CN1746171A - Heterocycle hepyramine derivative, preparation method and purposes - Google Patents

Abstract

The present invention relates to a series of heterocyclic pyrimidinone derivatives (1), their preparation methods, intermediates in the preparation process and pharmaceutically acceptable compositions containing them. These compounds can inhibit cGMP-specific phosphodiesterase, especially can effectively inhibit V-type phosphodiesterase (PDE5), so they can be applied to the treatment of various diseases.

Description

Heterocyclic pyrimidinone derivatives, preparation methods and uses

technical field

The present invention relates to a series of heterocyclic pyrimidinone derivatives (1), their preparation methods, intermediates in the preparation process and pharmaceutically acceptable compositions containing them. These compounds can inhibit cGMP-specific phosphodiesterase, especially can effectively inhibit V-type phosphodiesterase (PDE5), so they can be applied to the treatment of various diseases.

Background technique

International application WO 94/28902 (CN 1124926A) discloses the use of pyrazolo[4,3-d]pyrimidin-7-one derivatives as cGMP-specific phosphodiesterase inhibitors for the treatment of erectile dysfunction. There are imidazo[5,1-f][1,2,4]triazin-4-one derivatives of WO 99/24433 (CN1278822T), pyrrolo[4, 3-d] pyrimidin-7-one derivatives, and imidazoquinazolinone derivatives of WO 99/64004, all contain pyrimidinone structures, and have strong inhibitory activity of V-type phosphodiesterase (PDE5).

PDE5 inhibitors can increase the content of cGMP in smooth muscle cells, the latter activates protein kinase G (PKG), and PKG phosphorylates corresponding target proteins, including smooth muscle myosin phosphorylation, causing smooth muscle relaxation and vasodilation, thus affecting It has therapeutic effect on various vascular disorders. The first PDE5 inhibitor on the market, Sildenafil, is clinically used for male erectile dysfunction, and is also effective for female sexual dysfunction and essential hypertension. PDE5 inhibitors under development are also used for diabetic gastrointestinal symptoms, insulin resistance and hyperlipidemia.

Contents of the invention

The object of the present invention is to provide a new class of heterocyclic pyrimidinone derivatives.

Another object of the present invention is the preparation method of such derivatives.

Another object of the invention is the use of such derivatives.

The present inventors designed and synthesized a series of novel heterocyclic pyrimidinone derivatives (1), and found that these compounds can effectively inhibit PDE5. Therefore, these compounds can be used to treat or prevent a variety of vascular disorders in mammals (including humans), including male (male) erectile dysfunction, female (female) sexual dysfunction, premature birth, dysmenorrhea, benign prostatic hyperplasia, Bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis , chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disturbances in bowel motility (eg, irritable bowel syndrome).

in

Ring B is a substituted or unsubstituted pyridine ring, ring A is an imidazole or pyrazole ring, that is, ring B, ring A and pyrimidinone ring together form compounds of formulas (1A), (1B), (1C) and (1D) :

Among them, X is CH or N;

R is a substituent of ring B, n represents the number of substituents, n=1, 2, 3 or 4; R can be independently H, halogen, nitro, cyano, NR ³ R ⁴ , CO(CH ₂ ) _m NR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, wherein the hydrocarbon group can be optionally replaced by one or more Halogen atoms are substituted;

R ¹ is H, or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, the hydrocarbon group can be optionally replaced by one or more halogen atoms or C ₁ -C ₄ Alkoxy substitution;

R ² is SO ₂ NR ³ R ⁴ , NHSO ₂ NR ³ R ⁴ , NHSO ₂ R ⁵ , NHCOR ⁵ , NHCOOR ⁵ , NHCONHR ⁵ , CO(CH ₂ ) _m NR ³ R ⁴ , (CH ₂ ) _m Ar or ( CH ₂ ) _m Het, wherein CH ₂ can be optionally substituted by one or more halogen atoms or OH;

R ³ and R ⁴ are each independently H, or C ₁ -C ₆ alkyl, which can optionally be replaced by OH, CO ₂ H, C ₁ -C ₃ alkoxy, Ar, Het, NR ⁶ R ⁷ Substituted, or optionally substituted by one or more halogen atoms; or form a ring with the nitrogen atom to which they are attached, such as aziridine (aziridine), azetidine (azetidine), pyrrolidine , piperidine, morpholine, piperazine, homopiperazine, imidazole, imidazoline and pyrazole, wherein the nitrogen-containing heterocycle can be optionally substituted by R ⁸ ;

R ⁵ is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl optionally substituted by one or more halogen atoms; or (CH ₂ ) _m Ar or (CH ₂ ) _m Het;

R ⁶ and R ⁷ are each independently H, or C ₁ -C ₆ alkyl, the alkyl may be optionally substituted by OH, C ₁ -C ₃ alkoxy, hydroxyl C ₁ -C ₃ alkoxy;

R ⁸ is a C ₁ -C ₆ alkyl group, which may optionally be replaced by one or more halogen atoms, OH, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CO(CH ₂ )mNR ¹⁰ R ¹¹ , C ₁ - C ₃ alkoxy (which can optionally be replaced by one or more halogen atoms, OH, C ₁ -C ₃ alkoxy, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CO(CH ₂ ) _m NR ¹⁰ R ¹¹ replace) replace;

R ⁹ is H, or can optionally be replaced by OH, NR ¹⁰ R ¹¹ , one or more halogen atoms, or as a nitrogen-containing heterocycle (such as pyrrolidine, piperidine, piperazine, morpholine, pyrrolidine, and imidazole) Substituted C ₁ -C ₄ alkyl;

R ¹⁰ and R ¹¹ are each independently H or C ₁ -C ₄ alkyl;

of the above

m = 0, 1 or 2;

Ar represents phenyl substituted by one or two substituents selected from halogen, NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CONH ₂ , CN, SO ₂ NH ₂ ;

Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms are selected from N, S and O, and are optionally substituted by one or two substituents, the substituents are selected from halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ alkoxy.

In one aspect, the invention provides a compound of formula (1).

In the above definitions, unless otherwise specified, an alkyl or alkoxy group having three or more carbon atoms may be straight or branched. Halogen means fluorine, chlorine, bromine or iodine.

Compounds of formula (1) may contain one or more chiral centers and thus may exist as stereoisomers, ie enantiomers or diastereomers, and mixtures thereof. The present invention includes the individual stereoisomers of the compound of formula (1) and mixtures thereof. The diastereoisomers may be separated by conventional techniques, for example, a diastereomeric mixture of a compound of formula (1) or a suitable salt or derivative thereof by fractional crystallization or chromatography (including HPLC) . The single enantiomers of formula (1) can be prepared from the corresponding optically pure intermediates or by resolution using chiral columns, or by reacting with optically active acids or bases to form diastereoisomers The body salt crystallizes step by step.

The compound of formula (1) may exist in the form of tautomers, and the present invention includes mixtures and single tautomers thereof.

The present invention includes radiolabeled derivatives of compounds of formula (1), which derivatives are suitable for biological research.

The present invention includes pharmaceutically acceptable salts of compounds of formula (1), for example, non-toxic acid addition salts formed with inorganic salts such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, with organic carboxylic or organic sulfonic acids. Compounds of formula (1) can also be reacted with bases to provide pharmaceutically acceptable metal salts, especially non-toxic alkali metal salts (eg sodium and potassium salts). Preferred salts are methanesulfonate and hydrochloride.

The present invention includes pharmaceutically acceptable solvates (eg, hydrates) of compounds of formula (1).

The present invention also includes oxides of compounds of formula (1), and pharmaceutically acceptable salts and solvates thereof.

The present invention also includes prodrugs of the compound of formula (1), such as ester, amide, Schiff base and other forms of the compound of formula (1), and pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof.

Among preferred compounds of formula (1),

B ring is a substituted or unsubstituted pyridine ring, A ring is an imidazole or pyrazole ring, and X is CH; that is, B ring, A ring and pyrimidone ring together form the formula (1A ₁ ), (1B ₁ ), ( 1C ₁ ) and (1D ₁ ) compounds:

in

R is a substituent of ring B, n represents the number of substituents, n=1, 2, 3 or 4; R can be independently H, halogen, nitro, cyano, NR ³ R ⁴ , CONR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, wherein the hydrocarbon group can be optionally substituted by one or more halogen atoms;

R ¹ is H, or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, the hydrocarbon group can be optionally replaced by one or more halogen atoms or C ₁ -C ₄ Alkoxy substitution;

R ² is SO ₂ NR ³ R ⁴ , CONR ³ R ⁴ , Ar or Het, wherein CH ₂ may be optionally substituted by one or more halogen atoms or OH;

R ³ and R ⁴ are each independently H, or C ₁ -C ₆ alkyl, which can optionally be replaced by OH, CO ₂ H, C ₁ -C ₃ alkoxy, Ar, Het, NR ⁶ R ⁷ Substituted, or optionally substituted by one or more halogen atoms; or form a ring with the nitrogen atom to which they are attached, such as aziridine (aziridine), azetidine (azetidine), pyrrolidine , piperidine, morpholine, piperazine, homopiperazine, imidazole, imidazoline and pyrazole, wherein the nitrogen-containing heterocycle can be optionally substituted by R ⁸ ;

R ⁵ is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl optionally substituted by one or more halogen atoms; or Ar or Het;

R ⁶ and R ⁷ are each independently H, or C ₁ -C ₆ alkyl, the alkyl may be optionally substituted by OH, C ₁ -C ₃ alkoxy, hydroxyl C ₁ -C ₃ alkoxy;

R ⁸ is C ₁ -C ₆ alkyl, which can be optionally replaced by one or more halogen atoms, OH, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CONR ¹⁰ R ¹¹ , C ₁ -C ₃ alkoxy (which may be optionally substituted by one or more halogen atoms, OH, C ₁ -C ₃ alkoxy, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CONR ¹⁰ R ¹¹ substituted);

R ⁹ is H, or can optionally be replaced by OH, NR ¹⁰ R ¹¹ , one or more halogen atoms, or as a nitrogen-containing heterocycle (such as pyrrolidine, piperidine, piperazine, morpholine, pyrrolidine, and imidazole) Substituted C ₁ -C ₄ alkyl;

R ¹⁰ and R ¹¹ are each independently H or C ₁ -C ₄ alkyl;

of the above

Ar represents phenyl substituted by one or two substituents selected from halogen, NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CONH ₂ , CN, SO ₂ NH ₂ ;

Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms are selected from N, S and O, and are optionally substituted by one or two substituents, the substituents are selected from halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ alkoxy.

Among particularly preferred compounds of formula (1),

B ring is a substituted or unsubstituted pyridine ring, A ring is an imidazole or pyrazole ring, X is CH, R ² is SO ₂ NR ³ R ⁴ , that is, B ring, A ring and pyrimidone ring together form the formula (1A _1a ), and (1C _1a ) compounds:

R is a substituent of ring B, n represents the number of substituents, n=1 or 2; each R is independently H, halogen, nitro, cyano, NR ³ R ⁴ , CONR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl;

^R is ethyl, n-propyl or isopropyl;

R ³ and R ⁴ are each independently C ₁ -C ₄ alkyl, or form pyrrolidine, piperidine and piperazine together with their connected nitrogen atoms, wherein the group can be optionally substituted by R ⁸ ;

R ⁵ is C ₁ -C ₆ alkyl;

R ⁸ is C ₁ -C ₄ alkyl, which may be optionally substituted by OH, C ₁ -C ₃ alkoxy.

Particularly preferred specific compounds of the invention include:

2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-6-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-isopropylpiperazinyl)sulfonyl)phenyl)-6-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-8-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-8-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-9-ethyl-pyrido[1,2-e]purin-4(3H)-one

2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purine-4(3H )-ketone

2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3-d]pyrimidine -4(3H)-one

2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3-d]pyrimidine -4(3H)-one

and pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable solvates (eg hydrates).

In another aspect, the present invention provides a process for the preparation of compounds of formula (1), pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable solvates.

The present invention also includes any novel intermediates in the preparation process and their preparation methods, such as compounds of the following formulas (2), (9), (10) and (14) and their preparation methods.

Synthetic route 1. formula (1) compound can be obtained from formula (2) (wherein B ring is a pyridine ring, A ring is imidazole or pyrazole ring, X, R, n, R ¹ are as defined above; G is a sulfonyl halide, amino, cyano or haloformyl group, and Y represents a halogen atom, preferably a chlorine atom) compound preparation.

The reaction of the compound of formula (2) (when G is SO ₂ Y) with the compound of formula (3) (R ³ and R ⁴ are as defined above), usually at 0°C to room temperature, in a suitable solvent, such as ethanol, N,N-dimethylformamide, dimethyl sulfoxide, dichloromethane, dichloroethane, chloroform, ethyl acetate, tetrahydrofuran or water, for 0.1-20 hours, use excess (3), or add organic Alkali or inorganic base is used as acid scavenger, preferably triethylamine.

The reaction of the compound of formula (2) (when G _is NH ) with the compound of formula (4)-( ⁸ ) (wherein R is as defined above, and Y represents a halogen atom, preferably a chlorine atom), usually at 0°C to room temperature , in a suitable solvent, such as dichloromethane or tetrahydrofuran, for 1-48 hours, use an excess of formula (4)-(8) compound, or add an organic base or an inorganic base as an acid removal agent, preferably triethylamine .

Formula (2) compound (when G is CN) can be under Lewis acid catalysis, at the reflux temperature of suitable solvent, react with NaN ₃ reaction, be converted into corresponding tetrazole derivative; Reaction, into the corresponding imidazoline derivatives. The compound of formula (2) (when G is CN) can also be hydrolyzed into carboxylic acid under acidic or alkaline conditions, and the latter can react with the compound of formula (3) in the presence of dehydrating agents such as CDI or EDAC/HOBt to generate Corresponding compounds of formula (1) in which R ² is a COCH ₂ NR ³ R ⁴ group.

Formula (2) compound (when G is COCH ₂ Y time) can obtain corresponding derivative with excessive formula (3) compound in suitable solvent; reaction to generate the corresponding thiazole derivatives.

Compounds of formulas (3)-(8) are generally commercially available or, when not available, are prepared by known literature methods.

Utilize mature organic ^synthesis method, can prepare formula ( ² ) compound:

To prepare compounds of formula (2) (when G is _SO2Y ) from compounds of formula (9) (when G is H), known methods of introducing sulfonyl halides into aromatic rings can be applied, for example when the halogen is chlorine , React with excess chlorosulfonic acid at low temperature without additional solvent. To prepare compounds of formula (2) (when G is COCH ₂ Y) from compounds of formula (9) (when G is H), Friedel-Crafts reactions of haloacetyl halides in the presence of Lewis acids can be used. To prepare the compound of formula (2) (when G is NH ₂ ) from the compound of formula (9) (when G is NO ₂ ), reduction methods such as catalytic hydrogenation or metal reducing agents (zinc, iron, SnCl ₂ ) can be applied. From the compound of formula (9) (when G is Br) to prepare the compound of formula (2) (when G is CN), it can be applied to the replacement of CuCN in a high boiling solvent (such as 1-methyl-2-pyrrolidone) Reaction, the temperature is generally 100-250 ℃.

Formula (9) compound (when G is _NO ) can be obtained through nitration reaction by formula (9) compound (when G is H); similarly, formula (9) compound (when G is Br) can be obtained by formula (9) The compound (when G is H) is obtained by bromination.

Another way to prepare compounds of formula (9) (when G is H, _NO or Br) is to apply known pyrimidinone ring closure methods from formula (10) (wherein B, A, X, R, n, R ^a , R ¹ are as defined above, and G is H, nitro or bromine atom) the compound is obtained by ring closure. The reaction is usually carried out in an appropriate solvent (such as water, alcohol-water mixed solvent, halogenated hydrocarbon or acetonitrile) in the presence of acid or base, and the temperature is usually 50-200°C.

Formula (10) can be prepared from compounds of formula (11) and formula ( ¹² ) (wherein X and R are as defined above, and G is H, nitro or a bromine atom, Y is a hydroxyl group or a halogen, preferably chlorine) Compound:

Usually, the carboxylic acid (Y=OH) of the compound of formula (12) is first converted into the corresponding acid chloride, preferably SOCl ₂ or oxalyl chloride as the reaction reagent. Then with the excess acid chloride (Y=Cl) of the compound of formula (12), in the presence of an acid-removing agent (preferably triethylamine and pyridine), in an anhydrous inert solvent (such as chloroform or dichloromethane), with the formula ( 11) The compound completes the coupling reaction to obtain the compound of formula (10).

The carboxylic acid (Y=OH) of the compound of formula (12) is commercially available or obtained using methods known in the literature.

Compounds of formula (11) can generally be prepared from compounds of formula (13). For example, a method is that the compound of formula (13-1) (ie formula 13, when G ₁ is H, G ₂ is OCH ₃ or OC ₂ H ₅ ) is nitrated to obtain the compound of formula (13-2) (ie formula 13 , when G ₁ is NO ₂ , G ₂ is OCH ₃ or OC ₂ H ₅ ), the latter undergoes amidation to obtain a compound of formula (13-4) (that is, formula 13, when G ₁ is NO ₂ , G ₂ is NH ₂ ), then through reduction to obtain the compound of formula (11); Another method is the compound of formula (13-1) (i.e. formula 13, when G ₁ is H, G ₂ is OCH ₃ or OC ₂ H ₅ ) The compound of formula (13-3) is obtained through nitrosation (i.e. formula 13, when G ₁ is NO, G ₂ is OCH ₃ or OC ₂ H ₅ ), and the latter is reduced to obtain the compound of formula (13-5) (i.e. formula 13. When G ₁ is NH ₂ and G ₂ is OCH ₃ or OC ₂ H ₅ ), the compound of formula (11) can be obtained by amidation.

In some cases, however, compounds of formula (11) or (13) are directly commercially available, or can be obtained using methods known in the literature. For example, the amino group of the compound of formula (13-5) (that is, formula 13, when G ₁ is NH ₂ , G ₂ is OCH ₃ or OC ₂ H ₅ ) can be introduced in the heterocycle synthesis without going through nitro or nitroso Restoration steps.

Synthetic route 2. Utilize above-mentioned pyrimidinone cyclization method, formula (1) compound (when R ² is SO ₂ NR ³ R ⁴ , and B, A, X, R, n, R ¹ , R ³ , R ⁴ As defined above) can also be directly obtained from the compound of formula (14) (wherein G is SO ₂ NR ³ R ⁴ , and B, A, X, R, n, R ¹ , R ³ , R ⁴ are as defined above).

The reaction is usually carried out in an appropriate solvent (such as water, alcohol-water mixed solvent, halogenated hydrocarbon or acetonitrile) in the presence of acid or base, and the temperature is usually 50-200°C.

The compound of formula (14) can be prepared by the coupling reaction of compounds of formula (11) and formula (15) (wherein X, R ¹ , R ³ , R ⁴ are as defined above, and Y is hydroxyl or halogen, preferably chlorine). Usually, the carboxylic acid (Y=OH) of the compound of formula (15) is first converted into the corresponding acid chloride (Y=Cl) of the compound (15), and then with an excess of acid chloride, in the presence of an acid-removing agent, in anhydrous inert solvent The reaction is completed with the compound of formula (11).

The carboxylic acid (Y=OH) of the compound of formula (15) is commercially available or obtained by methods known in the literature. The preparation of the compound of formula (11) is as described above.

Synthetic route 3. formula (1) compound (when R ² is SO ₂ NR ³ R ⁴ , X is CH, and B, A, R, n, R ¹ , R ³ , R ⁴ are as defined above) and formula ( 9) Compounds (when R ² is H, X is CH, and B, A, R, n, R ¹ , R ³ , R ⁴ are as defined above) can also be obtained by combining the compound of formula (11) with the corresponding substituted benzene Reaction preparation of compound of formaldehyde formula (16) (wherein R ² is SO ₂ NR ³ R ⁴ or H, and R ¹ , R ³ , R ⁴ are as defined above). (The compound of the obtained formula (9) can obtain the compound of the formula (1) according to the synthetic route 1.)

There are many kinds of reaction conditions that can be applied, for example: i) in a suitable solvent, add NaHSO ₃ as an oxidant, and proceed under heating conditions (usually higher than 100 °C); ii) in a suitable solvent, first add a catalytic amount of acid (preferably p-toluenesulfonic acid), after heating for 2-20h, add DDQ as an oxidant, and continue the reaction for 2-48h; iii) in a suitable solvent, add a transition metal salt (preferably CuCl ₂ ) as a catalyst, under heating conditions ( Usually 50-200°C).

At the same time, the present invention provides a pharmaceutically acceptable composition, which is composed of the compound of formula (1) (or its pharmaceutically acceptable salt, or their pharmaceutically acceptable solvate) and appropriate pharmaceutically acceptable excipients. The selection of pharmaceutical excipients varies depending on the route of administration and the characteristics of the action, usually fillers, diluents, binders, wetting agents, disintegrants, lubricants, emulsifiers, suspending agents, etc.

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

The present invention also provides a preparation method of the pharmaceutically acceptable composition of the compound of formula (1). Usually, the compound of formula (1) is mixed with pharmaceutical excipients, and prepared into a form (dosage form) suitable for administration by a certain route through conventional preparation methods. Dosage forms include tablets, capsules, granules, pills, solutions, suspensions, emulsions, ointments, films, creams, aerosols, injections, suppositories, and the like. Tablets and capsules are preferred.

The composition of tablets and capsules may contain one or more compounds of formula (1), and one or more commonly used excipients, such as starch, sucrose, lactose, glucose, microcrystalline cellulose, mannose and other fillers; Binders such as carboxymethylcellulose, gelatin, alginate, and polyvinylpyrrolidone; wetting agents such as glycerin; disintegrants such as agar, ethyl cellulose, sodium carboxymethyl starch, calcium carbonate, etc.; magnesium stearate , talcum powder, polyethylene glycol and other lubricants.

In addition, the present invention also provides the compound of formula (1) or its pharmaceutically acceptable salt, or their pharmaceutically acceptable solvate, or a pharmaceutically acceptable composition containing any of them, as human (or animal) medicine use.

The present invention also provides the use of the compound of formula (1) or its pharmaceutically acceptable salt, or their pharmaceutically acceptable solvate in the preparation of human (or animal) medicines for treating or preventing diseases requiring the use of PDE5 inhibitors.

The present invention also provides a compound of formula (1) or its pharmaceutically acceptable salt, or their pharmaceutically acceptable solvate, or a pharmaceutically acceptable composition containing any of them, used for the treatment or prevention of erectile dysfunction, female Sexual dysfunction, premature labor, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral Vascular disease, Raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and diseases characterized by disturbance of bowel motility (such as irritable bowel syndrome) in humans (or animals) Use) in medicine.

In another aspect, the present invention provides a method for treating or preventing erectile dysfunction, female sexual dysfunction, premature birth, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, instability and variants in mammals (including humans). Prinzmetal Angina, Hypertension, Pulmonary Hypertension, Congestive Heart Failure, Renal Failure, Atherosclerosis, Stroke, Peripheral Vascular Disease, Raynaud's, Inflammatory Disease, Bronchitis, Chronic Asthma, Allergic Asthma, Allergic Rhinitis , glaucoma, and a method for diseases characterized by intestinal peristalsis (such as irritable bowel syndrome), the method comprising administering to a mammal a therapeutically effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable Solvates, or pharmaceutically acceptable compositions containing any of them.

Determination of PDE5 inhibitory activity of compounds

With reference to the literature (Methods Enzymol 1988,159,457-470) method, the inhibitory activity of the formula (1) compound of the present invention to human platelet PDE5 was measured, and the measurement results are shown in the table below: Compound (Example No.) _IC50 (mol/l) 2 4.87×10 ^-10 3 7.97×10 ^-7 4 1.11×10 ^-7 5 8.01×10 ^-8 6 8.98×10 ^-8 10 3.93×10 ^-7 12 8.69×10 ^-8

Detailed ways

Examples and Preparations

The following examples and preparation examples further explain the synthesis, formulation and preparation methods of the compounds of the present invention and their intermediates, but do not limit the scope of the present invention.

¹ H NMR was performed on a Mercury-400 nuclear magnetic resonance spectrometer (Varian Company), and the observation frequency of ¹ H NMR was 400.144 MHz. Conventional abbreviations are as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Mass spectrometry was performed on a MAT-95 mass spectrometer (Thermo Finnigan Company), ionization mode EI 70V source temperature 200°C, LR resolution 1000.

Room temperature refers to 20-25°C.

Preparation Example 1 3-nitro-imidazo[1,2-a]pyridine-2-carboxamide

Take ethyl 3-nitro-imidazo[1,2-a]pyridine-2-carboxylate (see Eur J Med Chem1978, 271-276 for preparation) (4.7g, 20mmol) in THF (35ml), add 33 % ammonia water (10ml), stirred at 50°C for 5-26h, and detected the end of the reaction by TLC. After the reaction, the reaction mixture was cooled to room temperature and left overnight, and crystals were precipitated. The crude product was recrystallized from MeOH to give the product (3.96g). Yield 96.1%. ¹ H NMR (DMSO-d ₆ ) δ7.52 (ddd, J=7.0Hz, 7.0Hz, 1.1Hz, 1H, H-6), 7.85 (ddd, J=8.9Hz, 7.0Hz, 1.2Hz, 1H, H-7), 7.93 (br s, 1H, CONH ₂ ), 7.98 (dd, J=8.9Hz, 1.1Hz, 1H, H-8), 8.09 (br s, 1H, CONH ₂ ), 9.33 (dd, J=7.0Hz, 1.2Hz 1H, H-5); EI-MS m/z 206.

Preparation Example 2 5-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxamide

According to the same method of Preparation Example 1, with ethyl 5-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxylate (see Eur J Med Chem 1978, 271-276 for the preparation method) and Ammonia reaction. The recrystallization solvent was MeOH. Yield 90.5%. ¹ HNMR (DMSO-d ₆ ) δ 2.53 (s, 3H, CH ₃ ), 7.22 (d, J=6.9Hz, 1H, H-6), 7.66 (dd, J=9.0Hz, 6.9Hz, 1H, H-7), 7.76(d, J=9.0Hz, 1H, H-8), 7.87(br s, 1H, CONH ₂ ), 8.15(br s, 1H, CONH ₂ ); EI- MS m/z 220.

Preparation Example 3 6-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxamide

According to the same method of Preparation Example 1, with ethyl 6-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxylate (see Bull Soc Chim Fr 1979, 529-535 for the preparation method) and Ammonia reaction. The recrystallization solvent was MeOH. Yield 93.6%. ¹ HNMR (DMSO-d ₆ ) δ 2.47 (s, 3H, CH ₃ ), 7.73 (d, J=9.0Hz, 1H, H-7), 7.89 (d, J=9.0Hz, 1H, H-8), 7.90 (br s, 1H, CONH ₂ ), 8.09 (br s, 1H, CONH ₂ ), 9.16 (s, 1H, H-5); EI-MS m/z 220.

Preparation Example 4 8-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxamide

According to the same method of Preparation Example 1, with ethyl 8-methyl-3-nitro-imidazo[1,2-a]pyridine-2-carboxylate (see Bull Soc Chim Fr 1979, 529-535 for the preparation method) and Ammonia reaction. The recrystallization solvent was MeOH. Yield 87.2%. ¹ HNMR (DMSO-d ₆ ) δ 2.57 (s, 3H, CH ₃ ), 7.41 (dd, J=7.6Hz, 7.1Hz, 1H, H-6), 7.67 (d, J= 6.7Hz, 1H, H-7), 7.92(br s, 1H, CONH ₂ ), 8.07(br s, 1H, CONH ₂ ), 9.17(d, J=7.6Hz, 1H, H-5); EI- MS m/z 220.

Preparation Example 5 3-amino-imidazo[1,2-a]pyridine-2-carboxamide

Method A Take the compound of Preparation 1 (3.1g, 15mmol), add EtOH (40ml), THF (20ml), 10% Pd-C (0.2g), react at 60°C and 15kg hydrogen pressure for 2-24h, and detect by TLC end point of the reaction. After the reaction was complete, the catalyst was filtered off and concentrated to dryness. Recrystallization from EtOH/Acetone gave the product (2.24g). Yield 84.9%. ¹ H NMR (DMSO-d ₆ ) δ6.08 (br s, 2H, NH ₂ ), 6.81 (dd, J=7.0Hz, 6.4Hz, 1H, H-6), 7.04 (br s , 1H, CONH ₂ ), 7.06 (dd, J=8.7Hz, 6.4Hz, 1H, H-7), 7.25 (br s, 1H, CONH ₂ ), 7.34 (d, J=8.7Hz, 1H, H- 8), 8.11 (d, J=7.0Hz, 1H, H-5); El-MS m/z 176.

Method B Suspend the compound of Preparation 1 (1.5g, 8.5mmol) in 2N hydrochloric acid (40ml), add zinc powder (1.65g, 25.4mmol) in batches under vigorous stirring, and stir at room temperature for 30min after the addition is complete. A small amount of insoluble matter was removed by filtration, the filtrate was adjusted to neutral with saturated Na ₂ CO ₃ solution, extracted with EtOAc, the combined organic phases were washed with saturated brine, dried, and concentrated to dryness to obtain a yellow solid. Recrystallization from EtOH/Acetone gave the product (1.03g). Yield 68.9%

Preparation Example 6 3-amino-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide

According to the same method as Method A of Preparation Example 5, the compound of Preparation Example 2 was used as the reaction raw material. The recrystallization solvent was MeOH/EtOAc. Yield 87.7%. ¹ H NMR (DMSO-d ₆ ) δ 2.88 (s, 3H, CH ₃ ), 5.84 (br s, 2H, NH ₂ ), 6.41 (d, J=6.5Hz, 1H, H- 6), 6.91 (d, J=9.1Hz, 1H, H-8), 7.13 (dd, J=9.1Hz, 6.5Hz 1H, H-7), 7.16 (br s, 1H, CONH ₂ ), 7.39 ( br s, 1H, CONH ₂ ); EI-MS m/z 190.

Preparation Example 7 3-amino-6-methyl-imidazo[1,2-a]pyridine-2-carboxamide hydrochloride

According to the same method as Method B of Preparation Example 5, the compound of Preparation Example 3 was used as the reaction raw material. The crude product was dissolved in MeOH, and hydrochloric acid-MeOH solution was added dropwise to pH2. Put it in a refrigerator at 4°C, and the product hydrochloride precipitates out. Recrystallized from MeOH/water. Yield 89.2%. ¹ H NMR (D ₂ O) δ 2.44 (s, 3H, CH ₃ ), 7.63 (d, J=9.4Hz, 1H, H-7), 7.76 (d, J=9.4Hz, 1H, H-8), 8.14(s, 1H, H-5); EI-MS m/z 190.

Preparation Example 8 3-amino-8-methyl-imidazo[1,2-a]pyridine-2-carboxamide

According to the same method as Method A of Preparation Example 5, the compound of Preparation Example 4 was used as the reaction raw material. The recrystallization solvent was MeOH/EtOAc. Yield 81.3%. ¹ H NMR (DMSO-d ₆ ) δ 2.38 (s, 3H, CH ₃ ), 6.01 (br s, 2H, NH ₂ ), 6.70 (dd, J=6.9Hz, 6.7Hz, 1H , H-6), 6.87 (d, J=6.7Hz, 1H, H-7), 6.96 (br s, 1H, CONH ₂ ), 7.14 (br s, 1H, CONH ₂ ), 7.96 (d, J= 6.9Hz, 1H, H-5); EI-MS m/z 190.

Preparation Example 9 3-amino-pyrido[1,5-a]pyrazole-2-carboxamide

Take 3-amino-pyrido[1,5-a]pyrazole-2-carboxylic acid methyl ester (see EP 0433854 for the preparation method, by nitrosation of pyrido[1,5-a]pyrazole-2-carboxylic acid methyl ester and reduction) (7.38g, 38.6mmol) was dissolved in MeOH (200ml), fed with ammonia gas to saturation, and heated to reflux under stirring for 48h. Heating was stopped, the reaction mixture was concentrated to dryness, water (60ml) was added and extracted with diethyl ether (3 x 150ml). The organic phase was dried, concentrated to dryness, and the crude product was recrystallized from MeOH to give the product (5.90 g). Yield 86.8%. ¹ H NMR (CDCl ₃ ) δ4.43 (br s, 2H, NH ₂ ), 5.41 (br s, 1H, CONH ₂ ), 6.75 (ddd, J=7.3Hz, 6.7Hz, 1.3Hz , 1H, H-7), 6.84 (br s, 1H, CONH ₂ ), 6.91 (ddd, J=8.8Hz, 6.7Hz, 1.0Hz, 1H, H-6), 7.42 (dd, J=8.8Hz, 1.3Hz, 1H, H-5), 8.16 (dd, J=7.3Hz, 1.0Hz, 1H, H-8); EI-MSm/z 176.

Preparation Example 10 3-(2-ethoxybenzamido)-imidazo[1,2-a]pyridine-2-carboxamide

Dissolve the solution of the compound of Preparation Example 5 (1.76g, 10mmol), pyridine (2.0ml, 24.8mmol) and DMAP (0.05g, 0.4mmol) in dry CH ₂ Cl ₂ (120ml) in an ice-salt bath, under stirring 2-Ethoxybenzoyl chloride (3.14 g, 17.0 mmol) was slowly added dropwise, and the internal temperature was kept below 5°C during the dropwise addition, and the dropwise was completed in about 20 minutes. The reaction mixture was stirred at room temperature for 1 h, then heated to reflux and stirring continued for 5 h. The reaction mixture was washed with water (100ml), and the _aqueous layer was extracted with _CH2Cl2 (2x60ml). The CH ₂ Cl ₂ phases were combined, washed with saturated brine (50 ml), dried over MgSO ₄ , and concentrated under reduced pressure to obtain a crude product (brown solid). The crude product was recrystallized from EtOH/DMF to give the product (2.36g). Yield 73.0%. ¹ HNMR (DMSO-d ₆ ) δ1.46 (t, J=7.0Hz, 3H), 4.32 (q, J=7.0Hz, 2H, OCH ₂ zCH ₃ ), 7.12 (dd, J= 7.5Hz, 7.0Hz, 1H, H-6), 7.17(dd, J=7.6Hz, 7.1Hz, 1H, H-5′), 7.26(d, J=8.4Hz, 1H, H-3′), 7.57 (dd, J=9.2Hz, 7.5Hz, 1H, H-7) 7.59 (dd, J=8.4Hz, 7.1Hz, 1H, H-4'), 7.63-7.77 (br s, 2H, ArCONH ₂ ) 7.70(d, J=9.2Hz, 1H, H-8), 7.94(ddd, J=7.6Hz, 2.4Hz, 2.4Hz, 1H, H-6′), 8.13(d, J=7.0Hz, 1H, H-5), 10.77 (br s, 1H, CONHAr); EI-MS m/z 324.

Preparation 11 3-(2-ethoxybenzamido)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide

In the same manner as in Preparation 10, the compound of Preparation 6 was reacted with 2-ethoxybenzoyl chloride. The recrystallization solvent was EtOH/DMF. Yield 73.4%. EI-MS m/z 338.

Preparation 12 3-(2-ethoxybenzamido)-6-methyl-imidazo[1,2-a]pyridine-2-carboxamide

In the same manner as in Preparation 10, the compound of Preparation 7 was reacted with 2-ethoxybenzoyl chloride. The recrystallization solvent was MeOH. Yield 84%. ¹ H NMR (DMSO-d ₆ ) δ 1.47 (t, J=7.1Hz, 3H, OCH ₂ CH ₃ ), 2.30 (s, 3H, CH ₃ ), 4.32 (q, J=7.1 Hz, 2H, OCH ₂ CH ₃ ), 7.12 (dd, J=7.7Hz, 7.4Hz, 1H, H-5′), 7.24 (dd, J=9.1Hz, 1.4Hz, 1H, H-7), 7.26 (d, J=7.8Hz, 1H, H-3′), 7.34 (br s, 1H, ArCONH ₂ ), 7.51 (d, J=9.1Hz, 7.5Hz, 1H, H-8), 7.56 (br s , 1H, ArCONH ₂ ), 7.58(ddd, J=7.8Hz, 7.4Hz, 1.4Hz, 1H, H-4'), 7.78(s, 1H, H-5), 7.98(dd, J=7.7Hz, 1.8 Hz, 1H, H-6'), 10.67 (br s, 1H, CONHAr); EI-MS m/z 338.

Preparation 13 3-(2-ethoxybenzamido)-8-methyl-imidazo[1,2-a]pyridine-2-carboxamide

In the same manner as in Preparation 10, the compound of Preparation 8 was reacted with 2-ethoxybenzoyl chloride. The recrystallization solvent was MeOH. Yield 78.1%. ¹ H NMR (DMSO-d ₆ ) δ 1.47 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.48 (s, 3H, CH ₃ ), 4.31 (q, J=7.0 Hz, 2H, OCH ₂ CH ₃ ), 6.93 (dd, J=7.1Hz, 7.0Hz, 1H, H-6), 7.11 (dd, J=7.5Hz, 7.0Hz, 1H, H-5′), 7.20 (d, J = 7.0Hz, 1H, H-7), 7.26 (d, J = 8.3Hz, 1H, H-3'), 7.43 (brs, 1H, _ArCONH2 ), 7.54 (brs, 1H, ArCONH ₂ ), 7.58 (dd, J=8.3Hz, 7.0Hz, 1H, H-4′), 7.86 (d, J=7.1Hz, 1H, H-5), 7.96 (d, J=7.5Hz, 1H, H-6'), 10.71 (br s, 1H, CONHAr); EI-MS m/z 338.

Preparation 14 3-(2-ethoxybenzamido)-pyrido[1,5-a]pyrazole-2-carboxamide

In the same manner as in Preparation 10, the compound of Preparation 9 was reacted with 2-ethoxybenzoyl chloride. The recrystallization solvent was EtOH/DMF. Yield 82.7%. ¹ H NMR (CDCl ₃ ) δ1.59 (t, J=7.0Hz, 3H, CH ₃ ), 4.40 (q, J=7.0Hz, 2H, CH ₂ ), 5.55 (br s, 1H , NH ₂ ), 6.84 (ddd, J=7.0Hz, 6.9Hz, 1.5Hz, 1H, H-7), 6.86 (br s, 1H, NH ₂ ), 7.04 (d, J=8.2Hz, 1H, H -3'), 7.08(dd, J=7.6Hz, 6.8Hz, 1H, H-5'), 7.10(ddd, J=8.8Hz, 6.9Hz, 1.0Hz, 1H, H-6), 7.48(ddd , J=8.2Hz, 6.8Hz, 1.9Hz, 1H, H-4′), 8.25(d, J=7.0Hz, 1.0Hz, 1H, H-8), 8.26(dd, J=8.8Hz, 1.5Hz , 1H, H-6'), 8.28 (dd, J=7.6Hz, 1.9Hz, 1H, H-6'), 11.26 (br s, 1H, NH). EI-MS m/z 324.

Preparation 15 2-(2-ethoxyphenyl)-pyrido[1,2-e]purin-4(3H)-one

Potassium tert-butoxide (0.12g, 1.1mmol) and the compound of Preparation Example 10 (0.32g, 1mmol) were successively added to tert-butanol (20ml), and the suspension was heated to reflux under stirring, and became clear after about 30min. Continue to reflux for 20h. Stop heating, add water (40ml) after cooling to room temperature, adjust to neutral with 4% dilute acetic acid, then cool to 5-10°C. A white solid precipitated, filtered, washed with cold water (3 x 15ml), dried, and recrystallized from EtOH/EtOAc to give the product (0.21g). Yield 68.6%. ¹ H NMR (CDCl ₃ ) δ 1.65 (t, J = 7.0 Hz, 3H, OCH ₂ CH ₃ ), 4.35 (q, J = 7.0 Hz, 2H, OCH ₂ CH ₃ ), 6.98 ( dd, J=7.9Hz, 6.6Hz, 1H, H-8), 7.09 (d, J=8.4Hz, 1H, H-3′), 7.18 (dd, J=8.0Hz, 7.8Hz, 1H, H- 5′), 7.42(dd, J=9.3Hz, 6.6Hz, 1.2Hz, 1H, H-7), 7.51(dd, J=8.4Hz, 7.8Hz, 1H, H-4′), 7.74(d, J=g.3Hz, 1H, H-6), 8.608(d, J=7.9Hz, 1H, H-9), 8.612(d, J=8.0Hz, 1H, H-6′), 11.63(br s , 1H, NH). EI-MS m/z 306.

Preparation 16 2-(2-ethoxyphenyl)-9-methyl-pyrido[1,2-e]purin-4(3H)-one

According to the same method as Preparation Example 15, the compound of Preparation Example 11 was used as the reaction raw material. The recrystallization solvent was EtOH/CHCl ₃ . Yield 70.6%. ¹ H NMR (DMSO-d ₆ ) δ1.40 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 3.08 (s, 3H, CH ₃ ), 4.20 (q, J=6.9 Hz, 2H, OCH ₂ CH ₃ ), 6.86 (d, J=6.7Hz, 1H, H-8), 7.13 (dd, J=7.7Hz, 7.4Hz, 1H, H-5′), 7.21(d, J=8.4Hz, 1H, H-3'), 7.42(dd, J=9.2Hz, 6.7Hz, 1H, H-7), 7.51(dd, J=7.7Hz, 1.6Hz, 1H, H-6' ), 7.92 (dd, J=8.4Hz, 7.4Hz, 1.6Hz, 1H, H-4′), 12.14 (br s, 1H, NH). EI-MSm/z 320.

Preparation 17 2-(2-ethoxyphenyl)-8-methyl-pyrido[1,2-e]purin-4(3H)-one

According to the same method as Preparation Example 15, the compound of Preparation Example 12 was used as the reaction raw material. The recrystallization solvent was EtOH/EtOAc. Yield 66.8%. ¹ H NMR (DMSO-d ₆ ) δ 1.38 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 2.36 (s, 3H, CH ₃ ), 4.19 (q, J=6.9 Hz, 2H, OCH ₂ CH ₃ ), 7.12(dd, J=7.6Hz, 7.1Hz, 1H, H-5′), 7.21(d, J=8.3Hz, 1H, H-3′), 7.40(dd , J=9.4Hz, 1.5Hz, 1H, H-7), 7.53(ddd, J=8.3Hz, 7.1Hz, 1.8Hz, 1H, H-4′), 7.63(d, J=9.47Hz, 1H, H-6), 7.93(dd, J=7.6Hz, 1.8Hz, 1H, H-6′), 8.53(s, 1H, H-9), 12.17(brs, 1H, NH).EI-MS m/ z 320.

Preparation 18 2-(2-ethoxyphenyl)-6-methyl-pyrido[1,2-e]purin-4(3H)-one

Following the same method as Preparation Example 15, the compound of Preparation Example 13 was used as the reaction raw material. The recrystallization solvent was EtOH/CHCl ₃ . Yield 79.6%. ¹ H NMR (CDCI ₃ ) δ1.64 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 2.69 (s, 3H, CH ₃ ), 4.36 (q, J=6.9Hz, 2H, OCH ₂ CH ₃ ), 6.88 (dd, J=6.9Hz, 6.7Hz, 1H, H-8), 7.08 (d, J=8.2Hz, 1H, H-3′), 7.17 (dd, J= 8.0Hz, 7.5Hz, 1H, H-5'), 7.19(d, J=6.7Hz, 1H, H-7), 7.50(ddd, J=8.2Hz, 7.5Hz, 1.8Hz, 1H, H-4 '), 8.47 (d, J=6.9Hz, 1H, H-9), 8.61 (dd, J=8.0Hz, 1.8Hz, 1H, H-6'), 11.57 (br s, 1H, NH).EI -MS m/z 320.

Preparation 19 2-(2-ethoxyphenyl-pyrido[2',1':5,1]pyrazolo[4,3-d]pyrimidin-4(3H)-one

Method A Follow the same method as Preparation Example 15, using the compound of Preparation Example 14 as the reaction raw material. The recrystallization solvent was EtOH/CHCl ₃ . Yield 77.2%. ¹ H NMR (CDCl ₃ ) δ 1.63 (t, J=7.0Hz, 3H, CH ₃ ), 4.32 (q, J=7.0Hz, 2H, CH ₂ ), 7.07 (d, J= 8.4Hz, 1H, H-3'), 7.16(ddd, J=7.1Hz, 6.9Hz, 1.2Hz, 1H, H-7), 7.17(dd, J=8.0Hz, 7.1Hz, 1H, H-5 '), 7.38(ddd, J=8.6Hz, 6.9Hz, 1.0Hz, 1H, H-8), 7.47(ddd, J=8.4Hz, 7.1Hz, 1.6Hz, 1H, H-4'), 8.21( dd, J=8.6Hz, 1.2Hz, 1H, H-9), 8.56(dd, J=8.0Hz, 1.6Hz, 1H, H-6'), 8.71(dd, J=7.1Hz, 1.0Hz, 1H , H-6), 11.31 (br s, 1H, NH). EI-MS m/z 306.

Method B Dissolve the compound of Preparation Example 9 (0.35g, 2.0mmol) and o-ethoxybenzaldehyde (0.33g, 2.2mmol) in DMF (10ml), add CuCl ₂ (0.27g, 2.0mmol), and heat to 100°C, react for 2-20h, and detect the end point of the reaction by TLC. After the reaction was completed, water (20ml) was added, and a yellow solid was precipitated, which was filtered and dried. Recrystallization from EtOH/CHCl ₃ gave yellow powdery crystals (0.46 g). Yield 75.3%.

Example 1 2-((2-ethoxy-5-(4-(2-hydroxyethyl)piperazinyl)sulfonyl)phenyl)-pyrido[1,2-e]purine-4(3H )-ketone

The compound of Preparation Example 15 (0.14 g, 0.46 mmol) was slowly added in batches to chlorosulfonic acid (1 ml, 15 mmol) under cooling and stirring in an ice-salt bath. During the addition, the internal temperature was maintained at 0-5°C, and the addition was completed in about 30 minutes. The reaction was continued to stir in the ice-salt bath, and the end point of the reaction was detected by TLC. After the reaction was complete, the reaction mixture was carefully poured into ice water (20 g). A large amount of precipitate precipitated, filtered, washed with water, and dried to obtain a light yellow solid. The solid without purification was directly added to CHCl ₃ (10 ml) dissolved with N-hydroxyethylpiperazine (0.072 g, 0.55 mmol), and the reaction solution was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure to obtain the crude product (yellow solid). Purify by silica gel column chromatography (mobile phase: 1-3% MeOH/CHCl ₃ ), and recrystallize from MeOH to obtain the target compound. 0.29 g was obtained, the two-step yield was 62.5%. ¹ H NMR (CDCl ₃ ) δ 1.43 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 2.55 (t, 2H, NCH ₂ CH ₂ O), 2.62(br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 3.01(br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 3.58(t, 2H, NCH ₂ CH ₂ O), 4.23 (q, J=6.9Hz, 2H, OCH ₂ CH ₃ ), 7.07 (dd, J=7.0Hz, 6.6Hz, 1H, H-8), 7.16 (d, J=8.7Hz, 1H, H-3'), 7.67(ddd, J=9.3Hz, 6.6Hz, 1.2Hz, 1H, H-7), 7.83(dd, J=8.7Hz, 2.5Hz, 1H, H-4'), 7.84( d, J=9.2Hz, 1H, H-6), 8.23(d, J=2.5Hz, 1H, H-6'), 8.80(dd, J=7.0Hz, 1.2Hz, 1H, H-9). EI-MS m/z 498.

Example 2 2-((2-ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl)-9-methyl-pyrido[1,2-e]purine-4(3H )-ketone (1b)

Method A According to the same method as in Example 1, the compound of Preparation Example 16 was first chlorosulfonylated, and then reacted with N-methylpiperazine. The recrystallization solvent was MeOH/Acetone. Two-step yield 65.6%. ¹ H NMR (CDCl ₃ ) δ1.69 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.27 (s, 3H, NCH ₃ ), 2.50 (br s, 4H, _SO2N ( _CH2CH2 ) _2N ), 3.08(br s, 4H _{, SO2N} ( _{CH2CH2 ) 2N} ), 3.16(s, 3H, _CH3 ), 4.43(q, J=7.0 Hz, 2H, OCH ₂ CH ₃ ), 6.70 (d, J=7.0Hz, 1H, H-8), 7.17 (d, J=8.7Hz, 1H, H-3′), 7.33 (dd, J=9.2 Hz, 7.0Hz, 1H, H-7), 7.59(d, J=9.2Hz, 1H, H-6), 7.80(dd, J=8.7Hz, 2.3Hz, 1H, H-4′), 8.81( d, J=2.3Hz, 1H, H-6′), 11.32 (br s, 1H, NH). EI-MS m/z 482.

Method B Dissolve the solution of the compound of Preparation 6 (1.25g, 6.6mmol), triethylamine (1.1ml, 8.0mmol) and DMAP (0.05g, 0.4mmol) in dry DMF (15ml) in an ice-salt bath. 2-Ethoxy-5-(4-methylpiperazinyl)sulfonylbenzoyl chloride (2.74 g, 7.9 mmol) was added in portions with stirring, maintaining the internal temperature below 5°C during the addition. After the addition was complete, the reaction mixture was heated to 95 °C and stirring was continued for 40 h. The reaction mixture was added with water (100ml) and extracted with EtOAc (3 x 20ml). The EtOAc phases were combined, washed with saturated brine (50 ml), dried over MgSO ₄ , and concentrated under reduced pressure to obtain a brown solid. Potassium tert-butoxide (1.23 g, 11 mmol) and tert-butanol (20 ml) were directly added to the intermediate without purification, and the suspension was heated to reflux under stirring, and reacted for 6-10 h. After the reaction, water (20ml) was added, adjusted to neutral with 4% dilute acetic acid, and concentrated to dryness under reduced pressure. Water (30ml) was added, extracted with _CHCl3 (3 x 15ml), the combined organic phases were dried, concentrated to a small volume, and left overnight to precipitate a crude product. Recrystallized from MeOH/DMF to obtain 1.82 g of the compound. Two-step yield 57.2%.

Example 3 2-((2-ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl)-8-methyl-pyrido[1,2-e]purine-4(3H )-ketone

Following the same method as Example 2, Method B, the compound of Preparation Example 7 was reacted with 2-ethoxy-5-(4-methylpiperazinyl)sulfonylbenzoyl chloride. The recrystallization solvent was EtOH. Two-step yield 53.9%. ¹ H NMR (CDCl ₃ ) δ1.69 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.28 (s, 3H, NCH ₃ ), 2.45 (s, 3H, CH ₃ ), 2.53 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 3.12 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 4.43 (q, J=7.0Hz , 2H, OCH ₂ CH ₃ ), 7.20 (d, J=8.8Hz, 1H, H-3′), 7.30 (d, J=9.4Hz, 1H, H-7), 7.63 (d, J=9.4Hz , 1H, H-6), 7.83 (dd, J=8.8Hz, 2.3Hz, 1H, H-4′), 8.41 (s, 1H, H-9), 8.96 (d, J=2.3Hz, 1H, H-6'), 11.35 (br s, 1H, NH). EI-MS m/z 482.

Example 4 2-((2-ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl)-8-methyl-pyrido[1,2-e]purine-4(3H )-ketone

Following the same method as Example 2, Method B, the compound of Preparation Example 8 was reacted with 2-ethoxy-5-(4-ethylpiperazinyl)sulfonylbenzoyl chloride. The recrystallization solvent was EtOH. Two-step yield 52.1%. ¹ H NMR (CDCl ₃ ) δ 1.02 (t, J=7.2Hz, 3H, NCH ₂ CH ₃ ), 1.70 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.40 (q, J=7.2 Hz, 2H, NCH ₂ CH ₃ ), 2.46 (s, 3H, CH ₃ ), 2.55 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 3.10 (br s, 4H, SO ₂ N (CH ₂ CH ₂ ) ₂ N), 4.42 (q, J = 7.0 Hz, 2H, OCH ₂ CH ₃ ), 7.19 (d, J = 8.8 Hz, 1H, H-3'), 7.30 (d, J = 9.4Hz, 1H, H-7), 7.63(d, J=9.4Hz, 1H, H-6), 7.83(dd, J=8.8Hz, 2.4Hz, 1H, H-4′), 8.42(s, 1H, H-9), 8.96 (d, J=2.3Hz, 1H, H-6′), 11.34 (br s, 1H, NH). EI-MS 496m/z.

Example 5 2-((2-ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl)-6-methyl-pyrido[1,2-e]purine-4(3H )-ketone

According to the same method as in Example 1, the compound of Preparation Example 18 was first chlorosulfonylated, and then reacted with N-ethylpiperazine. The recrystallization solvent was EtOH/DMF. Two-step yield 70.2%, ¹ H NMR (CDCl ₃ ) δ 1.03 (t, J=7.1Hz, 3H, NCH ₂ CH ₃ ), 1.69 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 2.41(q, J=7.1Hz, 2H, NCH ₂ CH ₃ ), 2.56(br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 2.71(s, 3H, CH ₃ ), 3.12(br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 4.44 (q, J=6.9Hz, 2H, OCH ₂ CH ₃ ), 6.94 (dd, J=6.9Hz, 6.3Hz, 1H, H- 8), 7.21 (d, J=8.8Hz, 1H, H-3′), 7.25 (d, J=6.9Hz, 1H, H-7), 7.87 (dd, J=8.8Hz, 2.4Hz, 1H, H-4'), 8.52(d, J=6.3Hz, 1H, H-9), 8.97(d, J=2.4Hz, 1H, H-6'), 11.32(br s, 1H, NH).EI -MS m/z 496.

Example 6 2-((2-ethoxy-5-(4-isopropylpiperazinyl)sulfonyl)phenyl)-6-methyl-pyrido[1,2-e]purine-4( 3H)-ketone

According to the same method as in Example 1, the compound of Preparation Example 18 was first chlorosulfonylated, and then reacted with N-isopropylpiperazine. The recrystallization solvent was EtOH/DMF. Two-step yield 67.4%. ¹ H NMR (CDCl ₃ ) δ 0.99 (d, J=6.7Hz, 6H, NCH(CH ₃ ) ₂ ), 1.69 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.62 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 2.67 (m, J=6.7Hz, 1H, NCH(CH ₃ ) ₂ ), 2.70 (s, 3H, CH ₃ ) , 3.09 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 4.44 (q, J=7.0Hz, 2H, OCH ₂ CH ₃ ), 6.93 (dd, J=7.0Hz, 6.7Hz, 1H, H-8), 7.20 (d, J=8.8Hz, 1H, H-3′), 7.23 (d, J=6.7Hz, 1H, H-7), 7.86 (dd, J=8.8Hz, 2.4 Hz, 1H, H-4′), 8.51(d, J=7.0Hz, 1H, H-9), 8.96(d, J=2.4Hz, 1H, H-6′), 11.31(br s, 1H, NH). EI-MS m/z 510.

Example 7 2-(2-ethoxy-5-nitrophenyl)-8-methyl-pyrido[1,2-e]purin-4(3H)-one

The compound of Preparation Example 17 (2.35g, 7.3mmol) was added in batches to sulfuric acid (20ml), the solution was placed in an ice-salt bath, and nitric acid (65%, d=1.41, 0.55ml) and sulfuric acid ( 10ml) of the mixed solution, keep the internal temperature below 5°C, and stir at room temperature for 3h after the dropwise completion. Then the reaction mixture was poured into crushed ice (50 g), extracted with CH ₂ Cl ₂ (3×30 ml), the combined organic phases were washed with water, dried over Na ₂ SO ₄ , and concentrated to dryness under reduced pressure to obtain a yellow solid. The crude product was recrystallized from MeOH to obtain 1.66 g of light yellow crystals. Yield 62.3%. ¹ H NMR (DMSO-d ₆ ) δ1.38 (t, J=6.9Hz, 3H, OCH ₂ CH ₃ ), 2.40 (s, 3H, CH ₃ ), 4.31 (q, J=6.9Hz, 2H, OCH ₂ CH ₃ ), 7.42 (d, J=9.2Hz, 1H, H-3′), 7.56 (d, J=9.3Hz, 1H, H-7), 7.71 (d, J=9.3Hz, 1H, H -6), 8.41(dd, J=9.2Hz, 2.9Hz, 1H, H-4'), 8.60(d, J=2.9Hz, 1H, H-6'), 8.66(s, 1H, H-9 ).EI-MS m/z 365.

Example 8 2-(2-ethoxy-5-aminophenyl)-8-methyl-pyrido[1,2-e]purin-4(3H)-one

The compound of Example 7 (1.5 g, 4.1 mmol) was dissolved in methanol (50 ml) and THF (25 ml), and Raney-Ni (0.2 g) was added, and hydrogen gas was introduced at room temperature. The reaction was stopped when no hydrogen was absorbed, the catalyst was filtered off, and the filtrate was concentrated to dryness to obtain 1.29 g of a light yellow solid. Yield 93.8%. ¹ H NMR (DMSO-d ₆ ) δ 1.35 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.50 (s, 3H, CH ₃ ), 4.09 (q, J=7.0 Hz, 2H, OCH ₂ CH ₃ ), 4.90 (br s, 2H, NH ₂ ), 6.78 (dd, J=8.8Hz, 2.9Hz, 1H, H-4′), 6.96 (d, J=8.8Hz, 1H, H-3'), 7.36 (d, J=2.9Hz, 1H, H-6'), 7.39 (dd, J=9.4Hz, 1.6Hz, 1H, H-7), 7.62 (dd, J= 9.4Hz, 1H, H-6), 8.45(d, J=1.6Hz, 1H, H-9), 11.98(br s, 1H, NH). EI-MS m/z 335.

Example 9 2-(2-ethoxy-5-acetylaminophenyl)-8-methyl-pyrido[1,2-e]purin-4(3H)-one

Dissolve the compound of Example 8 (0.6g, 1.79mmol) in CH ₂ Cl ₂ (40ml), add triethylamine (0.49ml, 3.58mmol) and acetic anhydride (0.34ml, 3.58mmol), then stir at room temperature for 1h . The reaction mixture was washed with water (20ml), and the organic phase was dried over anhydrous MgSO ₄ and concentrated to dryness to obtain a crude product. Recrystallization from EtOH gave yellow crystals (0.51 g), yield 75.6%. ¹ HNMR (DMSO-d ₆ ) δ1.34 (t, J=7.0 Hz, 3H, OCH ₂ CH ₃ ), 2.03 (s, 3H, CH ₃ ), 2.35 (s, 3H, COCH ₃ ), 4.13 (q, J=7.0Hz, 2H, OCH ₂ CH ₃ ), 7.14 (d, J=9.1Hz, 1H, H-3′), 7.40 ( dd, J=9.3Hz, 1.4Hz, 1H, H-7), 7.63(d, J=9.3Hz, 1H, H-6), 7.71(d, J=9.1Hz, 1H, H-4'), 8.06(s, 1H, H-6′), 8.45(s, 1H, H-9), 10.00(br s, 1H, NHCOCH ₃ ), 12.19(br s, 1H, NH).EI-MS m/z 377.

Example 10 2-(2-ethoxy-5-(2-methylthiazol-4-yl)phenyl)-8-methyl-pyrido[1,2-e]purine-4(3H)- ketone

Dissolve compound Preparation Example 16 (0.25g, 0.78mmol) in CHCl ₃ (20ml), add chloroacetyl chloride (0.31ml, 3.90mmol), place in ice-salt bath, slowly add AlCl ₃ (0.40g, 3.0mmol) , Stir at room temperature for 20h. The reaction mixture was poured into ice water (80 g), and stirred for 30 min to complete the hydrolysis. Add CHCl ₃ (3×20 ml) for extraction, and the combined organic phases are washed with saturated brine, dried (Na ₂ SO ₄ ), and concentrated to dryness to obtain a yellow solid. The crude product was dissolved in EtOH (20ml) without purification, added thioacetamide (38mg, 0.50mmol), and heated to reflux for 1h with stirring. The reaction mixture was concentrated to _dryness , water (30ml) was added and extracted with _CH2Cl2 (2x50ml). The combined organic phases were washed with brine, dried (Na ₂ SO ₄ ), and concentrated to dryness to obtain a yellow solid. Purified by silica gel column chromatography (eluent: 3-5% MeOH-CH ₂ Cl ₂ ), recrystallized from MeOH to give light yellow crystals (36 mg), yield 11.0%. ¹ H NMR (CDCl ₃ ) δ1.64 (t, J = 7.1 Hz, 3H, OCH ₂ CH ₃ ), 2.44 (s, 3H, CH ₃ ), 2.83 (s, 3H, CH ₃ of thiazole), 4.38 (q, J = 7.1 Hz, 2H, OCH ₂ CH ₃ ), 7.12 (d, J=8.8Hz, 1H, H-3′), 7.30 (d, J=9.2Hz, 1H, H-7), 7.40 (s, 3H, 1H of thiazole), 7.65 (d, J=9.2Hz, 1H, H-6), 8.02(dd, J=8.8Hz, 2.3Hz, 1H, H-4'), 8.45(s, 1H, H-9), 9.02(d, J=2.3Hz, 1H, H-6'), 11.55 (br s, 1H, NH). EI-MS m/z 417.

Example 11 2-(2-ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3- d] pyrimidin-4(3H)-one

According to the same method as in Example 1, the compound of Preparation Example 19 was first chlorosulfonylated, and then reacted with N-methylpiperazine. The recrystallization solvent was MeOH/Acetone. Two-step yield 82.3%. ¹ H NMR (CDCl ₃ ) δ1.69 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.27 (s, 3H, NCH ₃ ), 2.50 (br s, 4H, _SO2N ( _CH2CH2 ) _2N ), 3.08(br s, 4H _{, SO2N} ( _{CH2CH2 ) 2N} ), 3.16(s, 3H, _CH3 ), 4.43(q, J=7.0 Hz, 2H, OCH ₂ CH ₃ ), 6.70 (d, J=7.0Hz, 1H, H-8), 7.17 (d, J=8.7Hz, 1H, H-3′), 7.33 (dd, J=9.2 Hz, 7.0Hz, 1H, H-7), 7.59(d, J=9.2Hz, 1H, H-6), 7.80(dd, J=8.7Hz, 2.3Hz, 1H, H-4′), 8.81( d, J=2.3Hz, 1H, H-6′), 11.32 (br s, 1H, NH). EI-MS m/z 468.

Example 12 2-(2-ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3- d] pyrimidin-4(3H)-one

According to the same method as in Example 1, the compound of Preparation Example 19 was first chlorosulfonylated, and then reacted with N-ethylpiperazine. The recrystallization solvent was MeOH/Acetone. Yield 80.5%. ¹ H NMR (CDCl ₃ ) δ 1.02 (t, J=7.0Hz, 3H, NCH ₂ CH ₃ ), 1.67 (t, J=7.0Hz, 3H, OCH ₂ CH ₃ ), 2.40( q, J=7.0Hz, 2H, NCH ₂ CH ₃ ), 2.55 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 3.12 (br s, 4H, SO ₂ N(CH ₂ CH ₂ ) ₂ N), 4.40 (q, J=7.0Hz, 2H, OCH ₂ CH ₃ ), 7.17 (d, J=8.7Hz, 1H, H-3′), 7.21 (ddd, J=7.0Hz, 6.8Hz , 1.4Hz, 1H, H-7), 7.43(ddd, J=8.8Hz, 6.8Hz, 0.9Hz, 1H, H-8), 7.84(dd, J=8.7Hz, 2.5Hz, 1H, H-4 '), 8.26 (dd, J=8.8Hz, 1.4Hz, 1H, H-9), 8.71 (dd, J=7.0Hz, 0.9Hz, 1H, H-6), 8.95 (d, J=2.5Hz, 1H, H-6′), 11.06 (br s, 1H, NH). EI-MS m/z 482.

Embodiment 13 Tablet (powder tabletting method)

Prescription mg/tablet

active compound 20.0

Compressible starch 18.0

Microcrystalline Cellulose 8.8

PVP S630 3.0

Magnesium stearate 0.2

Tablet weight 50mg

Mix the active compound and excipient powder in a mixer, pass through a 40-mesh sieve twice, and repress the tablet according to the prescription.

Example 14 Tablet (wet granulation method)

Prescription mg/tablet

active compound 20.0

Starch 60.0

Microcrystalline Cellulose 15.0

8% Starch Slurry Appropriate amount

Sodium Carboxymethyl Starch 3.0

Magnesium stearate 1.0

Tablet Weight 100mg

Pass the active compound, microcrystalline cellulose, and starch through a 100-mesh sieve, mix well, use 8% starch slurry to make soft material, granulate with 16 mesh, dry and granulate, add sodium carboxymethyl starch, magnesium stearate and mix Evenly, press the prescription tablet to press the tablet.

Example 15 Capsules

Prescription mg/piece

active compound 20.0

Starch 25.0

Polyvinylpyrrolidone 4.5

Magnesium stearate 0.5

Total weight 50mg

The active compound is sieved, mixed with the powdered excipients, and the mixture is filled into gelatin capsules in the prescribed amount using suitable equipment.

Claims (9)

1. The heterocyclic pyrimidinone derivatives of the following formula (1) or their pharmaceutically acceptable salts, or their pharmaceutically acceptable solvates, It is characterized by B ring is a substituted or unsubstituted pyridine ring, and A ring is an imidazole or pyrazole ring, that is, B ring, A ring and pyrimidinone ring together form compounds of formulas (1A), (1B), (1C) and (1D):

Wherein, X is CH or N; R is a substituent of ring B, n represents the number of substituents, n=1, 2, 3 or 4; R can be independently H, halogen, nitro, cyano, NR ³ R ⁴ , CO(CH ₂ ) _m NR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, wherein the hydrocarbon group can be optionally replaced by one or more Halogen atoms are substituted; R ¹ is H, or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, the hydrocarbon group can be optionally replaced by one or more halogen atoms or C ₁ -C ₄ Alkoxy substitution; R ² is SO ₂ NR ³ R ⁴ , NHSO ₂ NR ³ R ⁴ , NHSO ₂ R ⁵ , NHCOR ⁵ , NHCOOR ⁵ , NHCONHR ⁵ , CO(CH ₂ ) _m NR ³ R ⁴ , (CH ₂ ) _m Ar or ( CH ₂ ) _m Het, wherein CH ₂ can be optionally substituted by one or more halogen atoms or OH; R ³ and R ⁴ are each independently H, or C ₁ -C ₆ alkyl, which can optionally be replaced by OH, CO ₂ H, C ₁ -C ₃ alkoxy, Ar, Het, NR ⁶ R ⁷ Substituted, or optionally substituted by one or more halogen atoms; or form a ring with the nitrogen atom to which they are attached, such as aziridine (aziridine), azetidine (azetidine), pyrrolidine , piperidine, morpholine, piperazine, homopiperazine, imidazole, imidazoline or pyrazole, wherein the nitrogen-containing heterocycle can be optionally substituted by R ⁸ ; R ⁵ is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl optionally substituted by one or more halogen atoms; or (CH ₂ ) _m Ar or (CH ₂ ) _m Het; R ⁶ and R ⁷ are each independently H, or C ₁ -C ₆ alkyl, the alkyl may be optionally substituted by OH, C ₁ -C ₃ alkoxy, hydroxyl C ₁ -C ₃ alkoxy; R ⁸ is C ₁ -C ₆ alkyl, which can be optionally replaced by one or more halogen atoms, OH, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CO(CH ₂ ) _m NR ¹⁰ R ¹¹ , C ₁ -C ₃ alkoxy (which can optionally be replaced by one or more halogen atoms, OH, C ₁ -C ₃ alkoxy, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CO(CH ₂ ) _m NR ¹⁰ R ¹¹ replaces) replaces; R ⁹ is H, or can optionally be replaced by OH, NR ¹⁰ R ¹¹ , one or more halogen atoms, or as a nitrogen-containing heterocycle (such as pyrrolidine, piperidine, piperazine, morpholine, pyrrolidine, and imidazole) Substituted C ₁ -C ₄ alkyl; R ¹⁰ and R ¹¹ are each independently H or C ₁ -C ₄ alkyl; of the above m = 0, 1 or 2; Ar represents phenyl substituted by one or two substituents selected from halogen, NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CONH ₂ , CN, SO ₂ NH ₂ ; Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms are selected from N, S and O, and are optionally substituted by one or two substituents, the substituents are selected from halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ alkoxy. 2. The heterocyclic pyrimidinone derivatives and physiologically acceptable salts according to claim 1, wherein B ring is a substituted or unsubstituted pyridine ring, A ring is an imidazole or pyrazole ring, and X is CH; that is, B ring, A ring and pyrimidone ring together form the formula (1A ₁ ), (1B ₁ ), ( 1C ₁ ) and (1D ₁ ) compounds:

in R is a substituent of ring B, n represents the number of substituents, n=1, 2, 3 or 4; R can be independently H, halogen, nitro, cyano, NR ³ R ⁴ , CONR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, wherein the hydrocarbon group can be optionally substituted by one or more halogen atoms; R ¹ is H, or C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl, C ₂ -C ₆ alkenyl, the hydrocarbon group can be optionally replaced by one or more halogen atoms or C ₁ -C ₄ Alkoxy substitution; R ² is SO ₂ NR ³ R ⁴ , CONR ³ R ⁴ , Ar or Het, wherein CH ₂ may be optionally substituted by one or more halogen atoms or OH; R ³ and R ⁴ are each independently H, or C ₁ -C ₆ alkyl, which can optionally be replaced by OH, CO ₂ H, C ₁ -C ₃ alkoxy, Ar, Het, NR ⁶ R ⁷ Substituted, or optionally substituted by one or more halogen atoms; or form a ring with the nitrogen atom to which they are attached, such as aziridine (aziridine), azetidine (azetidine), pyrrolidine , piperidine, morpholine, piperazine, homopiperazine, imidazole, imidazoline and pyrazole, wherein the nitrogen-containing heterocycle can be optionally substituted by R ⁸ ; R ⁵ is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl optionally substituted by one or more halogen atoms; or Ar or Het; R ⁶ and R ⁷ are each independently H, or C ₁ -C ₆ alkyl, the alkyl may be optionally substituted by OH, C ₁ -C ₃ alkoxy, hydroxyl C ₁ -C ₃ alkoxy; R ⁸ is C ₁ -C ₆ alkyl, which can be optionally replaced by one or more halogen atoms, OH, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CONR ¹⁰ R ¹¹ , C ₁ -C ₃ alkoxy (which may be optionally substituted by one or more halogen atoms, OH, C ₁ -C ₃ alkoxy, CO ₂ R ⁹ , NR ¹⁰ R ¹¹ , CONR ¹⁰ R ¹¹ substituted); R ⁹ is H, or can optionally be replaced by OH, NR ¹⁰ R ¹¹ , one or more halogen atoms, or as a nitrogen-containing heterocycle (such as pyrrolidine, piperidine, piperazine, morpholine, pyrrolidine, and imidazole) Substituted C ₁ -C ₄ alkyl; R ¹⁰ and R ¹¹ are each independently H or C ₁ -C ₄ alkyl; of the above Ar represents phenyl substituted by one or two substituents selected from halogen, NH ₂ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, CONH ₂ , CN, SO ₂ NH ₂ ; Het represents a 5- and 6-membered heterocyclic ring containing 1-4 heteroatoms, the heteroatoms are selected from N, S and O, and are optionally substituted by one or two substituents, the substituents are selected from halogen, C ₁ -C ₃ Alkyl, C ₁ -C ₃ alkoxy. 3. heterocyclic pyrimidinone derivatives and physiologically acceptable salts according to claim 2, characterized in that B ring is a substituted or unsubstituted pyridine ring, A ring is an imidazole or pyrazole ring, X is CH, R ² is SO ₂ NR ³ R ⁴ , that is, B ring, A ring and pyrimidone ring together form the formula (1A _1a ), and (1C _1a ) compounds:

R is a substituent of ring B, n represents the number of substituents, n=1 or 2; each R is independently H, halogen, nitro, cyano, NR ³ R ⁴ , CONR ³ R ⁴ , COR ⁵ , COOR ⁵ , or C ₁ -C ₆ alkyl; ^R is ethyl, n-propyl or isopropyl; R ³ and R ⁴ are each independently C ₁ -C ₄ alkyl, or form pyrrolidine, piperidine and piperazine together with their connected nitrogen atoms, wherein the group can be optionally substituted by R ⁸ ; R ⁵ is C ₁ -C ₆ alkyl; R ⁸ is C ₁ -C ₄ alkyl, which may be optionally substituted by OH, C ₁ -C ₃ alkoxy. 4. The heterocyclic pyrimidinone derivative according to claim 3 and physiologically acceptable, preferably selected from: 2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-6-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-isopropylpiperazinyl)sulfonyl)phenyl)-6-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-8-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-8-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-9-ethyl-pyrido[1,2-e]purin-4(3H)-one 2-(2-ethoxy-5-(4-(2-hydroxyethyl)piperazinyl)sulfonyl)phenyl-9-methyl-pyrido[1,2-e]purine-4(3H )-ketone 2-(2-Ethoxy-5-(4-methylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3-d]pyrimidine -4(3H)-one 2-(2-Ethoxy-5-(4-ethylpiperazinyl)sulfonyl)phenyl-pyrido[2',1':5,1]pyrazolo[4,3-d]pyrimidine -4(3H)-one. 5. A compound of formula 1 or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, and one or more pharmaceutically acceptable excipients to form a pharmaceutical composition. 6. The purposes of heterocyclic pyrimidinone derivatives and physiologically acceptable salts as claimed in claim 1, according to the compound of formula 1 or its pharmaceutically acceptable salt according to any one of claims 1-4, or claim 1 5 pharmaceutically acceptable compositions, in the treatment or prevention of erectile dysfunction, female sexual dysfunction, premature birth, dysmenorrhea, benign prostatic hyperplasia, bladder outlet obstruction, incontinence, unstable and variant Prinzmetal angina, hypertension, Pulmonary hypertension, congestive heart failure, renal failure, atherosclerosis, stroke, peripheral vascular disease, Raynaud's disease, inflammatory disease, bronchitis, chronic asthma, allergic asthma, allergic rhinitis, glaucoma, and characterized by intestinal Applied in diseases of peristalsis. 7. A compound of formula (2) and (9)

Wherein B, A, X, R, n, R ¹ are as defined in claim 1, and Y represents a halogen atom, preferably a chlorine atom. 8. A compound of formula (10) and (14)

wherein B, A, X, R, n, R ¹ , R ³ and R ⁴ are as defined in claim 1, and Y represents a halogen atom, preferably a chlorine atom. 9. The preparation method of heterocyclic pyrimidinone derivatives or pharmaceutically acceptable salts thereof as claimed in claim 1, characterized in that: (A): a method for preparing a compound of formula (1) and a pharmaceutically acceptable salt thereof:

Wherein B, A, X, R, n, R ¹ , R ² are as defined in claim 1. It includes: (i) compound of formula (2) (wherein B, A, X, R, n, R ¹ are as defined in claim 1, G=SO ₂ Y, NH ₂ , CN, COCH ₂ Y) and formula (3 )-(8) compound (wherein R ³ , R ⁴ , R ⁵ are as defined in claim 1) reacted to obtain; (ii) obtained by the intramolecular ring closure reaction of the compound of formula (14) (wherein B, A, X, R, n, R ¹ , R ³ , R ⁴ are as defined in claim 1): (iii) compound of formula (11) (wherein B, A, R, n are as defined in claim 1) and compound of formula (16a) (R ¹ , R ³ , R ⁴ are as defined in claim 1) The condensation reaction gives:

(B): a method for preparing a compound of formula (2):

Wherein B, A, X, R, n, R are as defined in claim ¹ , and Y represents a halogen atom, preferably a chlorine atom. It includes being transformed by formula (9) compound (wherein B, A, X, R, ⁿ , R are as defined in claim 1):

(C): a method for preparing a compound of formula (9):

Wherein B, A, X, R, n, R are as defined in claim ¹ . which includes (i) obtain by the intramolecular ring closure reaction of formula (10) compound (wherein B, A, X, R, n, R are as defined in claim ¹ ): (ii) obtain by the reaction of formula (11) compound (wherein B, A, X, R, n are as defined in claim 1) and (16b) compound (wherein R ¹ is as defined in claim 1):

(D): a method for preparing compounds of formula (10) and (14): wherein B, A, X, R, n, R ¹ , R ³ and R ⁴ are as defined in claim 1. It comprises by suitably converting formula (11) compound (wherein B, A, X, R, n are as defined in claim 1) and formula (12), (15) compound (wherein X, R ¹ are as claim 1 The definition in, Y is hydroxyl or halogen, preferably chlorine element) obtains: