thereto at room temperature. The resulting mixture was stirred at 100°C for 3 hours. After completion of the reaction, the mixture was allowed to cool to room temperature. Saturated saline was added to the reaction solution and the mixture was extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/ MeOH = 20 / 1) to yield the compound of Example 19 (10.4 mg) as a yellow solid.
1H NMR (DMSO-de) δ 9.039 (s, IH), 8.619 (s, IH)1 8.557 (s, IH),
7.476 (d, J = 2.10 Hz, IH), 7.378 (dd, J = 8.42, 2.14 Hz, IH), 7.059 (d, J =
8.43 Hz, IH), 5.082 (s, 2H), 4.840 (m, 2H), 3.866 (s, 3H), 3.639 (q, J = 7.02
Hz, 2H), 1.142 (t, J = 7.01 Hz, 3H). MS (ESI) m/z 419 (M+ + H)
Example 20, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-dimethylaminoethyl)-7- methoxy-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide
The compound of Example 20 as a light-yellow solid was prepared in the same manner as in Example 8.
1H-NMR (acetone -d6) 6 : 8.57 (s, IH), 8.52 (s, IH), 8.42 (m, IH), 7.47
(d, IH), 7.38 (dd, IH), 7.05 (d, IH), 4.83 (d, 2H), 3.94 (s, 3H), 3.85 (s, 3H),
3.56 (t, 2H), 3.38 (t, 2H), 2.96 (s, 6H).
Example 21, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-8-pyrrolidine-l-yl- methyl-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide
The compound of Example 21 as a light-yellow solid was prepared in the same manner as in Example 15.
1H-NMR (DMSO-de) δ : 8.64 (s, IH), 8.55 (m, IH), 8.20 (s, IH), 7.37
(d, IH), 7.26 (dd, IH), 7.07 (d, IH), 5.73 (s, IH), 4.60 (d, 2H), 4.49 (s, 2H),
3.80 (s, 3H), 3.18 (m, 4H), 1.90 (m, 4H).
Example 22, synthesis of the compound: [8-allyl-7-(2-dimethylaminoethoxy)-6-nitro-quinazolin-4-yl]-(3-chloro-4- methoxy-benzyl)-amine
The compound of Example 1 (39.4 mg, 0.098 mmol) and K2CO3 (67.9 mg) were dissolved in toluene/DMF (4:1, 4 ml) and ΛζN'-dimethylethylenediamine • HCl (42.5 mg) was added thereto. The resulting mixture was stirred at 1300C for 18 hours. After completion of the reaction, the reaction solution was diluted with ethyl acetate. The dilution was washed with water and brine. The reaction solution was dried over anhydrous MgSO4 and distilled under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2/ MeOH = 10 / 1) to yield the compound of Example 22 (34 mg, 73.3 %) as a yellow solid.
1H-NMR (CD3OD) δ 8.669 (s, IH), 8.468 (s, IH), 7.335 (d, / = 1.53
Hz, IH), 7.225 (dd, J = 8.47, 1.63 Hz, IH), 6.917 (d, J = 8.45 Hz, IH),
6.063-5.994 (m, IH), 4.951-4.844 (m, 2H), 4.664 (s, 2H), 4.109 (t, J = 5.66
Hz, 2H), 3.840 (m, 2H), 3.768 (s, 3H), 2.751 (t, J = 5.66 Hz, IH), 2.289 (s,
6H). MS (ESI) m/z 472 (M+ + H)
Example 23, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-(2-dimethylaminoethoxy)-8- propyl-quinazolin-6-yl]-2, 2, 2-trifIuoroacetamide
The compound of Example 22 (32.4 mg, 0.07 mmol) was dissolved in MeOH (3 mL) and PtO2 (3.12 mg, 20 mole %) was added at room temperature thereto. The resulting mixture was stirred under a hydrogen atmosphere for one hour. After completion of the reaction, the reaction solution was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was dissolved in CH2Cl2 (4 ml), and TFAA (14.6 μL) and pyridine (10.1 μL) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2;
CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 23 (10 mg, 26.8 %) as a white solid.
1H-NMR (CD3OD) δ 8.472 (s, IH), 8.447 (s, IH), 7.393 (d, J = 1.98
Hz, IH), 7.293 (dd, J = 8.43, 2.00 Hz, IH)1 7.000 (d, J = 8.46 Hz, IH),
4.738 (s, 2H), 4.250 (t, J = 5.05 Hz, IH), 3.845 (s, 3H), 3.083 (m, 2H),
2.749 (m, 2H), 2.426 (s, 6H), 1.686 (m, 2H), 1.040 (t, J = 7.27 Hz, 3H). MS
(ESI) m/z 540 (M+ + H)
Example 24, synthesis of the compound:
[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-yloxy]- acetic acid ethyl ester
The compound (71 %) of Example 24 as a yellow solid was prepared from the compound of Example 1 in the same manner as in Example 22. 1H-NMR (CD3OD) δ 8.795 (s, IH), 8.550 (s, IH), 7.403 (d, J = 2.05
Hz, IH), 7.297 (dd, J = 8.42, 2.06 Hz, IH), 6.992 (d, J = 8.49 Hz, IH),
6.116-6.047 (m, IH), 5.009-4.907 (m, 2H), 4.741 (s, 2H)1 4.713 (s, 2H),
4.280 (q, J = 7.12 Hz, IH), 3.941 (m, 2H), 3.838 (s, 3H), 1.292 (t, J = 7.12
Hz, 3H). MS (ESI) m/z 487 (M+ + H)
Example 25, synthesis of the compound:
[8-allyl-4-(3-chIoro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-yloxy]- acetic acid
The compound of Example 24 (24.7 mg, 0.05 mmol) was dissolved in MeOH/H2O (4:1, 4 ml) and LiOH (12 mg) was added thereto at room temperature. The resulting mixture was stirred at 50 0C for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to room temperature, diluted with CH2Cl2 and washed with water. IN HCl was added to the resulting solution to adjust to pH 1. An aqueous layer was extracted with EtOAc. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvents were removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 25 (19.2 mg, 82.1%) as a white solid.
1H ΝMR (CD3OD) δ 8.833 (s, IH), 8.584 (s, IH), 7.419 (d, J = 1.92
Hz, IH), 7.312 (dd, J = 8.44, 1.87 Hz, IH), 7.008 (d, J = 8.46 Hz, IH)1
6.137-6.069 (m, IH), 5.039-4.921 (m, 2H), 4.776 (s, 2H)1 4.694 (s, 2H)1
3.951 (m, 2H), 3.846 (s, 3H). MS (ESI) m/z 459 (M+ + H)
Example 26, synthesis of the compound: Ν- [4-(3-chloro-4-methoxy-benzylammo)-7-(2-dimethylaminoethoxy)- quinazolin-6-yl]-2, 2, 2-trifluoroacetamide The compound of Example 26 (10 mg, 9 %) as a yellow solid was prepared in the same manner as in Example 23.
1H-NMR (MeOH-Cl4) δ : 8.70 (s, IH), 8.40 (s, IH), 7.39 (d, IH), 7.29
(dd, IH), 7.00 (d, IH), 6.62 (s, IH), 4.80 (s, 2H), 4.32 (t, 2H), 3.84 (s, 3H),
2.74 (t, 2H), 2.29 (s, 6H).
Example 27, synthesis of the compound:
2-amino-N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl- quinazolin-6-yl] -acetamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (31.8 mg, 0.082 mmol), Fmoc-Gly-OH (29.3 mg) and DMAP (3.0 mg) were dissolved in CH2Cl2 (5 ml) and EDC (23.6 mg) was added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 20 / 1) to obtain a compound protected with Fmoc. The compound was dissolved in DMF (1 mL), piperidine (500 μL) was added thereto and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 15 / 1) to yield the compound of Example 27 (13.2 mg, 36.3%) as a white solid.
1H NMR (CD3OD, 400 MHz) δ 8.659 (s, IH), 8.404 (s, IH), 7.394 (d, J
= 2.09 Hz, IH), 7.290 (dd, J = 8.37, 2.08 Hz, IH), 6.994 (d, J = 8.50 Hz,
IH), 4.742 (s, 2H), 3.897 (s, 3H), 3.843 (s, 3H), 3.514 (s, 2H), 3.310 (m,
2H), 1.675 (m, 2H), 1.025 (t, J = 7.33 Hz, 3H). MS (ESI) m/z 444 (M+ + H)
Example 28, synthesis of the compound:
2-chloro-N-[4-(3-chIoro-4-methoxy-benzylamino)-7-methoxy-8-propyl- quinazolin-6-yl] -acetamide N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (78.2 mg, 0.2 mmol) was dissolved in CH2Cl2 (5 ml), and chloroacetyl chloride (13.9 μL) and pyridine (21.02 μL) were added thereto at 0°C . T he resulting mixture was stirred at room temperature for one hour. The reaction solution was extracted with EtOAc (30 mL). The organic layer was washed with saturated saline, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 28 (96.9 mg, yield: > 95 %) as a white solid.
MS (ESI) m/z 463 (M+ + H)
Example 29, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2-dimethylamino-acetamide
The compound of Example 28 (23.8 mg, 0.05 mmol) and KI (1.7 mg) were dissolved in THF (5 mL) and dimethyl amine (77 μL) was added thereto at room temperature. The resulting solution was stirred at 8O0C for 3 hours. After completion of the reaction, the reaction solution was allowed to cool to room temperature and extracted with EtOAc (30 mL). The organic layer was washed with saturated saline, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 29 (22.1 mg, 93.6 %) as a white solid.
1H NMR (CD3OD, 400 MHz) δ 8.677 (s, IH), 8.406 (s, IH), 7.389 (d, J
= 2.12 Hz, IH), 7.284 (dd, J = 8.42, 2.08 Hz, IH), 6.988 (d, J = 8.51 Hz,
IH), 4.739 (s, 2H), 3.883 (s, 3H), 3.839 (s, 3H), 3.210 (s, 2H), 3.054 (m,
2H), 2.449 (s, 6H), 1.680 (m, 2H), 1.027 (t, J = 7.34 Hz, 3H). MS (ESI) m/z
472 (M+ + H)
Example 30, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-9-propyl-5H-8-oxa-l,3,5-triaza- anthracen-6-one 6-amino-4-(3-chloro-4-methoxy-benzylamino)-8-propyl-quinazolin-7-ol (54 mg, 0.1448 mmol) was dissolved in chloroform (30 ml), and t-butyl benzylamine (40 mg, 0.1448 mmol) and NaHCO3 (49 mg, 0.5793 mmol) were sequentially added thereto. Chloroacetyl chloride (0.018 ml, 0.2172 mmol) was slowly added dropwise to the solution at 0 °C and the mixture was stirred at reflux for 5 hours. After allowed to cool to room temperature, the reaction solution was neutralized with a saturated aqueous ammonium chloride solution. The organic layer was sequentially washed with water and saturated saline, dried over anhydrous NaSO4, filtered and concentrated under reduced pressure. The resulting compound was dissolved in DMF (10 ml), potassium carbonate (20 mg, 0.1448 mmol) was added thereto and the resulting mixture was stirred at room temperature for one hour. The reaction solution was added to a saturated aqueous ammonium chloride solution (100 ml) and the resulting solution was extracted with EtOAc (100 ml). The organic layer was washed five times with brine (100 ml), dried over anhydrous NaSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 30 (20 mg, 33%, 2 steps).
1H NMR (400 MHz, DMSO-d6) δ : 0.89 (m, 3H), 1.52 (m, 2H), 2.95
(m, 3H), 3.79 (s, 3H), 4.72 (m, 4H)1 7.08 (s, IH), 7.29 (s, IH), 7.39 (s, IH),
7.48 (s, IH), 8.45 (s, IH), 11.21 (brs, NH).
Example 31, synthesis of the compound:
2-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7- yloxy]-propionic acid
The compound of Example 31 (5.2 mg, 17.7%) was prepared from 4-(3-chloro- 4-methoxy-benzylamino)-6-nitro-8-allyl-quinazolin-7-ol (42 mg, 0.11 mmol) in the same manner as in Examples 24 and 25. 1H NMR (CD3OD, 400 MHz) δ 8.742 (s, IH), 8.552 (s, IH), 7.415 (d, J
= 2.07 Hz, IH), 7.306 (dd, J = 8.40, 2.03 Hz, IH), 7.015 (d, J = 8.49 Hz,
IH), 6.088-6.047 (m, IH), 5.039-4.921 (m, 2H), 4.776 (s, 2H), 4.683 (m,
IH), 3.951 (m, 2H), 3.851 (s, 3H). 1.563 (d, J = 6.70 Hz, 3H). MS (ESl) m/z
473 (M+ + H).
Example 32, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-9-propyl-5H-8-oxa-l,3,5-triaza- anthracene-6,7-dione
6-amino-4-(3-chloro-4-methoxy-benzylamino)-8-propyl-quinazolin-7-ol (100 mg, 0.2682 mmol) was dissolved in DMF (20 ml) and K2CO3 (111 mg, 0.8046 mmol), oxalyl chloride (0.035 ml, 0.4023 mmol) was slowly added thereto. The resulting mixture was stirred at 80 °C for 15 hours. After the reaction solution was poured into a cold saturated aqueous ammonium chloride solution (100 ml), the resulting mixture was extracted with EtOAc (150 ml) and washed with brine until DMF was removed. The resulting solution was dried over anhydrous NaSO4, filtered and distilled under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 32 (30 mg, 26 %).
1H NMR (400 MHz, DMSO~d6) δ : 0.94 (m, 3H), 1.95 (m, 2H), 2.93
(m, 2H), 3.79 (s, 3H), 4.67 (s, 2H), 7.08 (d, IH, J = 8.53 Hz), 7.31 (m, IH),
7.40 (s, IH), 8.34 (s, IH), 8.63 (s, IH).
Example 33, synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -methanes ulf onamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (36.1 mg, 0.09 mmol) was dissolved in CH2Cl2 (5 ml) and pyridine (10.1 μL) and MsCl (9.8 μL) were added thereto at 0°C . The resulting solution was stirred at room temperature for two hours. The reaction solution was extracted with EtOAc (30 mL). The organic layer was washed with saturated saline, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 33 (12 mg, 28.7 %, the starting material was recovered) as a white solid.
1H NMR (CD3OD, 400 MHz) δ 8.409 (s, IH), 7.943 (s, IH), 7.388 (d,
J = 2.04 Hz, IH), 7.283 (dd, J = 8.44, 2.05 Hz, IH), 6.990 (d, J = 8.49 Hz1
IH), 4.738 (s, 2H), 3.895 (s, 3H), 3.839 (s, 3H), 3.175 (s, 3H), 3.052 (m,
2H), 1.672 (m, 2H), 1.019 (t, J = 7.34 Hz, 3H). MS (ESI) m/z 465 (M+ + H)
Example 34, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazoUn-6- yl]-acetamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (20.8 mg, 0.054 mmol) was dissolved in CH2Cl2 (2 ml), and anhydrous acetic acid (30.3 μL, 0.27 mmol), pyridine (26.1 μL, 0.27 mmol) and DMAP (cat.) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2 x 15 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 34 (10.5 mg, 44.6 %) as a yellow oil.
1H NMR (CDCl3) δ 8.67 (s, 2H), 7.99 (bs, IH), 7.39 (s, IH), 7.24 (d,
IH), 6.87 (d, IH), 4.78 (d, 2H), 3.88 (s, 6H), 3.13-3.02 (m, 2H), 2.67 (s,
3H), 1.76-1.67 (m, 2H), 1.05-1.01 (m, 3H);LC-MS (M+ ; 429).
Example 35, synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazoUn-6- yl] -2-oxo-propionamide N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (28 mg, 0.072 mmol) was dissolved in CH2Cl2 (2 ml), pyruvic acid (7.5 μL, 0.11 mmol) and DCC (222.4 μL, 0.11 mmol) were added thereto and the resulting mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2 x 15 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1) to yield the compound of Example 35 (5.34 mg, 16.1 %) as a yellow oil.
1H NMR (CDCl3) δ 9.61 (s, IH), 8.69-8.66 (m, 2H), 7.41 (s, IH), 7.27
(d, IH), 6.89 (d, IH), 4.80 (d, IH), 3.90 (s, 6H), 3.13-3.10 (m, 2H), 2.60 (s,
3H), 1.77-1.68 (m, 2H), 1.07-1.03 (m, 3H);LC-MS (M+ ; 457).
Example 36, synthesis of the compound: 4-(3-chloro-4-methoxy-benzylamino)-7-ethyI-9-propyl-5H-8-oxa-l,3,5- triaza-anthracene-6-one
6-amino-4-(3-chloro-4-methoxy-benzylamino)-8-propyl-quinazolin-7-ol (50 mg, 0.1341 mmol), 2-bromobutylic acid ethyl ester (0.03 ml, 0.2011 mmol) and KF (23 mg, 0.4023 mmol) were sequentially added to DMF (10 mL). The solution was stirred at 80 °C for 10 hours. The reaction solution was poured into ice water (100 mL) and the resulting solution was extracted with EtOAc/MeOH (5/1, 150 mL). The organic layer was washed five times with brine (100 mL X 5), dried over anhydrous MgSO4, filtered and distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 36 (30 mg, 51 %) as a yellow solid. 1H NMR (400 MHz, DMSO-de) δ : 0.92 (m, 3H), 1.05 (m, 3H), 1.57
(m, 2H), 1.78 (m, IH), 1.89 (m, IH), 2.97 (m, 2H), 3.80 (s, 3H), 4.62 (m,
3H), 6.87 (d, IH, J = 8.65 Hz), 7.08 (m, IH), 7.29 (m, IH), 7.43 (m, IH),
8.37 (s, IH), 8.55 (brs, NH).
Example 37, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazoUn-6- yl]-2-cyanoacetamide
The compound of Example 28 (34.2 mg, 0.07 mmol) was dissolved in EtOH (3 ml), KCN (14.5 mg) was added thereto at room temperature and the resulting mixture was stirred at 80 °C for 3 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 37 (4.09 mg, yield: > 10 %) as a white solid.
1H NMR (CD3OD, 400 MHz) δ 8.559 (s, IH), 8.417 (s, IH), 7.399 (d,
/ = 2.12 Hz, IH), 7.298 (dd, J = 8.45, 1.94 Hz, IH), 7.008 (d, J = 8.47 Hz,
IH), 5.494 (s, 2H), 4.744 (s, 2H), 3.052 (m, 2H), 1.654 (m, 2H), 1.024 (t, /
= 7.30 Hz, 3H). MS (ESI) m/z 454 (M+ + H)
Example 38, synthesis of the compound:
Cyclopropanecarboxylic acid [4-(3-chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine
(18.6 mg, 0.048 mmol) was dissolved in CH2Cl2 (2 ml), and cyclopropanecarbonyl chloride (5.67 μL, 0.063 mmol) and pyridine (6.1 μL, 0.075 mmol) were added thereto and the resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2 x 15 rnL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1) to yield the compound of Example 38 (181 mg, 82.6 %) as a white solid.
1H NMR (CD3OD) δ 8.49 (s, IH), 8.44 (s, IH), 7.37 (s, IH), 7.24 (d,
IH), 4.71 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.02-2.98 (m, 2H), 1.83 (m,
IH), 1.66-1.60 (m, 2H), 1.06-0.90 (m, 7H);LC-MS (M+ ; 455)
Example 39, synthesis of the compound:
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -carbamic acid methyl ester
N4-(3 -chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine
(30 mg, 0.0775 mmol) was dissolved in acetone (30 mL) and K2CO3 (64 mg, 0.4652 mmol) and methyl chloroformate (0.024 mL, 0.3101 mmol) were added thereto. The resulting solution was stirred at reflux for 15 hours. After being allowed to cool to room temperature, the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1) to yield the desired compound of Example 39 (25 mg, 72.5 %).
1H NMR (400 MHz, CD3OD) δ : 1.02 (m, 3H), 1.71 (m, 2H), 3.09 (m,
2H), 3.78 (s, 3H), 3.84 (s, 3H), 3.89 (s, 3H), 4.76 (d, 2H, J = 5.65 Hz), 6.87
(d, IH, J = 8.44 Hz), 7.24 (m, IH), 7.38 (s, IH), 7.45 (s, IH), 8.33 (s, IH),
8.64 (s, IH).
Example 40, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-7-methyl-7,8-dihydro-5H-l,3,5,8- tetraaza-anthracene-6-one
(3-chloro-4-methoxy-benzyl)-(7-fluoro-6-nitro-quinazolin-4-yl)-amine (500 mg, 1.3809 mmol) and alanine ethyl ester HCl (424 mg, 2.7619 mmol) were suspended in i-PrOH (30 mL), and diisopropylethylamine (0.71 mL, 4.1429 mmol) was added thereto. The resulting mixture was stirred at reflux for 36 hours. After being allowed to cool to room temperature, the reaction mixture was poured into a cold saturated aqueous ammonium chloride solution (100 mL). The resulting mixture was extracted with EtOAc (100 mL). The obtained organic phase was washed with water and brine, dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/Me0H = 20/1) to yield a compound (320 mg, 50 %) as a yellow solid .
1H NMR (400MHz, CDCl3) δ : 1.62 (m, 3H), 3.87 (s, 3H), 4.31 (m,
3H), 4.76 (d, 2H1 J = 5.65Hz), 6.89 (s, 2H), 7.25 (m, IH), 7.41 (s, IH), 8.21
(s, IH), 8.52 (s, IH), 8.79 (s, IH).
The compound (160 mg, 0.3479 mmol) thus obtained was dissolved in ethanol (30 mL) and SnCl2 (II) (392 mg, 1.7395 mmol) was added thereto. The resulting mixture was stirred at reflux for 20 hours. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield the compound of Example 40 (30 mg, 23 %) as a yellow solid.
1H NMR (400MHz, CD3OD) δ : 1.44 (d, 3H, J = 6.72Hz), 3.85 (s, 3H),
4.73 (s, 2H), 6.87 (s, IH), 7.02 (d, IH, J = 8.4Hz), 7.27 (m, 2H), 7.38 (s,
IH), 8.23 (s, IH).
Example 41, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-8-ethyl-7-methyl-7,8-dihydro-5H- l,3,5,8-tetraaza-anthracene-6-one
The compound of Example 40 (25 mg, 0.0651 mmol) was suspended in acetone (20 mL), and ethyl iodide (0.02 mL, 0.12 mmol) and K2CO3 (27 mg, 0.1953 mmol) were added thereto. The resulting mixture was stirred at reflux for 15 hours. After allowed to cool to room temperature, the reaction mixture was filtered through celite. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2ZMeOH^(Vl) to yield the compound of Example 41 (15 mg, 56 %) as a yellow solid .
1H NMR (400MHz, CD3OD) δ : 0.79 (m, 3H), 1.18 (m, 3H), 1.42 (m,
3H), 1.96 (s. 2H), 3.82 (s, 3H), 4.06 (m, 2H), 4.69 (s, 2H), 6.73 (s, IH), 6.88
(d, IH, J = 8.47Hz), 7.14 (s, 2H)1 7.19 (m, IH), 7.54 (s, IH)1 8.22 (s, IH).
Example 42, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-thioacetamide
The compound of Example 34 (32 mg, 0.075 mmol) was dissolved in toluene
(5 mL), and Lawesson's reagent (60.26 mg, 0.15 mmol) and DCC (222.4 μL, 0.11 mmol) were added thereto. The resulting mixture was stirred at reflux for 15 hours.
After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex
/ EA = 1.5 / 1) to yield the compound of Example 42 (24.8 mg, 24.8 %) as a yellow oil.
1H NMR (CD3OD) δ 8.43 (s, IH)1 8.31 (s, IH)1 7.38 (s, IH), 7.28 (d,
IH)1 7.00 (d, IH)1 4.73 (d, IH)1 3.86 (s, 3H), 3.83 (s, 3H), 3.07-3.04 (m,
2H)1 2.73 (s, 3H), 1.68-1.60 (m, 2H)1 1.04-0.98 (m, 3H).
Example 43, synthesis of the compound: Thiophene-2-carboxylic acid [4-(3-chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (25 mg, 0.065 mmol) was dissolved in CH2Cl2 (2 mL) and 2-thiophenecarbonyl chloride (8.99 μL, 0.084 mmol) and pyridine (6.27 μL, 0.078 mmol) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the resulting mixture was washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2x15 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex/EA=l/l) to yield the compound of Example 43 (23.8 mg, 74.4 %) as a light-yellow solid.
1H NMR (CD3OD) δ 8.44 (s, IH), 8.43 (s, IH), 7.95 (d, IH), 7.77 (d,
2H), 7.40 (s, IH), 7.30 (d, IH), 7.00 (d, IH), 4.75 (s, 2H), 3.89 (s, 3H), 3.85
(s, 3H), 3.10-3.06 (m, 2H), 1.71-1.66 (m, 2H), 1.06-1.02 (m, 3H);LC-MS
(M+ ; 497).
Example 44, synthesis of the compound:
Thiophene-2-sulfonic acid [4-(3-chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (15.8 mg, 0.041 mmol) was dissolved in CH2Cl2 (2 mL) and 2-thiophenesulfonyl chloride (11.2 mg, 0.061 mmol), Et3N (8.66 μL, 0.061 mmol) and DMAP (catalytic amount) were added thereto. The resulting mixture was stirred at room temperature for 48 hours. After completion of the reaction, the resulting mixture was washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2x15 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex/EA=l/l) to yield the compound of Example 44 (4.56 mg, 21 %) as a yellow solid.
1H NMR (CDCl3) δ 7.92-7.90 (m, 2H), 7.71-7.69 (m, 2H), 7.39 (s, IH),
7.13-7.11 (m, 2H), 6.95 (d, IH), 4.71 (s, 2H), 3.94 (s, 3H), 3.80 (s, 3H),
3.10 (bs, 2H), 1.73-1.67 (m, 2H), 1.04-0.98 (m, 3H);LC-MS (M+ ; 533).
Example 45, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-formamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (50 mg, 0.1292 mmol) was dissolved in THF (20 mL) and anhydrous acetic acid (0.032 niL, 0.336 mmol) and formic acid (0.016 mL, 0.4135 mmol) were added thereto. The resulting mixture was stirred at 60 °C for 2 hours. The reaction solution was distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 45 (45 mg, 84 %) as a yellow solid .
1H-NMR (DMSO-de) 6 : 1.01 (m, 3H), 1.59 (m, 2H), 2.99 (m, 2H)1
3.85 (s, 6H), 4.69 (s, 2H), 7.09 (m, IH), 7.31 (m, IH), 7.42 (s, IH)1 8.48 (s,
IH), 8.75 (s, IH)1 10.07 (s, IH).
Example 46, synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-propionamide
The compound of Example 46 (15.3 mg, 67 %) as a light-yellow solid was prepared from N4-(3 -chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6- diamine (20 mg, 0.052 mmol) and propionyl chloride (5.86 μL, 0.067 mmol) in the same manner as in Example 34.
1H NMR (CDCl3) δ 8.71 (s, IH), 8.67 (s, IH), 8.01 (s, IH), 7.39 (s,
IH), 7.24 (d, IH), 6.88 (d, IH), 4.71 (d, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.11
(bs, 2H), 2.54-2.48 (m, 2H), 1.75-1.67 (m, 2H), 1.31-1.25 (m, 3H),
1.05-1.01 (m, 3H);LC-MS (M+ ; 443).
Example 47, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-isonicotinamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (20 mg, 0.052 mmol) was dissolved in pyridine (2 mL), isonicotinoyl chloride-HCl (13.8 mg, 0.078 mmol) was added thereto and the resulting mixture was stirred at room temperature for 48 hours. After completion of the reaction, the resulting mixture was concentrated under reduced pressure, washed with a saturated NaHCO3 solution and extracted with CH2Cl2 (2x15 mL). The organic layer was dried over anhydrous MgSO4 and filtered.^ The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex/EA=l/l) to yield the compound of Example 47 (12.37 mg, 48.6 %) as a light-yellow solid.
1H NMR (CD3OD) δ 8.78 (d, 2H)1 8.54 (s IH), 8.45 (s, IH), 7.95 (d,
IH), 7.40 (s, IH), 7.30 (d, IH), 7.00 (d, IH), 4.75 (s, 2H), 3.89 (s, 3H), 3.85
(s, 3H), 3.11-3.07 (m, 2H), 1.71-1.65 (m, 2H), 1.06-1.02 (m, 3H).
Example 48, synthesis of the compound:
N-[8-allyl-4-(3-chloro-4-methoxy-benzyIamino)-7-methoxy-quinazolin-6- yl]-acetamide
The compound of Example 2 (260 mg, 0.627 mmol) was dissolved in EtOH (15 mL), SnCl2 (1.41 g, 6.27 mmol) was added thereto and the resulting mixture was stirred at reflux for 12 hours. After the reaction solution was poured into a cold saturated aqueous NaHCO3 solution (200 ml), the resulting mixture was extracted with EA (200 ml). The organic layer was washed three times with a saturated aqueous NaHCO3 solution (150 mL X 3) and once with brine (150 mL), dried over anhydrous magnesium sulfate and filtered. The filtrate was dried under reduced pressure to obtain a compound (240 mg, 0.624 mmol) as a yellow solid. The compound was dissolved in pyridine (5 mL) and Ac2O (0.065 mL, 0.686 mmol) and DMAP (cat.) were added thereto. The resulting mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction solution was poured into a cold saturated aqueous NaHCO3 solution (100 mL) and the resulting mixture was extracted with EtOAc (100 ml). The organic layer was washed twice with a saturated aqueous ammonium chloride solution (100 mL X 2), once with a saturated aqueous NaHCO3 solution (100 mL) and once with brine (100 mL). The collected organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield the compound of Example 48 (200 mg, 0.468 mmol) as a light-yellow solid. 1H-NMR (CD3OD) δ 8.532 (s, IH), 8.402 (s, IH), 7.395 (d, J = 1.98
Hz, IH), 7.289 (dd, J = 8.46, 1.98 Hz1 IH)1 6.995 (d, J = 8.46 Hz, IH),
6.135-6.066 (m, IH)1 4.989-4.893 (m, 2H), 4.737 (s, 2H), 3.843-3.840 (m,
8H), 2.256 (s, 3H).
Example 49, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide
The compound of Example 48 (200 mg, 0.468 mmol) was dissolved in a mixed solvent (acetone : H2O = 8 mL : 2 mL), and iV-methylmorpholine (110 mg, 0.937 mmol) and OsO4 (4.76 mL, 0.094 mmol) were added thereto at 0°C . The resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, sodium sulfite was added to the reaction solution. The resulting mixture was stirred for one hour. The reaction solution was diluted with EtOAc (100 mL) and washed three times with saturated saline (100 mL X 3). The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvents. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield the desired compound of Example 49 (185.5 mg, 81%) as a white solid.
1H-NMR (CD3OD) δ 8.519 (s, IH), 8.407 (s, IH), 7.361 (d, J = 2.13
Hz, IH), 7.235 (dd, J = 8.48, 2.13 Hz, IH), 6.931 (d, J = 8.52 Hz, IH),
4.698 (s, 2H), 3.951 (m, IH), 3.858 (s, 3H), 3.819 (s, 3H), 3.508-3.489 (m,
2H), 3.394 (dd, J = 13.4, 5.34 Hz, IH), 3.196 (dd, J = 13.4, 7.28 Hz, IH),
2.259 (s, 3H). MS (ESI) m/z 461 (M+ + H)
Example 50, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl]-acetamide The compound of Example 49 was dissolved in a mixed solvent (MeOH : H2O = 10 mL : 5 mL) and NaIO4 (97 mg, 0.456 mmol) was added thereto at 0°C . The resulting mixture was stirred for 30 min. After completion of the reaction, the reaction solution was poured into a cold saturated aqueous ammonium chloride solution (100 ml), the resulting mixture was extracted with EtOAc (100 ml). The extracted organic layer was washed twice with a saturated aqueous ammonium chloride solution (100 mL X 2), once with an aqueous solution of saturated NaHCO3 (100 mL) and once with brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to remove the solvents. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/MeOH=20/l) to yield the compound of Example 50 (66 mg, 0.154 mmol) as a yellow solid.
1H-NMR (CD3OD) δ 8.513 (s, IH), 8.415 (s, IH), 7.387 (d, J = 2.03
Hz, IH), 7.285 (dd, J = 8.45, 1.98 Hz, IH), 6.995 (d, J = 8.49 Hz, IH),
5.037-5.012 (m, IH), 4.735 (s, 2H), 3.870 (s, 3H), 3.844 (s, 3H), 3.466 (dd,
J = 13.4, 5.93 Hz, IH), 3.326 (m, IH), 2.254 (s, 3H).
Example 51, synthesis of the compound:
[6-acethylamino-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy- quinazolin-8-yl] -acetic acid
The compound of Example 49 (24.0 mg, 0.052 mmol) was dissolved in acetone/H2O (3 mL/1 mL) and NaIO4 (23.8 mg, 0.11 mmol) was added thereto at 0°C .
After KMnO4 (1.76 mg, 0.011 mmol) was added to the solution, the resulting mixture was allowed to react, while the reaction temperature was slowly elevated from 0 °C to room temperature. After completion of the reaction, the reaction mixture was filtered through celite and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2ZMeOH= 10/1) to yield the compound of Example 51 (20.7 mg, 85.8 %) as a yellow solid. 1H-NMR (DMSO-de) 6 8.513 (s, IH), 8.415 (s, IH), 7.39 (d, / = 2.1
Hz, IH), 7.28 (dd, J = 8.45, 1.98 Hz, IH), 6.995 (d, J = 8.45 Hz, IH), 4.70
(s, 2H), 4.01 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.25 (s, 3H).
Example 52, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -acetamide
The compound of Example 51 (66 mg, 0.154 mmol) was dissolved in MeOH (10 mL), NaBH4 (5.8 mg, 0.154 mmol) was added thereto at 0 °C and the resulting solution was stirred for 2 hours. After completion of the reaction, the reaction solution was diluted with a cold saturated aqueous ammonium chloride solution (100 mL) and extracted with EtOAc (100 mL). The organic layer was washed three times with a saturated aqueous ammonium chloride solution (100 mL X 3) and once with brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was dried under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 52 (30 mg, 45.2%) as a light-yellow foam-like solid.
1H-NMR (CD3OD) δ 8.514 (s, IH), 8.425 Cs, IH), 7.397 (d, J = 2.07
Hz, IH), 7.104 (dd, J = 8.48, 2.10 Hz, IH), 7.007 (d, J = 8.46 Hz, IH),
4.746 (s, 2H), 3.875-3.820 Cm, 8H), 3.361 (m, 2H), 2.267 (s, 3H). MS (ESI)
m/z 431 (M+ + H)
Example 53, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-ethoxy-8-propyl-quinazolin-6- yl] -acetamide
The compound of Example 53 as a yellow solid was prepared in the same manner as in Example 34. 1H-NMR (CD3OD) δ 8.40 (s, IH), 8.39 (s, IH), 7.38 (s, IH), 7.27 (d,
IH), 6.78 (d, IH), 4.72 (s, 2H), 4.01-3.95 (m, 2H), 3.84 (s, 3H), 3.06-3.02
(m, 2H), 2.24 (s, 3H), 1.67-1.64 (m, 2H), 1.48 (t, 3H), 1.02 (t, 3H); LC-MS
(M+ ; 443).
Example 54, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -2,2-dimethyl-propionamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (50 mg, 0.1292 mmol) was suspended in acetone (30 mL), and pivaloyl chloride (0.032 ml, 0.2584 mmol) and K2CO3 (150 mg, 1.0856 mmol) were added thereto. The resulting solution was stirred at reflux for 18 hours. After being allowed to cool to room temperature, the reaction solution was filtered through celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 54 (35 mg, 57.5 %) . .
1H-NMR (CDCl3) δ : 1.03 (m, 3H), 1.38 (s, 9H), 1.69 (m, 2H), 3.08
(m, 2H), 3.86 (s, 6H), 6.85 (d, IH, J = 8.44Hz), 7.26 (m, IH), 7.40 (s, IH),
8.46 (s, IH), 8.69 (s, IH), 8.92 (s, IH), 11.61 (brs, NH).
Example 55, synthesis of the compound:
(3-chloro-4-methoxy-benzyl)-[7-methoxy-8-(l-methyl-allyl)-6-nitro- quinazolin-4-yl] -amine
4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol (772 mg, 2.14 mmol) and K2CO3 (887.3 mg) were dissolved in DMF (5 ml) and crotyl bromide (413.5 μL) was added thereto at room temperature. The resulting mixture was stirred at 80 °C for 3 hours. The reaction solution was extracted with EtOAc (2 x 15 mL). The collected organic layer was washed with saturated saline, dried over anhydrous MgSO4 and filtered. The filtrate was distilled under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2/ MeOH=20/l) to obtain a compound. From the compound thus obtained, the compound of Example 55 (168 mg) was obtained in the same manner as in Example 2.
1H-NMR (CD3OD) δ 8.634 (s, IH), 8.492 (s, IH), 7.344 (d, J = 2.09
Hz, IH), 7.229 (dd, J = 8.38, 2.09 Hz, IH), 6.926 (d, J = 8.50 Hz1 IH),
6.449 (m, IH), 5.037-4.916 (m, 2H), 4.670 (s, 2H), 4.634-4.602 (m, IH),
3.821 (s, 3H), 3.906 (s, 3H), 1.509 (d, J = 7.14 Hz, 3H). MS (ESI) m/z 429
(M+ + H)
Example 56, synthesis of the compound:
N-[8-aIlyl-4-(3-chIoro-4-methoxy-benzylamino)-7-methoxy-quinazolin 6- yl] -propionamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (17.2 mg, 0.045 mmol) was dissolved in CH2Cl2 (3 mL), and propionyl chloride (5.07 μL, 0.058 mmol) and pyridine (4.34 μL, 0.054 mmol) were added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with CH2Cl2 (2x10 mL). The organic layer was washed with a saturated NaHCO3 solution and saturated saline, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex./EtOAc=l/l) to yield the compound of Example 56 (15.3 mg, 77.6 %) as a yellow oil. LC-MS (M+l ; 441).
Example 57, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(l-methyl-allyl)- quinazolin-6-yl] -propionamide
The compound of Example 57 as a colorless oil was prepared from the compound of Example 55 in the same manner as in Example 48. 1H-NMR (CD3OD) δ 8.435 (s, IH), 8.404 (s, IH), 7.307 (d, IH), 7.276
(dd, IH)1 6.988 (d, IH), 6.545-6.477 (m, IH), 5.062-4.947 (m, 2H), 4.716 (s,
2H), 4.633 (m, IH)1 3.857 (s, 3H)1 3.825 (s, 3H)1 2.530 (q, J = 7.51 Hz1 2H)1
1.557 (d, J = 7.51 Hz1 3H)1 1.273 (t, J = 7.24 Hz, 3H). MS (ESI) m/z 455
(M+ + H)
Example 58, synthesis of the compound:
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- yl]-butylamide
The compound of Example 58 as a yellow solid was prepared in the same manner as in Example 56.
1H-NMR (CD3OD) δ 8.77 (s, IH)1 8.68 (s, IH), 8.00 (s, IH)1 7.40 (s,
IH)1 7.25 (d, IH)1 6.88 (d, IH)1 6.22-6.13 (m, IH)1 5.00 (dd. 2H)1 4.78 (d.
2H)1 3.94 (d, 2H)1 3.89 (s, 6H)1 2.46-2.43 (m, 2H)1 1.82-1.75 (m, 2H),
1.06-1.02 (m, 3H);LC-MS (M+ ; 455).
Example 59, synthesis of the compound:
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- yl]-isobutylamide
The compound of Example 59 as a yellow oil was prepared in the same manner as in Example 56.
1H-NMR (CD3OD) δ 8.77 (s, IH)1 8.68 (s, IH)1 8.07 (s, IH)1 7.39 (s,
IH)1 7.24 (d, IH)1 6.88 (d, IH)1 6.23-6.14 (m, IH)1 5.04 (dd, 2H), 4.77 (d,
2H)1 3.95 (d, 2H), 3.89 (s, 6H), 2.67-2.59 (m, IH), 1.31 (s, 3H), 1.29 (s,
3H);LC-MS (M+ ; 455). Example 60, synthesis of the compound:
N-[8-5^c-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- acetamide
The compound of Example 60 as a colorless oil was prepared from the compound of Example 55 in the same manner as in Example 46.
1H-NMR (CD3OD) δ 8.421 (s, IH), 8.386 (s, IH), 7.398 (d, J = 2.09
Hz, IH), 7.289 (dd, J = 8.54, 2.18 Hz, IH), 7.004 (d, J = 8.47 Hz, IH),
4.724 (s, 2H), 3.855 (s, 3H), 3.827 (brs, 4H), 2.263 (s, 3H)7 2.100-1.987 (m,
2H), 1.489 (d, J = 7.02 Hz, 3H), 0.818 (t, J = 7.43 Hz, 3H). MS (ESI) m/z
443 (M+ + H)
Example 61, synthesis of the compound: N- [4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide
The compound of Example 56 (95.6 mg, 0.22 mmol) was dissolved in acetone/H2O (5 ml, v/v 4:1) and NMMO (50.8 mg) and OsO4 (3.26 ml, 20 mol%) were added thereto at 0°C . The resulting mixture was stirred at room temperature for 6 hours. After completion of the reaction, sodium sulfite was added to the reaction mixture and stirred for about one hour. The reaction solution was extracted with EtOAc (100 mL) and washed three times with saturated saline (100 niL X 3). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 61 (60 mg, 58.2 %) as a light-yellow solid. 1H NMR (CD3OD) δ 8.512 (s, IH), 8.401 (s, IH), 7.358 (d, J = 2.12
Hz, IH), 7.234 (dd, J = 8.40, 2.09 Hz, IH), 6.928 (d, J = 8.47 Hz, IH)1
4.693 (s, 2H), 3.941 (m, IH), 3.845 (s. 3H), 3.813 (s, 3H), 3.497-3.477 (m,
2H), 3.388 (dd, J = 13.4, 5.38 Hz, IH), 3.189 (dd, J = 13.4, 7.32 Hz, IH),
2.531 (q, J = 7.56 Hz, 2H), 1.244 (t, J = 7.56 Hz, 3H). MS (ESI) m/z 475
(M+ + H)
Example 62, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl]-propionamide
The compound of Example 62 as a yellow oil was prepared in the same manner as in Example 50.
MS (ESI) m/z 443 (M+ + H)
Example 63, synthesis of the compound:
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-propionylamino- quinazolin-8-yl] -acetic acid
The compound of Example 63 as a yellow solid was prepared in the same manner as in Example 51.
MS (ESI) m/z 459 (M+ + H)
Example 64, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -propionamide
The compound of Example 62 was dissolved in MeOH (3 ml), NaBH4 (7 mg) was added thereto at 0 °C and the resulting mixture was stirred for one hour. After completion of the reaction, the reaction solution was poured into a cold saturated aqueous ammonium chloride solution (100 ml) and the resulting mixture was extracted with EtOAc (100 ml). The organic layer was washed three times with a saturated aqueous ammonium chloride solution (100 mL X 3) and once with brine (100 niL). The EtOAc layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 64 (28.3 mg, 50.9 %) as a light-yellow solid.
1H NMR (CD3OD) δ 8.499 (s, IH), 8.411 (s, IH), 7.382 (d, J = 2.03
Hz, IH), 7.277 (dd, J = 8.50, 2.03 Hz, IH), 6.984 (d, J = 8.48 Hz, IH)7
4.726 (s, 2H), 3.885-3.807 (m, 8H), 3.350 (t, J = 6.87 Hz, 2H), 2.537 (q, J =
7.55 Hz, 2H), 1.253 (t, J = 7.57 Hz, 3H). MS (ESI) m/z 445 (M+ + H)
Example 65, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzyIamino)-7-methoxy-8-propyl-quinazolin-6- yl]-acrylamide
N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-6-propyl-quinazolin-4,6-diamine (43 mg, 0.11 mmol), 3-chloropropionyl chloride (0.043 mL, 0.44 mmol) and potassium carbonate (92 mg, 0.67 mmol) were dissolved in acetone (25 ml) and the resulting mixture was then stirred at reflux for 24 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 20 / 1) to yield the compound of Example 65 (33 mg, 67.3 %) as a yellow solid.
1H NMR (DMSO-de) δ : 1.04 (m, 3H), 1.73 (m, 2H), 3.15 (m, 2H),
3.88 (s, 6H), 4.78 (m, 2H), 5.87 (d, IH, J = 10.04Hz), 6.32 (d, IH, J =
10.1Hz), 6.48 (s, IH), 6.89 (s, IH), 7.24 (s, IH), 7.39 (s, IH), 8.12 (s, IH),
8.74 (s, IH), 8.81 (s, IH). Example 66, synthesis of the compound:
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-benzo[l,3]dioxol-5-ylmethyl- amine
The compound of Example 66 as a yellow solid was prepared with methylenedioxybenzylamine in the same manner as in Example 2. 1H-NMR (acetone) δ 8.64 Cs, IH), 8.56 (s, IH), 7.01-6.68 (m, 3H),
6.072-6.004 (m, IH), 6.01 (s, 2H), 5.015-4.964 (m, IH), 4.936-4.907 (m,
IH), 4.788 (m, 2H), 3.894-3.871 (m, 2H), 3.871 (s, 3H). MS (ESI) m/z 395
(M+ + 1)
Example 67, synthesis of the compound: (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3,4-dimethoxy-benzyI)-amine
The compound of Example 67 as a yellow solid was prepared with dimethoxybenzylamine in the same manner as in Example 2.
1H-NMR (acetone) δ 8.64 (s, IH), 8.56 (s, IH), 7.01-6.68 (m, 3H),
6.072-6.004 (m, IH), 6.01 (s, 2H), 5.015-4.964 (m, IH), 4.936-4.907 (m,
IH), 4.788 (in, 2H), 3.905 (s, 3H), 3.894-3.871 (m, 2H)1 3.73 (s, 3H). 3.71
(s, 3H) MS (ESI) m/z 413 (M+ + 1)
Example 68, synthesis of the compound:
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(4-methyl-benzyl)-amine
The compound of Example 68 as a yellow solid was prepared with methylbenzylamine in the same manner as in Example 2.
1H-NMR (acetone) δ 8.64 (s, IH), 8.26 (s, IH), 7.21-7.02 (m, 4H),
6.08-6.02 (m, IH), 6.01 (s, 2H), 5.015-4.964 (m, IH), 4.936-4.907 (m, IH),
4.788 (m, 2H), 3.894-3.871 (m, 2H), 3.905 (s, 3H), 2.37 (s, 3H); MS (ESI)
m/z 365 (M+ + 1)
Example 69, synthesis of the compound: (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-ethoxy-benzyl)- amine
The compound of Example 69 as a yellow solid was prepared with 3-chloro-4- ethoxy benzylamine in the same manner as in Example 2.
1H-NMR (acetone) δ 8.67 (s, IH), 8.58 (s, IH), 7.43 (d, J = 2.1 Hz,
IH), 7.33 (dd, J = 8.4, 2.1 Hz, IH), 7.009 (d, J = 8.4 Hz1 IH), 6.072-6.004
(m, IH), 5.015-4.964 (m, IH), 4.936-4.907 (m, IH), 4.788 (m, 2H), 4.12 (d,
J = 7.2 Hz, 2H), 3.905 (s, 3H), 3.894-3.871 (m, 2H)1 3.871 (s, 3H), 1.45 (t,
J = 7.2 Hz, 3H); MS (ESI) m/z 429 (M+ + 1)
Example 70, synthesis of the compound: [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- acetic acid
The compound of Example 70 as a yellow solid was prepared from the compound of Example 2 in the same manner as in Examples 49 and 51.
1H-NMR (DMSOd6) δ 9.26 (t, IH), 9.03 (s, IH), 8.57 (s, IH), 7.43 (s,
IH), 7.30 (d, IH), 7.08 (s, IH), 4.70 (d, 2H), 4.01 (s, 2H), 3.86 (s, 3H), 3.81
(s, 3H).
Example 71, synthesis of the compound:
(8-allyl-2-chloro-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy- benzyl)-amine
The compound 19 in Reaction scheme 5 (200 mg, 0.459 mmol) was added to xylene (10 mL) and the solution was heated in a sealed tube for 20 hours. The reaction solution was distilled under reduced pressure to remove the solvent. The resulting residue was methylated in the same manner as in Example 2 to yield the compound of Example 71 (62 mg) as a yellow solid.
1H-NMR (CDCl3) δ 8.23 (s, IH), 7.39 (s, IH), 7.24 (d, IH)1 6.91 (d,
IH), 6.12-6.03 (m, IH)1 5.88 (bs, IH), 5.13 (d, IH), 5.00 (d, 2H), 4.71 (d,
2H), 3.91 (s, 6H), 3.80 (d, 2H);LC-MS (M+ ; 449).
Example 72, synthesis of the compound:
(8-allyl-N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-N2,N2-dimethyI-6- nitro-quinazolin-2,4-diamine
Synthesis of the compound 16 in Reaction scheme 5
The compound 15 (4.29 g, 23.8 mmol) was added to H2SO4 (60 mL) and the mixture was cooled to 0°C with stirring. KNO3 was added to the reaction mixture, followed by stirring at 0°C for one hour. After completion of the reaction, the reaction mixture was poured into ice water with stirring and the resulting mixture was filtered under reduced pressure. The filtrate as a brown solid was added to MeOH. The resulting mixture was stirred for one hour and filtered to yield the compound 16 (3.55 g, 66%) as a brown solid.
1H-NMR (DMSO-de) δ 11.81 (s, IH), 11.75 (s, IH), 8.55 (d, IH), 7.10
(d, IH).
Synthesis of the compound 17
The compound 16 (3.55 mg, 17.6 mmol) was added to toluene (50 mL) and the resulting mixture was cooled to 0 °C with stirring. POCl3 (7.37 mL, 78.3 mmol) and Hunig's base (6.06 mL, 34.7 mmol) were added to the mixture and then stirred at about 70 "C for 4 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, washed with an NH4Cl solution and extracted with EtOAc (3 x 250 mL). The organic layer was washed with saturated saline and dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to yield a compound 17 (4.12 g, crude yield=99%) as a brown solid. Synthesis of the compound 18
The compound 17 (4.12 g, 15.7 mmol), 3-chloro-4-methylbenzylamineΗCl
(3.27 g, 15.7 mmol) and Et3N (4.9 mL, 34.6 mmol) were added to isopropanol (60 mL) and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the isopropanol, washed with a saturated NaHCO3 solution and extracted with
EtOAc (2 x 250 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1 — » 2 / 1) to yield the compound 18 (950 mg, 15.2%) as a brown solid.
Synthesis of the compound 19
Allyl alcohol (0.48 mL, 7.17 mmol) was dissolved in DMF, the solution was cooled to 0°C and NaH (382.6 mg, 9.57 mmol) was slowly added thereto. The resulting mixture was stirred at 0°C for 20 min. The compound 18 (950 mg, 2.39 mmol) was slowly added to the reaction mixture, followed by stirring at 0 "C for 3 hours.
After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous NH4Cl solution and extracted with EtOAc (3 x 30 ml). The collected organic layer was washed with saturated saline, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex/EA = 1 : 1) to yield the compound 19 (975 mg,
97.5%) as a brown solid.
1H NMR (CDCl3) δ 8.42 (s, IH), 7.39 (s, IH), 7.27 (d, IH), 7.19 (s,
IH), 6.83 (d, IH), 6.72 (t, IH), 6.06-5.99 (m, IH), 5.50 (d, IH), 5.36 (d,
IH), 4.76 (d, 2H), 4.72 (d, 2H), 3.87 (s, 3H);LC-MS (M+ ; 435).
Synthesis of the compound of Example 72
The compound 19 (846 mg, 1.94 mmol) was dissolved in DMF (100 mL) and the solution was stirred at reflux at 140 °C for 6 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with a saturated aqueous NaHCO3 solution (3 x 50 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to obtain a compound (675.2 mg, 78.3 %) as a red solid. The compound was dissolved in acetone (10 niL) and K2CO3 (643 mg, 4.65 mmol) and CH3I (289.7 μL, 4.65 mmol) were added thereto at room temperature. The resulting mixture was stirred at reflux for 3 hours. After completion of the reaction, MeOH was concentrated under reduced pressure, washed with saturated NaHCO3 (800 mL) and extracted with EtOAc (2 x 50 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex. / EA = 1 / 1) to yield the compound of Example 72 (473 mg, 67.9 %) as a yellow solid.
1H NMR (CDCl3) δ 8.23 (s, IH)1 7.42 (s, IH), 7.24 (d, IH), 6.90 (d,
IH), 6.12-6.03 (m. IH), 5.88 (bs, IH), 5.13 (d, IH), 5.00 (d, 2H), 4.71 (d,
2H), 3.91 (s, 6H), 3.80 (d, 2H), 3.27 (s, 6H);LC-MS (M+ ; 458).
Example 73, synthesis of the compound: l-[8-allyI-4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-6-nitro- quinazolin-2-yl] -piperidine-4-carboxylic acid
The compound 19 in Reaction scheme 5 (20 mg, 0.046 mmol) and isonipecotic acid (11.9 mg, 0.092 mmol) were added to EtOH and the resulting mixture was stirred at reflux for 8 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, washed with saturated NH4Cl and extracted with EtOAc (2 x 5 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound 20 (14 mg, 57.8 %) as a yellow solid.
1H-NMR (CD3OD) δ 8.72 (s, IH), 7.41 (s, IH), 7.30 (d, IH), 7.01 (s,
IH), 6.14-6.07 (m, IH), 5.55 (d, IH), 5.34 (d, IH), 4.76 (d, IH), 4.65-4.62
(m, 4H), 3.85 (s, 3H), 3.19 (t, 2H), 2.67-2.58 (m, IH), 2.01-1.95 (m, 2H),
1.68-1.56 (m, 2H).
The compound 20 (11.0 mg, 0.021 mmol) was dissolved in DMF (2 mL), followed by stirring at reflux at 140 °C for 3 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc and washed with a saturated NaHCO3 solution (3 x 50 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 73 (1.51 mg, 10 %) as a brown solid.
1H NMR (CD3OD) δ 8.84 (s, IH)1 7.41 (d, IH), 7.00 (d, IH), 6.00-5.93
(m, IH), 5.06 (d, IH), 4.83 (d, IH), 4.63 (s, 2H), 3.84 (s, 3H), 3.71-3.67 (m,
2H), 3.56 (d, 2H), 3.13-3.05 (m, 2H), 2.29-2.23 (m, 2H), 1.94-1.90 (m, 2H), 1.59-1.57 (m, 2H).
Example 74, synthesis of the compound: (8-allyl-2-imidazol-l-yl-7-methoxy-6-nitro-quinazolin-4-yI)-(3-chloro-4- methoxy-benzyl)-amine
To the compound 19 in Reaction scheme 5 (100 mg, 0.23 mmol) and imidazole (78.2 mg, 1.15 mmol) was added phenol, followed by stirring at reflux for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with EtOAc (2 x 20 mL) and washed with a NaOH solution (3 x 50 mL). The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 2 / 1) to yield a compound as a red solid. The compound was dissolved in acetone (5 mL) and K2CO3 (95.3 mg, 0.69 mmol) and CH3I (42.9 μL, 0.69 mmol) were added thereto at room temperature. The resulting mixture was stirred at reflux for 3 hours. After completion of the reaction, the methanol was removed by concentration under reduced pressure. The resulting mixture was diluted with EtOAc (2 x 20 mL), washed with saturated NaHCO3 (40 mL) and saturated saline, dried over anhydrous MgSO4 and filtered. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1) to yield the compound of Example 74 (40.3 mg, 36.6 %) as a yellow solid. 1H-NMR (CD3OD) δ 8.70 (s, IH), 7.48-7.44 (m, 2H), 7.32-7.01 (m,
3H), 6.99 (d, IH), 5.94-5.90 (m, IH), 4.92 (s, IH), 4.88 (d, IH), 4.61 (s,
2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.66 (d, 2H).
Example 75, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-N-methyl-propionamide
The compound of Example 46 (80 mg, 0.18 mmol) was dissolved in THF (2 niL), NaH (8 mg, 0.36 mmol) was slowly added thereto at 0°C and the resulting mixture was stirred at 0°C for 30 min. To the reaction mixture was added CH3I (36 μL, 0.6 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated NH4Cl solution and extracted with CH2Cl2 (2 x 10 mL). The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 4 / 1 -> 1 / 1) to yield the compound of Example 75 (56 mg, 68%) as a white solid. MS (ESI) m/z 457 (M+l)
Example 76, synthesis of the compound:
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-methyl-carbamic acid methyl ester
The compound of Example 76 (48 mg, light-yellow) was prepared from the compound of Example 39 (68 mg, 1.5 mmol) in the same manner as in Example 75.
MS (ESI) m/z 459 (M+l)
Example 77, synthesis of the compound:
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yI]-carbamic acid methyl ester
The compound 24 of Reaction scheme 6 (200 mg, 0.399 mmol) was dissolved in CH2Cl2(IO mL), pyridine (0.024 mL, 0.298 mmol) and methylchloroformate (0.023 mL, 0.298 mmol) were added thereto at room temperature and the resulting mixture was stirred for 90 min. To the reaction mixture were added a saturated aqueous NH4Cl solution (60 mL) and CH2Cl2 (30 mL). The organic layer was washed with a saturated aqueous NH4Cl solution and saturated saline, dried over anhydrous MgSO4 and filtered. The solvents were removed by concentration under reduced pressure to yield a compound (211 mg) as a light yellow powder.
1H-NMR (DMSO), δ, 9.09 (s, IH), 8.65 (t, IH, J = 5.8 Hz), 8.41 (s,
IH), 8.30 (s, IH), 7.39 (d, IH, J = 2.0 Hz), 7.28 (dd, IH, J = 6.4, 2.0 Hz),
7.06 (d, IH, J = 8.5 Hz), 4.79 (br, IH), 4.65 (d, 2H1 J = 5.8 Hz), 3.79 (s,
3H), 3.76 (s, 3H), 3.70 (s, 3H), 3.59 (br, 2H), 3.20 (t, 2H, J = 7.7 Hz), 0.71
(s, 9H), 0.00 (s, 6H)
The compound (184 mg) thus obtained was dissolved in MeOH (10 ml) and IM HCl (3 drops) was added thereto. The resulting mixture was stirred at room temperature for one hour. After completion of the reaction, CH2Cl2 (20 ml) was added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1 -> CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 77 (120 mg, 82 %) as a light-yellow powder.
1H-NMR (DMSO) δ, 9.09 (s, IH), 8.65 (t, IH, J = 5.8 Hz), 8.41 (s,
IH), 8.30 (s, IH), 7.39 (d, IH, J = 2.0 Hz), 7.28 (dd, IH1 J = 6.4, 2.0 Hz),
7.06 (d, IH, J = 8.5 Hz), 4.79 (br, IH), 4.65 (d, 2H, J = 5.8 Hz), 3.79 (s,
3H), 3.76 (s, 3H), 3.70 (s, 3H), 3.59 (br, 2H), 3.20 (t, 2H, J = 7.7 Hz)
Example 78, synthesis of the compound: N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide
The compound of Example 64 (2.225 g, 5.0 mmol) was dissolved in CH2Cl2 (50 mL) and imidazole (0.408 g, 6.0 mmol) was added thereto. TBSCl (0.904g, 6.0 mmol) was added to the resulting mixture in an ice bath, followed by stirring at room temperature for 2 hours. After completion of the reaction, a saturated NaHCO3 solution (20 mL) was added to the reaction mixture. The organic layer was washed with a saturated aqueous NH4Cl solution (60 mL) and saturated saline (60 mL), dried over anhydrous MgSO4 and filtered. The solvent was removed by distillation under reduced pressure to yield a compound (2.6 g, 93 %) as a colorless oil.
The compound thus obtained (2.5 g, 4.47 mmol) was dissolved in THF (50 mL), the solution was allowed to cool to 0 °C and NaH (60% dispersion in oil, 210 mg, 53.7 mmol) was added thereto. After stirring at room temperature for 30 min, the reaction solution was cooled to 0°C and CH3I (0.33 ml, 53.7 mmol) was added dropwise thereto, followed by stirring at room temperature for 30 min. Saturated saline (50 ml) was added to the reaction solution and the resulting solution was extracted with EtOAc (50 ml). The organic layer was washed with a saturated aqueous NH4Cl solution (50 ml) and saturated saline (50 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by distillation under reduced pressure to obtain a compound (2.5 g) as a colorless oil.
1H-NMR (DMSO) δ, 0.00 (s, 6H), 0.74 (s, 9H)( 0.91 (t, J=7.51Hz, 3H)1
1.97-2.11 (m, 2H), 3.13 (s, 3H), 3.18-3.30 (m, 2H), 3.74 (s, 3H), 3.80 (s,
3H), 3.82-3.85 (m, 2H), 4.61-4.71 (m, 2H), 7.00 (d, J=8.51Hz, IH), 7.28 (dd,
J=8.46Hz & J'=1.92Hz, IH), 7.38 (d, J=1.94Hz, IH), 8.17 (s, IH), 8.48 (s,
IH), 8.63 (t, J=5.86Hz, IH)
The compound (12.0 g, 21. 46 mmol) thus obtained was dissolved in a 1.0 M tetrabutyl ammonium fluoride solution in THF (50 ml) and the solution was stirred at room temperature for 2 hours. Saturated saline (50 mL) was added to the reaction solution and the resulting solution was extracted with EtOAc (50 ml). The organic layer was washed with a saturated aqueous NH4Cl solution (50 ml) and saturated saline
(50 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1 -> CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 78 as a light-yellow powder. 1H-NMR (DMSO-d6) δ, 0.91 (t, J=7.26Hz, 3H), 1.97-2.12 (m, 2H),
3.19 (s, 3H, amide N-CH3), 3.20-3.30 (m, 2H), 3.59 (br. s, 2H), 3.74 (s, 3H),
3.80 (s, 3H), 4.60-4.69 (m, 2H), 4.74 (br. s, IH), 7.08 (d, J=8.50Hz, IH),
7.29 (d, J=8.50Hz, IH), 7.41 (s. IH), 8.17 (s, IH), 8.49 (s, IH), 8.63 (t,
J=5.85Hz, IH)
Example 79, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-ό-ylj-methyl-carbamic acid methyl ester [Reaction scheme 6]
Synthesis of the compound 23
The compound of Example 64 (9.7 g, 0.0218 mmol) was suspended in 2N HCl (65.4 mL) with stirring, MeOH (65 mL) was added thereto and the resulting mixture was stirred at reflux for 15 hours. After being allowed to cool to room temperature, the reaction mixture was distilled under reduced pressure to remove the MeOH. To the resulting solid was added distilled water (200 mL). The resulting mixture was adjusted to pH 7.0 to 7.5 with solid NaOH and extracted with CH2Cl2 (500 ml). The organic layer was dried over anhydrous MgSO4 and filtered. The solvent was removed by distillation under reduced pressure to obtain a compound 23 (7.5 g) as a yellow solid. 1H-NMR (DMS0-d6), δ, 8.15 (s, IH), 8.09 (t, IH, J = 6.0 Hz), 7.29
(d, IH, J = 2.1 Hz), 7.20 (dd, IH, J = 6.3, 2.1 Hz), 7.07 (s, IH), 6.99 (d,
IH, J = 8.6 Hz), 5.78 (d, IH, J = 5.1 Hz), 5.20 (br, 2H), 4.56 (d, 2H, J = 5.9
Hz), 3.74 (s, 3H), 3.72 (m, 2H), 3.69 (s, 3H), 3.13 (t, 2H, J = 7.9 Hz)
Synthesis of the compound 24
The compound 23 (4 g, 10.3 mmol) was dissolved in CH2Cl2 (40 mL) and imidazole (735 mg, 10.8 mmol) and TBSCl (1.58 mg, 10.5 mmol) were added thereto at 0°C . The resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was washed with a saturated NH4Cl solution and extracted with EtOAc. The collected organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (n-Hex/ EA) to yield the compound 24 (4.4 g, 84.3 %) as a white solid.
1H-NMR (DMSO-d6), δ, 8.15 (s, IH), 8.09 (t, IH, J = 6.0 Hz)1 7.29
(d, IH, J = 2.1 Hz), 7.20 (dd, IH, J = 6.3, 2.1 Hz), 7.07 (s, IH), 6.99 (d,
IH, J = 8.6 Hz), 5.20 (br, 2H), 4.56 (d, 2H, J = 5.9 Hz), 3.74 (s, 3H), 3.72
(m, 2H), 3.69 (s, 3H), 3.13 (t, 2H, J = 7.9 Hz), 0.76 (s, 9H), 0.00 (s, 6H)
Synthesis of the compound 25
The compound 24 (3.3 g, 6.56 mmol) was dissolved in CH2Cl2 (50 mL) and methylchloroformate (760 μL, 9.84 mmol) and pyridine (1.1 mL, 13.1 mmol) were added thereto. The resulting mixture was stirred at room temperature for 2 hours. After completion of the reaction, CH2Cl2 (50 ml) was added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, n-Hex / EA =8 / 2 → 7 / 3) to yield the compound 25 (2.74 g, 74.4 %) as a colorless oil.
1H-NMR (CDCl3) δ 8.62 (s, IH), 8.35 (s, IH), 7.44 (s, IH), 7.37 (d,
J=2.1 Hz, IH), 7.23 (dd, J=2.1, J=8.4 Hz, IH), 6.86 (d, J=8.4, IH)1 4.76 (d,
J=5.6, IH), 6.96 (t, J=7.0 Hz, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 3.81 (s, 3H),
3.38 (t, J=I. Q, IH), 0.81 (s, 9H); MS (ESI) m/z 562 (M+ 1)
Synthesis of the compound 26
The compound 25 (2.74 g, 4.88 mmol) was dissolved in THF (10 mL) and NaH (426 mg, 9.77 mmol) was slowly added thereto at 0°C . After stirring at 0°C for 30 min, CH3I (912 μL, 14.7 mmol) was added thereto and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, CH2Cl2 (2 x 10 ml) was added to the reaction mixture. The organic layer was washed with a saturated NH4Cl solution, dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, n-Hex / EA =8 / 2 → 5 / 5) to yield a compound 26 (1.99 g, 71 %) as a colorless oil. MS (ESI) m/z 575 (M+l)
The compound 26 (67.8 mg, 0.12 mmol) was dissolved in 1,4-dioxane (2 niL) and IM HCl (3 drops) was added thereto. The resulting mixture was stirred at room temperature for one hour. After completion of the reaction, CH2Cl2 (20 ml) was added to the reaction mixture. The organic layer was washed with saturated NaHCO3, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, n-Hex / EA = 1 / 1 → CH2Cl2: MeOH = 10 / 1) to yield the compound of Example 79 (49.8 mg, 90 %) as a colorless oil.
1H NMR (Aceton-dβ) 6 8.53 (s, IH), 8.00 (s, IH), 7.96 (bs, IH), 7.46
(d, J=2.1 Hz, IH), 7.36 (dd, J=2.\, J=%A Hz, IH), 7.05 (d, J=8A, IH), 4.81
(d, J=5.3, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.81-3.78 (m, 2H) 3.57 (bs, 3H),
3.35 (bs, 2H), 3.23 (s, 3H); MS(ESI) m/z 461 (M+ 1).
Example 80, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzyIamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-isobuthylamide
In the same manner as in Example 77, the compound 23 (100 mg, 0.26 mmol) was dissolved in CH2Cl2, isobutyryl chloride (27.1 μL, 0.26 mmol) and pyridine (41.5 μL, 0.51 mmol) were added thereto and the resulting mixture was stirred at room temperature for 2 hours. CH2Cl2 (30 ml) was added to the reaction solution, followed by stirring for 2 hours. The organic layer was washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, n-Hex / EA = 3 / 1) to obtain a compound as a white solid.
The compound was dissolved in MeOH, K2CO3 (177.6 mg, 1.29 mmol) was added thereto and the resulting mixture was stirred at room temperature for 2 hours. The
MeOH was removed by concentration under reduced pressure. The resulting residue was diluted with CH2Cl2 (30 ml) and washed with H2O. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 80 (67.5 mg, 57.2 %) as a white solid.
1H NMR (DMSOd6) δ 9.50 (s, IH), 8.68 (t, IH, J=5.8 Hz), 8.46 (s,
IH), 8.42 (s, IH), 7.40 (d, IH, J=2.0 Hz), 7.30 (dd, IH, J=2.0 Hz1 8.5 Hz),
7.07 (d, IH, J=8.5 Hz), 4.80 (t, IH, ^=5.4 Hz), 4.66 (d, IH, ./=5.8 Hz), 3.81
(s, 3H), 3.77 (s, 3H), 3.64-3.59 (m, 2H), 3.24-3.20 (m, 2H), 2.87-2.83 (m,
IH); LC-MS (M+ 1; 459)
Example 81, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methanesulfonamide
A desired compound was prepared with the compound 24 in Reaction scheme
6 (200 mg, 0.399 mmol), CH2Cl2 (10 mL), pyridine (0.024 mL, 0.298 mmol) and methane sulfonyl chloride (0.063 mL, 0.798 mmol) in the same manner as in Example 77. HCl (3 drops) was added to the compound to yield the compound of Example 81 (light-yellow).
1H-NMR (DMSO), δ, 9.09 (s, IH), 8.65 (t, IH, J = 5.8 Hz), 8.41 (s,
IH), 8.30 (s, IH), 7.39 (d, IH, J = 2.0 Hz), 7.28 (dd, IH, J = 6.4, 2.0 Hz),
7.06 (d, IH, J = 8.5 Hz), 4.79 (br, IH), 4.65 (d, 2H, J = 5.8 Hz), 3.79 (s,
3H)1 3.76 (s, 3H), 3.59 (br, 2H), 3.20 (t, 2H, J = 7.7 Hz)1 3.12 (s, 3H)
Example 82, synthesis of the compound:
3-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8- yl]-propane-l,2-diol
The compound of Example 2 (300 mg, 0.72 mmol) was dissolved in acetone (5 mL), N-methylmorphine-TV-oxide (339 mg, 1.45 mmol; 50% w/w H2O) and OsO4 (442 μL, 0.072 mmol: 4 wt%) were added thereto at 0 "C and the resulting mixture was stirred at 0 °C for 4 hours. After completion of the reaction, sodium sulfite was added to the reaction mixture, followed by stirring for about one hour. The reaction solution was diluted with EtOAc (100 ml) and washed with saturated saline. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 82 (250 mg, 77 %) as a light yellow solid.
1H-NMR (DMSO-de) δ 9.19 (t, J = 8.48, IH), 8.92 (s, IH), 8.58 (s,
IH)1 7.43 (d, J = 2.1 Hz, IH), 7.31 (dd, J = 8.4, 2.1 Hz, IH)1 4.73-4.69 (m,
3H)1 4.58 (J = 5.8 Hz1 2H), 3.96-3.91 On1 IH), 3.89 (s, 3H)1 3.81 (s, 3H),
3.24-3.20 Gn1 IH)1 3.11-3.05 (m, IH); MS(ESI) m/z 449 (M+ 1)
Example 83, synthesis of the compound:
2-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8- yl]-ethanol
The compound of Example 82 (100 mg, 0.22 mmol) was dissolved in MeOH/H2O (10 mL, v/v 2:1) and NaIO4 (71.5 mg, 0.33 mmol) was added thereto at O0C and the resulting mixture was stirred for 3 hours. EtOAc (30 ml) was added to the reaction solution. The organic layer was washed with saturated saline (50 mL), dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. After MeOH (3 ml) was added to the resulting residue, NaBH4 (12.6 mg, 0.33 mmol) was added thereto at O0C, followed by stirring for one hour. EtOAc (30 ml) was added to the reaction solution. The organic layer was washed with a saturated NH4Cl solution, dried over anhydrous MgSO4 and filtered.
The solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2, CH2Cl2 : MeOH = 10 / 1) to yield the compound of Example 83 (45.7 mg, 48 %) as a yellow solid. 1H-NMR (CD3OD) δ 8.70 (s, IH), 8.56 (s, IH), 7.40 (d, J = 2.1 Hz,
IH), 7.25 (dd, J = 8.40, 2.1 Hz, IH), 7.10 (d, J = 8.4 Hz, IH), 4.73 (s, 2H),
3.94 (s, 3H), 3.86-3.82 (m, 5H), 3.35 (t, J = 6.5 Hz, 2H); MS (ESI) m/z 419
(M+ 1).
Example 84, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide
The compound 24 (500 mg, 0.99 mmol) was dissolved in THF (5 mL), and K2CO3 (137.4 mg, 0.99 mmol) and CH3I (61.9 μL, 0.99 mmol) were added thereto. After stiring at room tempersature for 72 hours, EtOAc (30 ml) was added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, n-Hex / EA = 7 / 3 -> 5 / 5) to obtain a compound (149 mg, 29 %) as a yellow solid.
1H-NMR (acetone -d6) δ 8.36 (s. IH), 7.60 (t, J = 5.8 Hz, IH), 7.42
(d, J = 2.1 Hz, IH), 7.32 (dd, J = 8.40, 2.1 Hz, IH), 7.03 (d, J = 8.4 Hz,
IH), 6.94 (s, IH), 5.37 (d, J = 5.2 Hz, IH), 4.79 (d, J = 5.8 Hz, 2H),
3.93-3.91 (m, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.35-3.31 (m, 2H), 2.86 (d, J
= 5.2 Hz, 3H), 0.87 (s, 9H), 0.032 (s, 6H); MS (ESI) m/z 517 (M+ 1).
The compound (60.6 mg, 0.11 mmol) thus obtained was dissolved in CH2Cl2 (2 ml) and isobutyryl chloride (16.8 μL, 0.16 mmol) and pyridine (12.8 μL, 0.16 mmol) were added thereto. The resulting mixture was stirred at room temperature for 3 hours. CH2Cl2 (20 ml) was added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure. The resulting residue was dissolved in 1,4-dioxane (5 ml) and IM HCl (3 drops) was added thereto. After stirring at room temperature for 30 min, CH2Cl2 (20 ml) was added to the reaction mixture. The organic layer was washed with a saturated NaHCO3 solution, dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, CH2Cl2 / MeOH = 20 / 1 → 10 / 1) to obtain the compound of Example 84 (5.2 mg, 10.1 %) as a white solid.
1H-NMR (acetone-de) δ 8.55 (s, IH), 8.12 (s, IH), 8.01 (bs, IH), 7.46
(d, J = 2.0 Hz, IH), 7.36 (dd, J = 8.40, 2.0 Hz, IH), 7.06 (d, J = 8.4 Hz,
IH), 4.87-4.75 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 3.81 (t, J = 6.7 Hz, 2H),
3.41-3.34 (m, 2H), 3.25 (s, 3H), 1.01 (d, J = 6.6 Hz, IH), 0.91 (d, J = 6.6
Hz, IH); MS (ESI) m/z 473 (M+ 1).
Example 85, synthesis of the compound:
Cyclopropanecarboxylic acid-[4-(3-chloro-4-methoxy-benzylamino)-8-(2- hydroxy-ethyl)-7-methoxy-quinazolin-6-yl]-methyIamide
The compound of Example 85 (54.4 %) as a white solid was prepared from cyclopropanecarbonyl chloride in the same manner as in Example 84.
1H-NMR (acetone-d6) δ 8.55 (s, IH), 8.10 (s, IH), 8.04 (bs, IH), 7.47
(d, J = 2.1 Hz, IH), 7.37 (dd, J = 8.40, 2.1 Hz, IH), 7.06 (d, J = 8.4 Hz,
IH), 4.84-4.81 (m, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.80 (t, J = 6.6 Hz, 2H),
3.41-3.34 (m, 2H), 3.23 (s, 3H), 1.48-1.44 (m, IH), 0.87-0.78 (m, 2H),
0.60-0.57 (m, 2H); MS (ESI) m/z 471 (M+ 1).
Example 86, synthesis of the compound:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-ethyl-propionamide
The compound of Example 64 (2.225 g, 5.0 mmol) was dissolved in CH2Cl2 (50 mL) and imidazole (0.408 g, 6.0 mmol) was added thereto. TBSCl (0.904g, 6.0 mmol) was added to the resulting mixture at 0°C, followed by stirring at room temperature for 2 hours. A saturated aqueous NaHCO3 solution (20 mL) and CH2Cl2 (30 mL) were added to the reaction mixture. The organic layer was washed with a saturated aqueous NH4Cl solution (60 mL) and saturated saline (60 mL), dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure to yield a compound (2.6 g, 93 %) as a colorless oil. The compound (313 mg, 0.56 mmol) thus obtained was dissolved in THF (10 mL) and NaH (60% dispersion in oil, 27 mg, 0.67 mmol) was added thereto at 0°C . After stirring at room temperature for 30 min, the reaction solution was cooled to 0°C, CH3CH2I (56 μ L, 0.67 mmol) was added dropwise thereto and stirred at room temperature for 30 min. Saturated saline (20 ml) and EtOAc (30 ml) were sequentially added to the reaction solution. The organic layer was washed with saturated saline (30 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 7 / 3 -> 5 / 5) to yield a compound (280 mg, 85.1 %) as a white solid. The compound (280 g, 0.48 mmol) thus obtained was dissolved in a 1.0 M tetrabutyl ammonium fluoride solution in THF (10 ml) and the solution was stirred at room temperature for 2 hours. Saturated saline (20 mL) and EtOAc (30 ml) were added to the reaction solution. The organic layer was sequentially washed once with a saturated aqueous NH4Cl solution (10 ml) and saturated saline (10 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 : MeOH = 20 / 1 -> 10 / 1) to yield the compound of Example 86 (195 mg, 87 %) as a white solid.
1H-NMR (DMSO-de) δ, 0.92 (t, J=7.26Hz, 3H), 1.07 (t, J=7.O8Hz,
3HX1.91-1.97 (m, IH), 2.10-2.14 (m, IH), 3.10-3.15 (m, IH), 3.19-3.24 (m,
2H), 3.58-3.61 (m, 2H), 3.76 (s, 3H), 3.80 (s, 3H), 4.10-4.15 (m, IH),
4.66-4.69 (m, 2H), 4.76 (br. s, IH, -OH), 7.08 (d, J=8.54Hz, IH), 7.29 (dd,
J=8.49Hz,J'=1.97Hz,lH), 7.41 (s, IH), 8.17 (s, IH), 8.50 (s, IH), 8.73 (t,
J=5.85Hz)
Example 87, synthesis of the compound: [4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-carbamic acid methyl ester
The compound (1.09 g, 2.832 mmol) obtained by reducing the compound of Example 2 with SnCl2 • 2H2O in the same manner as in Example 5 was dissolved in
CH2Cl2 (20 ml). Pyridine (0.503 niL, 6.23 mmol) and methyl chloroformate (0.436 mL, 5.66 mmol) were added to the solution at room temperature. The resulting mixture was stirred for 90 min. A saturated aqueous NH4Cl solution (500 ml) and
CH2Cl2 (20 ml) were added to the reaction solution. The organic layer was washed with saturated saline (50 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 : 1) to yield a compound (1.15 g, 91.7 %) as a light-yellow solid.
1H-NMR (DMSO-de) δ : 9.54 (s, IH), 8.66 (m, IH), 8.51 (s, IH), 8.41
(s, IH), 7.40 (d, IH, J = 2.0 Hz), 7.29 (dd, IH, J = 6.4, 2.0 Hz), 7.06 (d,
IH, J = 8.5 Hz), 6.01 (m, IH), 4.93 (m, 2H), 4.64 (d, 2H, J = 5.8 Hz), 4.09
(q, 2H, J = 5.3 Hz), 3.80 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H)
The compound (1.15 g, 2.596 mmol) thus obtained was dissolved in acetone (12 ml) and a solution Of NMO-H2O (0.7 g, 5.19 mmol) in distilled water (20 mL) was added thereto. A 4 wt% aqueous OsO4 solution (0.165 ml, 0.026 mmol, 1.0 % mol) was slowly added dropwise to the resulting solution and stirred for 12 hours. A Na2SO3 (3.2g, 25 mmol) solution in distilled water (50 ml) was added to the reaction solution, the resulting mixture was stirred for 20 min and a saturated aqueous NaHCO3 solution (100 ml) was added thereto. The reaction solution was extracted with CH2Cl2 (20 ml). The organic layer was washed with saturated saline (10 ml), dried over anhydrous MgSO4 and filtered. The solvent was removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2; CH2Cl2 / MeOH = 10 / 1) to yield the compound of Example 87 (1.2 g, 99.8 %) as a yellow solid. 1H-NMR (DMSO-dβ) δ : 9.53 (s, IH), 8.73 (m, IH), 8.51 (s, IH), 8.41
(s, IH), 7.40 (d, IH, J = 2.0 Hz), 7.28 (dd, IH, J = 6.4, 2.0 Hz), 7.06 (d,
IH, J = 8.5 Hz), 5. 02 (br, IH), 4.65 (d, 2H1 J = 5.8 Hz), 3.84 (m, IH), 3.80
(s, 3H), 3.77 (s, 3H), 3.71 (s, 3H), 3.29 (m, 2H), 3.20 (m, IH)1 3.04 (m, IH)
Example 88, synthesis of the compound:
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carbonitryl
The compound (1.0 g, 2.60 mmol) obtaind by reducing the compound of Example 2 with SnCl2-2H2O in the same manner as in Example 5 was suspended in 2N HCl (4.4 ml) with stirring and at the same time a solution Of NaNO2 (269 mg, 3.90 mmol) in H2O (2.4 ml) was added thereto at 0°C . The resulting mixture was allowed to react at 0 "C for 90 min and NaHCO3 was added thereto to neutralize to pH 7 (reaction solution 1). CuCN (303 mg, 3.38 mmol) and KCN (254 mg, 3.90 mmol) were added to H2O (3.6 ml) and EtOAc (7.3 ml), the mixture was cooled to 0 °C and the reaction solution 1 was added thereto with a dropping funnel for 10 min. The resulting mixture was allowed to react at 0 °C for one hour. After completion of the reaction, the reaction solution was filtered through celite. The filtrate was extracted with EtOAc, dried over anhydrous MgSO4 and filtered. The solvents were removed by concentration under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 8 / 2 — » 5 / 5) to yield the compound of Example 88 (330 mg, 32.2%) as a brown solid.
1H-NMR(acetoneacetone, 8.62 (s, IH), 8.60 (s, IH), 7.49 (d, IH, J = 2.1
Hz), 7.38 (dd, IH, J = 8.4, 2.1 Hz), 7.15 (d, IH, J = 8.4 Hz), 6.10-6.03 (m,
IH), 5.05-4.94 (m, 2H), 4.84 (d, IH, J = 5.7 Hz), 4.06 (s, 3H), 3.90-3.87 (m,
5H); MS(ESI) m/z 395 (M+ 1).
Example 89, synthesis of the compound: 8-aUyl-4-(3-chIoro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid
The compound of Example 88 (50 mg, 0.13 mmol) was added to EtOH, NaOH (32% aqueous, 1 ml) was added thereto and the resulting mixture was stirred at reflux for 6 hours. The EtOH was removed by distillion under reduced pressure. HCl was added to the resulting residue such that the acidity is adjusted to pH 7. The reation solution was extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA=3 / 7 → 4 / 1) to yield the compound of Example 89 (13.5 mg, 26 %) as a brown solid. MS(ESI) m/z 414 (M+l).
Example 90, synthesis of the compound: 8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid tert-butylamide
The compound of Example 88 (50 mg, 0.13 mmol) was added to t-butyl acetate
(2 ml), H2SO4 (5 drops) was added thereto and the resulting mixture was stirred at room temperature for 24 hours. A saturated NaHCO3 solution (10 ml) and EtOAc (20 ml) were added to the reaction solution. The extracted organic layer was dried over anhydrous MgSO4 and filtered. The solvents were remoed by distillation under reduced pressure. The resulting residue was purified by column chromatography
(SiO2; n-Hex / EA = 7 / 3 → 5 / 5) to yield the compound of Example 90 (35.5 mg, 60 %) as a brown solid.
MS (ESI) m/z 469 (M+l) 1H-NMR (CDCl3) δ 8.73 (s, IH), 8,46 (s, IH), 7.77 (bs, IH), 7.37 (d,
J = 2.2 Hz, IH)1 7.22 (dd, J = 8.40, 2.2 Hz, IH), 6.87 (d, J = 8.4 Hz, IH),
6.23-6.10 (m, IH), 5.03 (dd, J = 10.1, 1.7 Hz, IH), 4.93 (dd, J = 17.2, 1.7
Hz, IH), 4.73 (d, J = 5.3 Hz, IH), 3.93 (d, J = 5.8 Hz, IH)1 3.90 (s, 3H),
3.84 (s, 3H), 1.48 (s, 9H)
Example 91, synthesis of the compound: 4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyI)-7-methoxy- quinazolin-6-carbonitryl
The compound of Example 88 (100 mg, 0.25 mmol) was dissolved in acetone (5 ml), NMNO (119 mg, 0.51 mmol; 50% w/w H2O) and OsO4 (154 μL, 0.025 mmol; 4 wt%) were added thereto at O0C and the resulting mixture was stirred at 0°C for 4 hours.
Sodium sulfite was added to the reaction solution, followed by stirriung for one hour.
Then, EtOAc (100 mL) and saturated saline (50 mL) were added to the reaction solution. The organic layer was dried over anhydrous MgSO4 and filtered. The solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 1 / 1 → 1 / 2) to yield the compound of
Example 91 (68 mg, 63 %) as a yellow solid.
1H-NMR (DMSO-de) δ 9.06 (t, J = 5.9 IH), 8.76 (s, IH)1 8.57 (s, IH)1
7.44 (d, J = 2.1 Hz, IH), 7.31 (dd, J = 8.4, 2.1 Hz, IH), 7.10 (d, J = 8.4 Hz,
IH), 4.72-4.69 (m, 3H), 4.58 (t, J = 5.9 Hz, IH), 4.01 (s, 3H), 3.94-3.85 (m,
IH), 3.82 (s, 3H), 3.17 (dd, J = 12.6, 5.1 Hz, IH), 3.02 (dd, J = 12.6, 8.4
Hz, IH); MS (ESI) m/z 429 (M+ 1)
Example 92, synthesis of the compound:
4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl
The compound of Example 91 (40 mg, 0.093 mmol) was dissolved in MeOH/H2O (6 ml, v/v 2:1) and NaIO4 (29.9 mg, 0.14 mmol) was then added at 0°C thereto. The resulting mixture was stirred at O0C for one hour and at room temperature for one hour. EtOAc (30 mL) and saturated saline (20 mL) were added to the reaction solution. The organic layer was dried over anhydrous MgSO4 and filtered. The solvent was concentrated under reduced pressure. The resulting residue was dissolved in MeOH (2 ml), NaBH4 (5.3 mg, 0.14 mmol) was added thereto at 0°C and the resulting mixture was stirred for one hour. EtOAc (20 mL) and a saturated NH4Cl solution (20 mL) were added to the reaction solution. The organic layer was dried over anhydrous MgSO4 and filtered. The solvent was concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2; n-Hex / EA = 5 / 5) to yield the compound of Example 92 (22 mg, 59 %) as a light brown solid.
1H-NMR (CD3OD) δ 8.71 (s, IH), 8.68 (s, IH), 7.46 (d, J = 2.1 Hz,
IH), 7.35 (dd, J = 8.40, 2.1 Hz, IH), 7.05 (d, J = 8.4 Hz, IH), 4.20 (s, 3H),
3.90-3.80 (m, 5H), 3.31-3.24 (m, 2H); MS (ESI) m/z 3.99 (M+ 1).
Formulation Example 1: Tablet
Effective component 5.0 mg
Lactose BP 150.0 mg
Starch BP 30.0 mg
Pre-gelatinized corn starch BP 15.0 mg Magnesium stearate 1.0 mg
An effective component was passed through a sieve, mixed with lactose, starch and pre-gelatinized corn starch, an adequate volume of distilled water was added thereto and granulated into a powder. The granules were dried, mixed with magnesium stearate, and then compressed to prepare a tablet.
Formulation Example 2: Capsule
Effective component 5.0 mg
Starch 1500 100.0 mg Magnesium stearate BP 1.0 mg
(hydroxyimino)benzo[3,4,d]l,3-dioxolan-5-yl-methane was passed through a sieve and mixed with an excipient. The mixture was filled into a gelatin capsule to prepare a capsule.
Formulation Example 3: Injectable preparation
Effective component 100 βg/mi
Dilute hydrochloric acid BP until pH 3.5
Sodium chloride BP for injection Max. 1 ml
An effective component was dissolved in an appropriate volume of dilute sodium chloride BP and dilute hydrochloric acid BP was then used to adjust to pH 3.5. Then sodium chloride BP for injection was used to adjust the volume of the solution to a desired level and was thoroughly mixed. The resulting solution was filled into a 5 niL type I ampoule made of transparent glass, the glass was melted to seal the ampoule under the upper grid of air and then sterilized in an autoclave at 120 "C for 15 minutes or more to prepare an injectable preparation.
Biological activity test
Biological activity test: Phosphodiesterase inhibitory activity research {In Vitro)
1. Phosphodiesterase V activity test
1) Separation of phosphodiesterase V from bovine platelets
Phosphodiesterase V (hereinafter, referred to as "PDE-5") was known to exist in bovine platelets (Thrombosis Research, 1991, 62, 31, Journal of Biological Chemistry, 1990, 265, 14964, Molecular Pharmacology, 1999, 56, 124). Herein, PDE-5 was extracted from bovine platelets according to this reference.
i) Extraction of PDE-5 from bovine platelets
To extract PDE5 from bovine platelets, about 800 ml of fresh blood of domestic bovines was fed into a centrifugal tube containing 200 ml of a blood coagulation-inhibiting solution (0.8% (w/v) citric acid, 2.2% (w/v) sodium citrate • dihydrate) and homogeneously mixed. The mixture was fractioned into a 50 ml centrifugal tube and then centrifuged (Sorvall RC-5C, 900 x g, 10 min, 20 "C). The platelet-rich-plasma (PRP) (also called as a "buffy coat") where platelets are concentrated in the upper part of red blood cells was carefully separated with a pipette and transferred to another tube. The PRP was centrifuged (Sorvall RC-5C, 3,000 x g, 20 min, 20 °C) again to obtain a white platelet precipitate. The supernatant, platelet- poor-plasma (PPP) was separated from the platelet precipitate. The centrifugation of the PPP was conducted in the same manner as above to make the amount of red blood cells incorporated into the platelet precipitate as low as possible.
5 ml of a red blood cell (RBC) lysis buffer was each fed into seven tubes containing the platelet precipitate thus obtained and thus resuspended for about 5 minutes. The suspensions in the tubes were put together into one tube and centrifuged (Sorvall RC-5C, 3,000 x g, 20 min, 4 "C). The centrifugation was once repeated in the same manner as above. The resulting platelet precipitate was washed with a cold 10 mM sodium phosphate buffer (about 40 ml, pH 7.2) and centrifuged in the same manner as above. The mass of the resulting platelet precipitate was measured. The platelet precipitate was freezed in a freezer at -20 °C for about 20 minutes and then defrosted at room temperature. A series of freezing and defrosting was successively repeated five times in total. The resulting platelet precipitate was mixed with a storage buffer solution (10 mM sodium phosphate buffer containing 20% glycerol, pH 7.2) to prepare a platelet solution (concentration: ca. 20 mg/m£, based on the platelet mass). The platelet solution was temporarily stored at -70 "C . Then, the platelet solution was sonicated in an ice bath (Ulsso Hitech Sonosmasher®, Power: 25%, On: 15 sec, Off: 10 sec, Cycle: five times, Frequency: 19970). The platelet solution was diluted with a storage buffer solution (10 mM sodium phosphate buffer containing 20% glycerol, pH 7.2) according to a Bradford method to adjust the concentration of the solution to about 2 mg/iM. The dilution was aliquoted and stored at -70 °C for use in phosphodiesterase V tests.
ϋ) PDE-5 enzyme activity test
The PDE-5 enzyme solution stored at -70 °C was defrosted in an ice bath and diluted with a buffer solution for PDE-5 enzyme activity test (40 mM MOPS, pH 7.5, 0.5 mM Na-EDTA, 15 mM Mg-acetate) at a dilution of 1/50 to prepare a PDE-5 enzyme solution. In this test, 96-well plates (available from AB gene, 0.8 ml deep- well) were used and the total volume of the reaction solution was 200 μi.
To wells used as a negative control group (blank) in which neither enzyme nor inhibitor are contained, were added: 140 μi of a buffer solution for PDE-5 enzyme activity tests (40 mM MOPS, pH7.5, 0.5mM Na-EDTA, 15mM Mg-acetate) supplemented with 0.2 mg/m£ of bovine serum albumin; and 60 μi of a substrate solution consisting of ca. 0.13 μM of [8-3H]-labeled-guanosine 3',5'-cyclic phosphate ([8-3H] cGMP; Amersham Pharmacia; TRK392; 0.42 mCi; a substrate of the PDE-5 enzyme) and 0.5 μM of non-labeled (cold) guanosine 3', 5'-cyclic phosphate.
To wells used as a positive control group in which no inhibitor is contained, were added: 90 μi of the buffer solution for PDE-5 enzyme activity test; 60 μi of the substrate solution of the enzyme; and 50 μi of an enzyme solution which is diluted with a buffer such that the final concentration of protein is adjusted to 10 μglml.
The well plates, in which the lysis enzyme solution, and the substrate and enzyme buffer solutions are included, were thoroughly mixed with shaking for about 2 min and allowed to react in a water bath at 35 °C for 30 min. 20 μi of a snake venom solution (10 mg/m£ in 5 mM MOPS buffer; V-7000 available from Sigma Chemical Co.; pH 7.5) was added to each well, thoroughly mixed with shaking and further allowed to react in a water bath 35 °C for 30 min.
To isolate [8- H]-labeled-guanosine, which was obtained from enzyme activities, from unreacted [8-3H]-labeled-cGMP, etc., 100 μi of the reaction was loaded on 96-well filter plates (0.45/M, MAHVN4550; Millipore Inc.) filled with a 100 μi volume of an activated anionic-exchange resin (Sephadex A-25-125 available from Sigma Chemical Co.) and allowed to stand for about 2 min. The filter plate was placed on a vacuum manifold and filtered under about 600 mHg of vacuum pressure. The filtrate was collected on 96-well plates for cell culture. 20 μi of the collected filtrate was transferred to 96-well plates for radioactivity measurement (RI sample plate, Wallac; MicroBeta 1450). 100 μi of a cocktail for radioactivity measurement (RI cocktail; Wallac) was fed into each well and sealed with a sealing film (TopSeal-A®; Packard). The plates were slowly stirred for about one hour, or allowed to stand for about 18 hours, to allow the cocktail to be homogeneously mixed with the filtrate for measurement. Then, radioactivity (CPM; count per minute) of the the mixture was measured with β-counter (Wallac).
iii) Evaluation of drug inhibitory activity against PDE-5
To each well was added 200 μi of the total reaction solution comprising: 20 μi of a drug solution of a certain concentration diluted with the buffer solution for enzyme activity measurement in a given concentration; 70 μi of the buffer solution for
PDE-5 enzyme activity test; 60 μi of the substrate solution of the enzyme; and 50 μi of an enzyme solution diluted with a buffer such that the final concentration of protein is adjusted to 10 βg/vd. The inhibitory activity of drugs against PDE-5 was evaluated in the same manner as above.
The drug inhibition (%) against PDE-5 was calculated by the following equation:
Drug inhibition(%) = Jl Test ~ Blank I x j 00(o/o)
I Positive - Blank J
2. Phosphodiesterase VI enzyme activity test
1) Extraction of phosphodiesterase VI enzyme from bovine retina
It was reported by Journal of Cell Biology, 1965, 27, 459, PNAS, 1980, 77, 2500, Journal of Biological Chemistry, 1982, 257, 11094 that phosphodiesterase VI (hereinafter, referred to as "PDE-6") exists in bovine retina. The present invention was based on the report.
Sildenafil (sold under the name "Viagra"), a drug to treat male erectile dysfunction, causes cyanosis as a side effect. Such cyanosis is known to be caused by nonselective inhibition against PDE-6. Accordingly, to prevent the side effect, there is a need to develop a PDE-5-selective inhibitor that hardly exhibits inhibitory activity against PDE-6. To measure the selective inhibitory activities, PDE-6 enzyme was separated according to the afore-mentioned report and evaluated for inhibitory activity in the same manner as the case in PDE-5.
3. Test for human phosphodiesterase XIAl activity
Phosphodiesterase XIAl (hereinafter, referred to as "PDE XIAl") is known to be in human prostate and muscle tissues. It is not easy to obtain such a tissue for PDE XIAl separation, or separate PDE XIAl from the tissue and purify the enzyme. Accordingly, expression vectors containing genes in the catalytic domain of human phosphodiesterase XIAl were prepared according to genetic methods known in the art (PNAS, 2000, 97, 3702-3707) and insect cells were allowed to express the target genes (Bac-To-Bac Baculovirus expression system; Invitrogen). The human PDE XIAl activity was tested in the same manner as the cases of PDE-5 and PDE-6.
Results of biological activity test
The compounds thus prepared are useful in inhibiting PDE-5 enzyme. Inhibitory activity against enzyme was represented by an IC50 value (50% inhibition of enzyme activity). The IC50 values of the compounds according to the present invention are set forth below. In addition, a ratio of PDE VI IC50/PDE V IC50 is shown. As the ratio increases, the compounds show more selective inhibition for PDE V IC50, as compared to PDE VI IC50, thus enabling a reduction in side effects. Hereinafter, all activity values mean approximate values.
In vitro assay: IC50 (nM) results
1) Compounds (IC50: 100 nM - 10 nM)
Examples: 4, 6, 7, 8, 9, 12, 13, 14, 16, 17, 18, 19, 22, 24, 25, 26, 27, 31, 32, 33, 37,40, 41, 43, 44, 45, 49, 50, 51, 52, 53, 58, 59, 60, 66, 69, 70, 80, 81, 82, 84, 88
2) Compounds (IC50: 10 nM or less) Examples: 1, 2, 3, 5, 10, 11, 15, 20, 21, 28, 30, 34, 35, 36, 38, 39, 42, 46, 48, 54,
55, 56, 57, 61, 64, 65, 77, 78, 79, 83, 85, 86, 87 3) Compounds (PDE VI/PDE V: 100 or less)
Examples: 4, 38, 82, 83, 84, 85
4) Compounds (PDE VI/PDE V: 100 or more)
Examples : 1, 2, 3, 5, 8, 9, 10, 11, 13, 15, 18, 34, 36, 39, 46, 52, 54, 56, 57, 61, 64, 77, 78, 79, 80, 86, 87, 88
As apparent from the foregoing, the compounds of the present invention and salts thereof efficiently inhibit PDE V and have selevtivity for PDE VI.
Industrial Applicability
The compound of Formula (I) can be effectively used to treat cardiovascular diseases such as male erectile dysfunction, angina pectoris, hypertension and artery atherosclerosis.

Claims

1. A compound of Formula (I); or an isomer or pharmaceutically acceptable salt thereof; or a solvate or hydrate thereof:
Figure imgf000096_0001
wherein R1 is NO2, NH2, CN, CON(K), CON(K)2, COO(K), COO(K)2,
Figure imgf000096_0002
0 wherein K is hydrogen, or substituted or unsubstituted C1-C6 alkyl;
R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C1-C6 alkylamino, C1-C6 dialkylamino, CF3, substituted or unsubstituted C6-C12 arylalkyl, C1-C3 alkoxy or heterocyclyl-(C1-C6)alkyl;
R5 is substituted or unsubstituted C1-C6 alkyl, or substituted or unsubstituted 5 phenyl, n is 0, 1 or 2;
Rd is hydrogen, or substituted or unsubstituted C1-C3 alkyl;
R2 is fluoro, chloro, hydroxy, C1-C6 alkoxy or -0-Z,
wherein Z is a compound represented by R? or O 5 O wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl, p is an integer of 1 to 5, and R8 is hydroxy, alkoxy or amino;
Figure imgf000096_0003
RI and R2 may be bonded to form a ring compound represented by "= wherein A is -C-R9 or -C(O), and B is oxygen or N-R10, wherein R9 is5 substituted or unsubstituted C1-C6 alkyl; and R10 is hydrogen or substituted or unsubstituted C1-C6 alkyl; R3 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-
C6 alkenyl, 0H or Q , wherein q is 0, 1, 2 or 3, and Q is C(O)H, -N(R11)(R12), -0(R13) or -C(O)R14, wherein R11 and R12 are each independently hydrogen, or substituted or unsubstituted C1-C6 alkyl, and R11 and R12 may be bonded to form a ring, R13 is hydrogen, or substituted or unsubstituted C1-C6 alkyl, and R14 is hydroxy, amino, C1-C3 alkylamino or C1-C3 dialkylamino;
Figure imgf000097_0001
R2 and R3 may be bonded to form a ring compound represented by Y wherein X is oxygen; and Y is N-R15, wherein R15 is C1-C3 alkyl; Ra and Rb are each independently halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxy or methylenedioxy, and said
R3 and Rb are same or different;
R0 is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
represented by
Figure imgf000097_0002
, wherein R16 is hydroxy, CO2H or C1-C6 ester, E is C, O, S or C1-C6 alkylamine, s is 0 or 1, R17 is hydrogen or hydroxy, and r is an integer of 2 to 5.
2. The compound according to claim 1, wherein R1 is nitro.
3. The compound according to claim 1, wherein R1
Figure imgf000097_0003
4. The compound according to claim 1, wherein Ra is 3-chloro and Rb is 4- methoxy. O
-NAR4
5. The compound according to claim 1, wherein R1 is Rd ; Ra is 3-chloro; and Rb is 4-methoxy.
o 6. The compound according to claim 1, wherein R1 is Rd ; Ra is 3-chloro;
Rb is 4-methoxy; and R3 is propyl, allyl, 2-methylallyl, 2-methylpropyl, hydroxyethyl, dimethylaminoethyl, dimethylaminomethyl, 2,3-dihydroxypropyl, acetaldehyde, methylene carboxylic acid, ethylene carboxylic acid, methylene pyrrolidine or methylene piperidine.
7. The compound according to claim 1, wherein R1
Figure imgf000098_0001
Ra is 3-chloro;
Rb is 4-methoxy; R0 is hydrogen; and R3 is propyl, allyl, 2-methylallyl, 2-methylpropyl, hydroxyethyl, dimethylaminoethyl, dimethylaminomethyl, 2,3-dihydroxypropyl, acetaldehyde, methylene carboxylic acid, ethylene carboxylic acid, methylene pyrrolidine or methylene piperidine.
8. The compound according to claim 1, wherein R1 is NO2, NH2, CN, CON(K),
CON(K)25 COO(K)5 COO(K)2,
Figure imgf000098_0002
wherein K is hydrogen or substituted or unsubstituted C1-Ca alkyl;
R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, C1-C3 alkoxy, C1-Ca alkylamino, C1-C3 dialkylamino, CF3, substituted or unsubstituted C6-C12 arylalkyl, or heterocyclyl-(C1-C6)alkyl; R5 is substituted or unsubstituted C1-C6 alkyl or substituted or unsubstituted phenyl, n is 0, 1 or 2;
Rd is hydrogen, or substituted or unsubstituted C1-C3 alkyl; R2 is fluoro, chloro, hydroxy, C1-C6 alkoxy or -O-Z,
whrerin Z is a compound represented by R7 or O 5 wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen or substituted or unsubstituted C1-C6 alkyl, p is an integer of 1 to 5, and R8 is
Figure imgf000099_0001
R1 and R2 may be bonded to form a ring compound represented by wherein A is -C-R9 or -C(O), and B is oxygen or N-R10, wherein R9 is substituted or unsubstituted C1-C6 alkyl; and R10 is hydrogen or substituted or unsubstituted C1-C6 alkyl; and
R3 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-
Q alkenyl, 0H or Q , wherein q is 0, 1, 2 or 3, Q is C(O)H, -N(R11)(R12), -0(R13) or -C(O)R14, wherein R11 and R12 are each independently hydrogen, or substituted or unsubstituted
C1-C6 alkyl and R11 and R12 may be bonded to form a ring, R13 is hydrogen, or substituted or unsubstituted C1-C6 alkyl, R14 is hydroxy, amino, C1-C3 alkylamino or C1- C3 dialkylamino;
R2 and R3 may be bonded to form a ring compound represented by
Figure imgf000099_0002
wherein X is oxygen; and Y is N-R15, wherein R15 is C1-C3 alkyl; Ra and Rb are each independently halogen, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, hydroxy or methylenedioxy, and said Ra and Rb are same or different;
Rc is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
represented by
Figure imgf000099_0003
, wherein R16 is hydroxy, CO2H, or C1-C6 ester, E is C, O, S or C1-C6 alkylamine, s is O or 1, R17 is hydrogen or hydroxy, and r is an integer of 2 to 5.
9. The compound according to claim 1, wherein R1 is NO2, NH2, CN, CON(K),
CON(K)2, COO(K), COO(K)2,
Figure imgf000100_0001
wherein K is hydrogen, or substituted or unsubstituted C1-C6 alkyl; R4 is hydrogen, substituted or unsubstituted C1-C6 alkyl, halogenated methyl, cyanomethyl, cycloalkyl, Ci-C6 alkylamino, C1-C6 dialkylamino, CF3 or C1-C3 alkoxy; R5 is Ci-C3 alkyl, or substituted or unsubstituted phenyl, n is O;
Rd is hydrogen, or substituted or unsubstituted Ci-C3 alkyl; R2 is hydroxy, Ci-C6 alkoxy or -0-Z,
wherein Z is a compound represented by R? or o , wherein m is an integer of 2 to 5, R6 and R7 are each independently hydrogen, or Ci-C6 alkyl, p is an integer of 1 to 3, and R8 is hydroxy or alkoxy;
Ri and R2 may be bonded to form a ring compound represented by rx wherein A is -C-R9 Or -C(O), and B is oxygen or N-Ri o, wherein R9 is Ci-C3 alkyl; and R]0 is hydrogen or Cj-C6 alkyl;
R3 is substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted C1-
C6 alkenyl, or a compound represented by 0H or Q , wherein q is 1, 2 or 3, and Q is C(O)H, -N(Rn)(Ri2), -0(Ri3) or -C(O)R14, wherein Rn and Ri2 are each independently substituted or unsubstituted Ci-C6 alkyl, and Rn and R12 may be bonded to form a ring, Ri3 is hydrogen or Ci-C6 alkyl, and R]4 is hydroxy;
Figure imgf000100_0002
R2 and R3 may be bonded to form a ring compound represented by Y wherein X is oxygen; and Y is N-Rj5, wherein Ri5 is Ci-C3 alkyl; Ra and Rb are each independently halogen, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted Ci-C6 alkoxy, or methylenedioxy, and R3 and Rb are same or different; Rc is hydrogen, chloro, dimethlyamine, heterocycle, or a compound
represented by
Figure imgf000101_0001
wherein R16 is CO2H or C1-C6 ester, E is C or C1-C6 alkylamine, s is 0 or 1, R17 is hydrogen or hydroxy, and r is an integer of 2 to 5.
10. The compound according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of:
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol; (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy-benzyl)- amine;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2,2,2-trifluoroacetamide;
(3-chloro-4-methoxy-benzyl)-[7-methoxy-6-nitro-8-(2-piperidin-l-yl-ethyl)- quinazolin-4-yl] -amine;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- 2, 2, 2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxypropyl)-7-methoxy- quinazolin-6-yl]-2,2,2-trifluoroacetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl]-2,2,2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-piperidine-l-yl- ethyl)-quinazolin-6-yl]-2,2,2-trifluoroacetamide;
4-(3-chloro-4-methoxy-benzylamino)-8-(2-methyl-allyl)-6-nitro-quinazolin-7- ol;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-methyl-8-(2-methyl- allyl)-quinazolin-6-yl]-2,2,2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-isobutyl-7-methoxy-quinazolin-6- yl]-2, 2, 2-trifluoroacetamide; (3-chloro-4-methoxy-benzyl)-(3-methyl-10-nitro-3,4-dihydro-2H-l-oxa-3,5,7- triaza-penanthren-8-yl)-amine;
N-[8-(3-chloro-4-methoxy-benzylamino)-3-methyl-3,4-dihydro-2H-l-oxa- 3,5,7-triaza-penanthren-10-yl]-2,2,2-trifluoroacetamide; 4-(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-6-nitro- quinazolin-7-ol);
N-[4-(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-7-hydroxy- quinazolin-6-yl]-2, 2, 2-trifluoroacetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -4-methoxy-benzenesulfonamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -benzenesulfonamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]-2,2, 2- trifluoroacetamide;
4-(3-chloro-4-methoxy-benzylamino)-8-ethoxymethyl-6-nitro-quinazolin-7-ol;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-dimethylaminoethyl)-7- methoxy-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-8-pyrrolidine-l-yl- methyl-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide;
[8-allyl-7-(2-dimethylaminoethoxy)-6-nitro-quinazolin-4-yl]-(3-chloro-4- methoxy-benzyl)-amine;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-(2-dimethylaminoethoxy)-8- propyl-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide; [8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-yloxy]- acetic acid ethyl ester;
[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-yloxy]- acetic acid;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-(2-dimethylaminoethoxy)- quinazolin-6-yl]-2, 2, 2-trifluoroacetamide;
2-amino-N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-proρyl- quinazolin-6-yl]-acetamide;
2-chloro-N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl- quinazolin-6-yl] -acetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2-dimethylamino-acetamide;
4-(3-chloro-4-methoxy-benzylamino)-9-ρropyl-5H-8-oxa-l,3,5-triaza- anthracen-6-one;
2-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-yloxy]- propionic acid; 4-(3-chloro-4-methoxy-benzylamino)-9-propyl-5H-8-oxa-l,3,5-triaza- anthracene-6,7-dione;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -methanesulfonamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2-oxo-propionamide;
4-(3-chloro-4-methoxy-benzylamino)-7-ethyl-9-propyl-5H-8-oxa-l,3,5-triaza- anthracene-6-one;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -2-cyanoacetamide;
Cyclopropanecarboxylic acid [4-(3 -chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide; [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl] - carbamic acid methyl ester;
4-(3-chloro-4-methoxy-benzylamino)-7-methyl-7,8-dihydro-5H-l, 3,5,8- tetraaza-anthracene-6-one;
4-(3-chloro-4-methoxy-benzylamino)-8-ethyl-7-methyl-7,8-dihydro-5H- 1 ,3,5,8-tetraaza-anthracene-6-one;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -thioacetamide;
Thiophene-2-carboxylic acid [4-(3 -chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide; Thiophene-2-sulfonic acid [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-
8-propyl-quinazolin-6-yl]-amide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-forniamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-propionamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -isonicotinamide;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- acetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide; N-[4-(3-chloro-4-memoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl] -acetamide;
[6-acethylamino-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin- 8-yl] -acetic acid; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-ethoxy-8-propyl-quinazolin-6-yl]- acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-2,2-dimethyl-propionamide;
(3-chloro-4-methoxy-benzyl)-[7-methoxy-8-(l-methyl-allyl)-6-nitro- quinazolin-4-yl] -amine;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- propionamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(l -methyl-allyl)- quinazolin-6-yl]-propionamide;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- butylamide;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- isobutylamide;
N-[8-5ec-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-(2-oxo-ethyl)- quinazolin-6-yl] -propionamide;
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-propionylamino- quinazolin-8-yl]-acetic acid;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -propionamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-acrylamide;
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-benzo[l,3]dioxol-5-ylmethyl- amine; (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3 ,4-dimethoxy-benzyl)-amine;
(8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(4-methyl-benzyl)-amine; (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-ethoxy-benzyl)-amine;
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- acetic acid;
(8-allyl-2-chloro-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy- benzyl)-amine;
(8-allyl-N4-(3-chloro-4-methoxy-benzyl)-7-methoxy-N2,N2-dimethyl-6-nitro- quinazolin-2,4-diamine; l-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-6-nitro-quinazolin- 2-yl] -piperidine-4-carboxylic acid; (8-allyl-2-imidazol-l-yl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4- methoxy-benzyl)-amine;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-proρyl-quinazolin-6- yl] -N-methyl-propionamide;
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl]- methyl-carbamic acid methyl ester;
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide; [4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methyl-carbamic acid methyl ester;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-isobuthylamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methanesulfonamide;
3-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- propane-l,2-diol;
2-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- ethanol; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide;
Cyclopropanecarboxylic acid-[4-(3-chloro-4-methoxy-benzylamino)-8-(2- hydroxy-ethyl)-7-methoxy-quinazolin-6-yl]-methylamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-ethyl-propionamide; 4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester;
8-allyl-4-(3-chloro-4-memoxy-benzylamino)-7-methoxy-quinazolin-6- carbonitryl; 8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid;
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid tert-butylamide;
4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-carbonitryl; and
4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl.
11. The compound according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of:
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-6-nitro-quinazolin-7-ol; (8-allyl-7-methoxy-6-nitro-quinazolin-4-yl)-(3-chloro-4-methoxy-benzyl)- amine;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl- quinazolin-6- yl] -2,2,2-trifluoroacetamide;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- 2, 2, 2-trifluoroacetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxypropyl)-7-methoxy- quinazolin-6-yl]-2,2,2-trifluoroacetamide;
(3-chloro-4-methoxy-benzyl)-(3-methyl-10-nitro-3,4-dihydro-2H-l-oxa-3,5,7- triaza-penanthren- 8 -yl)-amine;
N-[8-(3-chloro-4-methoxy-benzylamino)-3-methyl-3,4-dihydro-2H-l-oxa- 3,5,7-triaza-penanthren-10-yl]-2,2,2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-dimethylaminomethyl-7-hydroxy- quinazolin-6-yl]-2, 2, 2-trifluoroacetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-dimethylaminoethyl)-7- methoxy-quinazolin-6-yl] -2,2, 2-trifluoroacetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-hydroxy-8-pyrrolidine-l-yl- methyl-quinazolin-6-yl]-2, 2, 2-trifluoroacetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-acetamide;
Cyclopropanecarboxylic acid [4-(3-chloro-4-methoxy-benzylamino)-7- methoxy-8-propyl-quinazolin-6-yl]-amide; [4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl] - carbamic acid methyl ester;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl] -propionamide;
N-[8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6-yl]- acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -acetamide; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -propionamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6- yl]-N-methyl-propionamide;
[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-8-propyl-quinazolin-6-yl]- methyl-carbamic acid methyl ester;
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide;
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methyl-carbamic acid methyl ester;
3-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- propane- 1 ,2-diol;
2-[4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-6-nitro-quinazolin-8-yl]- ethanol;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide; Cyclopropanecarboxylic acid-[4-(3-chloro-4-methoxy-benzylamino)-8-(2- hydroxy-ethyl)-7-methoxy-quinazolin-6-yl]-methylamide; N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-ethyl-propionamide;
4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester; 8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carbonitryl;
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid;
8-allyl-4-(3-chloro-4-methoxy-benzylamino)-7-methoxy-quinazolin-6- carboxylic acid tert-butylamide; and
4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl.
12. The compound according to claim 1, wherein the compound of Formula (I) is selected from the group consisting of:
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-acetamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7- methoxy-quinazolin-6-yl]-propionamide;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl] -propionamide; [4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methyl-propionamide;
[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-methyl-carbamic acid methyl ester;
N-[4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-yl]-N-methylisobutylamide;
4-(3-chloro-4-methoxy-benzylamino)-8-(2,3-dihydroxy-propyl)-7-methoxy- quinazolin-6-yl]-carbamic acid methyl ester; and 4-(3-chloro-4-methoxy-benzylamino)-8-(2-hydroxy-ethyl)-7-methoxy- quinazolin-6-carbonitryl.
13. A method for preparing the compound of Formula (I) according to claim 1 represented by Formula (VIII) by heating a compound of Formula (VII) below:
Figure imgf000109_0001
IVIt) (VHi^
14. The method according to claim 13, wherein the compound (VII) is prepared from a compound represented by the following Formula (V) with the use of allyl halide and a base or by a Mitsunobu reaction employing allyl alcohol.
Figure imgf000109_0002
(V)
15. The method according to claim 13, wherein the compound (VII) is prepared from a compound represented by the following Formula (VI) with the use of allyl alcohol and a base:
Figure imgf000109_0003
<\fl)
16. A pharmaceutical composition for treating a cardiovascular disease comprising: the compound according to any one of claims 1 to 12, an isomer or pharmaceutically acceptable salt thereof or a solvate or hydrate thereof; and a pharmaceutically acceptable carrier thereof.
17. The pharmaceutical composition according to claim 16, wherein the cardiovascular disease is male erectile dysfunction (ED), angina pectoris, hypertension, pulmonary hypertension or artery atherosclerosis.
18. A method for preventing or treating a cardiovascular disease by administering an effective amount of the composition according to claim 1 to a subject, wherein the cardiovascular disease includes male erectile dysfunction, angina pectoris, hypertension, pulmonary hypertension or artery atherosclerosis.
19. Use of the composition according to claim 1 for preventing or treating a cardiovascular disease via administration an effective amount of the compound to a patient, wherein the cardiovascular disease includes male erectile dysfunction, angina pectoris, hypertension, pulmonary hypertension or artery atherosclerosis.
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