WO2009062402A1 - Quinazolinone derivatives, the preparation methods and uses thereof - Google Patents

Abstract

The quinzolinone derivatives, the preparation methods and uses thereof. The quinzolinone compounds having the structure of general formula (I), or their pharmaceutical acceptable salts. Most of these compounds have strong activities of inhibiting PDE5, and have highly selectivity of PDE 6 which is distributed on the retina. So the present compounds are expected to exhibit good safety and effectiveness and have broad uses in clinic.

Description

 Quinazolinone derivative, preparation method and use thereof

 The invention relates to the technical field of medicine, in particular to a quinazolinone derivative, a preparation method thereof and a use thereof. Background technique

 Phosphodiesterase (PDE) includes 11 enzyme systems (PDE1-PDE11) that reduce the activity of intracellular second messengers by hydrolyzing cAMP or cGMP. Depending on the specificity of the particular PDE substrate blocked, PDE 5 inhibitors can increase intracellular cAMP levels, cGMP levels, or both cAMP and cGMP levels. These inhibitors are competitive inhibitors because they mimic the structure of cAMP and cGMP, while cAMP and cGMP are natural substrates for PDE. Unlike cAMP and cGMP, inhibitors are not degraded by PDE. PDE is known to be involved in a wide range of cellular functional activities. PDE 5 is a phosphodiesterase that is cGMP specific and highly expressed in corpus cavernosum smooth muscle cells. PDE 5 inhibitors enhance erectile function by maintaining adequate cGMP levels in the corpus cavernosum and supplying vascular smooth muscle cells during sexual stimulation, increasing the expansion of the cavernous sinus.

 For decades, non-selective PDE inhibitors such as caffeine, theophylline and 3-isobutyl-1-methylsulfonate (IBMX) have been used for cyclic nucleotide (cNMP) physiological and PDE activities. the study. Although they are of the same class, the above-mentioned inhibitors lack specificity, they block the catalytic activity of almost all known PDEs, and may be accompanied by excessive adverse reactions while being treated.

 PDE 5 inhibitors affect PDE 5 activity by inhibiting PDE 5 enzyme activity, affecting PDE 5 expression and metabolism, and affecting physiological and pathological processes. In theory, PDE 5 inhibitors can affect all physiological and pathological processes associated with PDE 5.

 The first PDE5 inhibitor, Sildenafil, is clinically used for male erectile dysfunction and is also effective for female sexual dysfunction and essential hypertension. PDE5 inhibitors in development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia.

Although sildenafil has achieved significant clinical efficacy, it also has different degrees of inhibition on other phosphodiesterase (PDE) isoenzymes other than PDE5, clinically showing headache, flushing, indigestion, nasal congestion, It is toxic and side effects such as blurred vision, light sensitivity and light color. On the one hand, these side effects are dose related, Therefore, it is found that a more potent PDE5 inhibitor can reduce the dose and reduce the side effects. On the other hand, the symptom of visual disorder is that sildenafil also inhibits the type VI phosphodiesterase (PDE6) present in the retina. As a result, increasing selectivity, especially relative to PDE6, is another goal in the search for new PDE5 inhibitors. Summary of the invention

 The technical problem to be solved by the present invention is to provide a novel PDE5 inhibitor, for which purpose the present invention discloses a quinazolinone derivative, and a process for its preparation, a composition and use thereof are disclosed.

 a quinazolinone compound having the following structural formula (I), or a pharmaceutically acceptable salt thereof,

 Its towel:

R ¹ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, dC ₃ haloalkyl, halo, hydroxy, _alkoxy substituted by hydroxy, alkoxy, amino, amido;

R ^2, R ³ and R ⁴ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, haloalkyl, ₃ dC, ₃ is dC ₃ alkoxy-substituted alkyl, or C ₃ -C ₆ cycloalkyl Substituted dC ₃ alkyl;

R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ , NR ⁹ R ¹⁰ , five-membered sugar, six-membered sugar, COR ¹¹ , NHCOOR ¹¹ , COOR ¹¹ ;

R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, COR ^{1 1} , S0 ₂ R ⁿ , dC ₃ alkyl substituted by a substituent selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ;

R ⁸ is benzyl, acyl, sulfonyl;

R ⁹ and R ^1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ; R ¹¹ is H, dC ₆ alkyl;

R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² and R ¹³ are bonded together with the nitrogen atom to which they are attached Constitute Het;

^ ⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy;

R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine. Or a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and optionally selected from OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl Substituted with one or more substituents in Het;

 Among the above,

 m = 0, 1, 2;

Y stands for 0, S, NR ¹⁴ ;

Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy, CONH ₂ , CN, S0 ₂ NH ₂ ;

 Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.

 Preferred compounds of formula I,

R ¹ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, dC ₃ haloalkyl, halo, hydroxy, _alkoxy substituted by hydroxy, alkoxy, amino, amido;

R ² , R ³ and R ⁴ are each independently H, dC ₆ alkyl, dC ₆ alkenyl, C ₃ -C ₆ cycloalkyl, dC ₆ haloalkyl or halogen;

R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ , NR ⁹ R ¹⁰ , five-membered sugar, six-membered sugar, COR ¹¹ , NHCOOR ¹¹ , COOR ¹¹ ;

R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, COR ^{1 1} , S0 ₂ R ⁿ , dC ₃ alkyl substituted by a substituent selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ;

R ⁸ is benzyl, acyl, sulfonyl;

R ⁹ and R ^1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ; R ¹¹ is H, dC ₆ alkyl;

R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² , R ¹³ together with their attached nitrogen atoms constitute Het;

^ ⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy; R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine. Or a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and optionally selected from OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl Substituted with one or more substituents in Het;

 Among the above,

 m = 0, 1, 2;

Y stands for 0, S, NR ¹⁴ ;

Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy, CONH ₂ , CN, S0 ₂ NH ₂ ;

 Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.

 Further preferred compounds of formula I,

R ¹ is H, dC ₆ alkyl, dC ₆ alkenyl or halogen;

 R is a C-Ce thiol group;

R ³ is 11 or dC ₆ alkyl;

R ⁴ is a Ci-C ₆ yard base;

R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ ,

NRV°, acetyl group;

R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl , NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is selectively Replaced by R ¹⁴ ;

R ⁸ is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl;

R ⁹ and R ^1Q are each independently H, five-membered sugar, six-membered sugar, acyl group, methylsulfonyl group, p-toluenesulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ;

R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² , R ¹³ together with their attached nitrogen atoms constitute Het;

^ ⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy;

R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may together with the nitrogen atom to which they are attached form a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and may be optionally The ground is substituted with one or more substituents selected from the group consisting of OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl and Het; Among the above,

 m = 0, 1, 2;

Y stands for 0, S, NR ¹⁴ ;

Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy, CONH ₂ , CN, S0 ₂ NH ₂ ;

 Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0.

 Particularly preferred compounds of formula I,

R ¹ is H, dC ₆ alkyl, dC ₆ alkenyl or halogen;

R ² is H or methyl;

R ³ is H or methyl;

R ⁴ is ethyl or n-propyl;

R ⁵ is H, OH, halogen, nitro, carboxy, acetyl, CN, S0 ₂ NR ⁶ R ⁷ , CONR ⁶ R ⁷ ,

COCH ₂ NR ⁶ R7, OR ⁸ , NRV° ;

R ⁶ and R ⁷ are each independently H, dC ₃ alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC ₄ alkoxy, NR ¹² R ¹³ ; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ;

R ⁸ is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl;

R ⁹ and R ^1Q are each independently H, glucose, mannose, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl, C NR ¹⁵ R ¹⁶ ;

R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² and R ¹³ together with the nitrogen atom to which they are attached constitute morpholine, piperidine, pyrrolidine heterocycle;

R ¹⁴ is methyl, ethyl or propyl;

R ¹⁵ and R ¹⁶ each independently represent 11, dC ₃ alkyl; R ¹⁵ and R ¹⁶ may together with the nitrogen atom to which they are attached form a piperidinyl, pyrrolidinyl or piperazinyl group;

 Among the above,

Y stands for 0, S, NR ¹⁴ .

 Preferred specific compounds of the invention include:

2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) - 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline-4 (3H )-ketone;

 2-{2-propoxy-5-[N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4(3H)-one;

 2-{2-propoxy-5-[N-(3-morpholin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4(3H)-one;

 2-{2-propoxy-5-[N-(2-diethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl 5,7-dimethyl Oxy- 8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-methyl-N- 3-pyrrolidin-1-yl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8 -Bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-methoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl 5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-ethoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl 5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-ethyl-N-(3-piperidin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-ethyl-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-(2-hydroxyethoxy)ethyl)-N-(2-morpholin-1-yl)-aminosulfonyl]-benzene -5-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-(2-(2-methoxyethoxy)ethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl] -phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-methyl-N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8 -Bromo-quinazolin-4(3H)-one;

2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7 -dimethoxy-8-bromo-quinazolin-4(3H)-one; 2-{2-propoxy-5-[[l-(4-pyridylmethyl)-l-(2-morpholin-1-yl)ethyl]aminosulfonyl]phenyl}-5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-benzyl-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl 5,7-dimethoxy-8- Bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-benzyl-N- 3-morpholin-1-propyl)-aminosulfonyl]-phenyl 5,7-dimethoxy-8-bromo -quinazoline-4(3H)-one;

 2-{2-propoxy-5-[N-methyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy Base-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-ethyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy Base-8-bromo-quinazolin-4(3H)-one;

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) - ketone;

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-chloro-quinazoline-4 (3H) - ketone;

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-fluoro-quinazoline-4 (3H) - ketone;

 2-[2-ethoxy-5-(4-methylpiperazine-1 -1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4(3H)-one ; 8-ethyl-2-[2-ethoxy-5-(4-methylpiperazine-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline- 4(3H)-one;

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4(3H)-one; 8 -methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

 8-ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

 8-propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

8-butyl- _2- [ ₂ -ethoxy- _5- (4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

8-butyl- _2- [ ₂ -ethoxy- _5- (4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one; 8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

 8-allyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline

-4(3H)-one;

 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-chloro-quinazoline

-4(3H)-one;

 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-fluoro-quinazoline

-4(3H)-one;

 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline

-4(3H)-one;

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazolin-4(3H)-one; 8-Methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3H)-ketone;

 8-ethyl-2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazolin-4 ( 3H)-ketone;

8-propyl- _2- ( ₂ -ethoxy- _5- (4-methylpiperazin-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3H)-ketone;

8-butyl- _2- [ ₂ -ethoxy- _5- (4-methylpiperazin-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazolin-4 ( 3H)-ketone;

 8-vinyl-2-[2-ethoxy-5-(4-methylpiperazin-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3H)-ketone;

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline

-4(3H)-one;

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3H) - ketone;

 2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl 5,7-dimethyl Oxy- 8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-phenyl-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl 5,7-dimethoxy-8- Bromo-quinazolin-4(3H)-one;

2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(3-indolyl-1-propyl)-aminosulfonyl]-phenyl}-5,7 - two Methoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-benzyl-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-(pyridine-4-methyl)-N-(3-indolyl-1-propyl)-aminosulfonyl]-phenyl}-5,7 -dimethoxy-8-bromo-quinazolin-4(3H)-one;

 2-{2-propoxy-5-[N-ethyl-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one;

 2-[2-propoxy-5-(acetamido)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-{2-propoxy-5-[1-(2-methyl-3-ethyl)thioureido]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4(3H)-one;

 2-{2-propoxy-5-[2-(1-ethyl-2-diethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4(3H)-one;

 2-(2-ethoxy-5-acetyl-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-{2-propoxy-5-[N,N-bis-(4-methylbenzenesulfonyl)-amino]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4(3H)-one;

 2-{2-propoxy-5-[(N,N-dimethylsulfonyl)amino)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone;

 2-[2-propoxy-5-(2-methylpropionamido)-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one; 2 -{2-propoxy-5-[N-(4-methylbenzenesulfonyl)amino]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H )- ketone;

 2-(2-ethoxy-5-cyano-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-(2-ethoxy-5-benzyloxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-(2-ethoxy-5-hydroxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-(2-propoxy-5-acetoxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-(2-propoxy-5-(4-methylphenylsulfonyl)-phenyl)-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one ;

2-(2-propoxy-5-benzoyloxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one;

 2-[2-propoxy-5-(N,N-diethyl)-aminoacyl-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) - ketone;

2-[2-propoxy-5-(4-methylpiperazin-1-yl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4(3H)- Ketone; 2-(2-propoxy-5-glycosylamino-phenyl)-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one; 2-(2-propoxy-ί-mannosylamino-phenyl)-5,7-dimethoxy-8-bromo-quinazolin-4(3Η)-one; 2-{2- Propoxy-:-[Ν-(Ν'-ethylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4(3Η)-one;

 2-{2-propoxy-:-[Ν-(Ν'-ethylureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3Η) -ketone; 2-{2-propoxy-:-[Ν-(Ν'-phenylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline- 4(3Η)- ketone;

 2-{2-propoxy-:-[Ν-(Ν'-methylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3Η )- ketone;

 2-{2-propoxy-: -{2-[1-ethyl-2-(2-methylethyl)]indolyl}-phenyl}-5,7-dimethoxy-8- Bromo-quinazolin-4(3Η)-one;

 2-{2-propoxy-:-[2-(1,3-diethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 ( 3Η)- ketone;

 2-{2-propoxy-:-[2-(1-ethyl-2-phenylmethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin

-4(3Η)-ketone;

 2-{2-propoxy-:-[2-(1-ethyl-2-piperidyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline

-4(3Η)-ketone;

 2-(2-propoxy-ί-bromo-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3Η)-one;

 2-(2-propoxy-ί-carboxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3Η)-one;

 2-(2-propoxy-ί-acetyl-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3Η)-one;

 2-[2-propoxy-ί-(2-methyl-propionyloxy)-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4(3Η)-one . In addition to the compounds represented by the general formula (I), the present invention also includes pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites of these compounds, and pharmaceutically acceptable salts of these metabolites .

 The compounds of formula I may contain one or more chiral centers, and thus stereoisomers, i.e., enantiomers or diastereomers, and mixtures thereof may be present. The invention includes individual stereoisomers of the mixture of Formula I and mixtures thereof.

 The compounds of formula I may exist in the form of tautomers, and the invention includes mixtures thereof and single tautomers.

 The invention includes pharmaceutically acceptable salts of the compounds of formula I. Preferred salts are the methanesulfonate and the hydrochloride.

Another aspect of the invention also discloses a pharmaceutical composition comprising an effective amount of the compound of the formula (I) And a pharmaceutically acceptable carrier.

 The invention also includes pharmaceutically acceptable oxides of the compounds of formula I, and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. Further, the present invention provides the use of a compound of the formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, as a human medicament.

 The invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, for the manufacture of a medicament for the PDE5 inhibitor.

 The invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, for use in the treatment or prevention of erectile dysfunction in men, benign prostatic hyperplasia, Female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, instability and variation of Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Renault Use in human medicine for inflammatory disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by intestinal motility disorders such as stress bowel syndrome. The invention also provides a process for the preparation of the compounds of formula I. (A): A method for preparing the compound of the formula I-A, I-B, I-C) and a pharmaceutically acceptable salt thereof:

其中 R R²、 R³、 R⁴、 R⁵如权利要求 1中的定义。 其包括：

Wherein RR ² , R ³ , R ⁴ , R ^{5 are} as defined in claim 1. It includes:

(i) a first type of moiety I-A (R ¹ is halogen, R ^{3 is} not H, R ² , R ⁴ , R ^{5 are} as defined in claim 1) a compound may be a compound of formula 2 in the presence of a base, The temperature is usually from 30 to 200 ° C, and the reaction is carried out in a suitable solvent for 1 to 12 hours. Preferred bases include alkali metal alkoxides (preferably potassium t-butoxide, sodium ethoxide), alkali metal or alkaline earth metal hydrides, amines (preferably triethylamine), metal salts of amines, hydroxides (preferably sodium hydroxide). , carbonates and hydrogencarbonates; preferred solvents include alcohols (eg t-butanol, ethanol, methanol, isopropanol, ethylene glycol, ethylene glycol monomethyl ether), aromatic hydrocarbons (eg benzene, toluene, chlorobenzene) , pyridine, halogenated hydrocarbon, B Nitrile, tetrahydrofuran, dioxane, dimethyl sulfoxide, N,N-dimethylformamide, N-methylpyrrolidin-2-one, and the like.

 Π I -A

(ii) a second type of moiety I-B (R ^{1 is} not halogen, R ^{3 is} not H, R ² , R ⁴ , R ^{5 are} as defined in claim 1) The compound may be represented by the corresponding first class I -A compound and a hydrocarbyl metal reagent (hydrocarbon based metal reagent may be Cul, CH ₃ ZnCl / [(t-Bu) ₃ P] ₂ Pd, C ₂ H ₅ ZnI / [(t-Bu) ₃ P] ₂ Pd ,

nC ₃ H ₇ ZnI/[(t-Bu) ₃ P]2Pd, [(t-Bu) ₃ P] ₂ Pd, etc.) in a suitable solvent (solvent preferably N,N-dimethylformamide, dimethyl It is obtained by heating in sulfone, ethylene glycol monomethyl ether and N-methylpyrrolidone. Reaction equation:

 I -A I -B

Where RR ² , R ³ , R ⁴ , R ^{5 are} as defined above

(iii) Part III of the formula I-C (R ³ is H) may be in the corresponding solvent of the corresponding first type of the compound of formula I-A or I-B (solvent preferably dichloromethane, chloroform) And reacting with a dealkylating agent (dealkylating agent is preferably aluminum trichloride, boron tribromide, boron tetrafluoride). Reaction equation:

Wherein RR ² , R ³ , R ⁴ , and R ^{5 are} as defined above. (B): The compound of formula II can generally be prepared from the reaction of a compound of formula III with a compound of formula IX.

 Method 1: First, the carboxyl group of the compound of the formula IX is converted into an acid chloride or a mixed acid anhydride with thionyl chloride, oxalyl chloride, ethyl chloroformate or the like, and then reacted with the compound of the formula III to obtain the corresponding amide II. The acylation reaction is usually carried out in the presence of a deacidifying agent in a usual solvent. Preferred deacidification agents include organic bases (preferably triethylamine, diisopropylethylamine, pyridine) and inorganic bases (preferably hydroxides, carbonates). Preferred solvents include alkanes (preferably petroleum ether, n-hexane, cyclohexane), halogenated hydrocarbons (preferably dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic solvents (preferably toluene). ), and alcohols (preferably t-butanol, isopropanol).

 Method 2, direct condensation of a carboxylic acid and an amine to give an amide II. The reaction is usually carried out in the presence of an activator or a dehydrating agent in an anhydrous inert solvent. Preferred activators or dehydrating agents include DCC, EDCK EEDQ, CDI, HOBt and the like. Preferred solvents include halogenated hydrocarbons (preferably dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic hydrocarbons (preferably benzene, toluene), polar aprotic solvents (dimethyl sulfoxide, N, N-dimethylformamide), or a mixture of these solvents.

 Reaction equation:

其中 R R²、 R³、 R⁴、 R⁵如上述定义。

Wherein RR ² , R ³ , R ⁴ , and R ^{5 are} as defined above.

(C): a compound of Formula III can generally be of formula IV NH ₃ was prepared in a condensation reaction. The reaction is usually carried out in the presence of an activator or a dehydrating agent in an anhydrous inert solvent. Preferred activators or dehydrating agents include DCC, EDCI, EEDQ, CDI, HOBt, and the like. Preferred solvents include halogenated hydrocarbons (preferably dichloromethane or chloroform), ethers (preferably tetrahydrofuran, dioxane, diethyl ether), aromatic hydrocarbons (preferably benzene, toluene), polar aprotic solvents (dimethyl sulfoxide, N, N-dimethylformamide), or a mixture of these solvents. Reaction equation:

II: where RR ² and R ^{3 are} as defined above.

(D): The compound of formula IV can generally be prepared by reacting a compound of formula V in a 5%-10% NaOH solution with 30% 3⁄40 ₂ . Reaction equation:

 V IV

Where RR ² and R ^{3 are} as defined above.

 (E): The compound of the formula V can be usually obtained by reacting a compound of the formula VI with oxalyl chloride in a suitable solvent (solvent preferably dichloromethane, methyl chloride, 1,3-dichloropropane) at a temperature of usually 30 to 100 °C. Reaction equation:

 V

Where RR ² and R ^{3 are} as defined above.

(F): The compound of formula VI can generally be prepared by refluxing a compound of formula VII in a solution of HCl/MeOH.

 VI

Where RR ² and R ^{3 are} as defined above.

(G): The compound of the formula YD can usually be obtained from a compound of the formula VIII with a suitable halogenating agent (the halogenating agent can be NBS, NCS, F-TEDA-BF ₄ , Nal/t-BuOCl) in a suitable solvent (solvent preferably acetonitrile, two Prepared by reaction in methyl chloride, chloroform, 1,3-dichloropropane, usually at -20-50 °C.

 m

 Where R2 and R3 are as defined above.

 Compounds of formula IX, formula VIII can be prepared by literature methods or are commercially available.

 The present inventors designed and synthesized a series of new quinazolinone derivatives I, most of which have stronger PDE5 inhibitory activity than sildenafil and have higher selectivity than PDE6 distributed in the retina. . Therefore, the compounds provided by the present invention are expected to exhibit better safety and efficacy in clinical practice, and have a promising clinical application. detailed description

 The invention will be further elucidated below in conjunction with specific embodiments. It is to be understood that the examples are merely illustrative of the invention and are not intended to limit the scope of the invention. The experimental methods in which the specific conditions are not specified in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Proportions and percentages are based on weight unless otherwise stated.

 Some of the terms used in the present invention are defined as follows:

"Halogen" means fluorine, chlorine, bromine and iodine. "Alkyl" as a group or part of a group refers to a straight or branched aliphatic hydrocarbon group. The alkyl group having a C1-C14 alkyl group is preferred; more preferred is: C1-C10 alkyl; the most preferred is C1-C6 unless otherwise indicated. Examples of straight-chain or branched C1-C6 alkyl groups include, but are not limited to: methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, hexyl Wait.

 "Alkenyl" as a group or part of a group means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond, which may be straight or branched. An alkenyl group having C2-C14 is preferred. C2-C12 is even better; the most preferred is the C2-C6 alkenyl group. The group may contain a plurality of double bonds in its backbone and its conformation may each be £ or ∑. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl, and the like.

 "Cycloalkyl" means a saturated or partially saturated monocyclic, fused or spiro carbon ring. A ring composed of 3-9 carbon atoms is preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

 "Aryl" as a group or a part of a group means: (1) an aromatic monocyclic or fused ring; an aromatic carbocyclic ring having 5 to 12 carbon atoms is preferred (the ring atoms are all carbon) Ring structure). Examples of the aryl group include, but are not limited to: phenyl, naphthyl; (2) a partially saturated carbocyclic ring may be attached, for example: a phenyl group and a C5-7 cycloalkyl group or a C5-7 cycloalkenyl group are mutually thick. Together form a ring structure. Examples include, but are not limited to, tetrahydronaphthyl, anthracenyl or hydroquinone. An aryl group can be substituted with one or more substituents.

 The present invention includes the compounds represented by the formula (I) and various possible isomeric forms thereof. These include: non-mirror isomers, mirror image isomers, tautomers, and geometric isomers of the "E" or "Z" configurational isomers. Any of the above-mentioned chemists can isolate the above optically pure or stereoisomerically pure compounds.

 The invention includes mixtures of the compounds represented by the general formula (I) and their possible racemates or / and mirror image isomers / or / and non-image mirror isomers.

 Further, the compound represented by the formula (I) also covers the solvated and unsolvated forms of the compound in application. Thus, each formula includes compounds having the indicated configurations, including hydrated and anhydrous forms thereof.

The term "pharmaceutically acceptable salt" refers to certain salts of the above compounds which retain their original biological activity and which are suitable for pharmaceutical use. The pharmaceutically acceptable salt of the compound represented by the formula (I) has two forms of formation: one is a salt formed with an acid; the other is a salt formed with an alkali or an alkali metal. The acid which forms a pharmaceutically acceptable salt with the compound represented by the formula (I) includes inorganic acids and organic acids. Suitable inorganic acids include: hydrochloric acid, sulfuric acid and phosphoric acid. Suitable organic acids may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, heterocyclic carboxylic acid and sulfonic acid organic acids; examples of which include, but are not limited to: formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, glucose Acid, lactic acid, malic acid, tartaric acid, glycine, arginine, citric acid, fumaric acid, alkylsulfonic acid, arylsulfonic acid and the like. With general formula (I) The alkali metal in which the compound represented forms a pharmaceutically acceptable salt includes: lithium, sodium, potassium, magnesium, calcium, aluminum, zinc, etc.; a base which forms a pharmaceutically acceptable salt with the compound represented by the formula (I) Including: choline, diethanolamine, morpholine and the like.

 A "prodrug" is a derivative represented by the formula (I) which is converted in vivo by means of metabolism in the body (for example: by hydrolysis, reduction or oxidation) to form a formula (I) compound of. For example, a compound having a hydroxyl group represented by the formula (I) can be reacted with an acid to prepare a corresponding ester. The corresponding ester is a prodrug that can hydrolyze the parent drug in vivo. Acids suitable for the preparation of "prodrugs" include, but are not limited to: acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, oxalic acid, salicylic acid, succinic acid, fumaric acid, maleic acid, methylene Base-bis-β-hydroxynaphthoic acid, gentisic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

 The compound represented by the formula (I) can be administered in a gastrointestinal or parenteral manner. Gastrointestinal administration: Oral or rectal. Parenteral administration includes: subcutaneous, intramuscular, intravenous and intradermal routes. In general, the active compound represented by the formula (I), when administered, may be a pharmaceutically acceptable carrier or diluent.

 "Therapeutically effective amount" or "therapeutic amount" refers to an amount sufficient to produce a therapeutic effect. An effective amount can be administered in one or more divided doses. Generally, an effective amount is sufficient to alleviate, improve, stabilize, slow or delay further progression of the disease.

 Also, the invention provides a pharmaceutically acceptable composition comprising the compound of formula I. The composition consists of one or more compounds of formula I (or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof) and at least one pharmaceutically acceptable adjuvant. The choice of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, and is usually a filler, a diluent, a binder, a wetting agent, a disintegrant, a lubricant, an emulsifier, a suspending agent, and the like.

 The compositions of the invention may be administered orally, by injection (intravenous, intramuscular, subcutaneous and intracoronary), sublingual, buccal, rectal, transurethral, vaginal, nasal, inhalation or topical routes. The preferred route is oral.

 The proportion of the compound of the formula I in the above composition is from 0.1% to 99.9% by weight, preferably

1% to 99%.

 The invention also provides a process for the preparation of a pharmaceutically acceptable composition of a compound of formula I. The compound of the formula I is usually mixed with a pharmaceutically acceptable adjuvant and prepared in a form suitable for administration by a conventional preparation method (dosage form). The dosage form includes tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Preference is given to tablets and capsules.

The combination of tablets and capsules may contain one or more of Formula I and one or more conventional excipients, such as Fillers such as powder, sucrose, lactose, glucose, microcrystalline cellulose, mannose; binders such as carboxymethyl cellulose, gelatin, alginate and polyvinylpyrrolidone; wetting agents such as glycerin; agar, ethyl fiber a disintegrant such as sodium carboxymethyl starch or calcium carbonate; a lubricant such as magnesium stearate, talc or polyethylene glycol.

 The compound of the present invention is usually administered in a dose of from 1 to 500 mg, preferably from 10 to 100 mg per day, in single or multiple doses. However, if necessary, the above doses may be appropriately deviated. Professionals can determine the optimal dose based on the specific situation and expertise. These conditions include the severity of the disease, individual differences in the patient, the nature of the formulation, and the route of administration.

The following examples further illustrate the synthesis of the compounds of the present invention and intermediates thereof, but do not limit the scope of the invention. 1H NMR was performed on a Mercury-400 or Mercury-300 NMR spectrometer (Varian). The general abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad.

 Example 1 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H)-ketone

 Step 1: 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzoylamino]-5,7-dimethoxy-8-bromobenzoylamide

 2-Ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]benzoic acid (0.34 g, 1 mmol) was dissolved in dichloromethane (20 mL) and carbonyldiimidazole (CDI, 3mmol) After stirring at room temperature for 0.5 h, 2-amino-4,6-dimethoxy-3-bromobenzoylamide (0.28 g, 1 mmol) was added to the mixture, and stirring was continued for -6 h, using TLC. The endpoint of the reaction was tested. After completion of the reaction, the mixture was washed with aq. ammonium chloride and brine, and the methylene chloride phase was dried over anhydrous magnesium sulfate. %.

Step 2: Preparation of 2-{2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]phenyl 5,7-dimethoxy-8-bromo-quino-4 ( 3H)-ketone

 Potassium tert-butoxide (0.06 g, 0.55 mmol) and the product from step 1 (0.3 g, 0.5 mmol) were added to t-butanol (15 ml), and the suspension was heated to reflux with stirring and clarified after about 30 min. Continue to reflux for 10 h. Heating was stopped, and after cooling to room temperature, water (20 ml) was added, adjusted to neutral with 4% dilute acetic acid, and then cooled to 5-10 °C. A white solid precipitated, filtered, washed with cold water (3 x 10 ml), dried, and then recrystallized from methanol/ethyl acetate to give the product 0.22 g. 1H-NMR (300 MHz, CDC13), δ 10.56 (brs, 1H), 9.17 (d, J = 2.7 Hz, 1H) 7.88 (dd, J = 8.8, 2.7 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54(s, 1H), 4.37(q, J = 7.0 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.21(m, 4H), 2.57(m, 4H ), 2.34(s, 3H), 1.63(t, J = 7.0 Hz, 3H).

 Example 2 8-Methyl-2-[2-ethoxy-5-(4-methylpiperazine-1 -sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline- 4(3H)-ketone

 Anhydrous zinc chloride 408 mg (3.0 mmol) was dissolved in 5 mL of dry NMP, and 2 mL of 2 mol/L methylmagnesium chloride (2.0 mmol) in THF was added dropwise under ice cooling, and stirred at room temperature for 1 hour to obtain a methyl zinc reagent.

2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) - ketone 567 mg (10i, 1.0 mmol) was mixed in 5 mL of dry NMP, and the methyl zinc reagent prepared above was added, and [(t-Bu)3P]2Pd 25 mg (0.05 mmol) was added under nitrogen atmosphere, and heated at 40 °C. 4 hours, to room temperature, force B 10mL dichloromethane, 20mL of water, the aqueous phase was extracted once with 3mL of dichloromethane, the organic phase was combined, washed twice with 2mL water, saturated brine, dried over anhydrous sodium sulfate. Silica gel column chromatography (CH2C12/CH30H) gave pale yellow 8-methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7 -Dimethoxy-quinazoline-4(3H)-one (10b) solid 41 1 mg, yield 82%. 1H-NMR (300 MHz, CDC13), δ 10.44 (brs, 1H), 8.93 (d, J = 2.4 Hz, 1H), 7.86 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54(s, 1H), 4.35(q, J = 7.0 Hz, 2H), 4.02(s, 3H), 3.98(s, 3H), 3.12(m, 4H), 2.51(m, 4H), 2.44 (s, 3H), 2.28(s, 3H), 1.63(t, J = 7.0 Hz, 3H).

 Example 3 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline- 4 (3 ketone

 The compound of Example 1 (0.57 g, 1.0 mmol) was dissolved in 20 mL of dry dichloromethane, and 2 mL of a solution of boron tribromide (104 uL, 1.1 mmol) in dichloromethane was added dropwise with stirring at -10 ° C, stirring was continued. In an hour, force B lmL diethyl ether, continue stirring for 30 minutes, add 20 mL of dichloromethane and 50 mL of 5 % NaHCO3, and extract the aqueous phase with 10 mL of dichloromethane. The organic phase is combined and washed with 5 mL of 5 % NaHC03 and saturated brine. After 1 time, it was dried over anhydrous sodium sulfate. 1H-NMR (300 MHz, CDC13), δ 11.62 (s, 1H), 10.82 (brs, 1H), 9.11 (d, J = 2.3 Hz, 1H), 7.90 (dd, J = 8.8, 2.3 Hz, 1H) , 7.17(d, J = 8.8 Hz, 1H), 6.57(s, 1H), 4.41(q, J = 7.0 Hz, 2H), 4.00(s, 3H), 3.18(m, 4H), 2.56(m, 4H), 2.31(s, 3H), 1.67 (t, J = 7.0 Hz, 3H).

Example 4~50

2-{2-丙氧基 -5-[N-(3-吗啉 -1-丙基) -胺基磺酰基] - 苯基 }-5，7-二甲氧基 -8-溴-喹唑啉 -4(3H)-酮 The compounds of Examples 4 to 50 were prepared in the same manner as in Example 1, 2 or 3, using starting materials of different substituents. (The solvent used in the NMR data is not specifically described as CDC13 unless otherwise specified.

2-{2-propoxy-5-[N-(3-morpholin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4(3H)-one

 10.73(brs, 1H), 9.13(d, J = 2.6 Hz, 1H), 7.99(dd, J = 〇

 8.9, 2.6 Hz, 1H), 7.14 (d, J = 8.9 Hz, 1H), 6.54(s, 1H), 4.25(t, J = 6.3 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.70(t, J = 4.7 Hz, 4H), 3.21(t, J = 5.8 Hz, 2H), 2.44(m, 6H), 2.02(m, 2H), 1.71(m, 2H), 1.18( t, J = 7.6 Hz, 3H)

1H), 4.26(t, J = 6.4 Hz, 2H), 4.05(s， 3H), 4.03(s, 2-{2-propoxy-5-[N-(2-diethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4(3H)-one 10.74 (brs, 1H), 9.20 (d, J = 2.7 Hz, 1H), 8.01 (dd, J = 8.8, 2.7 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54(s,

1H), 4.26(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.03(s,

 3H), 3.05(t, J = 5.8 Hz, 2H), 2.53(t, J = 5.8 Hz, 2H), 2.40(q, J = 7.1 Hz, 4H), 2.03(m, 2H), 1.18(t, J = 7.4 Hz, 3H), 0.91 (t, J = 7.1 Hz, 6H)

1H), 4.26(t, J = 6.2 Hz, 2H), 4.05(s， 3H), 4.03(s, 2-{2-propoxy-5-[N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4(3H)-one 10.75 (brs, 1H), 9.20 (d, J = 2.3 Hz, 1H), 8.02 (dd, J = 8.7, 2.3 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.54(s,

1H), 4.26(t, J = 6.2 Hz, 2H), 4.05(s, 3H), 4.03(s,

 3H), 3.08(t, J = 5.8 Hz, 2H), 2.39(t, J = 5.8 Hz, 2H), 2.12(s, 6H), 2.03(m, 2H), 1.18(t, J = 7.5 Hz, 3H)

2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7- Dimethoxy-8-bromo-quinazolin-4(3H)-one

 10.67(brs, 1H), 9.13(d, J = 2.4 Hz, 1H), 7.95 (dd, J = 8.9, 2.4 Hz, 1H), 7.15(d, J = 8.9 Hz, 1H), 6.54(s, 1H ), 6.25(brs, 1H), 4.26(t, J = 6.2 Hz, 2H), 4.06(s, 3H), 4.04(s, 3H), 3.84(t, J = 4.3 Hz, 2H), 3.75(t , J = 4.6 Hz, 4H), 3.37 (t, J = 5.3 Hz, 2H), 3.27 (t, J = 4.3 Hz, 2H), 2.73 (t, J = 5.3 Hz, 2H), 2.60 (m, 4H) ),

2.03(m, 2H), 1.18(t, J = 7.5 Hz, 3H) 2-{2-propoxy-5-[N-methyl-N-(3-pyrrolidin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one

8.8， 2.6 Hz, 1H), 7.14(d, J = 8.8 Hz, 1H), 6.54(s， 10.70(brs, 1H), 9.10(d, J = 2.6 Hz, 1H), 7.94(dd, J =

8.8, 2.6 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54 (s,

 1H), 4.25(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.20(t, J = 7.2 Hz, 2H), 2.84(s, 3H), 2.51( m, 6H), 2.02(m, 2H), 1.80(m, 6H), 1.18(t, J = 7.5 Hz, 3H)

 2-{2-propoxy-5-[N-(2-methoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-dimethoxy-8-bromo-quinazolin-4(3H)-one

1H), 4.26(t, J = 6.5 Hz, 2H), 4.06(s， 3H), 4.04(s， 10.74(brs, 1H), 9.16(d, J = 2.2 Hz, 1H), 7.98(dd, J = 8.9, 2.2 Hz, 1H), 7.12(d, J = 8.9 Hz, 1H), 6.54(s,

1H), 4.26(t, J = 6.5 Hz, 2H), 4.06(s, 3H), 4.04(s,

 3H), 3.65 (t, J = 4.6 Hz, 4H), 3.58 (t, J = 5.7 Hz, 2H), 3.46 (m, 4H), 3.29 (s, 3H), 2.63 (t, J = 7.4 Hz, 2H), 2.47(t, J = 4.6 Hz, 4H), 2.03(m, 2H), 1.18(t, J = 7.4 Hz, 3H)

 2-{2-propoxy-5-[N-(2-ethoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-dimethoxy-8-bromo-quinazolin-4(3H)-one

1H), 4.26(t, J = 6.5 Hz, 2H), 4.05(s， 3H), 4.04(s， 10.73(brs, 1H), 9.16(d, J = 2.4 Hz, 1H), 7.98(dd, J = 8.8, 2.4 Hz, 1H), 7.12(d, J = 8.8 Hz, 1H), 6.54(s,

1H), 4.26(t, J = 6.5 Hz, 2H), 4.05(s, 3H), 4.04(s,

 3H), 3.63(m, 6H), 3.45(m, 6H), 2.64(m, 2H), 2.48(m, 4H), 2.03(m, 2H), 1.15(m, 6H)

1H), 5.31(brs, 1H)， 4.25(t, J = 6.2 Hz, 2H), 4.05(s， 2-{2-propoxy-5-[N-ethyl-N-(3-piperidin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one 10.74 (brs, 1H), 9.13 (d, J = 2.1 Hz, 1H), 7.96 (dd, J = 8.8, 2.1 Hz, 1H), 7.12 (d , J = 8.8 Hz, 1H), 6.54(s,

1H), 5.31(brs, 1H), 4.25(t, J = 6.2 Hz, 2H), 4.05(s,

2-{2-丙氧基 -5-[N- (吡啶 -3-甲基） 3H), 4.03(s, 3H), 3.3 l(m, 4H), 2.37(m, 6H), 2.02(m, 2H), 1.84(m, 2H), 1.58(m, 4H), 1.42(m, 2H), 1.18(m, 6H)

2-{2-propoxy-5-[N-(pyridine-3-methyl)

 -N-(2-morpholin-1-ethyl)-aminosulfonyl]-benzene

 }5,7-dimethoxy-8-bromo-quinazolyl-4(3H)-one

 〇 〇 10.74(brs, 1H), 9.21(d, J = 2.4 Hz, 1H), 8.53(m,

7.29(m, 1H)， 7.15(d, J = 8.8 Hz, 1H)， 6.55(s， 1H)， 2H), 8.00 (dd, J = 8.8, 2.4 Hz, 1H), 7.85 (m, 1H),

7.29(m, 1H), 7.15(d, J = 8.8 Hz, 1H), 6.55(s, 1H),

 4.56(s, 2H), 4.28(t, J = 6.4 Hz, 2H), 4.05(s, 3H),

O o ~ ~ 4.04(s, 3H), 3.54(t, J = 4.6 Hz , 4H), 3.36(t, J = 6.8

 Hz, 2H), 2.36(t, J = 6.8, 2H), 2.25(t, J = 4.6 Hz, 4H), 2.04(m, 2H), 1.19(t, J = 7.5 Hz, 3H)

 2-{2-propoxy-5-[N-(pyridine-4-methyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7 -dimethoxy-8-bromo-quinazolin-4(3H)-one

 10.74(brs, 1H), 9.21(d, J = 2.4 Hz, 1H), 8.53(m, 2H), 8.00(dd, J = 8.8, 2.4 Hz, 1H), 7.85(m, 1H), 7.29(m , 1H), 7.15(d, J = 8.8 Hz, 1H), 6.55(s, 1H), 4.56(s, 2H), 4.28(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.04 (s, 3H), 3.54 (t, J = 4.6 Hz, 4H), 3.36 (t, J = 6.8 Hz, 2H), 2.36 (t, J = 6.8, 2H), 2.25 (t, J = 4.6 Hz, 4H), 2.04(m, 2H), 1.19(t, J = 7.5 Hz, 3H).

 2-{2-propoxy-5-[N-benzyl-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one 10.75 (brs, 1H), 9.22 (d, J = 2.9 Hz, 1H), 8.01 (dd, J = 8.7, 2.9 Hz, 1H), 7.33 (m) , 5H), 7.14(d, J = 8.7 Hz, 1H), 6.55(s, 1H), 4.55(s, 2H), 4.27(t, J = 6.5 Hz, 2H), 4.06(s, 3H), 4.04 (s, 3H), 3.53 (m, 4H), 3.34 (m, 2H), 2.33 (m, 2H), 2.23 (m, 4H), 2.04 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H)

2-{2-propoxy-5-[N-benzyl-N-(3-morpholin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4(3H)-one 10.74 (brs, 1H), 9.19 (d, J = 2.8 Hz, 1H), 7.99 (dd, J = 8.8, 2.8 Hz, 1H), 7.31 (m) , 5H), 7.14(d, J = 8.8 Hz, 1H), 6.54(s, 1H), 4.44(s, 2H), 4.27(t, J = 6.3 Hz,

2H), 4.05(s, 3H), 4.04(s, 3H), 3.55(m, 4H), 3.27(m, 2H), 2.17(m, 6H), 2.04(m, 2H), 1.60(m, 2H ), 1.19(t, J = 7.6 Hz, 3H). 2-{2-propoxy-5-[N-methyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy -8-bromo-quinazolin-4(3H)-one

 〇

 o o 〇 10.68(brs, 1H), 9.09(d, J = 2.2 Hz, 1H), 7.93(dd, J =

 8.8, 2.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54(s, 1H), 4.25(t, J = 6.3 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.13(m, 1H), 3.06(m, 2H), 2.91(s, 3H), 2.82(m, 1H), 2.69(m, 1H), 2.30(m, 1H), 2.18(m, 1H) ),

 2.02(m, 2H), 1.81(m, 4H), 1.17(t, J = 7.3 Hz, 3H), 1.07(t, J = 7.2 Hz, 3H)

 2-{2-propoxy-5-[N-ethyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy -8-bromo-quinazolin-4(3H)-one

 10.71(brs, 1H), 9.13(d, J = 2.6 Hz, 1H), 7.96(dd, J = 8.7, 2.6 Hz, 1H), 7.11(d, J = 8.7 Hz, 1H), 6.54(s, 1H ), 4.25(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.35(m, 2H), 3.19(m, 2H), 3.12(m, 1H),

 2.83(m, 1H), 2.72(m, 1H), 2.31(m, 1H), 2.18(m, 1H), 2.02(m, 2H), 1.83(m, 4H), 1.17(m, 6H), 1.08 (t, J = 7.2 Hz, 3H)

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) Ketone

 10.70(brs, 1H), 9.12(d, J = 2.5 Hz, 1H), 7.89(dd, J = 9.0, 2.5 Hz, 1H), 7.15(d, J = 9.0 Hz, 1H), 6.54(s, 1H ), 4.26(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 3.15(m, 4H), 2.50(m, 4H), 2.27(s, 3H), 2.03 (m, 2H), 1.18(t, J = 7.3 Hz, 3H)

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-chloro-quinazoline-4 (3H) Ketone

1H), 4.37(q, J = 7.0 Hz, 2H), 4.05(s, 3H), 4.03(s, 10.62(brs, 1H), 9.06(d, J = 2.5 Hz, 1H), 7.89(dd, J = 9.0, 2.5 Hz, 1H), 7.14(d, J = 9.0 Hz, 1H), 6.56(s,

1H), 4.37(q, J = 7.0 Hz, 2H), 4.05(s, 3H), 4.03(s,

3H), 3.19(m, 4H), 2.56(m, 4H), 2.31(s, 3H), 1.63(t, J = 7.0 Hz, 3H) 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-fluoro-quinazoline-4 (3H) -ketone

6.6 Hz, 1H)， 4.36(q, J = 7.0 Hz, 2H), 4.05(s, 3H), 10.54(brs, 1H), 8.92(d, J = 2.4 Hz, 1H), 7.88(dd, J = 8.8, 2.4 Hz, 1H), 7.14(d, J = 8.8 Hz, 1H), 6.55(d, J =

6.6 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 4.05(s, 3H),

 4.00(s, 3H), 3.12(m, 4H), 2.50(m, 4H), 2.27(s, 3H), 1.62(t, J = 7.0 Hz, 3H)

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3H) Ketone

 10.68(brs, 1H), 9.19(d, J = 2.5 Hz, 1H), 7.89(dd, J =

1H), 4.38(q, J = 7.0 Hz, 2H), 4.04(m， 6H)， 3.16(m, 8.7, 2.5 Hz, 1H), 7.14 (d, J = 8.7 Hz, 1H), 6.51 (s,

1H), 4.38 (q, J = 7.0 Hz, 2H), 4.04 (m, 6H), 3.16 (m,

 4H), 2.50(m, 4H), 2.26(s, 3H), 1.64(t, J = 7.0 Hz,

3H)

 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4(3H)-one

2.3 Hz 1H)， 6.47(d, J = 2.3 Hz 1H)， 4.36(q, J = 7.0 10.53(brs, 1H), 8.89(d, J = 2.5 Hz, 1H), 7.84(dd, J = 8.8, 2.5 Hz, 1H), 7.15(d, J = 8.8 Hz, 1H), 6.84(d, J =

2.3 Hz 1H), 6.47 (d, J = 2.3 Hz 1H), 4.36 (q, J = 7.0

 Hz, 2H), 3.97(s, 3H), 3.95(s, 3H), 3.17(m, 4H), 2.60(m, 4H), 2.34(s, 3H), 1.63(t, J = 7.0 Hz, 3H )

8-Methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H )-ketone

1H), 4.35(q, J = 7.0 Hz, 2H), 4.02(s, 3H), 3.98(s, 10.44(brs, 1H), 8.93(d, J = 2.4 Hz, 1H), 7.86(dd, J = 8.8, 2.4 Hz, 1H), 7.14(d, J = 8.8 Hz, 1H), 6.54(s,

1H), 4.35(q, J = 7.0 Hz, 2H), 4.02(s, 3H), 3.98(s,

 3H), 3.12(m, 4H), 2.51(m, 4H), 2.44(s, 3H), 2.28(s, 3H), 1.63(t, J = 7.0 Hz, 3H)

= 7.0 Hz, 2H), 4.01(s， 3H), 3.96(s, 3H), 3.23(m, 8-ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H )-ketone 10.46 (brs, 1H), 8.95 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.53 ( s, 1H), 4.30(q, J

= 7.0 Hz, 2H), 4.01(s, 3H), 3.96(s, 3H), 3.23(m,

4H), 3.04(q, J = 7.5Hz, 2H), 2.67(m, 4H), 2.39(s, 3H), 1.63(t, J = 7.0 Hz, 3H), 1.16(t, J = 7.5 Hz, 3H) 8-propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H )-ketone

1H), 4.36(q, J = 6.9 Hz, 2H), 4.01(s， 3H), 3.95(s, 10.50 (brs, 1H), 8.95 (d, J = 2.4 Hz, 1H), 7.84 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.52 (s,

1H), 4.36(q, J = 6.9 Hz, 2H), 4.01(s, 3H), 3.95(s,

 3H), 3.17(m, 4H), 2.99(t, J = 7.7Hz, 2H), 2.60(m, 4H), 2.34(s, 3H), 1.72-1.48(m, 5H), 0.98(t, J = 7.3 Hz, 3H)

 8-butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H )-ketone

1H), 4.36(q, J = 6.9 Hz, 2H), 4.01(s， 3H), 3.96(s, 10.49(brs, 1H), 8.94(d, J = 2.5 Hz, 1H), 7.85(dd, J = 8.6, 2.5 Hz, 1H), 7.14(d, J = 8.4 Hz, 1H), 6.52(s,

1H), 4.36(q, J = 6.9 Hz, 2H), 4.01(s, 3H), 3.96(s,

 3H), 3.08(m, 4H), 3.03(t, J = 7.6Hz, 2H), 2.48(m, 4H), 2.26(s, 3H), 1.63(t, J = 6.9 Hz, 3H),

 1.57-1.33(m, 4H), 0.93(t, J = 7.2Hz, 3H)

 8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3H )-ketone

7.14(d, J = 8.8 Hz, 1H), 6.55(s， 1H), 6.18(dd， J = 10.52 (brs, 1H), 8.89 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 8.8, 2.4 Hz, 1H), 7.48 (dd, J = 18.1, 12.1 Hz, 1H),

7.14(d, J = 8.8 Hz, 1H), 6.55(s, 1H), 6.18(dd, J =

 18.1, 2.8 Hz, 1H), 5.53 (dd, J = 12.1, 2.8 Hz, 1H), 4.36 (q, J = 7.0 Hz, 2H), 4.04(s, 3H), 4.01(s, 3H), 3.11( m, 4H), 2.49(m, 4H), 2.26(s, 3H), 1.62(t, J = 7.0 Hz, 3H)

 8-allyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4 ( 3H)-ketone

1H), 6.06-5.92(m, 1H), 5.12-5.03(m, 1H)， 10.50 (brs, 1H), 8.96 (d, J = 2.4 Hz, 1H), 7.85 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.54 (s,

1H), 6.06-5.92 (m, 1H), 5.12-5.03 (m, 1H),

4.95-4.89(m, 1H), 4.36(q, J = 7.0 Hz, 2H), 4.02(s, 3H), 3.97(s, 3H), 3.83-3.77(m, 2H), 3.15(m, 4H) , 2.57(m, 4H), 2.32(s, 3H), 1.63(t, J = 7.0 Hz, 3H) 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-chloro-quinazoline-4 (3H )-ketone

 11.58(s, 1H), 10.81(brs, 1H), 9.08(d, J = 2.6 Hz,

Hz, 1H)， 6.60(s， 1H)， 4.42(q, J = 7.0 Hz, 2H), 〇1H), 7.92 (dd, J = 9.0, 2.6 Hz, 1H), 7.17 (d, J = 9.0

Hz, 1H), 6.60(s, 1H), 4.42(q, J = 7.0 Hz, 2H),

 4.01(s, 3H), 3.16(m, 4H), 2.53(m, 4H), 2.29(s, 3H), 1.67(t, J = 7.0 Hz, 3H)

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-fluoro-quinazoline-4 (3H )-ketone

 1 11.28(s, 1H), 10.76(brs, 1H), 9.00(d, J = 2.4 Hz, o

 1H), 7.94 (dd, J = 8.7, 2.4 Hz, 1H), 7.21 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 6.1 Hz, 1H), 4.44 (q, J = 7.0 Hz, 2H), 4.02(s, 3H), 3.16(m, 4H), 2.55(m, 4H), 2.32(s, 3H), 1.70(t, J = 7.0 Hz, 3H)

 2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4 (3H )-ketone

Hz, 1H)， 6.54(s， 1H)， 4.41(q, J = 7.0 Hz, 2H), 11.67(s, 1H), 10.85(brs, 1H), 9.18(d, J = 2.5 Hz, 1H), 7.90(dd, J = 8.8, 2.5 Hz, 1H), 7.16(d, J = 8.8

Hz, 1H), 6.54(s, 1H), 4.41(q, J = 7.0 Hz, 2H),

 3.99(s, 3H), 3.16(m, 4H), 2.51(m, 4H), 2.27(s, 3H), 1.67(t, J = 7.0 Hz, 3H)

 2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4(3H)-one

Hz, 1H)， 6.83(d, J = 2.3 Hz, 1H)， 6.54(d， J = 2.3 Hz, 11.43(s, 1H), 10.77(brs, 1H), 8.97(d, J = 2.4 Hz, 1H), 7.91(dd, J = 8.8, 2.4 Hz, 1H), 7.21(d, J = 8.8

Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.54 (d, J = 2.3 Hz,

 1H), 4.44 (q, J = 7.0 Hz, 2H), 3.95(s, 3H), 3.14(m, 4H), 2.54(m, 4H), 2.31(s, 3H), 1.70(t, J = 7.0 Hz, 3H)

 8-ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazolin-4 ( 3H)-ketone

Hz, 1H), 6.58(s， 1H), 4.44(q， J = 7.0 Hz, 2H), 11.55(s, 1H), 10.66(brs, 1H), 9.01(d, J = 2.5 Hz, 1H), 7.92(dd, J = 8.8, 2.5 Hz, 1H), 7.20(d, J = 8.8

Hz, 1H), 6.58(s, 1H), 4.44(q, J = 7.0 Hz, 2H),

3.97(s, 3H), 3.15(m, 4H), 3.05(q, J = 7.5 Hz, 2H), 2.54(m, 4H), 2.31(s, 3H), 1.70(t, J = 7.0 Hz, 3H ), 1.19(t, J = 7.5 Hz, 3H) 8-propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3H)-ketone

 11.52(s, 1H), 10.64(brs, 1H), 8.97(d, J = 2.5 Hz, 〇 〇 〇 〇

 〇 1H), 7.87 (dd, J = 8.8, 2.5 Hz, 1H), 7.16 (d, J = 8.8

 Hz, 1H), 6.54(s, 1H), 4.39(q, J = 7.0 Hz, 2H), 3.91(s, 3H), 3.10(m, 4H), 2.97(t, J = 7.5 Hz, 2H), 2.50(m, 4H), 2.28(s, 3H), 1.66(t, J = 7.0 Hz, 3H), 1.63-1.55(m, 2H), 0.96(t, J = 7.5 Hz, 3H)

 8-butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-benzene

〇 〇 〇 ]]]-5-hydroxy-7-methoxy-quinazoline-4(3H)-one

 11.58(s, 1H), 10.70(brs, 1H), 9.01(d, J = 2.2 Hz, 1H), 7.91(dd, J = 8.7, 2.2 Hz, 1H), 7.21(d, J = 8.7 Hz, 1H ), 6.58(s, 1H), 4.44(q, J = 7.0 Hz, 2H), 3.95(s, 3H), 3.17(m, 4H), 3.04(t, J = 7.5 Hz, 2H), 2.59(m , 4H), 2.34(s, 3H), 1.71(t, J = 7.0 Hz, 3H), 1.61-1.35(m, 4H), 0.97(t, J = 7.2 Hz, 3H)

 8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3H)-ketone

 11.84(s, 1H), 10.75(brs, 1H), 8.95(d, J = 2.5 Hz, 1H), 7.91(dd, J = 8.9, 2.5 Hz, 1H), 7.44(dd, J = 18.0, 12.2 Hz , 1H), 7.20 (d, J = 8.9 Hz, 1H), 6.60(s, 1H), 6.24 (dd, J = 18.0, 2.8 Hz, 1H), 5.55 (dd, J = 12.2, 2.8 Hz, 1H) , 4.44 (q, J = 7.0 Hz, 2H), 4.01 (s, 3H), 3.15 (m, 4H), 2.55 (m, 4H), 2.32 (s, 3H), 1.70 (t, J = 7.0 Hz, 3H)

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline-4 (3H )-ketone

 11.58(s, 1H), 10.83(brs, 1H), 9.08(d, J = 2.6 Hz, 1H), 7.88(dd, J = 8.7, 2.6 Hz, 1H), 7.16(d, J = 8.7 Hz, 1H ), 6.56(s, 1H), 4.27(t, J = 6.5 Hz, 2H), 4.00(s, 3H), 3.16(m, 4H), 2.53(m, 4H), 2.28(s, 3H), 2.03 (m, 2H), 1.19(t, J = 7.6 Hz, 3H)

 2-[2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4 (3H )-ketone

11.65(s, 1H), 10.86(brs, 1H), 9.17(d, J = 2.2 Hz, 1H), 7.90(dd, J = 9.0, 2.2 Hz, 1H), 7.17(d, J = 9.0

2-[2-丙氧基 -5-(2-甲基丙酰胺基) -苯基 ]-5，7-二甲 氧基 -8-溴-喹唑啉 -4(3H)-酮 Hz, 1H), 6.54(s, 1H), 4.29(t, J = 6.6 Hz, 2H), 4.00(s,

2-[2-propoxy-5-(2-methylpropionamido)-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4(3H)-one

 1 1.08(s, 1H), 8.25(d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.8, 2.2 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.43 ( s,

〇

 〇 1H), 4.13(t, J = 6.1 Hz, 2H), 4.04(s, 3H), 4.02(s,

 3H), 2.58(m, 1H), 1.98(m, 2H), 1.30(s, 3H). 1.28(s, // ^ 〇

 3H). 1.15(t, J = 7.3 Hz, 3H).

 Propyloxy-5-[N-(4-methylphenylsulfonyl)amino]-benzene

 Work

 }}-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one

 ,

Workers 10.90 (s, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.45 (dd, J = 8.8, 2.2 Hz, 1H), 7.25 (d , J =

 8.3 Hz, 2H), 6.96 (d, J = 8.8 Hz, 1H), 6.50(s, 1H), 4.14(t, J = 6.1 Hz, 2H), 4.04(s, 3H), 4.01(s, 3H) , 2.36(s, 3H), 2.00(m, 2H), 1.15(t, J = 7.3 Hz, 3H).

2-(2-ethoxy-5-cyano-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one

 8.50 (d, J = 2.3 Hz, 1H), 8.1 l (dd, J = 8.7, 2.3 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.55(s, 1H), 4.12(t, J = 6.2 Hz, 2H), 4.08(s, 6H), 1.91(m, 2H), 1.13(t, J = 7.4 Hz, 3H)

 2-(2-ethoxy-5-benzyloxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one

= 6.3 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 2.03(m, 10.22(s, 1H), 8.48(d, J = 2.4 Hz, 1H), 7.52(d, J=7.2, 2H), 7.43(t, J=7.2, 3H), 7.12(dd, J=7.3, J =6.3), 6.98(d, J=7.3, lH), 6.52(s, 1H), 5.18(s, 2H), 4.12(t, J

= 6.3 Hz, 2H), 4.05(s, 3H), 4.03(s, 3H), 2.03(m,

 2H), 1.20(t, J=7.2, 3H)

 2-(2-ethoxy-5-hydroxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4(3H)-one

10.23(s, 1H), 9.04(d, J = 2.2 Hz, 1H), 7.65(dd, J = 8.8, 2.2 Hz, 1H), 7.12(d, J = 8.8 Hz, 1H), 6.54(s, 1H ), 4.26(t, J = 6.4 Hz, 2H), 4.05(s, 3H), 4.04(s,

2- 2-丙氧基 -5-葡萄糖基胺基 -苯基 )-5，7-二甲氧基 工工 -8-溴-喹唑啉 -4(3Η)-酮 3H), 2.03(m, 2H), 1.18(t, J = 7.3 Hz, 3H)

2- 2-propoxy-5-glucosylamino-phenyl)-5,7-dimethoxy--8-bromo-quinazoline-4(3Η)-one

 O 〇 o 11.48(s, 1H), 7.46(d, J = 2.5 Hz, 1H), 7.04(dd, J =

" \工 9.0, 2.5 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.76(s, 1H), 6.26(m, 1H), 4.84(m, 1H), 4.34(t, J = 6.4 Hz, 2H), 4.02(s, 3H), 3.95(s, 3H), 3.66(m, 1H), 3.48 (m,

" \工

 1H), 3.22(m, 2H), 1.74(m, 2H), 1.00(t, J = 7.3 Hz, \ / \ o― 3H).

y ^ω = " 1 workman

 2-(2-propoxy-5-mannosylamino-phenyl)-5,7-dimethoxybenzene-8-bromo-quinazoline-4(3H)-one

3H), 3.74(m, 1H), 3.61 (m, 1H), 3.46(m, 3H), 11.49(s, 1H), 7.45(d, J = 2.5 Hz, 1H), 7.01 (dd, J = 9.0, 2.5 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 6.77(s, 1H) ), 4.73(t, J = 6.4 Hz, 2H), 4.00(s, 3H), 3.92(s,

3H), 3.74(m, 1H), 3.61 (m, 1H), 3.46(m, 3H),

 3.14(m, 1H), 1.74(m, 2H), 1.00(t, J = 7.3 Hz, 3H).

2-{2-propoxy-5-[Ν-(Ν'-ethylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H )-ketone

 11.56(s, 1H), 7.82(s, 1H), 7.64(dd, J = 8.8, 2.2 Hz, 1H), 7.18(d, J = 8.8 Hz, 1H), 6.78(s, 1H), 6.05(brs , 1H), 4.03(m,5H), 3.94(s, 3H), 3.18(m, 2H), 1.74(m, 2H), 1.04(t, J = 7.3 Hz, 3H), 0.97(t, J = 7.3 Hz, 3H)

2-{2-propoxy-5-[Ν-(Ν'-ethylureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H) Ketone

 9.50(s, 1H), 7.90(s, 1H), 7.59(dd, J = 8.8, 2.2 Hz, 1H), 7.20(d, J = 8.8 Hz, 1H), 6.81(s, 1H),,

 4.07(m,5H), 3.97(s, 3H), 3.48(m, 2H), 1.81(m, 2H), 1.13(t, J = 7.3 Hz, 3H), 1.10(t, J = 7.3 Hz, 3H )

2-{2-propoxy-5-[Ν-(Ν'-phenylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H )-ketone

7.16(t, J = 7.5, 1H)， 6.78(s, 1H)， 4.11(t， J = 6.0 Hz, 11.48(s, 1H), 9.78(d, J = 7.5 Hz, 2H), 8.02(d, J = 2.3, 1H), 7.66(dd, J = 7.2 Hz, J =2.3, 1H), 7.48(d, J = 7.5, 2H), 7.32(t, J = 7.3, 2H), 7.21(d, J = 7.3, 1H),

7.16(t, J = 7.5, 1H), 6.78(s, 1H), 4.11(t, J = 6.0 Hz,

2H), 4.12(s, 3H), 3.98(s, 3H), 1.78(m, 4H), 1.03(t, J = 7.3 Hz, 3H)

Prescription

Active compound containing pyridopyrimidinone derivative 20.0g starch 80.0g Lactose 60.0g Microcrystalline cellulose 35g

 10% polyvinylpyrrolidone ethanol solution

 Magnesium stearate 0.5g

 Co-made 1000 capsules

 The active compound containing the pyridopyrimidinone derivative and various excipients are sieved through an 80 mesh sieve, and weighed according to the prescription, using a 0% polyvinylpyrrolidone ethanol solution as a binder, and a 16 mesh sieve to prepare suitable granules, 65 Dry at °C, sieve the whole mesh with 14 mesh, add the magnesium stearate and mix evenly, measure the particle content, calculate the loading, and put it into the capsule.

Example 82 Tablets (Wet Granulation Method) Prescription

 Active compound containing pyridopyrimidinone derivative 20.0g

 Lactose 120.0g

 Microcrystalline cellulose 40.0g

 8% starch slurry

 Sodium carboxymethyl starch lO.Og

 Magnesium stearate 1.0 g

 A total of 1000 active compounds containing a pyridopyrimidinone derivative, microcrystalline cellulose, lactose, sodium carboxymethyl starch, and sieved, mixed with 8% starch slurry, 16 mesh granules, dried, After the whole granules, the magnesium stearate is added and mixed, and the content of the granules is measured, and the tablet weight is calculated, and the tablet is obtained.

 Example 83 Tablets (Powder tableting method)

 Prescription

 Active compound containing pyridopyrimidinone derivative 20.0g

 Microcrystalline cellulose 30.0g

 Anhydrous lactose 45.0g

Polyvinylpyrrolidone 3.0g Micronized silica gel 0.2g

 Magnesium stearate 0.5g

 Co-made 1000 pieces

 The active compound containing the pyridopyrimidinone derivative is mixed with microcrystalline cellulose, anhydrous lactose, polyvinylpyrrolidone, and microsilica gel in a mixer, and then mixed with magnesium stearate to obtain a tablet. Test 84 Pharmacodynamic test

 Reference male methods (International Journal of Impotence Research 2002, 14, 251 and The Journal of Urology 1992, 147, 1124), SD male rats were fasted for 12 hours, randomized, 4 rats each, with sodium pentobarbital (50mg/kg) was anesthetized by intraperitoneal injection, and the rat corpus cavernosum was exposed. The needle was inserted into the right corpus cavernosum and connected with electrophysiological instrument to monitor intracavernous pressure (ICP). The right common carotid artery was freed. The hose is connected to an electrophysiometer to continuously monitor arterial blood pressure (BP). Median incision in the lower abdomen, exposed the posterior lateral lobe of the rat, looking for the cavernous nerve on the surface, hooking the nerve with the electrode, the stimulation parameters were 3v, 2Hz, 0.5ms, the stimulation time was 60s, and the dosage was 30mg/ Kg, continuous observation of ICP and BP changes before and after treatment, comprehensive evaluation of the effect of drugs on nerve-induced erection by the ratio of ICP to BP, the parameters (ICP/BPM乍 as an indicator to judge the effect of compounds on the rat corpus cavernosum. We tested the effects of sildenafil and some of the example compounds on rat corpus cavernosum as described above. Statistical analysis was performed using Duncan's multiple comparison method to measure the difference between the blank group and the test compound. Significance, the statistical results are as follows:

 Note: *P<0.05, **P<0.01 compared with the blank group

It can be seen from the experimental data that the test compound can significantly increase the ICP of the rat corpus cavernosum, increase the ICP/BP, and enhance the penile erectile function. Therefore, it can be used as an oral drug for the treatment of erectile dysfunction. Test 55 enzyme inhibition activity test

 The enzyme used in the enzyme inhibition activity test was similar to that reported in the literature (Thrombosis Res.

1991, 62, 31 and J. Biol. Chem. 1997, 272, 2714), different tissues were appropriately treated, and the enzyme required for the test was isolated by FPLC. Specifically, PDE5 is obtained from human platelets, and PDE6 o enzyme is isolated from the retina of cattle. The enzyme inhibition test is performed immediately after isolation. The enzyme inhibition test is performed by liquid scintillation counting using the TRKQ7100 kit. This was done by adding ΙΟμΙ buffer (50 mM Tris/HCl pH 7.5, 8.3 mM MgCl ₂ , 1.7 mM EGTA) to a final volume of 100 μl at a fixed inhibitor concentration and a small amount of substrate. The enzyme initiated the reaction, incubated at 30 ° C for 30 minutes, and then terminated with 50 μl of zinc sulphate-containing yttrium silicate beads. After shaking for 20 minutes, it was allowed to settle in the dark for 30 minutes, counted on a MicroBetal 450 liquid scintillation meter, and then calculated based on the count value. The half inhibition rate (IC _5Q ) of the compound of the present invention to the enzyme.

 PDE5 inhibitory activity experiment

 According to the above method, the inhibitory activity of sildenafil and a part of the compound of the present invention on human platelet PDE5 was measured, and the results are shown in the following table:

From the inhibitory activity of the above compounds against PDE5 (IC _5Q ), it is _understood that most of the compounds of the present invention have strong PDE5 inhibitory activity.

 PDE6 inhibitory activity experiment

In view of the fact that the compound of the present invention may inhibit PDE6 distributed in the retina and thereby cause visual dysfunction, we determined the inhibition of bovine retinal PDE6 by a part of the compound of the present invention according to the above method. The activity is measured and the results are shown in the following table:

The present invention employs IC ₅ . PDE6/ IC ₅₀ PDE5 ratio to judge the patented compound for PDE6 and

The selectivity of PDE5, the results indicate that most of the example compounds have greater selectivity than sildenafil, and therefore, the compounds of the present invention are less likely to cause visual impairment than sildenafil.

Test 3 Acute toxicity test

20 10 0 0 In this test, 18-22 g of Kunming male mice were randomly divided into groups of 10 each. The compound of the example was suspended in a 0.5% sodium carboxymethylcellulose solution, administered intragastrically at a dose of 3 g/kg, and fasted for 12 hours before administration, and the virus or clinical death signal of the animal after administration was observed. The test results are shown in the following table:

20 10 0 0

 During the test, no significant clinical signs of poisoning, weight changes and death were observed in the mice after the administration. The test results show that most of the compounds described in the present invention have no significant toxicity to mice.

 The scope of the present invention is not limited by the specific embodiments, which are intended to be a single example of the various aspects of the invention, and the functionally equivalent methods and components are included within the scope of the invention. In fact, various modifications of the present invention can be readily made by those skilled in the art in light of the above description and the accompanying drawings. Such modifications are also intended to fall within the scope of the appended claims. Each of the references mentioned above is incorporated herein by reference in its entirety.

Claims

Rights request  A quinazolinone compound having the following structural formula (I), or a pharmaceutically acceptable salt thereof

 Its towel: R ¹ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, dC ₃ haloalkyl, halo, hydroxy, _alkoxy substituted by hydroxy, alkoxy, amino, amido; R ^2, R ³ and R ⁴ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, haloalkyl, ₃ dC, ₃ is dC ₃ alkoxy-substituted alkyl, or C ₃ -C ₆ cycloalkyl Substituted dC ₃ alkyl; R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ , NR ⁹ R ¹⁰ , five-membered sugar, six-membered sugar, COR ¹¹ , NHCOOR ¹¹ , COOR ¹¹ ; R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, COR ^{1 1} , S0 ₂ R ⁿ , dC ₃ alkyl substituted by a substituent selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ; R ⁸ is benzyl, acyl, sulfonyl; R ⁹ and R ^1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ; R ¹¹ is H, dC ₆ alkyl; R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² , R ¹³ together with their attached nitrogen atoms constitute Het; ^ ⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy; R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine. Or a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and optionally selected from OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl Substituted with one or more substituents in Het; Among the above,  m = 0, 1, 2; Y stands for 0, S, NR ¹⁴ ; Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy, CONH ₂ , CN, S0 ₂ NH ₂ ;  Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0. The quinazolinone compound or a pharmaceutically acceptable salt thereof according to claim 1, which is characterized in that: R ¹ is H, dC ₆ hydrocarbyl, C ₃ -C ₆ cycloalkyl, dC ₃ haloalkyl, halo, hydroxy, _alkoxy substituted by hydroxy, alkoxy, amino, amido; R ² , R ³ and R ⁴ are each independently H, dC ₆ alkyl, dC ₆ alkenyl, C ₃ -C ₆ cycloalkyl, dC ₆ haloalkyl or halogen; R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ , NR ⁹ R ¹⁰ , five-membered sugar, six-membered sugar, COR ^{1 1} , NHCOOR ^{1 1} , COOR ^{1 1} ; R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, COR ^{1 1} , S0 ₂ R ⁿ , dC ₃ alkyl substituted by a substituent selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein The nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ; R ⁸ is benzyl, acyl, sulfonyl; R ⁹ and R ^1Q are each independently H, a five-membered sugar, a six-membered sugar, an acyl group, a sulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ; R ^{1 1} is H, dC ₆ alkyl; R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² , R ¹³ together with their attached nitrogen atoms constitute Het; 11 ¹⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy; R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may form a 4 to 8 membered heterocyclic group together with the nitrogen atom to which they are attached, and the heterocyclic group is morpholinyl, thiomorpholine. Or a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and optionally selected from OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl Substituted with one or more substituents in Het; Among the above, m = 0, 1, 2; Y stands for 0, S, NR ¹⁴ ; Ar represents an aryl group substituted by one or two substituents selected from the group consisting of halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy, CONH ₂ , CN, S0 ₂ NH ₂ ;  Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0. The quinazolinone compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, dC ₆ alkyl, dC ₆ alkenyl or halogen; 11 ² is dC ₆ alkyl; R ³ is 11 or dC ₆ alkyl; 11 ⁴ is dC ₆ alkyl; R ⁵ is H, OH, halogen, nitro, carboxy, CN, S0 ₂ NR ⁶ R ⁷ , CO(CH ₂ ) _m NR ⁶ R ⁷ , OR ⁸ , NRV°, acetyl group; R ⁶ and R ⁷ are each independently H, dC ₆ alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl , NR ¹² R ¹³ , Ar or Het; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is selectively Replaced by R ¹⁴ ; R ⁸ is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl; R ⁹ and R ^1Q are each independently H, five-membered sugar, six-membered sugar, acyl group, methylsulfonyl group, p-toluenesulfonyl group, C(Y)NR ¹⁵ R ¹⁶ ; R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² , R ¹³ together with their attached nitrogen atoms constitute Het; 11 ¹⁴ is a ₆ alkyl group, which may be optionally substituted by OH, dC ₃ alkoxy; R ¹⁵ and R ¹⁶ each independently represent 11, dC ₆ alkyl; R ¹⁵ and R ¹⁶ may together with the nitrogen atom to which they are attached form a piperidinyl group, a pyrrolidinyl group or a piperazinyl group, the above heterocyclic group and may be optionally The ground is substituted with one or more substituents selected from the group consisting of OH, dC ₆ alkyl, dC ₄ alkoxy, C ₃ -C ₆ cycloalkyl, aryl and Het;  m = 0, 1, 2; Y stands for 0, S, NR ¹⁴ ; Ar represents an aryl group substituted by one or two substituents selected from halogen, NH ₂ , dC ₃ alkyl, dC ₃ alkoxy group, CONH ₂ , CN, SO2NH2  Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms selected from N, S and 0. The quinazolinone compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, dC ₆ alkyl, dC ₆ alkenyl or halogen; R ² is H or methyl; R ³ is H or methyl; R ⁴ is ethyl or n-propyl; R ⁵ is H, OH, halogen, nitro, carboxy, acetyl, CN, S0 ₂ NR ⁶ R ⁷ , CONR ⁶ R ⁷ , COCH ₂ NR ⁶ R ⁷ , OR ⁸ , NR ⁹ R ¹⁰ ; R ⁶ and R ⁷ are each independently H, dC ₃ alkyl, substituted by a substituent, and the substituent is selected from OH, decyl, dC ₄ alkoxy, NR ¹² R ¹³ ; R ⁶ and R ⁷ together with the nitrogen atom to which they are attached constitute pyrrolidine, piperidine, morpholine, piperazine, imidazole or pyrazole, wherein the nitrogen-containing heterocycle is optionally substituted by R ¹⁴ ; R ⁸ is benzyl, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl; R ⁹ and R ^1Q are each independently H, glucose, mannose, acetyl, isopropionyl, methylsulfonyl, p-toluenesulfonyl, C NR ¹⁵ R ¹⁶ ; R ¹² and R ¹³ are each independently H, dC ₆ alkyl; or R ¹² and R ¹³ together with the nitrogen atom to which they are attached constitute morpholine, piperidine, pyrrolidine heterocycle; R ¹⁴ is methyl, ethyl or propyl; R ¹⁵ and R ¹⁶ each independently represent 11, dC ₃ alkyl; R ¹⁵ and R ¹⁶ may together with the nitrogen atom to which they are attached form a piperidinyl, pyrrolidinyl or piperazinyl group;  Among the above, Y stands for 0, S, NR ¹⁴ .  The quinazolinone compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of:  2-[2-Ethoxy-5_(4-methylpiperazine- 1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3// )-ketone;  2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-bromo-quinazoline-4 (3 //) - ketone; 2-{2-propoxy-5-[N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8- Bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-(3-morpholin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4 (3//)-one;  2-{2-propoxy-5-[N-(2-diethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4 (3//)-ketone;  2-{2-propoxy-5-[N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4 (3//)-one;  2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7- Dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-methyl-N-(3-pyrrolidin-1-yl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-(2-methoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-Dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-(2-ethoxyethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7-Dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-ethyl-N-(3-piperidin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-ethyl-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-(2-(2-hydroxyethoxy)ethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-benzene -5,7-dimethoxy-8-bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-(2-(2-methoxyethoxy)ethyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl] -phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-methyl-N-(2-dimethylaminoethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy-8 - bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5, 7 -dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[[1-(4-pyridylmethyl)-1-(2-morpholin-1-yl)ethyl]aminosulfonyl]phenyl}-5, 7- Dimethoxy-8-bromo-quinazolin-4 (3H)-one; 2-{2-propoxy-5-[N-benzyl-N-(2-morpholin-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethyl Oxy-8-bromo-quinazolin-4 (3M)-one;  2-{2-propoxy-5-[N-benzyl-N-(3-morpholin-1-propyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 (3H)-one;  2-{2-propoxy-5-[N-methyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy Base-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-ethyl-N-(N-ethylpyrrolidin-2-methyl)-aminosulfonyl]-phenyl}-5, 7-dimethoxy Base-8-bromo-quinazolin-4 (3//)-one;  2-(2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (3//) Ketone  2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-chloro-quinazoline-4 (3// )-ketone;  2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-fluoro-quinazoline-4 (3// )-ketone;  2-[2-Ethoxy-5-(4-methylpiperazine-1 -1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3//) Ketone  8-ethyl_2-[2-ethoxy-5-(4-methylpiperazine-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3//)-ketone;  2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4 (3//)-one;  8-Methyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4 (3 //)-ketone;  8-ethyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3 //)-ketone;  8-propyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4 (3 //)-ketone;  8-butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3 //)-ketone;  8-butyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazoline-4 (3 //)-ketone; 8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quin Oxazoline-4 (3//)-one;  8-allyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-quinazolin-4 ( 3//)-ketone;  2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-chloro-quinazoline-4 (3 //)-ketone;  2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-fluoro-quinazoline-4 (3 //)-ketone;  2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4 (3 //)-ketone;  2-[2-Ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline -4 (3//)-ketone;  8-Methyl--2- [2-ethoxylated 5-5-(4-methylpiperazine-1-sulfonyl)phenyl]-5-hydroxy-7-methoxy-quinazoline- 4(3//)--ketone;  8-ethyl--2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)phenyl]-5-hydroxy-7-methoxy-quinazoline- 4(3//)--ketone;  8-propyl--2-[2-ethoxyethoxy-5-(4-methylpiperazin-1-sulfonyl)phenyl]-5-hydroxy-7-methoxy-quinazoline- 4(3//)--ketone;  8-butyl--2-[2-ethoxylated-5-(4-methylpiperazine-1-sulfonyl)phenyl]-5-hydroxy-7-methoxy-quinazoline- 4(3//)--ketone;  8-vinyl-2-[2-ethoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-quinazoline-4 ( 3//)-ketone;  2-(2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5-hydroxy-7-methoxy-8-iodo-quinazoline-4 (3/ /)-ketone;  2-(2-propoxy-5-(4-methylpiperazine-1-sulfonyl)-phenyl]-5,7-dimethoxy-8-iodo-quinazoline-4 (3//) Ketone  2-{2-propoxy-5-[N-(2-hydroxyethyl)-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl}-5, 7- Dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-phenyl-N-(2-mercapto-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 (3H)-one; 2-{2-propoxy-5-[N-(pyridine-3-methyl)-N-(3-mercapto-1-propyl)-aminosulfonyl]-benzene -5,7-dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-benzyl-N-(2-indolyl-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 ( 3H)-one;  2-{2-propoxy-5-[N-(pyridine-4-methyl)-N-(3-mercapto- 1-propyl)-aminosulfonyl]-phenyl} -5, 7 -dimethoxy-8-bromo-quinazolin-4 (3//)-one;  2-{2-propoxy-5-[N-ethyl-N-(2-indolyl-1-ethyl)-aminosulfonyl]-phenyl}-5,7-dimethoxy- 8-bromo-quinazolin-4 ( 3H)-one;  2-[2-propoxy-5-(acetamido)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-{2-propoxy-5-[1-(2-methyl-3-ethyl)thioureido]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4 (3H ketone;  2-{2-propoxy-5-[2-(1-ethyl-2-diethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4 (3H ketone;  2-(2-ethoxy-5-acetyl-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-{2-propoxy-5-[N,N-bis-(4-methylbenzenesulfonyl)-amino]-phenyl}-5,7-dimethoxy-8-bromo-quin Oxazoline-4 (3H ketone;  2-{2-propoxy-5-[(N,N-dimethylsulfonyl)amino)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (3H ketone;  2-[2-propoxy-5-(2-methylpropionamido)-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone; 2-{ 2-propoxy-5-[N-(4-methylphenylsulfonyl)amino]-phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone;  2-(2-ethoxy-5-cyano-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-ethoxy-5-benzyloxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-ethoxy-5-hydroxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-propoxy-5-acetoxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-propoxy-5-(4-methylbenzenesulfonyl)-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone; 2-(2-propoxy-5-benzoyloxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone; 2-[2-propoxy-5-(N,N-diethyl)-aminoacyl-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone ; 2-[2-propoxy-5-(4-methylpiperazin-1-yl)-phenyl]-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone; 2-(2-propoxy-5-glycosylamino-phenyl)-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone; 2-(2-propoxy) -5-mannosylamino-phenyl)-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone; 2-{2-propoxy-5-[Ν-( Ν'-ethylthioureido]]-phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 (JH ketone;  2-{2-propoxy-5-[Ν-(Ν'-ethylureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone ; 2-{2-propoxy-5-[Ν-(Ν'-phenylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 ( JH ketone;  2-{2-propoxy-5-[Ν-(Ν'-methylthioureido)]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline-4 (JH Ketone  2-{2-propoxy-5-{2-[1-ethyl-2-(2-methylethyl)]indolyl}-phenyl}-5,7-dimethoxy-8- Bromo-quinazolin-4 (JH ketone;  2-{2-propoxy-5-[2-(1,3-diethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazolin-4 ( JH ketone;  2-{2-propoxy-5-[2-(1-ethyl-2-phenylmethyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline Porphyrin-4 (3H ketone;  2-{2-propoxy-5-[2-(1-ethyl-2-piperidyl)indolyl]-phenyl}-5,7-dimethoxy-8-bromo-quinazoline -4 (3H ketone;  2-(2-propoxy-5-bromo-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-propoxy-5-carboxy-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-(2-propoxy-5-acetyl-phenyl)-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone;  2-[2-Propoxy-5-(2-methyl-propionyloxy)-phenyl]-5,7-dimethoxy-8-bromo-quinazoline-4 (JH ketone.  The quinazolinone compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride, a sulfate, a phosphate, a formate, an acetate or a propionic acid. Salt, succinate, glycolate, gluconate, lactate, malate, tartrate, glycinate, arginine, citrate, fumarate, aryl sulfonate Alkyl sulfonate, especially methanesulfonate. A pharmaceutical composition comprising an effective amount of the quinazolinone compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier. The use of the quinazolinone compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for PDE5 inhibitor.  The quinazolinone compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, or a pharmaceutically acceptable composition thereof, which is prepared for treatment or Prevention of male erectile dysfunction, benign prostatic hyperplasia, female sexual dysfunction, premature labor, dysmenorrhea, bladder outlet obstruction, incontinence, instability and variation of Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, arterial atherosclerosis Uses of humans with drugs such as sclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory diseases, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by bowel movements.  A process for the preparation of a quinazolinone compound of the formula (I) according to claim 1, which is characterized in that: When R ¹ is halogen, R ^{3 is} not H, and R ² , R ⁴ , R ^{5 are} as defined in claim 1 (I-A), and are obtained from anthracene ring;

When R ^{1 is} not halogen, R ^{3 is} not H, R ² , R ⁴ , R ^{5 are} as defined in claim 1, and the compound in I-A can be reacted with a hydrocarbyl metal reagent to obtain I -B;

 I -A I -B When R ³ is H, RR ² , R ⁴ , R ^{5 are} as defined in claim 1, and can be obtained by reacting a compound of the corresponding first type of moiety I-A or I-B with a dealkylating agent. IC.

 I -A, I -B I -C 11. The preparation method according to claim 10, wherein: 制 is obtained by the following reaction:

 m κ II  The preparation method according to claim 11, wherein: m is obtained by the following reaction:

m iv

RR ² , R ³ , R ⁴ , R5 are as defined in claim 1.