CN1218472A - pharmaceutically useful compound - Google Patents

Abstract

The invention relates to 2-arylpyrazolisoquinoline and cinnolinone derivatives, methods for their preparation, their use as medicaments, and pharmaceutical formulations including them.

Description

pharmaceutically useful compound

The present invention relates to pharmaceutically useful compounds, processes for their preparation, their use as medicaments, and pharmaceutical preparations containing them.

Certain pyrazolo[4,3-c]isoquinolin-3-ones are well known from J. Chem. Soc. 599 (1959) (Hinton et al.). Its use as a medicine has not been discussed. Synthesis of certain pyrazolo[4,3-c]isoquinolin-3-ols and their ability to inhibit the binding of radioligands to benzodiazepine receptors in J.Med.Chem.35,368(1992 ) (Allen et al.) have been reported in detail. Certain other pyrazolo[4,3-c]isoquinolin-3-ols have been disclosed in Gaodeng Xuexiao Huaxue Xuebao 1991, 12, 1620-1622 (Qian Jian-hua et al.). None of the pharmaceutical uses of the compounds discussed are mentioned.

其中：2-Arylpyrazoleisoquinoline and cinnolinone derivatives have been found to exhibit anti-allergic and anti-inflammatory activities. Therefore, at first the present invention provides the compound of formula I and its pharmaceutically acceptable derivatives as medicine:

in:

B, D, E and G each represent CH, CA or N, provided that not more than one of B, D, E and G represents CA and not more than one of B, D, E and G represents N;

·X stands for C=O, C=S, C=NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;

· Y stands for N or N ⁺ R ⁷ or CR ¹⁸ ;

Z stands for OR ⁸ or O;

R ¹ represents OH or C _1-6 alkyl, or forms a bond with R ² or R ⁵ ;

R ² represents H, C _1-6 alkyl (optionally substituted by phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl, or with R ¹ , R ³ or R ⁴ forms a bond;

· ^R3 represents H or forms a bond with ^R2 ;

R ⁴ represents a C _1-6 alkyl group or forms a bond with R ² ;

· R ⁵ represents a bond with R ¹ or R ⁸ ;

R ⁶ represents H, C _1-6 alkyl (optionally substituted by phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio , C _1-6 alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;

R ⁷ represents C _1-6 alkyl (optionally substituted by phenyl) or C _3-7 cycloalkyl, both of which can be represented by halogen, hydroxyl, C _1-6 alkoxy, C _1-6 alkylthio Group, C _1-6 alkylsulfinyl, NR ¹⁶ R ¹⁷ , COOH, COO (C _1-6 alkyl) or cyano optionally substituted;

Or R ⁶ and R ⁷ together represent a C _3-5 alkylene group, X and Y thus form a 5-7 membered ring;

R ⁸ represents H, C _1-6 alkyl or forms a bond with R ⁵ ;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;

· R ¹³ and R ¹⁴ are independently C _1-6 alkyl, H, or together with the nitrogen atom to which they are attached, form a 3 which may optionally contain additional oxygen or nitrogen atoms optionally substituted by C _1-6 alkyl -7-membered saturated ring;

^Ar represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolinyl or 2-quinoxalinyl, all of which may optionally be selected from halogen, nitro , cyano, phenyl, benzenesulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO(C _{1 -6} alkyl), C _1-6 alkyl substituted by phenyl, or one or more substituents of phenyl, wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl can be optionally is optionally substituted by fluorine; and

· A represents halogen, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy; wherein the phenyl on R ² , R ⁶ , R ⁷ or as a substitution on Ar ¹ The phenyl group of the group can be optionally substituted by C _1-6 alkyl, halogen or C _1-6 alkoxy; provided that: (i) when X represents C=O, C=S or C=NR ¹⁵ , then Y represents N; (ii) when R ⁴ represents the bond with R ² , then Y represents N ⁺ R ⁷ ; (iii) when Y represents N ⁺ R ₇ , then Z represents ^O- , and R ² represents the bond with R ³ Or the bond of R ⁴ , and R ¹ and R ⁵ form a bond; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then X represents C=O, Y represents N , Z represents OR ⁸ and R ⁵ represents a bond with R ⁸ ; (ⅵ) when R ¹ represents an alkyl group, then R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ; (ⅶ) when R ¹ represents a bond with R ² , then R ⁵ and R ⁸ form a bond, and if X represents NR ⁴ , then R ⁴ represents an alkyl group; (ⅷ) when R ⁶ represents an aryl group , halogen, alkoxy, sulfanyl, then R ² and R ³ form a bond; (ⅸ) when Y represents N or N ⁺ R ⁷ and R ² is any one of NR ¹⁰ R ¹¹ , OR ¹² or F When substituted, the substituent and the ring nitrogen atom of Y cannot be connected to the same carbon atom of R ² ; (ⅹ) when R ⁷ is substituted by any one of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, then the The above-mentioned substituent and the ring nitrogen atom of Y cannot be connected with the same carbon atom of R ⁷ ; (ⅹi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ; (ⅹii) when Y When representing CR ¹⁸ , then X represents CR ³ R ⁶ ; the further condition is: wherein: When B, D, E and G all represent CH, X represents CHR ³ , Y represents nitrogen, R ¹ and R ⁵ form a bond , R ⁸ represents H and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl.

Certain compounds of formula (I) are novel compounds. Further provided according to the present invention is a compound of formula I or a pharmaceutically acceptable derivative thereof:

Each of B, D, E and G represents CH, CA or N, provided that not more than one of B, D, E and G represents CA and not more than one of B, D, E and G represents N;

·X stands for C=O, C=S, C=NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ;

· Y stands for N or N ⁺ R ⁷ or CR ¹⁸ ;

Z stands for OR ⁸ or O;

R ¹ represents OH or C _1-6 alkyl, or forms a bond with R ² or R ⁵ ;

R ² represents H, C _1-6 alkyl (optionally substituted by phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl, or with R ¹ , R ³ or R ⁴ forms a bond;

· ^R3 represents H or forms a bond with ^R2 ;

R ⁴ represents a C _1-6 alkyl group or forms a bond with R ² ;

· R ⁵ represents a bond with R ¹ or R ⁸ ;

R ⁶ represents H, C _1-6 alkyl (optionally substituted by phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio , C _1-6 alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ;

R ⁷ represents C _1-6 alkyl (optionally substituted by phenyl) or C _3-7 cycloalkyl, both of which can be represented by halogen, hydroxyl, C _1-6 alkoxy, C _1-6 alkylthio Group, C _1-6 alkylsulfinyl, NR ¹⁶ R ¹⁷ , COOH, COO (C _1-6 alkyl) or cyano optionally substituted;

· Or R ⁶ and R ⁷ together represent C _3-5 alkylene, X and Y thus form a 5-7 membered ring;

R ⁸ represents H, C _1-6 alkyl or forms a bond with R ⁵ ;

R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H;

· R ¹³ and R ¹⁴ are independently C _1-6 alkyl, H, or together with the nitrogen atom to which they are attached, form a 3 which may optionally contain additional oxygen or nitrogen atoms optionally substituted by C _1-6 alkyl -7-membered saturated ring;

^Ar represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolinyl or 2-quinoxalinyl, all of which may optionally be selected from halogen, nitro , cyano, phenyl, benzenesulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO(C _{1 -6} alkyl), C _1-6 alkyl substituted by phenyl, or one or more substituents of phenyl, wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl can be optionally is optionally substituted by fluorine; and

· A represents halogen, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy; wherein the phenyl on R ² , R ⁶ , R ⁷ or as a substitution on Ar ¹ The phenyl group of the group can be optionally substituted by C _1-6 alkyl, halogen or C _1-6 alkoxy; provided that: (i) when X represents C=O, C=S or C=NR ¹⁵ , then Y represents N; (ii) when R ⁴ represents the bond with R ² , then Y represents N ⁺ R ⁷ ; (iii) when Y represents N ⁺ R ⁷ , then Z represents ^O- , and R ² represents the bond with R ³ A bond with R ⁴ , and R ¹ and R ⁵ form a bond; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then X represents C=O, and Y represents N , Z represents OR ⁸ , R ⁵ represents a bond with R ⁸ ; (ⅵ) when R ¹ represents an alkyl group, then R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ; (ⅶ) when R ¹ represents a bond with R ² , then R ⁵ and R ⁸ form a bond, and if X represents NR ⁴ , R ⁴ represents an alkyl group; (ⅷ) when R ⁶ represents an aryl group, a halogen , alkoxy, thioalkyl, R ² and R ³ form a bond; (ⅸ) when Y represents N or N ⁺ R ⁷ and R ² is substituted by any one of NR ¹⁰ R ¹¹ , OR ¹² or F , then the substituent and the ring nitrogen atom of Y cannot be connected to the same carbon atom of R ² ; (ⅹ) when R ⁷ is substituted by any one of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, then the substitution (ⅹi) when one of B, D, E and G represents ^N , then X does not represent ^NR4 ; (ⅹii) when Y represents CR At ¹⁸ , X represents CR ³ R ⁶ ; the further conditions are: (a) when B, D, E and G all represent CH, X represents CHR ³ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ When representing H and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl; (b) when B, D, E and G all represent CH, X represents CHR ³ , Y represents N ⁺ R ⁷ , R ¹ and R ⁵ form a bond, R ² and R ³ represent a bond, R ⁸ represents H and R ⁷ represents a methyl group, then Ar ¹ does not represent unsubstituted phenyl; (c) when B, D, E and G all represent CH, X represents CH ₂ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H and R ² represents When isopropyl, then Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl; and (d) when B, D, E and G all represent CH, X and Y represent CH ₂ and R ¹ and R ⁵ When a bond is formed, then Ar ¹ does not represent unsubstituted phenyl.

Preferably ^Ar1 represents phenyl or pyridyl, most preferably phenyl. The phenyl group Ar ¹ preferably has a substituent in the para position, more preferably a Cl, Br, CF ₃ , C ₂ F ₅ , OCF ₃ , or SCH ₃ substituent in the para position, especially CF ₃ in the para position , C ₂ F ₅ , OCF ₃ or SCH ₃ substituents.

Preferably Y represents N ⁺ R ⁷ and X represents CR ³ R ⁶ , wherein R ³ forms a bond with R ² and R ⁶ represents an alkyl group. In this case, ^R6 is preferably a branched chain alkyl group. Alternatively, X may represent NR ⁴ , where R ⁴ represents a bond to R ² and Y represents N ⁺ R ⁷ .

Preferably B represents CA. A preferably represents F in this case.

In case one of B, D, E and G represents N, preferably D or G represents N.

Preferably R ¹ represents a bond to R ² or R ⁵ . In this case, R ¹ preferably represents a bond to R ⁵ .

Particularly preferred compounds of the invention include those compounds exemplified herein, including their free forms and all salts and solvates thereof.

Pharmaceutically acceptable derivatives include solvates and salts. Particular salts that may be mentioned include hydrochloride, hydrobromide, benzenesulfonate, toluenesulfonate and methanesulfonate.

Compounds of formula I may exhibit tautomerism. All tautomers and mixtures thereof are included within the scope of the present invention. The compounds of formula I may also contain one or more asymmetric carbon atoms and thus exhibit optical and/or diastereoisomerism. All diastereoisomers can be separated by common techniques such as chromatography or partial recrystallization. The various optical isomers can be separated by separation of the racemic or other mixtures of the compounds by common techniques such as partial crystallization or HPLC. In addition, the desired optical isomer can be obtained by reacting or derivatizing an appropriate optically active raw material under conditions that do not cause racemization, such as with a monochiral acid, and then by common techniques (such as HPLC, on silica gel Chromatography) separation of diastereoisomeric derivatives to prepare. All stereoisomers are included within the scope of the present invention.

All R ¹ , R ² , R ⁴ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R 10 , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , ^{R 15} , R ¹⁶ , R ¹⁷ and R ¹⁸ can represent The alkyl group or the alkyl group substituted on one or more aromatic rings forming part of ^Ar1 may be saturated or unsaturated, straight or branched chain. C _3-7 cycloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COO (C _1-6 alkyl) and C _3-5 alkenes Kee explained it in the same way.

The present invention also provides a method for preparing the compound of formula I, which comprises:

(a) The compound of formula I (wherein X represents CH ₂ or C=O, Y represents N, Z represents OR ⁸ , R ⁵ and R ⁸ form a bond and R ¹ and R ² form a bond) can be obtained by the corresponding formula I compound Oxidation (where R ¹ and R ² represent H, and B, D, E, G, X, Y, Z, Ar ¹ and R ⁵ are as defined above), for example at room temperature with a suitable oxidizing agent (such as manganese dioxide ) and appropriate organic solvents;

(b) Compounds of formula I (where B, D, E and G represent CA and A represents amino) can be prepared by reduction of the corresponding compound of formula I (one of B, D, E and G represents CA and A represents nitric acid) and the remaining B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above), such as with iron powder and ammonium chloride under reflux ethanol;

(c) Compounds of formula I (one of B, D, E and G representing CA wherein A represents halogen) can be prepared by diazotization of the corresponding compound of formula I (one of B, D, E and G Represent CA wherein A represents amino and the rest of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) and diazonium salts in halide anion or (to fluorine ) in the presence of sodium tetrafluoroborate, decomposed under reflux in dichlorobenzene to obtain;

(d) Compounds of formula I (one of B, D, E and G representing CA wherein A represents a cyano group) can be prepared by corresponding compounds of formula I (one of B, D, E and G representing CA wherein A represents bromine and the remaining B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) react with copper cyanide, such as refluxing in N-methylpyrrolidone get;

(e) Preparation of compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkylthio group ) can be obtained by the corresponding compound of formula (I) (where X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , R ³ and R ⁵ are as defined above) in the presence of a base, such as sodium hydride, in a suitable solvent such as DMF, the displacement reaction with the compound of formula II is carried out:

Wherein R ^6a represents C _1-6 alkyl;

(f) Preparation of compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkylthio group ) can be obtained by the corresponding compound of formula (I) (where X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , ^R3 and ^R5 are as defined above) in the presence of a base such as sodium hydride, in a suitable solvent such as DMF, the displacement reaction with the compound of formula III is carried out:

Wherein R ^6a is as defined before;

(g) Preparation of compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents NR ¹³ R ¹⁴ ) through the corresponding formula (I) compound (where X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² , R ³ and R ⁵ are as defined above) in the presence of a base, such as sodium bicarbonate, in a suitable solvent such as DMF, at 100 ° C with the displacement reaction of the compound of formula IV to carry out:

Wherein R ¹³ and R ¹⁴ are as defined above.

(h) Preparation of compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents a methylthio group ) can be obtained by the corresponding compound of formula (I) (wherein X represents C=S, Y represents N, Z represents OH and B, D, E, G, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) such as Reaction with a methylating reagent such as methyl iodide under reflux;

(i) The compound of formula I (wherein X represents C=S, Y represents N, Z represents OH and R ¹ represents the bond with R ⁵ ) can be obtained by corresponding formula (I) compound (wherein X represents C=O and B , D, E, G, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ as defined above) reaction such as by sulfidation, such as with Lawesson's reagent, in a suitable solvent, such as dioxane, in flow back down;

(j) compound of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents ^O- and R ⁶ represents halogen) can be obtained by corresponding formula (I) compound (wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ⁸ represents the bond with R ⁵ and B, D, E, G, Ar ¹ , R ¹ and R ² are as defined above) reaction such as by halogenation, such as oxidation with trihalide Phosphorus, if carried out at 100°C;

(k) Preparation of a compound of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkyl group) Can be by corresponding formula (I) compound (wherein X represents C=O, Y represents N, Z represents OH, R' represents the bond with R ⁵ and B, D, E, G and Ar ¹ are defined as before and R ² Represents a group corresponding to ^R as defined above) such as in the presence of a copper salt such as copper(I) bromide, in a suitable solvent such as dimethoxyethane, such as under reflux with a nucleophilic alkylating agent For example, the reaction of the compound of formula V is carried out:

Wherein R ⁶ is as defined above and Hal represents halogen;

(1) Compound of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkyl group) Can pass corresponding formula (I) compound (wherein X represents CR ³ R ⁶ wherein R ⁶ represents H and B, D, E, G, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) In a suitable solvent such as THF, such as at 0°C, reacting with a nucleophilic alkylating agent such as a compound of formula V as defined above;

(m) Compounds of formula I (wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ¹ represents a bond with R ⁵ , and R ⁸ represents an alkyl group) can be prepared by corresponding compounds of formula I (wherein Z Represents OR ⁸ wherein R ⁸ represents H and B, D, E, G, X, Y, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) such as in the presence of a base such as sodium hydride in a suitable solvent such as DMF In the reaction with the compound of formula VI to carry out;

R ⁸ Hal (Ⅵ)

Wherein R ⁸ and Hal are as defined above;

(n) the compound of formula I (wherein R ¹ represents OH, X represents C=O, Y represents N, Z represents OR ⁸ and R ⁵ represents the bond with R ⁸ ) can be through the reaction of corresponding formula I compound such as by using Oxidizing agents, such as ceric ammonium nitrate, are carried out in a suitable solvent such as acetonitrile, such as at room temperature (where Z represents O ⁻ , R ¹ and R ⁵ form a bond and B, D, E, G, X, Y, Ar ¹ and R ² are as defined above);

(o) Compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, and R ¹ and R ⁵ form a bond) can be obtained through the corresponding formula I Compound (wherein Y represents N, Z represents OH and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above) in a base such as sodium hydride, in a suitable solvent such as DMF, such as Carried out by reacting with a compound of formula IX at room temperature;

R ⁷ Hal (Ⅸ)

Wherein R ⁷ and Hal are as defined before;

(p) Compounds of formula I (wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond with R ⁵ ) can be prepared by corresponding compounds of formula 1 (wherein R ² represents H and B, D, E, G, X, Y, Z, Ar ¹ , R ¹ and R ⁵ are as defined above) in a suitable solvent such as DMF, such as at room temperature with a base such as sodium hydride, and with formula VII Compound reactions to proceed:

R ² Hal (VII)

Wherein R ² does not represent H, and Hal is defined as before;

(q) Preparation of compounds of formula I (wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁴ and R ² form a bond and R ¹ and R ⁵ to form a bond) can be obtained by a compound of formula VIII:

Wherein A and Ar ¹ are defined as before, in a suitable solvent such as DMF, such as at room temperature with a base, such as sodium hydride and the compound of formula IX as defined above to react;

(r) Preparation of compounds of formula I (wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N, Z represents OR ⁸ , R ² and R ¹ form a bond and R ⁵ and R ⁸ form a bond ) is carried out by reacting a compound of formula VIII as defined above in a suitable solvent such as DMF, as at room temperature with a base, such as sodium hydride, and a compound of formula X:

R ₄ Hal (X)

Wherein R ⁴ and Hal are as defined before;

(s) Compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond and R ¹ represents a bond with R ⁵ ) can be prepared by, for example, using an acid such as Treat the corresponding compound of formula I with trifluoroacetic acid (wherein Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁷ represents CH ₂ C ₆ H ₄ O alkyl and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ are defined the same as before) to carry out;

(t) Compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond and R ¹ represents a bond with R ⁵ ) can be obtained by e.g. in the presence of a catalyst such as palladium carbon The corresponding compound of formula I (wherein Y represents N ⁺ R ⁷ , Z represents O ^- , and R ⁷ represents CH ₂ phenyl (optionally substituted by C _1-6 alkyl or C _1-6 alkoxy) is treated with hydrogen ) and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ are as defined above);

(u) Compounds of formula I (wherein X represents C=O, Y represents N, Z represents OH, R ² represents H and R ¹ represents the bond formed with R ⁵ ) can be obtained by, for example, using an acid such as trifluoroacetic acid under reflux Treat the corresponding formula I compound (wherein Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁷ represents CH ₂ C ₆ H ₄ O alkyl and B, D, E, G, X, Ar ¹ , R ¹ , R ² and R ⁵ are defined the same as before) to carry out;

(v) Compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents H) can be By the compound of formula XI:

Wherein X represents CH ₂ , R ¹ represents H, R ² represents the group corresponding to R ⁷ as defined above in the compound of formula I, B, D, E and G are as defined above and R is an alkyl group, as in xylene Middle reflux reacts with formula XII compound to carry out:

Ar ¹ NHNH ₂ (Ⅻ)

Wherein Ar ¹ is as defined above;

(w) preparation of formula I compound (wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH, and R ¹ represents and R ⁵ R ⁵ passes through the compound of formula XI as defined above (wherein X Represents C=O, R ¹ represents H, R ² is as defined above and B, D, E, G and R are as defined above) and the compound of formula XII as defined above is carried out as reflux reaction in xylene, wherein Ar ¹ as defined above;

(x) Compounds of formula I (where X represents CH ₂ , Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents an alkyl group) can be prepared by formula XI compounds as defined above (wherein X represents CH ₂ , R ¹ represents an alkyl group and B, D, E, G, R ² and R are as defined above) such as reacting a compound of formula XII as defined above under reflux in xylene, wherein Ar' is as defined above; or

(y) compound of formula I (wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents an alkyl group) can be obtained by formula XI compound as defined above (wherein X Represents C=O, R ¹ represents an alkyl group, R ² represents H or an alkyl group, and B, D, E, G and R are as defined above) such as reacting with a compound of formula XII as defined above in reflux in xylene Carry out, wherein Ar' is as defined above;

(z) Compounds of formula I (wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ¹ and R ⁵ form a bond and R ² and R ³ form a bond) can be obtained by oxidation of the corresponding compound of formula I In which X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H, R ¹ and R ⁵ form a bond and B, D, E, G, Ar ¹ , R ⁶ as defined above for R ¹⁸ ; or

(aa) The compound of formula I (wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ form a bond and R ¹ and R ⁵ form a bond) can be obtained by the formula XII compound as defined above The reaction with the compound of formula XX is carried out:

wherein B, D, E, G, R ⁶ , R ¹⁸ and R are as defined above.

A compound of formula I, wherein X represents CHR ³ , R ² and R ³ together represent a bond, R ¹ and R ⁵ form a bond and either:

· Y stands for N ^{+ R7} and Z stands for ^O- , or

• Y represents N, and Z represents OH, and can be prepared by a method similar to that described in J. Med. Chem. 35, 368 (1992). Compounds of formula VIII are known from European Patent Application No. EP-A-187551, or can be prepared by analogous methods to those described therein. The compound of formula XI can be obtained by the compound of formula XIII: Wherein B, D, E, G, R, ^R2 and X are as defined above and R' is an alkyl group, prepared by reacting with a base such as sodium hydride, such as in DMSO at 60°C in the presence of alcohol. The compound of formula XI, wherein X represents C=O and R ² represents H, is known from Japanese Examined Patent Publication No. JP-B-8254152, or can be prepared by an analogous method described therein.

Compounds of formula XIII, wherein X represents C=O, can be obtained by compounds of formula XVI: Wherein B, D, E, G, R and R are ^as defined above, prepared by alkylation reaction with a compound of formula XVII in the presence of a base such as potassium carbonate, such as in acetone at 50°C:

(R ¹ O) ₂ SO ₂ (XVII) wherein R ¹ is as defined above.

其中B、D、E、G和R定义同前，与式ⅩⅤ化合物：

其中R¹、R²和R’定义同前，在碱如三乙胺存在下，在适当的溶剂如乙醚中，在回流下反应来制备。Compounds of formula XIII, wherein X represents _CH2 , can be obtained by compounds of formula XIV:

Wherein B, D, E, G and R are as defined above, and the compound of formula XV:

wherein R ¹ , R ² and R' are as defined above, prepared by reacting under reflux in a suitable solvent such as diethyl ether in the presence of a base such as triethylamine.

其中B、D、E、G和R定义同前，与溴化剂如NBS，如在二氯乙烷中回流下，光解照射下反应来制备。The compound of formula XIV can be obtained by the compound of formula XVIII:

Wherein B, D, E, G and R have the same definitions as above, and are prepared by reacting with a brominating agent such as NBS under reflux in dichloroethane and photolysis irradiation.

其中B、D、E和G定义同前，与如前定义的式ⅩⅤ化合物(其中R¹、R²和R’定义同前)在适当的溶剂如丙酮中，在50℃下反应来制备。The compound of formula XVI can be obtained by the compound of formula XIX:

wherein B, D, E and G are as defined above, and prepared by reacting the compound of formula XV as defined above (wherein R ¹ , R ² and R' are as defined above) in a suitable solvent such as acetone at 50°C.

Compounds of formula II, III, IV, V, VI, VII, IX, X, XII, XV, XVI, XVII, XVIII and XX are either commercially available, well known in the literature, or obtained by known techniques.

Those skilled in the art understand that in the preparation steps described above, the functional groups of the intermediate compounds may need to be protected by protecting groups. Protection of functional groups is performed prior to any of the steps described above. For example, the nitrogen atom of compounds of formulas XI, XIII and XVI may be protected with a suitable protecting group such as benzyl or preferably a 4-methoxyphenylmethyl group prior to further reaction. Protecting groups can be removed with the reaction steps or at the end of the reaction process using techniques well known in the art (eg acid hydrolysis).

The compounds of the present invention possess useful pharmacological activity and are thus indicated as pharmaceuticals for use in medicine.

The present invention further provides a compound of formula I as defined above without limitation (C) as a medicament.

In particular the compounds of the invention have antiallergic and antiinflammatory activity, as shown, for example, in the experiments described below. Therefore, it is shown that the compounds of the present invention can be used for the treatment of allergic airway inflammatory diseases such as asthma (such as bronchial asthma, allergic asthma, internal asthma, exogenous asthma and dust asthma), especially chronic or intractable asthma (such as advanced asthma and airway susceptible), bronchitis, etc. In addition, it is shown that the compounds of the present invention are useful in the treatment of diseases including inflammatory/allergic diseases such as rhinitis, including all characterized by inflammation of the nasal mucosa, such as acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis including caseous rhinitis, hypertrophic rhinitis , purulent rhinitis, dry rhinitis, drug-induced rhinitis, mucous membrane rhinitis including Grubb's, fibrinous, pseudomembranous rhinitis, lymphotuberculous rhinitis, seasonal rhinitis including neurological rhinitis (hay fever) and vascular Atrophic rhinitis.

The compounds of the present invention have also been shown to be useful in the treatment of chronic allergic diseases, allergic dermatitis, eosinophilia of the skin, eosinophilic fasciitis, hyper IgE syndrome, vernal conjunctivitis, systemic lupus erythematosus, thyroiditis , leprosy nodular leprosy, sezary syndrome (erythroderma), chronic graft-versus-host disease, myasthenia, essential thrombocytopenia pupura, etc.

The compound of the present invention also has the activity of prevention and prophylactic treatment of acquired immunodeficiency syndrome (AIDS), has the activity of preventing chronic rejection of allografts caused by humoral immunity, and treats autoimmune diseases such as multiple sclerosis and the like. rheumatoid arthritis.

Most important among the above indications is the use of the compounds according to the invention for asthma, especially for the prophylaxis of asthma, and for rhinitis, especially allergic rhinitis and seasonal rhinitis including nervous rhinitis (hay fever).

Another aspect of the present invention provides a method of treating or preventing allergic or inflammatory diseases, the method comprising administering to a human infected or susceptible to these diseases a therapeutically effective amount of (b) or (c) as defined above without limitation A compound of formula I or a pharmaceutically acceptable derivative thereof.

Administration of the compounds of the invention may be localized (eg, by inhalation into the lungs). The compounds of the present invention may be inhaled in pressurized or non-pressurized dry powder form.

In unpressurized powder compositions, the active ingredient in finely divided form is admixed with larger scale pharmaceutically acceptable inert carriers. Alternatively the composition may be pressurized and contain in combination a compressed gas, such as nitrogen, or a liquefied gaseous propellant. In these pressurized compositions the active ingredient is well dispersed. The pressurized composition may also contain a surfactant. The pressurized composition can be prepared by a general method.

The compounds of the invention may be administered systemically (eg, orally into the gastrointestinal tract). The active ingredient can be formulated into tablets or capsules for oral administration to the gastrointestinal tract together with well-known excipients, diluents or carriers by common techniques. Examples of suitable excipients, diluents or carriers for tablets, capsules and dragees for oral administration include microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugars such as lactose, dextran or mantel, talc, hard Fatty acids, starch, sodium bicarbonate and/or gelatin.

Another aspect of the present invention provides a pharmaceutical composition, which includes the compound of formula I or its pharmaceutically acceptable derivative as defined above but without limitation (c), and a pharmaceutically acceptable auxiliary agent, diluted agent or carrier mixture.

Suitable dosages for topical or oral administration are in the range 0.01-30 mgkg ^-1 per day, for example 0.3 mgkg ^-1 per day.

Those skilled in the art understand that certain functional groups in the compounds of the present invention can be protected with appropriate protecting groups to form protected derivatives of the compounds of the present invention. It should also be understood that although these protected derivatives do not have the aforementioned pharmacological activity, they can be metabolized in vivo to form the pharmacologically active compound of the present invention after administration. These derivatives are therefore called "prodrugs". All protected derivatives and prodrugs of the compounds of formula I are included within the scope of the present invention.

The invention is illustrated by the following examples. General notes:

Column chromatography was performed on silica gel (35-70 μm) at atmospheric pressure, typically at a 0.5 grating. The following hydrazines are used as intermediates in the subsequent examples:

5-hydrazino-2-methylpyridine

An aqueous solution (2ml) of sodium nitrite (0.3g) was added to 5-amino-2-picoline (J.Chem.Soc.(C)., 1971, 3257) (3.61g) maintained below 5°C In a cold solution of water (6ml) and concentrated hydrochloric acid (1ml). The mixture was stirred at 0°C for 15 minutes and then cooled to -10°C. A solution of tin(II) chloride (0.253 g) in concentrated hydrochloric acid (5 ml) was then added dropwise. After stirring at -10°C for 10 minutes, the solution was allowed to warm to room temperature and anhydrous potassium carbonate was added until a thick slurry formed. The slurry was stirred with ethyl acetate, the organic phase was decanted and evaporated to an oil. The slurry was then diluted with water and extracted with dichloromethane (three times). The organic phase was dried over sodium sulfate, filtered, evaporated and combined with the above oil. Purification by column chromatography eluting with dichloromethane:methanol (20:1) afforded the title compound as a beige solid (0.09g), mp 68-70°C. ¹ H NMR(CDCl ₃ )δ2.47(3H,s),3.60(2H,br s),5.13(1H,br s),7.03(1H,d),7.12(1H,dd),8.12(1H. d).

4-(pentafluoroethyl)phenylhydrazine

Prepared according to the method for preparing 5-hydrazino-2-picoline, using 4-(pentafluoroethyl)aniline (J. Chem. Soc. Perkin Trans. 1, 1990, 2293). MS(EI)226(M ⁺ ) ^1HNMR ( _CDCl3 )δ4.15(2H,br),6.87(2H.d),7.30(2H,d),7.45(1H,br)

2-hydrazino-5-methylpyridine (J.Org.Chem.1966,31,251)

2-Chloro-5-hydrazinopyridine (Atti R. Accad. dei Lincei, Roma, 1925, 2, 125); Chem. Zent. 1926, 1, 672

2-Hydrazinopyrimidine J.Chem.Soc.1955,3478 Example 13-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H -pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (a) 2-[N-(methoxycarbonylmethyl)-N-(4-methoxyphenyl)methyl base) amino] methyl benzoate

Methyl 2-bromomethylbenzoate (23.47 g; prepared similarly to ethyl ester in J. Med. Chem., 1992, 35, 368) and triethylamine (15.7 ml) were dissolved in dry ether ( 200ml). N-[(4-Methoxyphenyl)methyl]glycine methyl ester (23.6 g; J. Am. Chem Soc., 1993, 115, 536) was added dropwise. The mixture was heated at reflux for 16 hours and then cooled to room temperature. Water was added and the organic phase was separated. The aqueous phase was then extracted with ethyl acetate (three times). The combined organic phases were washed with brine, dried over sodium sulfate. Filtration, removal of solvent by evaporation, and further purification of the residue by column chromatography eluting with ethyl acetate:isohexane (1:9) afforded the subtitle compound as an oil (27.85 g); MS (APCI) 358 ( (M+H) ⁺ ) ¹ H NMR (CDCl ₃ ); δ3.23(2H,s),3.66(3H,s),3.71(2H,s),3.78(3H,s),3.88(3H,s ),4.16(2H,s),6.8(2H,d),7.2(2H,d),7.3(1H,td),7.45(1H,td),7.6(1H,dd),7.75(1H,dd) .(b) Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate

Methyl 2-[N-(methoxycarbonylmethyl)-N-(4-methoxyphenyl)methyl)amino]methylbenzoate (27.85 g; obtained from the previous step (a)) Dissolve in dry toluene (150ml), then add dropwise to a mixture of refluxing oil-free sodium hydride (4.37g of 60% sodium hydride) in dry toluene (300ml) and 2-methylpropan-2-ol (2.0ml) in suspension. Continue heating for 12 hours. The mixture was then cooled to room temperature, poured into saturated ammonium chloride solution, and extracted with ethyl acetate (three times). The combined organic layers were then washed with brine and dried over sodium sulfate. Filtration, evaporation and purification by column chromatography eluting with ether:isohexane (1:4) gave the subtitle compound as an oil (20.41g). ¹ H NMR (CDCl ₃ ) (main component - enol tautomer) δ3.60(2H,s),3.81(3H,s),3.91(5H,s),6.86(2H,d),7.09 (1H,d),7.25(2H,d),7.35-7.43(2H,m),7.77(1H,d) and 11.58(1H,s).(c)3-Hydroxy-4-[(4-methyl Oxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate (1.0 g; obtained from step (b) above) , 4-(trifluoromethyl)phenylhydrazine (1.08 g) and a catalytic amount of 4-toluenesulfonic acid were melted together at 150° C. for 10 minutes. Xylene (20ml) was then added and heating continued for 1 hour. After cooling to room temperature the solvent was removed by evaporation. The solid residue was triturated with ether to give the title compound (0.5 g). mp220-221°C. MS(APCI)450((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ3.72(3H,s),6.08(2H,s),6.95(2H,m),7.7(2H,m ), 7.8(3H, m), 7.95(1H, td), 8.15(1H, d), 8.35(1H, d), 8.6(2H, d), 8.96(1H, s). Example 22-(4 -Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]iso Quinolinium hydroxide, inner salt (0.26g; from step (c) above) was heated at reflux in trifluoroacetic acid (2ml) for 16 hours. After cooling to room temperature, the solvent was evaporated. Toluene was added to the residue and evaporated (twice). Methanol was added and evaporated, and the red residue was triturated with ethyl acetate. Recrystallization from ethanol gave the title compound as a red solid (14 mg). mp＞250℃MS(APCI)330((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.9(3H,m),8.0(1H,t),8.3(4H.m).9.03 (1H,bs)Example 32-(4-chlorophenyl)-2,5-dihydro-5-methyl-3H-pyrazolo[4,3-c]cinnolin-3-one

2-(4-Chlorophenyl)-2,5-dihydro-pyrazolo[4,3-c]cinnolin-3-one (0.33 g; European Patent Application EP-A-0187551) was dissolved under nitrogen To a stirred suspension of oil-free sodium hydride (49 mg of a 60% dispersion) in dry dimethylformamide (5 ml) was added in portions. After 0.5 hours iodomethane (0.076ml) was added dropwise and the resulting solution was stirred at room temperature for 2 hours. The solution was poured into brine and extracted with dichloromethane/methanol (three times). The organic phase was washed with 2M hydrochloric acid and brine, then dried over sodium sulfate, filtered, and concentrated to a red solid. Purification by column chromatography (3:2 ethyl acetate: hexanes) followed by recrystallization from dimethylformamide afforded the title compound as red crystals (55 mg). mp＞250℃MS(EI)310.312(M ⁺ ) ¹ H NMR(CDCl ₃ )δ4.33(3H,s),7.4(2H,dd),7.65(2H,t),7.75(1H,td), 8.20(2H,dd), 8.35(1H,d).Example 42-(4-chlorophenyl)-2,3a,4,5-tetrahydro-3a,4-dimethylpyrazolo[4, 3-c]isoquinolin-3-one (a) methyl 2-[((1-methoxycarbonyl)ethyl)methylamino]methylbenzoate

Methyl 2-bromomethylbenzoate (3.51 g) and diisopropylethylamine (5.86 ml) were dissolved in ether (30 ml) under nitrogen, and the solution was cooled to 0°C. N-methylalanine methyl ester trifluoroacetate (3.89g) dissolved in dry diethyl ether (10ml) and dry dichloromethane (5ml) was added dropwise and the mixture was allowed to warm to room temperature overnight. Water was added, the organic phase was separated, washed with brine and dried over sodium sulfate. Filtration, evaporation, and column chromatography (1:9 ethyl acetate:hexanes) gave the subtitle compound (2.87g). MS(EI)265(M ⁺ )(b)1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinolinecarboxylic acid methyl ester

A solution of methyl 2-[((1-methoxycarbonyl)ethyl)methylamino]methylbenzoate (2 g) in dry toluene (10 ml) was added dropwise to refluxing oil-free sodium hydride (0.42 g of 60% dispersion) in dry toluene (30ml) and 2-methyl-2-propanol (5 drops) suspension. After heating to reflux for 45 minutes, the solution was cooled in an ice bath, then poured into saturated ammonium chloride solution, and extracted with ethyl acetate (three times). The organic phase was washed with brine and dried over sodium sulfate. Filtration, evaporation and column chromatography (1:4 ethyl acetate:hexanes) gave the subtitle compound as a yellow oil (0.95g). MS(EI) 234((M+H) ⁺ )(c) 2-(4-chlorophenyl)-2,3a,4,5-tetrahydro-3a,4-dimethylpyrazolo[4, 3-c]isoquinolin-3-one

Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-4-oxo-3-isoquinolinecarboxylate (0.84g), 4-chlorophenylhydrazine (1.54g) and 4-Toluenesulfonic acid (20 mg) was melted together at 150°C for 10 minutes. Xylene (10ml) was then added and the mixture was heated to 150°C for 6 hours. After cooling to room temperature, the solvent was removed by evaporation and the residue was dissolved in dichloromethane/methanol. The solution was washed with 2M hydrochloric acid and brine, then dried over sodium sulfate. Filtration, evaporation and column chromatography (1:99 methanol:dichloromethane) gave the title compound as a colorless solid (50 mg). mp 128-129°C. MS(EI) 325,327(M ⁺ )Example 52-(4-chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-2H-pyrazolo[4,3-c]isoquine Phenyl-3,5-dione (a) methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate

1,2-Dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylic acid methyl ester (JP-B-82 54,152; 1.5g) in dry dimethyl The formamide (5ml) solution was added dropwise to a stirred suspension of oil-free sodium hydride (from 0.28g of a 60% dispersion) in dry dimethylformamide (10ml). After 30 minutes, iodomethane (0.4ml) was added dropwise. The solution was stirred at room temperature for 3 hours, then poured into 2M hydrochloric acid and extracted with ethyl acetate (three times). The organic phase was washed with brine and dried over sodium sulfate. Filtration, evaporation and purification by column chromatography (1:1 ether:hexanes) gave the subtitle compound as a yellow oil (0.53g). MS(ESI) 248((M+H) ⁺ )(b) 2-(4-chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-2H-pyrazolo[4,3 -c]isoquinoline-3,5-dione

Methyl 1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxo-3-isoquinolinecarboxylate (0.53g), 4-chlorophenylhydrazine (0.92 g) Melted with 4-toluenesulfonic acid (10 mg) at 150°C for 10 minutes. After cooling to room temperature, the solvent was removed by evaporation, and the residue was dissolved in dichloromethane/methanol, washed with 2M hydrochloric acid, sodium bicarbonate solution and brine. The solution was dried over sodium sulfate, filtered and evaporated. Purification by column chromatography (1:9 ethyl acetate:hexanes) followed by recrystallization from propan-2-ol afforded the title compound as a beige solid (0.13g). mp192-193°C. MS (EI) 339,341 (M ⁺ ) Example 62-(4-chlorophenyl)-2,4-dihydro-3-hydroxy-4-methylpyrido[4,3-c]isoquinoline-5 -ketone

Methyl 1,2-dihydro-4-hydroxy-2-methyl-1-oxo-3-isoquinolinecarboxylate (JP8254152; 0.5g), 4-chlorophenylhydrazine (0.91g) and 4 -Toluenesulfonic acid (10 mg) was melted together at 150°C for 10 minutes. Xylene (5ml) was then added and the mixture was heated to 150°C for 5 hours. After cooling to room temperature, the yellow precipitate was collected by filtration and washed with ether. Purification by column chromatography (1:49 methanol:dichloromethane) followed by recrystallization from ethanol afforded the title compound as a beige solid (0.1 g). mp>250°C. MS (EI) 325,327 (M ⁺ ) Example 73-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolo[4,3 -c] Isoquinolinium hydroxide, inner salt

The title compound was prepared using 3-hydrazinoquinoline as described in Example 1(c). mp232-233°C. MS(APCI)433((M+H) ⁺ )NMR(d ₆ -DMSO)δ3.7(3H,s),6.1(2H,s),6.7(2H,d),7.65(1H,t), 7.70(3H,m),7.80(1H,t),8.05(3H,m),8.20(1H,d),8.40(1H,d),9.00(1H,s),9.20(1H,d),9.90 (1H, d). Example 82-(3-quinolinyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, with 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(3-quinolyl)-2H-pyrazolo[4,3- c] Isoquinolinium hydroxide, inner salt (0.66g) The title compound (0.21g) was prepared. mp247-248℃MS(APCI)313((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.70(1H,td),7.80(1H,td),7.90(1H,bt),8.00 (1H,t), 8.15(2H,m), 8.35(2H,m), 8.90(1H,d), 9.05(1H), 9.70(1H,d), 12.20(1H,bs)Example 92-( 3,4-dichlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 3,4-dichlorophenylhydrazine. mp 239-240℃MS(APCI)448,450,452((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO):δ3.72(3H,s),6.06(2H,s),6.96(2H,d) , 7.70(3H,m), 7.79(1H,t), 7.97(1H,t), 8.16(1H,d), 8.37(2H,m), 8.72(1H,d), 8.97(1H,s). Implementation Example 10 2-(3,4-dichlorophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, 2-(3,4-dichlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4 ,3-c] Isoquinolinium hydroxide, inner salt (0.26g) The title compound (0.028g) was prepared, mp>230°C. MS(APCI)330.332.334((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.82(1H,d),7.86(1H,t),7.97(1H,t),8.13(1H ,dd),8.24(1H,d),8.32(1H,d),8.42(1H,d),8.94(1H,s).Example 112-([1,1'-diphenyl]-4- Base)-2H-pyrazolo[4,3-c]isoquinolin-3-ol (a)2-([1,1'-diphenyl]-4-yl)-3-hydroxyl-4- [(4-Methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The subtitled compound was prepared according to the method described in Example 1(c) using [1,1'-diphenyl]-4-ylhydrazine (see J. Chem. Soc. Perkin Trans. I, (1975) 1280). (b) 2-([1,1’-diphenyl]-4-yl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, with 2-([1,1'-diphenyl]-4-yl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]- 2H-Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.29g; from step (a) above) to prepare the title compound (0.082g). mp＞220°(decomposition)MS(APCI)338((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.37(1H,m),7.51(2H,m),7.75(2H,m ),7.89(3H,m),7.98(1H,m).8.05(2H,m).8.31(2H,m),9.02(1H,s,br)Example 123-Hydroxy-4-[(4- Methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the procedure described in Example 1(c) using 4-methylphenylhydrazine. mp＞100℃(decomposition) MS(APCI)396((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.34(3H,s),3.72(3H,s),6.10(2H,s ),6.96(2H,m),7.26(2H,m),7.74(3H,m),7.94(1H,m),8.13(1H,d),8.23(2H,d)8.33(1H,d), 8.89 (1H, s) Example 13 2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, with 3-hydroxy-4-[(4-methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4, 3-c] Isoquinolinium hydroxide, inner salt (0.20 g) The title compound (0.043 g) was prepared. mp202-209°C (decomposition). MS(APCI)276((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.37(3H,s),7.37(2H,d),7.88(3H,m),7.94(1H,m ), 8.29(2H,m), 9.02(1H,br), 11.90(1H,br)Example 142-(4-bromophenyl)-3-hydroxy-4-[(4-methoxyphenyl) Methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared according to the method described in Example 1(c) using 4-bromophenylhydrazine. mp>220°C (decomposition). MS(APCI)460,462((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)δ3.70(3H,s),6.08(2H,s),6.96(2H,m),7.66(2H, m), 7.76(2H, m), 7.77(1H, t), 7.96(1H, m), 8.15(1H, d), 8.36(3H, m), 8.94(1H, s) Example 152-(4 -Bromophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, 2-(4-bromophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3- c] Isoquinolinium hydroxide, inner salt (0.164g) The title compound was prepared (0.053g), mp>250°C. MS(APCI)340,342((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)δ7.76(2H,d),7.89(1H,m),8.02(3H,m),8.31(2H, m), 9.07 (1H, br), 11.92 (1H, br) Example 16 2-(3-trifluoromethylphenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl] -2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

According to the method described in Example 1(c), the oil was prepared with 3-trifluoromethylphenylhydrazine and purified twice by column chromatography, eluting with ethyl acetate for the first time and diethyl ether for the second time: Elution with the ethyl acetate mixture gave the title compound as an oil. MS(APCI)450((M+H) ^- ) ¹ H NMR(CDCl ₃ )δ3.81(3H,s),6.19(2H,s),6.96(2H,d),7.45(1H,m), 7.54(3H,m),7.79(2H,m),7.86(1H,t),8.52(1H,d),8.68(1H,d),8.72(1H,s) Example 172-(3-trifluoro Methylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, 2-(3-trifluoromethylphenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4 ,3-c] Isoquinolinium hydroxide, inner salt The title compound was prepared, mp 250°C decomposed. MS(APCI)330((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.67(1H,d),7.81(1H,t),7.88(1H,t),7.99(1H,t ), 8.42(3H, m), 8.48(1H, s), 9.01(1H, s) Example 182-[4-(1,1-dimethylethyl)phenyl]-2H-pyrazolo[ 4,3-c]isoquinolin-3-ol (a) 3-hydroxy-2-[4-(1,1-dimethylethyl)phenyl]-4-[(4-methoxybenzene Base) methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The subtitle compound was prepared using 4-[(1,1-dimethylethyl)phenyl]hydrazine according to the method described in Example 1(c), and was used directly in the next step without purification. (b) 2-[4-(1,1-Dimethylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, with 3-hydroxy-2-[4-(1,1-dimethylethyl)phenyl]-4-(4-methoxyphenylmethyl)-2H- Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt The title compound was prepared. mp>210°C (decomposition). MS(APCI)318((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ1.33(9H,s),7.51(2H,d),7.75(1H,t),7.84(1H,t ), 8.01(2H,d), 8.12(1H,d), 8.25(1H,d), 8.74(1H,s)Example 192-(4-trifluoromethoxyphenyl)-2H-pyrazolo [4,3-c]isoquinolin-3-ol (a) 2-(4-trifluoromethoxyphenyl)-3-hydroxyl-2-[(4-methoxyphenyl)methyl] -2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

The title compound was prepared using 4-trifluoromethoxyphenylhydrazine according to the method described in Example 1(c), and was used in the next step without further purification. (b) 2-(4-trifluoromethoxyphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol

According to the method described in Example 2, 2-(4-trifluoromethoxyphenyl)-3-hydroxy-2-[(4-methoxyphenyl)methyl]-2H-pyrazolo[ 4,3-c] Isoquinolinium Hydroxide, Inner Salt The title compound was prepared. mp>230°C. MS(APCI)346((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ7.58(2H,d),7.91(1H,t),7.99(1H,t),8.14(2H,d ), 8.29 (2H, m), 9.03 (1H, br s). Example 20 2-(4-chlorophenyl)-3-hydroxyl-4-methyl-2H-pyrazolo[4,3-c] Isoquinolinium hydroxide, inner salt

Methyl 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylate (0.5g) (IGHinton & F.G.Mann, J.Chem.Soc.1959,599) , 4-Chlorophenylhydrazine (0.98g) and 4-toluenesulfonic acid (10mg) were melted together under nitrogen at 150°C for 10 minutes. Xylene (10ml) was then added and the mixture was heated to 150°C for 6 hours. The reaction solution was cooled, and the resulting red precipitate was filtered off and washed with ether. Recrystallization from methanol gave the title compound (0.27 g). mp 247-248°C. MS(EI)309,311(M ⁺ ). ¹ H NMR(d ₆ -DMSO)δ4.5(3H,s),7.5(2H,d),7.75(1H,t),7.95(1H,t),8.1 (1H, d), 8.3 (1H, d), 8.4 (2H, d), 8.6 (1H, s). Example 212-(4-chlorophenyl)-3-hydroxy-4-methyl-2H- Pyrazolo[4,3-c]cinnilinium hydroxide, inner salt

2-(4-Chlorophenyl)-2,5-dihydro-pyrrolo[4,3-c]cinnolin-3-one (0.33g) was added under nitrogen (European patent application EP-A-0187551) Add in portions to a stirred suspension of oil-free sodium hydride (from 49mg of a 60% dispersion) in dry dimethylformamide (5ml). After 0.5 hour, iodomethane (0.076 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The solution was poured into brine and extracted with dichloromethane/methanol mixtures (three times). The organic phase was washed with 2N hydrochloric acid and brine, dried over sodium sulfate, filtered, and concentrated to give a red solid. Purification by column chromatography (2:3 ethyl acetate:hexanes) followed by recrystallization from dimethylformamide afforded the title compound as purple crystals (65 mg). mp 249-250°C. MS(EI) 310,312(M ⁺ ). ¹ H NMR(CDCl ₃ ) 4.81(3H,s), 7.40(2H,d), 7.75(2H,m), 8.00(1H,dd), 8.25(2H,d ), 8.35(1H,dd).Example 222-(4-chlorophenyl)-3-hydroxyl-4-[(4-methoxyphenyl)methyl-2H-pyrazolo[4,3- c] Isoquinolinium hydroxide, inner salt

According to the method described in Example 20, methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenyl)methyl-4-oxo-3-isoquinolinecarboxylate (the latter The compound was prepared by a similar method in IGHinton & F.G. Mann, J. Chem. Soc. 1959, 599) to prepare the title compound. mp 227-228°C. MS(EI) 416,418((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO) 3.70(3H,s), 6.08(2H,s), 6.95(2H,d), 7.50(2H,d) ,7.70(2H,d),7.75(1H,t),7.95(1H,t),8.15(1H,d),8.35(1H,d),8.40(2H,d),8.93(1H,s).

The following compounds, Examples 23-56, were prepared by methods analogous to Examples 20 & 22: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ twenty three 3-Hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 201-203 344(M+H) ⁺ 4.51(3H,s),7.80(3H,m),7.97(1H,t),8.10(1H,d),8.35(1H,d),8.60(2H,d),8.66(1H,s) twenty four 3-Hydroxy-4-methyl-2-(3-quinolyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 327(M+H) ⁺ 4.55(3H,s).7.60(1H,td),7.70(1H,td),7.82(1H,td),8.00(3H,m),8.10(1H,d),8.40(1H,d),8.69 (1H,s),9.13(1H,d),9.93(1H,d), 25 2-(6-Hydroxy-3-pyridyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 311/313(M+H) ⁺ 4.50(3H,s),7.61(1H,d),7.80(1H,t),7.97(1H,t),8.12(1H,d),8.35(1H,d),8.68(1H,s),8.74 (1H,dd),9.37(1H,s) 26 2-(3,4-Dichlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 223-229 344/346/348(M+H) ⁺ 4.49(3H,s),7.70(1H,d),7.78(1H,t),7.96(1H,t),8.11(1H,d),8.35(2H,m),8.67(2H,m) Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 27 3-Hydroxy-4-methyl-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 247-248 290(M+H) ^- 2.33(3H,s),4.52(3H,s),7.24(2H,m),7.74(1H,m),7.93(1H,m),8.09(1H,m),8.20(2H,m),8.33 (1H,d),8.59(1H,s) 28 2-(4-Bromophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 244 354/356(M+H) ⁺ 4.50(3H,s),7.63(2H,d),7.76(1H,t),7.96(1H,t),8.10(1H,d)8.34(3H,m),8.63(1H,s) 29 3-Hydroxy-4-methyl-2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 222-6 344(M+H) ⁺ 4.51(3H,s),7.53(1H,d),7.69(1H,t),7.78(1H,t).7.96(1H,t),8.12(1H,d),8.35(1H,d),8.63( 1H,d),8.66(1H,s),8.81(1H,s) 30 2-[4-(1,1-Dimethylethyl)phenyl]-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, endo Salt ＞220°(decomposition) 332(M+H) ^- 1.35(9H,s),4.65(3H,dt),7.46(2H,m),7.62(1H,dt),7.71(1H,s),7.83(2H,m),8.15(2H,m),8.50( 1H,d)(CDCl3 not DMSO d6) 31 2-(6-Chloro-3-pyridyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydrogen oxides, inner salts 223-224 417/419(M+H) ⁺ 3.72(3H,s),6.07(2H,s),6.97(2H,d),7.62(1H,d),7.70(2H,d),7.81(1H,t),8.00(1H,t),8.16 (1H,d),8.36(1H,d),8.79(1H,dd),8.98(1H,dd),9.38(1H,d) 32 3-Hydroxy-4-methyl-2-(6-methyl-3-pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 291(M+H) 2.50(3H,s),4.51(3H,s),7.33(1H,d),7.77(1H,t),7.98(1H,t),8.10(1H,d),8.34(1H,d),8.50 (1H,dd),8.64(1H,s),9.38(1H,d) 33 2-(4-Trifluoromethylphenyl)-3-hydroxy-4-(2-hydroxyethyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 374(M+H) ⁺ 3.99(2H,m),4.92(2H,m),5.19(1H,t),7.79(3H,m).7.99(1H,m),8.20(1H,d),8.38(1H,d),8.60 (2H,d),8.65(1H,s) Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 34 3-Hydroxy-4-methyl-2-(5-methyl-2-pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 237-240 291(M+H) ⁺ 2.34(3H,s),4.50(3H,s),7.75(2H,m),7.98(1H,t),8.11(1H,d),8.18(1H,d),8.36(1H,d),8.40 (1H,d),8.59(1H,s) 35 3-Hydroxy-4-methyl-2-[4-(1-methylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 171-172 318(M+H) ⁺ 1.25(6H,d),2.92(1H,m),4.53(3H,s),7.34(2H,d),7.78(1H,t),7.97(1H,t),8.14(3H,m),8.35 (1H,d),8.69(1H,s) 36 3-Hydroxy-4-methyl-2-(4-nitrophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >230 321(M+H) ^- 3.93(3H,s),7.79(1H,t),7.99(1H,t),8.12(1H,d),8.33(3H,m),8.62(2H,d),8.71(1H,s) 37 2-(4-Cyanophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 225-227 301(M+H) ⁺ 4.49(3H,s),7.79(1H,t),7.89(2H,t),7.95(1H,t),8.00(1H,d),8.34(1H,d),8.56(2H,d),8.67 (1H,s). 38 2-(4-Carboxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >230 320(M+H) ⁺ 4.51(3H,s),7.78(1H,t),7.99(1H,t),8.01(2H,d),8.12(1H,d),8.09(1H,d),8.47(2H,d),8.64 (1H,s),12.74(1H,s). 39 2-(4-Chloro-3-trifluoromethylphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >230 378/380(M+H) ⁺ 4.50(3H,s),7.81(2H,m),8.00(1H,t),8.13(1H,t),8.38(1H,d),8.59(1H,dd),8.68(1H,s),8.98 (1H,d) 40 2-(4-Trifluoromethoxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 195-196 360(M+H) ⁺ 4.51(3H,s),7.46(2H,d),7.79(1H,t),7.96(1H,t),8.12(1H,d),8.35(1H,d),8.45(2H,d),8.64 (1H,s) Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 41 3-Hydroxy-4-methyl-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 197-198 322(M+H) ⁺ 2.50(3H,s),4.51(3H,s),7.33(2H,d),7.72(1H,t),7.91(1H,t),8.08(1H,d),8.27(2H,d),8.31 (1H,d),8.60(1H,s) 42 4-Cyclopropyl-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt salt >250 370(M+H) ⁺ 1.33(2H,m),1.54(2H,m),5.03(1H,m),7.78(3H,m),7.96(1H,m),8.15(1H,d),8.34(1H,d),8.61 (2H,m),8.65(1H,s) 43 4-Cycloendyl-3-hydroxy-2-(6-methyl-3-pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 226-240 317(M+H) ⁺ 1.32(2H,d),1.54(2H,m),2.51(3H,s),5.08(1H,m),7.33(1H,d),7.56(1H,td),7.94(1H,td),8.13 (1H,d),8.32(1H,d),8.54(1H,dd),8.62(1H,s),9.40(1H,d) 44 4-[(1,1-Dimethyl-2-hydroxy)ethyl]-3-hydroxy-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c ] Isoquinolinium hydroxide, inner salt >220 402(M+H) ⁺ 1.94(6H,s),4.28(2H,d),5.15(1H,t),7.79(3H,m),8.00(1H,m),8.37(2H,t),8.62(2H,d),8.77 (1H,s) 45 3-Hydroxy-4-(2-methoxyethyl)-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide , inner salt 195-197 388(M+H) ^- 3.28(3H,s),3.96(2H,t),5.06(2H,t),7.79(3H,m),7.99(1H,m),8.18(1H,d),8.37(1H,d),8.58 (2H,d),8.71(1H,s) 46 2-(4-Chlorophenyl)-3-hydroxy-4-[2-(methylthio)ethyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 187-188 370/372(M+H) ⁺ 2.19(3H,s),3.20(2H,t),5.03(2H,t),7.50(2H,m),7.79(1H,m),7.99(1H,m),8.15(1H,d),8.38 (3H,m),8.77(1H,s) Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 47 3-Hydroxy-4-[2-(methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide , inner salt 193-195 404(M+H) ⁺ 2.20(3H,s),3.21(2H,t),5.04(2H,t),7.81(3H,m),8.01(1H,m),8.17(1H,d),8.39(1H,d),8.59 (2H,d),8.80(1H,s) 48 4-Cyclopropyl-2-(4-trifluoromethoxyphenyl)-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 188-189 386(M+H) ⁺ 1.34(2H,m),1.54(2H,m),5.08(1H,m),7.46(2H,d),7.78(1H,t),7.95(1H,t),8.15(1H,d),8.31 (1H,d),8.46(2H,d),8.62(1H,s) 49 2-(4-Chloro-3-trifluoromethylphenyl)-4-cyclopropyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >220 404/406(M+H) ⁺ 1.33(2H,m),1.53(2H,m),4.98(1H,m),7.78(2H,m),7.97(1H,t)8.17(1H,d),8.36(1H,d),8.62( 1H,dd),8.67(1H,s),9.03(1H,dd) 50 4-Cyclopropyl-3-hydroxy-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 166-167 348(M+H) ⁺ 1.30(2H,m),1.51(2H,m),2.51(3H,s),5.24(1H,m),7.37(2H,d),7.74(1H,t),7.93(1H,t),8.14 (1H,d),8.33(3H,m),8.58(1H,s) 51 3-Hydroxy-4-phenyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 255 406(M+H) ^- 7.69(3H,m),7.76(2H,m),7.82(3H,m),8.05(1H,m),8.25(1H,d),8.45(1H,d),8.53(2H,m),8.85 (1H,s) 52 4-Ethyl-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 192-198 358(M+H) ⁺ 1.63(3H,d),4.88(2H,quart),7.75(1H,t),7.79(2H,d),7.96(1H,t),8.09(1H,d),8.33(1H,d),8.59 (2H,d),8.76(1H,s) 53 2-(4-Trifluoromethylphenyl)-4-(1-ethoxycarbonylmethyl)-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 167-169 416(M+H) ⁺ 1.27(3H,t),4.27(2H,q),5.83(2H,s),7.82(2H,d),7.82(1H,t),8.04(1H,t),8.17(1H,d),8.39 (1H,d),8.54(2H,d),8.71(1H,d) Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 54 3-Hydroxy-4-[(4-methoxyphenyl)methyl]-2-phenyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt Foam 382(M+H) ⁺ 3.72(3H,s),6.10(2H,s),6.95(2H,d),7.20(1H,t),7.48(2H,t),7.75(3H,m),7.95(1H,t),8.15 (1H,d),8.35(3H,m),8.91(1H,s) 55 3-Hydroxy-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 201-203 372(M+H) ⁺ 1.70(6H,d),6.26(1H,br s),7.79(1H,t),7.79(2H,d),7.98(1H,t),8.22(1H,d),8.38(1H,d), 8.62(2H,d),8.93(1H,d) 56 3-Hydroxy-4-(1-methylethyl)-2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt 220-222 372(M+H) ^- 1.71(6H,d),6.27(1H,br s),7.54(1H,d),7.70(1H,t),7.78(1H,t),7.96(1H,t).8.22(1H,d), 8.40(1H,d),8.64(1H,d),8.85(1H,s),8.94(1H,s) Example 57 3-Hydroxy-2-(4-iodophenyl)-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

Mix 1,2,3,4-tetrahydro-2-methyl-4-oxo-3-isoquinolinecarboxylic acid methyl ester (0.485g) and 4-iodophenylhydrazine (1.053g) in ethanol (15ml) , heated to reflux for 20 hours. Cooling precipitated a solid, which was recrystallized from ethanol and propan-2-ol to give the title compound (0.054 g). mp>260°C. MS(+ve ESI)402((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO): δ4.50(3H,s),7.76(1H,t),7.77(2H,d),7.94 (1H,t),8.09(1H,d),8.19(2H,d),8.32(1H,d),8.62(1H,s)

The following compounds, Examples 58-60, were followed in a similar manner to that used in Example 2 Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 58 2-(6-Chloro-3-pyridyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 297/299(M+H) ⁺ 7.71(1H,d),7.89(1H,t),8.00(1H,t),8.31(2H,m),8.56(1H,brd),9.00(1H,br s),9.13(1H,s) 59 2-[4-(1-Methylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolin-3-ol 218-219 304(M+H) ⁺ 1.25(6H,d),2.97(1H,m),7.42(2H,d),7.93(4H,m),8.27(2H,m),9.00(1H,s) 60 2-(4-Pentafluoroethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol 219-223 380(M+H) ⁺ 7.68(1H,t),7.76(3H,m),8.02(1H,d),8.24(1H,d),8.54(3H,m)

The following compounds, Examples 61-68, were prepared according to a method similar to that used in Example 6: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 61 2,4-Dihydro-3-hydroxy-4-methyl-2-(2-pyrimidinyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 294(M+H) ^- 3.79(3H,s),7.48(1H,t),7.75(1H,t),7.89(1H,t),8.18(1H,d),8.35(1H,d).8.92(2H,d) 62 2-([1,1'-biphenyl]-4-yl)-2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo[4,3-c]isoquinoline -5-keto 241-244 368(M+H) ^- 3.83(3H,s),7.39(1H,m),7.50(2H,t),7.75(3H,m),7.9l(3H,m),8.05(3H,m).8,38(1H,d ) 63 2,4-Dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 360(M+H) ^- 3.81(3H,s),7.77(1H,t),7.94(3H,m),8.05(1H,d),8.18(2H,d),8.37(1H,d),11.37(1H,s) 64 2-(6-Chloro-3-pyridyl)-2,4-dihydro-3-hydroxy-4-methyl-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 327/329(M+H) ^- 3.79(3H,s),7.73(1H,d),7.76(1H,t),7.92(1H,t),8.02(1H,d),8.38(2H,m),8.97(1H,d) Example name mp/°C MS 1H NMR(d ₆ -DMSO)δ 65 2,4-Dihydro-3-hydroxy-2-(4-iodophenyl)-4-methyl-5H-pyrazolo[4,3-c]isoquinolin-5-one >250 418(M+H) ^- 3.80(3H,s),7.74(3H,m),7.89(3H,m),8.02(1H,d),8.36(1H,d) 66 2,4-Dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c] Isoquinolin-5-one >230 (decomposition) 466(M+H) ^- 3.68(3H,s),5.59(2H,s),6.83(2H,d),7.40(2H,d),7.75(1H,t),7.90(3H,m),8.07(1H,d),8.20 (2H,d),8.38(1H,d),11.50(1H,s) 67 2,4-Dihydro-3-hydroxy-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinoline -5-keto 228-230 (decomposition) 388(M+H) ^- 1.59(6H,d),5.85(1H,brs),7.76(1H,t),7.92(3H,d),8.04(1H,d),8.18(2H,d),8.36(1H,d) 6S 2,4-Dihydro-3-hydroxy-4-methyl-2-[4-(1-methylethylphenyl]-5H-pyrazolo[4,3-c]isoquinoline-5- ketone 238-240 334(M+H) ^- 1.25(6H,d),2.96(1H,hept),3.81(3H,s),7.42(2H,d),7.72(1H,t),7.78(2H,d),7.89(1H,c),8.01 (1H,d),8.36(1H,d) Example 692,4-dihydro-3-hydroxyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-C]isoquinolin-5-one

Trifluoroacetic acid (4ml) was added to 2,4-dihydro-3-hydroxy-4-(methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazolo [4,3-C]isoquinolin-5-one (Example 66) (425 mg), the mixture was heated under reflux for 12 hours. After cooling to room temperature, the solvent was removed by evaporation. The resulting residue was recrystallized from methanol/water to give a yellow solid, which was purified by trituration with isohexane to give the title compound (150 mg). mp>200°C. MS(APCI)346((M+H) ⁺ ), ¹ H NMR(d ₆ -DMSO)δ7.76(1H,t),7.92(3H,m),8.02(1H,d),8.18(2H, d),8.34(1H,d),11.20(1H,s)

The following examples were prepared in a manner analogous to Example 69: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 70 2,4-Dihydro-3-hydroxy-2-[4-(1-methylethyl)phenyl]-5H-pyrazolo[4,3-c]isoquinolin-5-one >250° 320(M+H) ⁺ 1.24(6H,d),2.95(1H,m),7.40(2H,d),7.70(1H,t),7.78(2H,d),7.88(1H,t),7.99(1H,d),8.32 (1H,d),11.00(1H,s) 71 2,4-Dihydro-3-hydroxy-2-([1,1'-biphenyl]-4-yl)-5H-pyrazolo[4,3-c]isoquinolin-5-one 273(decomposition) 354(M+H) ⁺ 7.39(1H,t),7.50(2H,t),7.74(3H,d),7.87(3H,m),8.01(3H,m),8.34(1H,d),11.13(1H,s),11.76 (1H,s)

Example 72

2-(4-Chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo[4,3-c]isoquinoline Onium hydroxide, inner salt

A 3M solution of methylmagnesium bromide in ether (2.0ml) was added dropwise to ice-cold 2-(4-chlorophenyl)-3-hydroxyl-4-[(4-methoxyphenyl)methyl]- 2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (Example 22) (0.5g) and copper(I) bromide (17mg) in dry tetrahydrofuran (20ml) suspension middle. The mixture was stirred under cooling for 1 hour, and saturated aqueous ammonium chloride solution and ethyl acetate were added thereto. The mixture was stirred at room temperature for 16 hours, then the aqueous phase was extracted (three times) with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The solid residue was purified by column chromatography (99:1 dichloromethane:methanol) to give a purple solid (0.38g). A sample (0.1 g) was recrystallized from ethanol to give the title compound (31 mg). mp 212-216°C. MS(APCI)430,432((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.88(3H,s),3.71(3H,s),6.50(2H,br s),6.93(2H, d), 7.32(2H,d), 7.51(2H,d), 7.76(1H,t), 7.98(1H,t), 8.32(1H,d), 8.43(3H,m). Example 732-( 4-Chlorophenyl)-5-methyl-2H-pyrazolo[4,3-c]isoquinolin-3-ol

2-(4-Chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2H-pyrazolo[4,3-c]isoquine The linium hydroxide, inner salt (0.29g) was dissolved in trifluoroacetic acid (10ml) and heated to reflux for 2 hours under nitrogen. After cooling to room temperature, the solvent was removed by evaporation and the residue was co-evaporated with toluene (three times). Purification by column chromatography (20:1 dichloromethane:methanol) and trituration with methanol afforded the title compound as an orange solid (0.07g). mp＞250℃MS(APCI)310,312((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.77(3H,s),7.47(2H,d),7.68(1H,t),7.77 (1H,t),8.10(1H,d),8.25(1H,d),8.31(2H,d).

The following examples were prepared by the method of Example 72: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 74 4-Cyclopropyl-3-hydroxy-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 384(M+H) ⁺ 1.32(2H,m),1.48(2H,m),3.07(3H,s),4.04(1H,m),7.76(3H,m),7.95(1H,t),8.36(2H,m),8.62 (2H,d) 75 3-Hydroxy-4-(2-methoxyethyl-5-methyl-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinoline Onium hydroxide, inner salt 202-204 402(M+H) ⁺ 3.00(3H,s),3.29(3H,s),4.08(2H,t),5.37(2H,br s),7.68(3H,m),7.88(1H,t),8.10(1H,d), 8.56(3H,m) Example 76 2-(4-Chlorophenyl)-3-hydroxy-4,5-dimethyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

2-(4-chlorophenyl)-2,4-dihydro-3-hydroxyl-4-methylpyrazolo[4,3-c]isoquinolin-5-one (0.48g) (Example 6) Soluble in dry 1,2-dimethoxyethane (150ml). Methylmagnesium bromide solution (3 ml of 3M ether solution) was added and the mixture was heated to reflux for 0.75 hours. Additional methylmagnesium bromide (1 mL) was added and heating continued for 3 hours. The reaction was cooled to room temperature, and then quenched by slowly adding dilute hydrochloric acid. The mixture was basified with aqueous sodium bicarbonate and extracted with ethyl acetate (three times). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography (silica gel, 97:3-95:5 dichloromethane:methanol) to give a red solid which was triturated with ether to give the title compound (0.060g). mp>250°C. MS(APCI)324/326((M+H) ⁺ ), ¹ H NMR(d ₆ -DMSO)δ2.90(3H,s),4.63(3H,s),7.49(2H,d),7.77( 1H,t),7.95(1H,t),8.39(4H,m).

The following examples were prepared by the method of Example 76: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 77 5-Ethyl-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 372(M+H) ⁺ 1.45(3H,t),3.32(2H,q),4.78(3H,s),7.68(3H,m),7.88(1H,td),8.03(1H,d),8.54(2H,d),8.58 (1H,dd) 78 3-Hydroxy-5-methyl-4-(1-methylethyl)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydrogen oxides, inner salts 205-210 386(M+H) ⁺ 1.76&1.90(6H,2×m.roramers),3.07(3H,s),5.42&7.40(1H,2×br,rotamers),7.77(3H,m),7.97(1H,t),8.41( 2H,m),8.62(2H,m), 79 4-Methyl-5-(1-methylethyl)-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydrogen oxides, inner salts 236-238 386(M+H) ⁺ 1.61(6H,d),4.05(1H,br),4.75(3H,s),7.76(1H,t),7.80(2H,d),7.94(1H,t),8.43(1H,dd),8.52 (1H,d),8.60(2H,d) 80 3-Hydroxy-4,5-dimethyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 358(M+H) ⁺ 2.87(3H,s),4.72(3H,s),7.66(3H,m),7.86(1H,t),8.01(1H,d),8.53(3H,m) Example 815-Chloro-2-(4-trifluoromethylphenyl)-2H-pyrazol[4,3-c]isoquinolin-3-alcohol

Phosphorus oxychloride (5ml) was added to 2,4-dihydro-3-hydroxy-4-(methoxyphenylmethyl)-2-(4-trifluoromethylphenyl)-5H-pyrazole And[4,3-c]isoquinolin-5-one (Example 66) (350 mg), heated under reflux for 1 hour. After cooling to room temperature, the solvent was removed and the residue was purified by column chromatography eluting with isohexane:ethyl acetate:acetic acid (80:20:2) and triturated with acetonitrile to give the title compound (25mg). mp>250°C decomposes. MS(APCI)364/366((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)δ7.96(5H,m),8.07(1H,t),8.25(1H,d),8.43( 1H, d) Example 823a, 4-dihydro-3a-hydroxyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinoline-3,5- diketone

Add ceric ammonium nitrate (700 mg) to 2,4-dihydro-3-hydroxy-4-(methoxyphenylmethyl)-2-(trifluoromethylphenyl)-5H-pyrazolo at room temperature [4,3-c]Isoquinolin-5-one (Example 66) (200 mg) was suspended in acetonitrile (4 ml) and water (1 ml). After 2 hours, the mixture was added to silica gel and purified by column chromatography, eluting with isohexane:propan-2-ol (9:1), and then by HPLC, eluting with isohexane:ethyl acetate (4:1) After removal, the title compound (50 mg) was obtained. mp 175-185°C. MS (ESI) 360 (MH) ^{+ 1} H NMR (d ₆ -DMSO) δ7.7-8.0 (5H, m), 8.08-8.12 (4H, m), 9.78 (1H, s), Example 832,4 -Dihydro-3-methoxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one

2,4-dihydro-3-hydroxyl-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one ( A solution of 0.2 g) (Example 63) in dry DMF (5 ml) was added dropwise to a mixture of oil-free sodium hydride (0.022 g of a 60% dispersion) in dry DMF (1 ml) stirred at 0°C. in suspension. After 0.5 hour iodomethane (0.038ml) was added. Stirring was continued for 16 hours. The mixture was diluted with water, acidified with dilute hydrochloric acid and extracted with ethyl acetate (three times). The organic phase was washed with brine (seven times), then dried over magnesium sulfate, filtered and concentrated. Purification by chromatography (25:75 to 50:50 ethyl acetate:dichloromethane then 30:70 ethyl acetate:isohexane) afforded the title compound as a colorless solid (0.015g). mp163-164℃MS(APCI)374((M+H) ⁺ ) ¹ H NMR(CDCl ₃ )δ3.78(3H,s),3.83(3H,s),7.60(1H,td),7.74(1H ,td),7.80(2H,d),8.04(2H,d),8.27(1H,dd),8.48(1H,dd).Example 842-(4-Chlorophenyl)-4-(2-( N,N-Dimethylamino)ethyl}-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

2-(4-Chlorophenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol (0.3 g) was added to oil-free sodium hydride (81 mg 60% disperse body) in dry dimethylformamide (5ml) suspension. After 30 minutes, 2-methylaminoethyl chloride hydrochloride (0.15 g) was added and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed with brine, then dried over sodium sulfate, filtered, and concentrated to a purple solid. Purification by column chromatography (20:1 dichloromethane:ethanol) followed by recrystallization from 4:1 cyclohexane:ethyl acetate afforded the title compound as a red solid (125 mg). mp173-174°C. MS(APCI)367,369((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)δ2.32(6H,s),3.02(2H,t),5.03(2H,t),7.4(2H, d), 7.65(1H, t), 7.85(3H, m), 8.30(2H, d), 8.50(1H, d). Example 85 3-hydroxyl-4-methyl-2-(4-methylidene Sulfonylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

3-Hydroxy-4-methyl-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt (0.10 g) (executed Example 41) was dissolved in dichloromethane (15ml) and cooled to -78°C. 3-Chloroperbenzoic acid (0.055 g) was added, the mixture was stirred for 10 minutes, poured into aqueous sodium metabisulfite solution, and extracted with ethyl acetate (three times). The combined extracts were shaken with aqueous sodium bicarbonate, dried over sodium sulfate and evaporated to give a residue which was purified by column chromatography (3:2 ethyl acetate:methanol) to give the title compound as a red powder (0.012g). mp>230°C. MS(APCI):338(M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO):δ2.77(3H,s),4.52(3H.s).7.80(3H,m),7.96(1H ,t), 8.13(1H,d), 8.37(1H,d), 8.57(2H,d), 8.64(1H,s).Example 862-(4-Chlorophenyl)-3-Hydroxy-4- [2-(Methylsulfinyl)ethyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

3-Chloroperbenzoic acid (0.86g) was dissolved in dichloromethane (20ml) at -78°C. Add 6ml of the resulting solution dropwise to 2-(4-chlorophenyl)-3-hydroxyl-4-[2-(methylthio)ethyl]-2H-pyrazolo[4,3-c]isoquine A solution of linium hydroxide, inner salt (Example 46) (0.43 g) in dichloromethane. After 30 minutes aqueous sodium metabisulfite was added and the reaction mixture was partitioned between water and dichloromethane. The organic phase was washed with aqueous sodium hydroxide solution, then dried (magnesium sulfate), filtered and evaporated. The residue was chromatographed using methanol (2-6% by volume) in dichloromethane as eluent to give a purple solid (0.46g).

mp228-230℃MS(APCI+)386,388((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.69(3H,s),3.47(1H,m),3.64(1H,m),5.11 (1H,m),5.34(1H,m),7.50(2H,m),7.79(1H,m),7.99(1H,m),8.17(1H,d),8.38(3H,m),8.83( 1H, s). Example 87 3-Hydroxy-4-[2-(methylsulfinyl) ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3- c] Isoquinolinium hydroxide, inner salt

3-Hydroxy-4-[2-(methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide compound, inner salt (Example 47) according to the method of Example 86 to obtain the title compound as a purple solid. mp 241-243°C. MS(APCI+)420((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ2.70(3H,s),3.47(1H,m),3.64(1H,m),5.11(1H,m ),5.36(1H,m),7.81(3H,m),8.01(1H,m),8.19(1H,d),8.38(1H,d),8.60(2H,d),8.86(1H,s) , Example 885-[2-(4-methoxyphenyl)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinoline- 3-alcohol, sodium salt

Methylmagnesium bromide (3M in diethyl ether, 8.6ml) was slowly added to the stirred 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4-tris Fluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one (Example 66) (500mg) and copper (I) bromide (15mg) 1,2-bis methoxyethane (50ml) and then heated to 100°C for 24 hours. After cooling to room temperature, the mixture was poured into cooled dilute hydrochloric acid and then basified with sodium bicarbonate and sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine and dried over magnesium sulfate. Filtration, evaporation and purification by column chromatography, eluting successively with isohexane:ethyl acetate (1:1), and ethyl acetate:methanol (9:1), afforded the title compound as a red solid (90 mg). mp>200°C decomposes. MS(APCI)464((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO/TFA)δ3.08(2H,t),3.59(2H,t),3.73(3H,s),6.87(2H ,d),7.25(2H,d),7.92(3H,m),8.05(1H,t),8.33(2H,d),8.40(1H,d),8.50(1H,d),12.05(TFA/ water/1H) Example 899-fluoro-3-hydroxyl-4-[(4-methoxyphenyl) methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4 ,3-c]isoquinolinium hydroxide, inner salt (a) 2,6-difluoro-N-(2-hydroxy-1,1-dimethylethyl)benzamide

A solution of 2,6-difluorobenzoyl chloride (20 g) in dry dichloromethane (100 ml) was added dropwise to ice-cooled 2-amino-2-methylpropanol (20.2 g) kept below 5°C under nitrogen. Dry the solution in dichloromethane (150ml). After the addition was complete, the ice bath was removed and stirring was continued at room temperature for another 16 hours. The organic phase was diluted with water and separated. The aqueous phase was then extracted (twice) with dichloromethane. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated. Trituration with hexane gave the subtitle compound (24.65g). MS(APCI)230((M+H) ⁺ ) ¹ H NMR(CDCl ₃ ):δ1.41(6H,s),3.70(2H,d),3.95(1H,t),6.00(1H,br s ),6.95(2H,m),7.38(1H,m).(b)2-(2,6-difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole

Thionyl chloride (12.6ml) was added dropwise to an ice-cold solution of 2,6-difluoro-N-(2-hydroxy-1,1-dimethylethyl)benzamide (24.65g) under nitrogen. Chloromethane (100ml) solution. After the dropwise addition was complete, the ice bath was removed, and stirring was continued at room temperature for 1 hour. The solvent was then removed by evaporation and the residue was triturated with ether. The resulting solid was dissolved in a very small amount of water (80ml) and then basified with sodium hydroxide pellets. The basic phase was extracted again with ethyl acetate (three times). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to an oil which was purified by column chromatography (4:1 hexane:ethyl acetate) to give the subtitle compound (20.86g). MS(EI) 211(M ⁺ ). ¹ H NMR(CDCl ₃ ): δ1.42(6H,s),4.14(2H,s),6.95(2H,m),7.40(1H,m).(c )4,5-dihydro-2-(2-fluoro-6-methylphenyl)-4,4-dimethyloxazole

Under nitrogen, a solution of 3M methylmagnesium chloride in tetrahydrofuran (86ml) was added dropwise to 2-(2,6-difluorophenyl)-4,5-dihydro-4,4-dimethyloxazole ( 18.23g) in dry tetrahydrofuran (60ml) solution. The solution was stirred at 0 °C for 1 hour, then at room temperature for 16 hours. Sat. ammonium chloride solution was added carefully, and the reaction mixture was extracted (three times) with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated to give the subtitle compound as a pale yellow oil (18.18g). MS(APCI)208((M+H) ⁺ ) ¹ H NMR(CDCl ₃ ):δ1.42(6H,s),2.40(3H,s),4.12(2H,s),6.93(1H,t) ,7.00(1H,d),7.26(1H,m).(d)2-fluoro-6-methylbenzoic acid

4,5-dihydro-2-(2-fluoro-6-methylphenyl)-4,4-dimethyloxazole (18.18g) and excess iodomethane (20ml) were heated in acetonitrile (150ml) Reflux for 4 hours, then cool to room temperature. The solvent was removed by evaporation and the solid residue was triturated with ether. Then the obtained solid was dissolved in a mixture of methanol (80 ml) and 10% sodium hydroxide solution (80 ml), and heated to reflux for 4 hours. The mixture was cooled to room temperature, and methanol was distilled off. The aqueous phase was washed with ethyl acetate (three times) and then acidified to pH 1 with dilute hydrochloric acid. The acid phase was extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give 2-chloro-6-methylbenzoic acid (10.85g). A sample (0.27g) was recrystallized from 4:1 hexane:ethyl acetate to give the subtitle compound (0.15g). mp 123-124°C. MS(EI)154(M ⁺ ). ¹ H NMR(CDCl ₃ )δ2.52(3H,s),7.02(2H,m),7.35(1H,m).(e)2-fluoro-6-methanol methyl benzoate

Cerium carbonate (16g) and iodomethane (4.6ml) were added to a stirred solution of 2-fluoro-6-methylbenzoic acid (3.78g) in dry dimethylformamide (25ml) under nitrogen. Stirring was continued at room temperature for 16 hours, then the reaction was diluted with water and extracted with ethyl acetate (three times). The organic phase was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered and evaporated to give the subtitle compound as a yellow oil (4.07g). ¹ H NMR(CDCl ₃ ),δ2.40(3H,s),3.94(3H,s),6.94(1H,t),7.01(1H,d),7.30(1H,m),(f)2- (Bromomethyl)-6-fluorobenzoic acid methyl ester

Methyl 2-fluoro-6-methylbenzoate (35.53g), N-bromosuccinimide (37.6g) and azabis(isobutyronitrile) (2g) in dry dichloromethane (150ml) were mixed The suspension was irradiated (100W halogen lamp) under nitrogen for 4 hours. The resulting solution was poured into 10% sodium hydroxide solution and extracted with dichloromethane (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give a mixture of the subtitle compound and starting material (52.33g) as a yellow oil. MS (EI) 246/248 (M ^- ) ¹ H NMR (CDCl ₃ ) δ3.99 (3H, s), 4.66 (2H, s), 7.06 (1H, t), 7.23 (1H, d), 7.40 ( 1H,m).(g) Methyl 2-fluoro-6-{[(2-methoxy-2-oxoethyl)-(4-methoxyphenylmethyl)amino]methyl}benzoate

N-(4-methoxyphenylmethyl)glycine methyl ester (10.2g) was added dropwise to stirred 2-(bromomethyl)-6-fluorobenzoic acid methyl ester (11g) and triethylamine (6.8 ml) in dry diethyl ether (50ml). The mixture was heated to reflux under nitrogen for 16 hours. The reaction was cooled, diluted with water, and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by column chromatography (20:1 hexane:ethyl acetate) to afford the subtitle compound as a colorless oil (8.82g). MS(APCI)376((M+H) ⁺ ) ¹ H NMR(CDCl ₃ ):δ3.21(2H,s),3.67(3H,s),3.68(2H,s),3.78(3H,s) ,3.88(3H,s),4.01(2H,s),6.82(2H,d),7.05(1H,t),7.18(3H,m),7.35(1H,m).(h)5-fluoro- Methyl 1,2,3,4-tetrahydro-2-(4-methoxyphenylmethyl)-4-oxo-3-isoquinolinecarboxylate

Methyl 2-fluoro-6-{[(2-methoxy-2-oxyethyl)-(4-methoxyphenylmethyl)amino]methyl}benzoate (8.82g) was dissolved under nitrogen A dry toluene (50ml) solution of NaCl was added dropwise to a suspension of sodium hydride (1.32g 60% dispersion, oil-free) and tert-butanol (1ml) in dry toluene (100ml) heated to reflux. Heating was continued for another 12 hours then the reaction was cooled to room temperature. The mixture was then poured into saturated aqueous ammonium chloride and extracted with ethyl acetate (three times). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to give the subtitle compound (7.96g). MS(APCI)344((M+H) ⁺ ). ¹ H NMR(CDCl ₃ ): δ3.60(2H,s),3.81(3H,s),3.89(2H,s),3.92(3H,s ),6.86(3H,m),7.05(1H,m),7.22(2H,m),7.38(1H,m),11.83(1H,s).(i)9-fluoro-3-hydroxy-4- [(4-Methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

Methyl 5-fluoro-1,2,3,4-tetrahydro-2-(4-methoxyphenylmethyl)-4-oxo-3-isoquinolinecarboxylate (1.0g), 4-tri Fluoromethylphenylhydrazine (1.03 g) and p-toluenesulfonic acid (20 mg) were melted together under nitrogen at 150°C for 15 minutes. Then 20 ml of xylene was added, and heating was continued for 2 hours. After cooling to room temperature, the solvent was removed by evaporation and the solid residue was purified by column chromatography (99:1 dichloromethane:methanol) to give the title compound as purple needles (0.425g). MS(APCI)468((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)δ3.72(3H,s),6.10(2H,s),6.96(2H,d),7.70(2H,d ), 7.80(4H,m), 8.00(1H,dd), 8.59(2H,d), 8.98(1H,s).Example 909-fluoro-2-(4-trifluoromethylphenyl)-2H -pyrazolo[4,3-c]isoquinolin-3-ol

9-fluoro-3-hydroxyl-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c] Isoquinolinium hydroxide, inner salt (0.43g) was dissolved in trifluoroacetic acid (5ml) and heated to reflux under nitrogen atmosphere for 16 hours. After cooling to room temperature the solvent was removed by evaporation and the residue was co-evaporated with toluene (three times). The residue was triturated successively with methanol and ether and finally recrystallized from ethyl acetate to give the title compound as a red solid (0.08g). mp>250°C. NMS(APCI)348((M+H) ^- ). ¹ H NMR(d ₆ -DMSO)δ7.86(2H,m),7.95(2H,d),8.14(1H,d),8.24(2H, br d),9.09(1H,br s),11.85(1H,br s).

The following examples were prepared in a similar manner to Example 90. Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 91 2-(4-Chlorophenyl)-7-fluoro-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 328/330(M+H) ⁺ 4.51(3H,s),7.46(2H,d),7.77(1H,td),7.87(1H,dd),8.36(3H,m),8.45(1H,s)

Example name m.p./℃ MS ¹ H NMR (d ₆ -DMSO)δ 92 7-Fluoro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 362(M+H) ⁺ 4.51(3H,s),7.75(2H,d),7.80(1H,m),7.87(1H,dd),8.38(1H,dd),8.47(1H,s),8.54(2H,d) 93 2-(4-Chlorophenyl)-4-cyclopropyl-9-fluoro-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >214217 354/356(M+H) ⁺ 1.35(2H,m),1.54(2H,m),5.11(1H,m),7.51(2H,d),7.75(2H,m),7.95(1H,dd),8.38(2H,d),8.63 (1H,s), 94 4-Cyclopropyl-9-fluoro-3-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 388(M+H) ⁺ 1.36(2H,m),1.55(2H,m),5.06(1H,m),7.77(4H,m),7.97(1H,m),8.58(2H,d),8.66(1H,s) 95 2-(4-Chlorophenyl)-9-fluoro-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 328/330(M+H) ⁺ 4.51(3H,s),7.51(2H,d),7.76(2H,m),7.91(1H,m),8.35(2H,d),8.65(1H,s) 96 2-(4-Chlorophenyl)-9-fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 434/436(M+H) ⁺ 3.72(3H,s),6.10(2H,s),6.95(2H,d),7.54(2H,d),7.70(2H,d),7.77(2H,m),7.97(1H,m),8.39 (2H,d),8.96(1H,s) 97 9-Fluoro-3-hydroxy-4-methyl-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt >250 362(M+H) ⁺ 4.51(3H,s),7.77(4H,m),7.93(1H,m),8.56(2H,d),8.68(1H,s)

The following compounds (Embodiments 98-100) were prepared according to the method of Example 2: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 98 2-(4-Chlorophenyl)-9-fluoro-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 314/316(M+H) ⁺ 7.63(2H,d),7.82(2H,br m),8.01(2H,d),8.11(1H,br d),9.05(1H,br s),11.80(1H,br s) 99 7-Fluoro-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 348(M+H) ⁺ 7.93(3H,d),8.14(1H,d),8.28(2H,d),8.41(1H,dd),9.02(1H,br s) 100 2-(4-Chlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 314/316 7.63(2H,d),7.91(1H,br t),8.05(2H,d),8.13(1H,d),8.40(1H,dd),9.00(1H,br s),12.00(1H,br s )

The following compounds were prepared according to the method of Example 69: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 101 9-fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4, 3-c] Isoquinolinium hydroxide, inner salt 225-227 482(M+H) ⁺ 2.86(3H,s),3.73(3H,s),6.53(2H,s),6.92(2H,d),7.30(2H,d),7.74(4H,m),8.11(1H,d),8.58 (2H,d) 102 2-(4-Chlorophenyl)-9-fluoro-3-hydroxy-4-[(4-methoxyphenyl)methyl-5-methyl-2H-pyrazolo[4,3-c] Isoquinolinium hydroxide, inner salt 222-223 448/450(M+H) ^- 2.85(3H,s),3.73(3H,s),6.53(2H,s),6.91(2H,d),7.29(2H,d),7.44(2H,d),7.70(2H,m),8.08 (1H,d),8.37(2H,d)

The following compounds were prepared by the method of Example 2: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 103 9-Fluoro-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 362(M+H) ^- 2.80(3H,s),7.79(2H,m),7.88(2H,d),8.10(1H,d),8.32(2H,d) 104 2-(4-Chlorophenyl)-9-fluoro-5-methyl-2H-pyrazolo[4,3-c]isoquinolin-3-ol >250 328/330(M+H) ⁺ 2.89(3H,s),7.58(2H,d),7.79(2H,br m),8.08(3H,br m) Example 105 2,4-Dihydro-3-hydroxyl-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinoline-5-sulfur ketone

2,4-dihydro-3-hydroxyl-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one ( Example 63) (0.25g) and Lawesson's reagent (0.7g) in dioxane (20ml) were stirred and heated at reflux for 18 hours. The mixture was cooled and absorbed on silica gel. Purification by chromatography (1:99-3:97 methanol:dichloromethane) gave the title compound, which was recrystallized from ethanol to give a yellow solid (0.075g). mp255-259°C. MS(APCI)376((M+H) ⁺ ) ¹ H NMR(D ₂ O/NaOD)δ8.47(1H,d),7.71(2H,d),7.61(3H,m),7.34(1H, t), 7.22 (1Ht), 4.08 (3H, s). Example 106 3-hydroxyl-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo [4,3-c]isoquinolinium hydroxide, inner salt

2,4-dihydro-3-hydroxyl-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinoline-5-thione (0.46g) (Example 105) and iodomethane (0.095ml) in acetone (50ml) was stirred and heated at reflux for 4 hours. Potassium carbonate (0.170 g) was added and the mixture was heated for a further 2 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (2:98 methanol:dichloromethane) to afford the title compound as a purple solid (0.375g). MS(APCI)390((M+H) ⁺ ) ¹ H NMR(CDCl ₃ )δ8.54(4H,m),7.86(1H,t),7.72(3H,m),4.98(3H,s), 2.52(3H,s), Example 107 2-(4-trifluoromethylphenyl)-2,4-dihydro-5-imino-4-methyl-5H-pyrazolo[4,3-c ]isoquinolin-3-ol

3-Hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, A suspension of the salt (0.013 g) (Example 106) in ethanol (7 ml) and ammonia solution (0.880 specific gravity; 15 ml) was stirred at 20°C for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (5:95-10:90 methanol:dichloromethane) to afford the title compound as an orange solid (0.043g). mp253-255°C. MS(APCI)717((2M+H) ⁺ ),359((M+H) ^- ), ¹ H NMR(d ₆ -DMSO)δ8.60(2H,d),8.46(1H,d),8.29 (3H, m), 7.90 (1H, t), 7.71 (3H, m), 4.19 (3H, s) Example 108 3-Hydroxy-4-(4-methoxyphenyl)methyl-2-(4 -Trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt

(a) 2-(bromomethyl)-nicotinic acid methyl ester

Methyl 2-methylnicotinate (10.0 g) and N-bromosuccinimide (14.9 g) were mixed in 1,2-dichloroethane (80 ml). Acetic acid (3.8ml) and 2,2'-azabis(2-methylpropionitrile) (1.0g) were added, and the mixture was heated to reflux under irradiation with a 500W lamp. After 2 hours the reaction was cooled, and the mixture was poured into sodium bicarbonate solution. The organic phase was separated, washed twice with brine, then dried, filtered and evaporated to an oil (18.2g) which was used immediately in the next step. (b) N-[(4-methoxyphenyl)methyl]-N-[(3-methoxycarbonyl-2-pyridyl)methyl]glycine methyl ester

According to the method of Example 1, step (a), 2-(bromomethyl) nicotinic acid methyl ester (9.10g), N-(4-methoxyphenyl) methyl glycine methyl ester (10.2g) and three Ethylamine (5.5ml) in ether (100ml) prepared the subtitled compound (3.20g). MS(DESC SI) 358(M ^- ) ¹ H NMR(d ₆ -DMSO) 3.17(s.2H), 3.34(s,3H), 3.58(s,2H), 3.71(s,3H), 3.82(s ,3H),4.23(s,2H),6.82(d,2H),7.04(d,2H),7.43(dd,1H),8.03(dd,1H),8.61(dd,1H)(c)7, Methyl 8-dihydro-5-hydroxy-7-(4-methoxyphenyl)methyl[1,7]naphthyridine-6-carboxylate

According to the method of embodiment 1 step (b), use N-[(4-methoxyphenyl) methyl]-N-[(3-methoxycarbonyl-2-pyridyl) methyl] glycine methyl ester (1.00g), sodium hydride (60% dispersion in oil) (160mg), 2-methylpropan-2-ol (0.10ml) and toluene (15ml) gave the subtitled compound (790mg). MS (APCI) 327 ((M+H) ⁺ ) ¹ H NMR (d ₆ -DMSO) 3.65-3.97 (m, 10H), 6.79 (m, 2H), 7.11-7.39 (m, 3H), 7.86-8.25 (m,1H),8.52-8.75(m,1H),11.25(s,1H)(d)3-Hydroxy-4-(4-methoxyphenyl)methyl-2-(4-trifluoromethane phenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt

According to the method of embodiment 1 step (c), with 7,8-dihydro-5-hydroxyl-7-(4-methoxyphenyl)methyl-1,7-naphthyridine-6-carboxylic acid methyl ester ( 200mg), 4-trifluoromethylphenylhydrazine (1.00g) and ethanol (3ml) to prepare the title compound (21mg). mp201-203°C. MS(APCI) 451((M+H) ^- ) ¹ H NMR(d ₆ -DMSO) 3.72(s,3H),6.13(s,2H),6.96(d,2H),7.76(d,2H), 7.84(d, 2H), 7.88(dd, 1H), 8.59(d, 2H), 8.72(dd, 1H), 9.00(s, 1H), 9.05(dd, 1H)Example 1092-(4-trifluoro Methylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridin-3-ol

According to the method of Example 2, with 3-hydroxyl-4-(4-methoxyphenyl)methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-f [1,7]Naphthyridinium hydroxide, inner salt (135mg) and trifluoroacetic acid (5ml) to prepare the title compound (19mg). mp 239-241°C (decomposition). MS (APCI) 331 ((M+H) ⁺ ) ¹ H NMR (d ₆ -DMSO) 7.94 (d, 2H), 7.95 (m, 1H), 8.28 (d, 2H), 8.74 (d, 1H), 9.01(br,1H),9.16(d,1H)

The following examples were prepared in a manner analogous to Example 109 using methyl 2-(bromomethyl)nicotinate, methyl sarcosinate and the appropriate hydrazine: Example name mp/°C MS ¹ H NMR (d ₆ -DMSO)δ 110 3-Hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt >260 345(M+H) ^- 4.56(s,3H),7.82(d,2H),7.88(dd.1H),8.56(d,2H),8.70(s,1H),8.73(5,1H),9.05(d,1H) 111 2-(4-Chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt >260 311/313(M+H) ^- 4.56(5,3H),7.51(d,2H),7.88(dd,1H),8.35(d,2H),8.68(s,1H),8.70(dd,1H),9.03(dd,1H) Example 112 3-hydroxyl-4-methyl-5-(dimethylamino)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide substance, inner salt

3-Hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, A solution of the salt (0.39g) (Example 106) in acetone (10ml) and 40% aqueous dimethylamine (2ml) was stirred at 20°C for 24 hours. Concentrate the reaction solution in vacuo. The residue was purified by chromatography (1:99-2.5:97.5 methanol:dichloromethane) to give the title compound as a red solid (0.129g). mp 256-259°C. MS(APCI)387((M+H) ⁺ ). ¹ H NMR(CDCl ₃ )d 3.19(6H,s),4.52(3H,s),7.64(3H,m),7.84(1H,td), 7.95 (1H, d), 8.54 (3H, d) Example 113 3-Hydroxy-4-methyl-5-morpholinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4 ,3-c]isoquinolinium hydroxide, inner salt

3-Hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, A solution of the salt (0.52g) (Example 106) in dry tetrahydrofuran (7ml) and morpholine (2.3ml) was heated to 70°C for 12 hours and then at 95°C for 2 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (5:95 methanol:dichloromethane) to afford the title compound as a red solid (0.165g). mp278-281°C. MS(APCI)429((M+H) ^- ). ¹ H NMR(d ₆ -DMSO)d 3.49(4H,m),3.87(4H,m),4.49(3H,s),7.77(2H,m ), 7.94(1H,t), 8.28(1H,d), 8.38(1H,d), 8.59(2H,d).Example 1143-Hydroxy-4-methyl-5-piperazinyl-2-( 4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt

3-Hydroxy-4-methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, A solution of the salt (0.29g) (Example 106) in toluene (20ml) was added dropwise to a stirred solution of piperazine (1.28g) in toluene (50ml) heated to 110°C. The mixture was stirred at 110°C for 6 hours. It was then stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by chromatography (5:95-10:90 methanol:dichloromethane) and crystallized from ethanol to give the title compound as a red solid (0.107g). mp260-262°C. MS(APCI)428((M+H) ⁺ ). ¹ H NMR(DMSO)d 2.96(4H,m),3.37(4H,m),4.44(3H,s),7.76(3H,m),7.93 (1H,t), 8.27(1H,d), 8.37(1H,d), 8.59(2H,d).Example 1154,5-dihydro-2-[4-(trifluoromethyl)phenyl] -2H-Benzo[g]indazol-3-ol

Methyl 1-oxotetrahydronaphthalene-2-carboxylate (Mander, LN and Sethi, SP; Tetrahedron Lett, 1983, 24, 5425-8) (2.0 g) and 4-trifluoromethylphenylhydrazine (3.47 g) in Heat in toluene (15ml) at reflux for 8 hours. The reaction mixture was cooled, and the product was filtered. The solid was washed with ether, dried and recrystallized from toluene to give the title compound as colorless crystals (1.45g). mp 189-190°C. MS(APCI)331((M+H) ⁺ ) ¹ H NMR(d ₆ -DMSO)d 2.67(2H,m),2.90(2H,m),7.29(3H,m),7.75(1H,m) , 7.84 (2H, d), 8.10 (2H, d), 11.70 (1H, s, br), Example 1164, 5-dihydro-2-(5-methyl-2-pyridyl)-2H-benzene And[g]indazol-3-ol

Methyl 1-oxytetralin-2-carboxylate (2.18g) and 2-hydrazino-5-picoline (2.85g) were heated together in xylene (15ml) at reflux for 6 hours. The reaction was cooled, then the product was filtered and dried. Recrystallization from ether/isohexane gave the title compound as beige needles (0.69g). mp112°C. MS(APCI) 278((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)d 2.36(3H,s),2.73(2H,t),2.95(2H,t),7.29(3H,m ),7.68(1H,dd),7.92(1H,d),7.94(1H,m),8.07(1H,s),12.73(1H,s,br).Example 1172-[4-(trifluoroform Base) phenyl] -2H-benzo [g] indazol-3-ol

4,5-dihydro-2-[4-(trifluoromethyl)phenyl]-2H-benzo[g]indazol-3-ol (0.30g) and palladium carbon (0.10g) in dimethyl Acetamide (5ml) and cyclohexane (5ml) were heated under reflux for 1 hour to obtain the title compound (0.26g). mp>235°C (decomposition). MS(APCI)329((M+H) ⁺ ). ¹ H NMR(d ₆ -DMSO)d 7.70(4H,m),7.85(2H,d),8.07(1H,m),8.27(2H,d ), 8.30 (1H, m), 11.70 (1H, s, br). Example 118 2-(5-methyl-2-pyridyl)-2H-benzo[g]indazol-3-ol

4,5-dihydro-2-(5-methyl-2-pyridyl)-2H-benzo[g]indazol-3-ol (0.40g) and 10% palladium on carbon (0.20g) Methylacetamide (15ml) and cyclohexane (15ml) were heated at reflux for 8 hours. The reaction solution was cooled to room temperature and filtered. The filtrate was distilled (100°C/1 mmHg) and the residue was recrystallized from ethyl acetate to give the title compound as light orange crystals (0.12g). mp214°C. MS(APCI)276((MH) ^- ) ¹ H NMR(d ₆ -DMSO)d 2.36(3H,s),7.52(1H,d),7.66(3H,m),7.82(1H,dd),8.02 (1H, d), 8.41 (1H, s, br), 8.53 (2H, m). Pharmacological data test A-chronic transplantation to host test

The pharmacological activity of the compound of the present invention can be confirmed by the method of J.M.Doutrelepont et al. [J.Clin.Exp.Immunol., 1991, vol.83, 133-6; Inhibition of host (c-GVH) disease by chronic transplantation in mice]. The compounds to be tested were administered subcutaneously to mice daily for 21 days as a suspension in saline and Tween-80. Test B - Inhibition of Eosinophilia

The effect of the compounds of the present invention on inflammatory cells in the lungs of mice was determined by the following method adapted from Brusselle et al., Clin. Exp. Allergy, 1994, 24, 73-80. The determination of eosinophil peroxidase as an indicator of the number of eosinophils adopts the method of Cheng et al., J. Pharmacol Exp. Ther. 1993, 264, 922-929.

Adult Balb/c mice were challenged with ovalbumin/Al(OH) ₃ mixture.

Compound administration to the mice was started 14 days after the challenge. Compounds were administered orally or subcutaneously in the form of 5% Tween-80 suspension or solution (depending on dose and compound solubility) daily.

Seventeen days after the challenge, one hour after the fourth compound administration, the mice were placed in a Plexiglas chamber sprayed with ovalbumin solution (2% w/v). Allow mice to inhale ovalbumin for 30-40 min. The test was repeated daily at the same time for a further 3 or 7 days.

In the 4-day trial, the test ovalbumin was additionally administered 4 hours after the first dose on the day of the last dose.

Animals were sacrificed the next day, and the following inhibition parameters were measured by comparison with control animals:

(1) The number of inflammatory cells, especially eosinophils, was increased in bronchioalveolar lavage (4 days after administration).

(2) The accumulation of eosinophils in the lung tissue is determined by the increase of eosinophil peroxidase activity in the homogenized lung tissue (8 days after administration).

(3) Antibody titers (IgE, IgG1 and IgG2a) exhibited in plasma obtained from whole blood increased (8 days after administration).

Certain compounds of the present invention exhibit activity in the chronic transplantation-to-host test and in the eosinophilia inhibition test with an ED ₅₀ in the range of 0.1-10 mg/kg.

Claims (16)

1. Compounds of formula I and pharmaceutically acceptable derivatives thereof as medicines:

in: B, D, E and G each represent CH, CA or N, provided that not more than one of B, D, E and G represents CA and not more than one of B, D, E and G represents N; ·X stands for C=O, C=S, C=NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ; · Y stands for N or N ⁺ R ⁷ or CR ¹⁸ ; Z stands for OR ⁸ or O; R ¹ represents OH or C _1-6 alkyl, or forms a bond with R ² or R ⁵ ; R ² represents H, C _1-6 alkyl (optionally substituted by phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl, or with R ¹ , R ³ or R ⁴ forms a bond; · ^R3 represents H or forms a bond with ^R2 ; R ⁴ represents a C _1-6 alkyl group or forms a bond with R ² ; · R ⁵ represents a bond with R ¹ or R ⁸ ; R ⁶ represents H, C _1-6 alkyl (optionally substituted by phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio , C _1-6 alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ; R ⁷ represents C _1-6 alkyl (optionally substituted by phenyl) or C _3-7 cycloalkyl, both of which can be represented by halogen, hydroxyl, C _1-6 alkoxy, C _1-6 alkylthio Group, C _1-6 alkylsulfinyl, NR ¹⁶ R ¹⁷ , COOH, COO (C _1-6 alkyl) or cyano optionally substituted; Or R ⁶ and R ⁷ together represent a C _3-5 alkylene group, X and Y thus form a 5-7 membered ring; R ⁸ represents H, C _1-6 alkyl or forms a bond with R ⁵ ; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H; · R ¹³ and R ¹⁴ are independently C _1-6 alkyl, H, or together with the nitrogen atom to which they are attached, form a 3 which may optionally contain additional oxygen or nitrogen atoms optionally substituted by C _1-6 alkyl -7-membered saturated ring; ^Ar represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolinyl or 2-quinoxalinyl, all of which may optionally be selected from halogen, nitro , cyano, phenyl, benzenesulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO(C _{1 -6} alkyl), C _1-6 alkyl substituted by phenyl, or one or more substituents of phenyl, wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl can be optionally is optionally substituted by fluorine; and · A represents halogen, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy; wherein the phenyl on R ² , R ⁶ , R ⁷ or as a substitution on Ar ¹ The phenyl group of the group can be optionally substituted by C _1-6 alkyl, halogen or C _1-6 alkoxy; provided that: (i) when X represents C=O, C=S or C=NR ¹⁵ , then Y represents N; (ii) when R ⁴ represents the bond with R ² , then Y represents N ⁺ R ⁷ ; (iii) when Y represents N ⁺ R ⁷ , then Z represents ^O- , and R ² represents the bond with R ³ Or the bond of R ⁴ , forming a bond with R ¹ and R ⁵ ; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then X represents C=O, Y represents N , Z represents OR ⁸ , R ⁵ represents a bond with R ⁸ ; (ⅵ) when R ¹ represents an alkyl group, then R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represent NR ⁴ ; (ⅶ) when R ¹ represents a bond with R ² , R ⁵ and R ⁸ form a bond, and if X represents NR ⁴ , then R ⁴ represents an alkyl group; (ⅷ) when R ⁶ represents an aryl group, a halogen , alkoxy, sulfanyl, then R ² and R ³ form a bond; (ⅸ) when Y represents N or N ⁺ R ⁷ and R ² is substituted by any one of NR ¹⁰ R ¹¹ , OR ¹² or F , then the substituent and the ring nitrogen atom of Y cannot be connected to the same carbon atom of R ² ; (ⅹ) when R ⁷ is substituted by any one of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, then the substitution (ⅹi) when one of B, D, E and G represents ^N , then X does not represent ^NR4 ; (ⅹii) when Y represents CR At ¹⁸ , X represents CR ³ R ⁶ ; the further conditions are: when B, D, E and G all represent CH, X represents CHR ³ , Y represents nitrogen, R ¹ and R ⁵ form a bond, and R ⁸ represents H And when R ² and R ³ together represent a bond, then Ar ¹ does not represent 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl. 2. A compound of formula (I) or a pharmaceutically acceptable derivative thereof: in: B, D, E and G each represent CH, CA or N, provided that not more than one of B, D, E and G represents CA and not more than one of B, D, E and G represents N; ·X stands for C=O, C=S, C=NR ¹⁵ , CR ³ R ⁶ or NR ⁴ ; · Y stands for N or N ⁺ R ⁷ or CR ¹⁸ ; Z stands for OR ⁸ or O; R ¹ represents OH or C _1-6 alkyl, or forms a bond with R ² or R ⁵ ; R ² represents H, C _1-6 alkyl (optionally substituted by phenyl, COOR ⁹ , NR ¹⁰ R ¹¹ , OR ¹² or F) or C _3-7 cycloalkyl, or with R ¹ , R ³ or R ⁴ forms a bond; · ^R3 represents H or forms a bond with ^R2 ; R ⁴ represents a C _1-6 alkyl group or forms a bond with R ² ; · R ⁵ represents a bond with R ¹ or R ⁸ ; R ⁶ represents H, C _1-6 alkyl (optionally substituted by phenyl), C _3-7 cycloalkyl, phenyl, halogen, C _1-6 alkoxy, C _1-6 alkylthio , C _1-6 alkylsulfinyl, cyano or NR ¹³ R ¹⁴ ; R ⁷ represents C _1-6 alkyl (optionally substituted by phenyl) or C _3-7 cycloalkyl, both of which can be represented by halogen, hydroxyl, C _1-6 alkoxy, C _1-6 alkylthio Group, C _1-6 alkylsulfinyl, NR ¹⁶ R ¹⁷ , COOH, COO (C _1-6 alkyl) or cyano optionally substituted; · Or R ⁶ and R ⁷ together represent C _3-5 alkylene, X and Y thus form a 5-7 membered ring; R ⁸ represents H, C _1-6 alkyl or forms a bond with R ⁵ ; R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹⁵ , R ¹⁶ , R ¹⁷ and R ¹⁸ independently represent C _1-6 alkyl or H; · R ¹³ and R ¹⁴ are independently C _1-6 alkyl, H or together with the nitrogen atom to which they are attached _form a 3- 7-membered saturated ring; ^Ar represents phenyl, pyridyl, pyrimidinyl, 2-benzothiazolyl, 2- or 3-quinolinyl or 2-quinoxalinyl, all of which may optionally be selected from halogen, nitro , cyano, phenyl, benzenesulfonyl, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylsulfinyl, COOH, COO(C _{1 -6} alkyl), C _1-6 alkyl substituted by phenyl, or one or more substituents of phenyl, wherein any alkyl, alkoxy, alkylthio and alkylsulfinyl can be optionally is optionally substituted by fluorine; and · A represents halogen, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy; wherein the phenyl on R ² , R ⁶ , R ⁷ or as a substitution on Ar ¹ The phenyl group of the group can be optionally substituted by C _1-6 alkyl, halogen or C _1-6 alkoxy; provided that: (i) when X represents C=O, C=S or C=NR ¹⁵ , then Y represents N; (ii) when R ⁴ represents the bond with R ² , then Y represents N ⁺ R ⁷ ; (iii) when Y represents N ⁺ R ⁷ , then Z represents ^O- , and R ² represents the bond with R ³ and R ⁴ bond, and R ¹ and R ⁵ form a bond; (iv) when Y represents N, then Z represents OR ⁸ ; (v) when R ¹ represents OH, then X represents C=O, Y represents N , Z represents OR ⁸ , and R ⁵ represents a bond with R ⁸ ; (ⅵ) when R ¹ represents an alkyl group, then R ⁵ represents a bond with R ⁸ , Y represents N, R ² does not represent a bond, and X does not represents NR ⁴ ; (ⅶ) when R ¹ represents a bond with R ² , then R ⁵ and R ⁸ form a bond, and if X represents NR ⁴ , R ⁴ represents an alkyl group; (ⅷ) when R ⁶ represents an aryl group, When halogen, alkoxy, thioalkyl, then R ² and R ³ form a bond; (ⅸ) when Y represents N or N ⁺ R ⁷ and R ² is any one of NR ¹⁰ R ¹¹ , OR ¹² or F When substituting, the substituent and the ring nitrogen atom of Y cannot be connected with the same carbon atom of R ² ; (ⅹ) when R ⁷ is substituted by any one of NR ¹⁶ R ¹⁷ , OR ¹² or halogen, then the The substituent and the ring nitrogen atom of Y cannot be connected with the same carbon atom of R ⁷ ; (ⅹi) when one of B, D, E and G represents N, then X does not represent NR ⁴ ; (ⅹii) when Y represents CR At ¹⁸ , X represents CR ³ R ⁶ ; the further conditions are: (a) when B, D, E and G all represent CH, X represents CHR ³ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ When representing H and R ² and R ³ together represent a bond, then Ar ¹ does not represent unsubstituted phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methoxyphenyl; (b) when B, D, E and G all represent CH, X represents CHR ³ , Y represents N ⁺ R ⁷ , R ¹ and R ⁵ form a bond, R ² and R ³ represent a bond, R ⁸ represents H and R ⁷ represents a methyl group, then Ar ¹ does not represent unsubstituted phenyl; (c) when B, D, E and G all represent CH, X represents CH ₂ , Y represents N, R ¹ and R ⁵ form a bond, R ⁸ represents H and R ² represents When isopropyl, then Ar ¹ does not represent unsubstituted phenyl or 4-bromophenyl; and (d) when B, D, E and G all represent CH, X and Y represent CH ₂ and R ¹ and R ⁵ When a bond is formed, then Ar ¹ does not represent unsubstituted phenyl. 3. A compound of formula I according to claim 1 or 2, wherein ^Ar1 represents phenyl or pyridyl. 4. A compound of formula I according to claim 3, wherein ^Ar1 represents phenyl. 5. A compound of formula I according to claim 3 or 4, wherein ^Ar1 has a substituent in the para position. 6. The compound of formula I according to claim 5, wherein Ar ¹ has a Cl, Br, CF ₃ , C ₂ F ₅ , DCF ₃ or SCH ₃ substituent in the para position. 7. A compound of formula I as claimed in any preceding claim, wherein Y represents N ⁺ R ⁷ , and X represents CR ³ R ⁶ wherein R ³ forms a bond with R ² and R ⁶ represents alkyl. 8. The compound of formula I according to claim 7, wherein R ⁶ represents branched chain alkyl. 9. ^{3. Compounds of formula I according to any one of claims 1-6, wherein X represents NR4 wherein R4 represents} a bond to ^R2 and Y represents N ^{+ R7} . 10. A compound of formula I as claimed in any preceding claim, wherein B represents CA. 11. A compound of formula I according to claim 10, wherein A represents F. 12. A compound of formula I as claimed in any preceding claim, wherein D or G represents N. 13. A compound of formula I as claimed in any preceding claim, wherein ^R1 represents a bond to ^R2 or ^R5 . 14. A compound of formula I according to claim 13, wherein R ¹ represents a bond with R ⁵ . 15. The compound and pharmaceutically acceptable derivatives thereof according to claim 2, which are: 3-hydroxyl-4-[(4-methoxyphenyl)methyl]-2-(4-trifluoromethylphenyl )-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c] Isoquinolin-3-ol, 2-(4-chlorophenyl)-2,5-dihydro-5-methyl-3H-pyrazolo[4,3-c]cinnolin-3-one, 2 -(4-Chlorophenyl)-2,3a,4,5-tetrahydro-3a,4-dimethylpyrazolo[4,3-c]isoquinolin-3-one, 2-(4- Chlorophenyl)-3a,4-dihydro-3a,4-dimethyl-2H-pyrazolo[4,3-c]isoquinoline-3,5-dione, 2-(4-chlorobenzene base)-2,4-dihydro-3-hydroxy-4-methylpyrido[4,3-c]isoquinolin-5-one, 3-hydroxy-4-[(4-methoxyphenyl )methyl]-2-(3-quinolinyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(3-quinolinyl)-2H- Pyrazolo[4,3-c]isoquinolin-3-ol, 2-(3,4-dichlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl] -2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(3,4-dichlorophenyl)-2H-pyrazolo[4,3-c]iso Quinolin-3-ol, 2-([1,1'-diphenyl]-4-yl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 3-hydroxy- 4-[(4-methoxyphenyl)methyl]-2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-methylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2-(4-bromophenyl)-3-hydroxyl-4-[(4 -Methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-bromophenyl)-2H-pyrazolo[ 4,3-c]isoquinolin-3-ol, 2-(3-trifluoromethylphenyl)-3-hydroxyl-4-[(4-methoxyphenyl)methyl]-2H-pyridine Azolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(3-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium-3 -alcohol, 2-[4-(1,1-dimethylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2-(4-trifluoro Methoxyphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2-(4-chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazole A[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c] Cinnolinium hydroxide, inner salt, 2-(4-chlorophenyl)-3-hydroxy-4-[(4-methoxyphenyl)methyl-2H-pyrazolo[4,3-c ]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium Hydroxide, inner salt, 3-Hydroxy-4-methyl-2-(3-quinolyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2 -(6-Hydroxy-3-pyridyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(3,4 -Dichlorophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2- (4-Methylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-bromophenyl)-3-hydroxy-4-methyl -2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2-(3-trifluoromethylphenyl)-2H-pyrazole A[4,3-c]isoquinolinium hydroxide, inner salt, 2-[4-(1,1-dimethylethyl)phenyl]-3-hydroxy-4-methyl-2H- Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(6-chloro-3-pyridyl)-3-hydroxy-4-[(4-methoxyphenyl) Methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2-(6-methyl-3-pyridyl)- 2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-trifluoromethylphenyl)-3-hydroxy-4-(2-hydroxyethyl)- 2H-Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-Hydroxy-4-methyl-2-(5-methyl-2-pyridyl)-2H-pyrazole A[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2-[4-(1-methylethyl)phenyl]-2H-pyrazolo [4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-2-(4-nitrophenyl)-2H-pyrazolo[4,3-c] Isoquinolinium hydroxide, inner salt, 2-(4-cyanophenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide , inner salt, 2-(4-carboxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4 -Chloro-3-trifluoromethylphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4- Trifluoromethoxyphenyl)-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl- 2-(4-Methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-cyclopropyl-3-hydroxy-2-(4- Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-cyclopropyl-3-hydroxy-2-(6-methyl-3 -pyridyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-[(1,1-dimethyl-2-hydroxy)ethyl]-3- Hydroxy-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-(2-methyl Oxyethyl)-2-[(4-trifluoromethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chloro Phenyl)-3-hydroxy-4-[2-(methylthio)ethyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4 -[2-(Methylthio)ethyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4 -Cyclopropyl-2-(4-trifluoromethoxyphenyl)-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4 -Chloro-3-trifluoromethylphenyl)-4-cyclopropyl-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-cyclopropane Base-3-hydroxy-2-(4-methylthiophenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-phenyl- 2-(4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-ethyl-3-hydroxy-2-(4- Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-trifluoromethylphenyl)-4-(1-ethyl Oxycarbonylmethyl)-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-[(4-methoxyphenyl) Methyl]-2-phenyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-(1-methylethyl)-2-( 4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-(1-methylethyl)-2- (3-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-2-(4-iodophenyl)-4- Methyl-2H-pyrazolo[4,3-c]isoquinoline hydroxide, inner salt, 2-(6-chloro-3-pyridyl)-2H-pyrazolo[4,3-c] Isoquinolin-3-ol, 2-[4-(1-methylethyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2-(4- Pentafluoroethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2,4-dihydro-3-hydroxy-4-methyl-2-(2-pyrimidine Base)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2-([1,1-biphenyl]-4-yl)-2,4-dihydro-3- Hydroxy-4-methyl-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-4-methyl-2-(4-trifluoro Methylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2-(6-chloro-3-pyridyl)-2,4-dihydro-3-hydroxy- 4-Methyl-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-2-(4-iodophenyl)-4-methyl -5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-4-(4-methoxyphenylmethyl)-2-(4 -trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-4-(1-methylethyl) -2-(4-Trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-4-methyl- 2-[4-(1-methylethylphenyl]-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxyl-2-( 4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxy-2-[4-(1-methyl Ethyl)phenyl]-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2,4-dihydro-3-hydroxyl-2-([1,1'-diphenyl Base]-4-yl)-5H-pyrazolo[4,3-c]isoquinolin-5-one, 2-(4-chlorophenyl)-3-hydroxy-4-[(4-methoxy ylphenyl)methyl]-5-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-5-methyl -2H-pyrazolo[4,3-c]isoquinolin-3-ol, 4-cyclopropyl-3-hydroxy-5-methyl-2-(4-trifluoromethylphenyl)-2H -pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-(2-methoxyethyl-5-methyl-2-[(4-trifluoro Methyl)phenyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-3-hydroxy-4,5-dimethyl 2H-pyrazolo[4,3-c]isoquinoline hydroxide, inner salt, 5-ethyl-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl) -2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-5-methyl-4-(1-methylethyl)-2-(4-tri Fluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-methyl-5-(1-methylethyl)-3-hydroxy- 2-(4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4,5-dimethyl-2- (4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 5-chloro-2-(4-trifluoromethylphenyl) -2H-pyrazolo[4,3-c]isoquinolin-3-ol, 3a,4-dihydro-3a-hydroxy-2-(4-trifluoromethylphenyl)-2H-pyrazolo[ 4,3-c]isoquinoline-3,5-dione, 2,4-dihydro-3-methoxy-4-methyl-2-(4-trifluoromethylphenyl)-5H- Pyrazolo[4,3-c]isoquinolin-5-one, 2-(4-chlorophenyl)-4-{2-(N,N-dimethylamino)ethyl}-3-hydroxy- 2H-Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-Hydroxy-4-methyl-2-(4-methylsulfinylphenyl)-2H-pyrazole Con[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-3-hydroxy-4-[2-(methylsulfinyl)ethyl]-2H -Pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-[2-(methylsulfinyl)ethyl]-2-(4-trifluoromethane phenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 5-[2-(4-methoxyphenyl)ethyl]-2-(4 -trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin-3-ol, sodium salt, 9-fluoro-3-hydroxy-4-[(4-methoxybenzene base)methyl]-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl )-7-fluoro-3-hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 7-fluoro-3-hydroxy-4-methyl -2-(4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-4-cyclo Propyl-9-fluoro-3-hydroxy-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4-cyclopropyl-9-fluoro-3-hydroxy-2- (4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-9-fluoro-3- Hydroxy-4-methyl-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-9-fluoro-3-hydroxy-4- [(4-Methoxyphenyl)methyl]-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 9-fluoro-3-hydroxy-4-methyl- (4-Trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-(4-chlorophenyl)-9-fluoro-2H- Pyrazolo[4,3-c]isoquinolin-3-ol, 7-fluoro-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolin -3-ol, 2-(4-chlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 9-fluoro-3-hydroxyl-4-[ (4-methoxyphenyl)methyl]-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide , inner salt, 2-(4-chlorophenyl)-9-fluoro-3-hydroxyl-4-[(4-methoxyphenyl)methyl-5-methyl-2H-pyrazolo[4, 3-c]isoquinolinium hydroxide, inner salt, 9-fluoro-5-methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]iso Quinolin-3-ol, 2-(4-chlorophenyl)-9-fluoro-5-methyl-2H-pyrazolo[4,3-c]isoquinolin-3-ol, 2,4- Dihydro-3-hydroxy-4-methyl-2-(4-trifluoromethylphenyl)-5H-pyrazolo[4,3-c]isoquinoline-5-thione, 3-hydroxy- 4-Methyl-5-methylthio-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 2-( 4-trifluoromethylphenyl)-2,4-dihydro-5-imino-4-methyl-5H-pyrazolo[4,3-c]isoquinolin-3-ol, 3-hydroxy -4-(4-methoxyphenyl)methyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide compound, inner salt, 2-(4-trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridin-3-ol, 3-hydroxy-4-methyl -2-(4-Trifluoromethylphenyl)-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt, 2-(4-chlorophenyl) -3-Hydroxy-4-methyl-2H-pyrazolo[3,4-f][1,7]naphthyridinium hydroxide, inner salt, 3-hydroxy-4-methyl-5-(di Methylamino)-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl-5 -Morpholinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 3-hydroxy-4-methyl- 5-Piperazinyl-2-(4-trifluoromethylphenyl)-2H-pyrazolo[4,3-c]isoquinolinium hydroxide, inner salt, 4,5-dihydro-2 -[4-(trifluoromethyl)phenyl]-2H-benzo[g]indazol-3-ol, 4,5-dihydro-2-(5-methyl-2-pyridyl)-2H -Benzo[g]indazol-3-ol, 2-[4-(trifluoromethyl)phenyl]-2H-benzo[g]indazol-3-ol, 2-(5-methyl- 2-pyridyl)-2H-benzo[g]indazol-3-ol, 16. The method for preparing the compound of formula I defined in claim 1 or 2, which comprises: (a) prepare formula I compound (wherein X represents CH ₂ or C=O, Y represents N, Z represents OR ⁸ , R ⁵ and R ⁸ form a bond and R ¹ and R ² form a bond, through the corresponding formula I compound Oxidation is carried out, wherein R ¹ and R ² all represent H, X, Y, Z and R ⁵ are as defined above, and B, D, E, G and Ar ¹ are as defined in claim 1; (b) Preparation of compounds of formula I, wherein B, D, E and G represent CA wherein A represents amino, obtained by reduction of the corresponding compound of formula I, wherein one of B, D, E and G represents CA wherein A represents Nitro and the rest of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined in claim 1; (c) Preparation of compounds of formula I, wherein one of B, D, E and G represents CA wherein A represents halogen, by diazotization of the corresponding compound of formula I, wherein one of B, D, E and G represents CA wherein A represents amino and the rest of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined in claim 1, and the diazonium salt is in the halide anion or decomposed in the presence of the source material; (d) Preparation of a compound of formula I, wherein one of B, D, E and G represents CA wherein A represents a cyano group, obtained by reacting the corresponding compound of formula I, wherein one of B, D, E and G represents CA wherein A represents bromine and the rest of B, D, E and G, and X, Y, Z, Ar ¹ , R ¹ , R ² and R ⁵ are as defined in claim 1; (e) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkylthio group , through the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ are as defined above and B, D, E, G and Ar are as defined in claim ¹ , obtained by displacement reaction with the compound of formula II: Wherein R ^6a represents C _1-6 alkyl; (f) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkoxy group , through the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ are as defined above and B, D, E, G and Ar are as defined in claim ¹ , obtained by displacement reaction with the compound of formula III:

Wherein R ^6a is as defined before; (g) Preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents NR ¹³ R ¹⁴ , through the corresponding compound of formula I, wherein X represents CR ³ R ⁶ , wherein R ⁶ represents methylthio or halogen, Y, Z, R ¹ , R ² , R ³ and R ⁵ are as defined above and B, D, E , G and Ar ¹ are as defined in claim 1, obtained by displacement reaction with the compound of formula IV:

Wherein R ¹³ and R ¹⁴ are as defined in claim 1; (h) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents a methylthio group , through the corresponding compound of formula I, wherein X represents C=S, Y represents N, Z represents OH, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1 , obtained by reacting with a methylating reagent; (i) Preparation of a compound of formula I, wherein X represents C=S, Y represents N, Z represents OH and R ¹ represents a bond formed with R ⁵ , obtained by sulfuration of the corresponding compound of formula I, wherein X represents C= O, Y, Z, R ¹ and R ⁵ are as defined above and B, D, E, G, Ar ¹ and R ² are as defined in claim 1; (j) Preparation of compounds of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents ^O- and R ⁶ represents halogen, which is obtained by halogenation of the corresponding compound of formula I, wherein X represents C= O, Y represents N, Z represents OR ⁸ , R ⁸ represents the bond with R ⁵ and B, D, E, G, Ar ¹ , R ¹ and R ² are as defined in claim 1; (k) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkyl group, By the corresponding compound of formula I, wherein X represents C=O, Y represents N, Z represents OH, R ¹ represents the bond formed with R ⁵ , B, D, E, G and Ar ¹ are as defined in claim 1 and R ² represents R ⁷ corresponding to the definition in claim 1 obtained by reacting with a nucleophilic alkylating agent comprising a compound of formula V: Wherein R ⁶ is as defined above and Hal represents a halogen or an anion corresponding to R ⁶ from another source; (1) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ⁻ , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents an alkyl group, By the corresponding compound of formula I, wherein X represents CR ³ R ⁶ wherein R ⁶ represents H, Y, Z, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as in claim 1 Definition, obtained by reacting with a nucleophilic alkylating agent, said nucleophilic alkylating agent comprising a compound of formula V as defined above, or an anion corresponding to ^R from another source; (m) Preparation of a compound of formula I, wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ¹ represents a bond formed with R ⁵ , and R ⁸ represents an alkyl group, through the corresponding compound of formula I, wherein Z Represents OR ⁸ wherein R ⁸ represents H, X, Y, R ¹ and R ⁵ are as defined above and B, D, E, G, Ar ¹ and R ² are as defined in claim 1, obtained by reacting with the compound of formula VI: R ⁸ Hal (VI) wherein R ⁸ represents an alkyl group and Hal is as defined above; (n) Preparation of a compound of formula I, wherein R ¹ represents OH, X represents C=O, Y represents N, Z represents OR ⁸ and R ⁵ represents a bond formed with R ⁸ , by using the corresponding compound of formula I, wherein Z represents O ^- , R ¹ and R ⁵ form a bond, X, Y and R ² are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1, obtained by treating and reacting with an oxidizing agent; (o) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond, through the corresponding formula I compound , wherein Y represents N, Z represents OH, X, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1, obtained by reacting with the compound of formula IX: R ⁷ Hal (IX) wherein R ⁷ is as defined in claim 1 and Hal is as defined above; (p) Preparation of a compound of formula I, wherein X represents C=O, R ² does not represent H, Y represents N, Z represents OH and R ¹ represents a bond formed with R ⁵ , through the corresponding compound of formula I, wherein R ² represents H, X, Y, Z, R ¹ and R ⁵ are as defined above and B, D, E, G and Ar ¹ are as defined in claim 1, obtained by reacting with the compound of formula VII: R ² Hal (VII) wherein R ² does not represent H, as defined in claim 1 and Hal as defined above; (q) Preparation of a compound of formula I, wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁴ and R ² form a bond, and R ¹ and ^R forms a bond through the compound of formula VIII: Wherein A and Ar ¹ are obtained by reacting with the compound of formula IX as defined above as defined in claim 1; (r) Preparation of a compound of formula I, wherein B, D, E and G represent CH or CA, X represents NR ⁴ , Y represents N, Z represents OR ⁸ , R ² and R ¹ form a bond and R ⁵ and R ⁸ form a bond , obtained by reacting a compound of formula VIII as defined above with a compound of formula X: R ⁴ Hal (X) wherein R ⁴ is as defined in claim 1 and Hal is as defined above; (s) prepare formula I compound, wherein X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond and R ¹ represents a bond formed with R ⁵ , by combining the corresponding formula I compound with Acid reaction, wherein Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁷ represents CH ₂ C ₆ H ₄ O alkyl, X, R ¹ , R ² and R ⁵ are as defined above and B, D, E, G and Ar are as defined in claim ¹ ; (t) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N, Z represents OH, R ³ and R ² form a bond and R ¹ represents a bond with R ⁵ , by combining the corresponding compound of formula I with hydrogen obtained by treatment, wherein Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁷ represents CH ₂ phenyl (optionally substituted by C _1-6 alkyl or C _1-6 alkoxy), X, R ¹ , R ² and R ⁵ are as defined above, and B, E, G and Ar ¹ are as defined in claim 1; (u) Preparation of a compound of formula I, wherein X represents C=O, Y represents N, Z represents OH, ^R2 represents H and ^R1 represents a bond formed with ^R5 , obtained by treating the corresponding compound of formula I with an acid , wherein Y represents N ⁺ R ⁷ , Z represents O ^- , R ⁷ represents CH ₂ C ₆ H ₄ O alkyl, X, R ¹ , R ² and R ⁵ are as defined above, while B, D, E, G and Ar ¹ as defined in claim 1; (v) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents N ⁺ R ⁷ , Z represents O ^- , R ³ and R ² form a bond, R ¹ and R ⁵ form a bond and R ⁶ represents H, by Formula XI compound:

Wherein X represents CH ₂ , R ¹ represents H, R ² represents the group corresponding to R ⁷ as defined in claim 1 in the compound of formula I, B, D, E and G are as defined in claim 1 and R is an alkyl group , react with the compound of formula XII to obtain: Ar ¹ NHNH ₂ (XII) wherein Ar ¹ is as defined in claim 1; (w) Preparation of a compound of formula I, wherein X represents C=O, R ^does not represent H, Y represents N, Z represents OH, and ^R represents a bond with R ⁵ , through a compound of formula XI as previously defined, wherein X Represents C=O, R ¹ represents H, R ² is as defined above and B, D, E and G are as defined in claim 1, obtained by reacting with the compound of formula XII as defined above, wherein Ar ¹ is as defined in claim 1 ; (x) Preparation of a compound of formula I, wherein X represents CH ₂ , Y represents N ⁺ R ⁷ , Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents an alkyl group, by a compound of formula XI as defined above, wherein X represents CH ₂ , R ¹ represents an alkyl group, R is as defined above and B, D, E, G and R ² are as defined in claim 1, obtained by reacting with the compound of formula XII as defined above, wherein Ar ¹ is as defined above; (y) Preparation of a compound of formula I, wherein X represents C=O, Y represents N, Z represents OR ⁸ , R ⁸ and R ⁵ form a bond and R ¹ represents an alkyl group, through a compound of formula XI as defined above, wherein X represents C=O, R ¹ represents an alkyl group, R ² represents H or an alkyl group, R is as defined above and B, D, E and G are as defined in claim 1, obtained by reacting with the compound of formula XII as defined above, wherein Ar ¹ as defined above; (z) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ¹ and R ⁵ form a bond and R ² and R ³ form a bond, by oxidation of the corresponding compound of formula I And, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H, R ¹ and R ⁵ form a bond and B, D, E, G, Ar ¹ , R ⁶ and R ¹⁸ is as defined in claim 1; or (aa) Preparation of a compound of formula I, wherein X represents CR ³ R ⁶ , Y represents CR ¹⁸ , Z represents OH, R ² and R ³ represent H and R ¹ and R ⁵ form a bond, by combining the compound of formula XII as defined above with the formula XX compound reacts to obtain:

wherein R is as defined above and B, D, E, G, ^R6 and ^R18 are as defined in claim 1.