MXPA99009760A - Inhibitors pirazolopirimidinone of cgmp pde5 for the treatment of sex dysfunction - Google Patents

Abstract

Compounds of formula IA and of formula IB are provided, which R1, R2 R3 and R4 and A have the meaning given in the description, which are useful in the curative and prophylactic treatment of a medical disorder for which inhibition is desired. a guanosine 3 ', 5'-cyclic phosphodiesterase monophosphate (eg, cGMP PDE

Description

PIRAZOLOPIRIMIDINONE INHIBITORS OF cGMP PDE5 FOR THE TREATMENT OF SEXUAL DYSFUNCTION FIELD OF THE INVENTION This invention relates to pharmaceutically useful compounds, in particular to compounds that are useful in the inhibition of cyclic guanosine 3 ', 5'-monophosphate phosphodiesterases (cGMP PDE), such as guanosine 3', 5'-cyclic monophosphate phosphodiesterases of the type 5 (cGMP PDE5). Therefore, the compounds have utility in a variety of therapeutic areas, including erectile dysfunction in men (MED).

PREVIOUS TECHNIQUE The international patent application WO 94/28902 describes the use of certain pyrazolopyrimidinone compounds in the treatment of impotence.

DESCRIPTION OF THE INVENTION According to a first aspect of the invention, compounds of formulas IA and IB are provided: IA IB wherein A represents CH or N; R1 represents Het, alkylHet1, aryl or alkylaryl, all of which are optionally substituted with one or more substituents selected from halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10 and S? 2NR11aRH.

R2 and R3 independently represent H or lower alkyl, the latter group being optionally substituted and / or terminated by one or more substituents selected from aryl, Het1, halogen, cyano, nitro, OR5, C (0) R6, C (0) OR7 , C (0) NR8R9, NR10aR10b and S02NR11aR11b; R4 represents S02NR12R13; R12 and R13 independently represent H; lower alkyl optionally substituted and / or terminated with one or more substituents selected from ary, Het1, halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10R10a and S02NR11aR11b; Het1; or together with nitrogen to which they are bound form Het or a structural fragment of formula lia: R14 and R15 independently represent H, lower alkyl, C (0) R6, C (0) OR7 or C (0) NR8R9; Het1 represents a heterocyclic group with optionally substituted four to twelve links, group containing at least one nitrogen atom, and optionally, one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; Het2 represents an optionally substituted three to twelve membered heterocyclic group, a group containing at least one nitrogen atom, and optionally, one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; and R, R, R, R, R, R, R, R, R and R independently represent each time they appear in the present, H or lower alkyl; or a pharmaceutically or veterinarily acceptable derivative thereof, with the proviso that when R2 represents Ci-β alkyl and: (a) A represents CH; R1 represents Het1 or CH2Het1 (in both Cases Het1 represents a 6-membered heterocyclic group linked by C, containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide or a 5-membered heterocyclic group linked by C containing from one to four selected heteroatoms between nitrogen, oxygen and sulfur, each of said heterocyclic groups being optionally substituted with one or two substituents selected from C 1-4 alkyl, the alkyl group optionally being substituted with akoxy d-4, halogen or NH 2), phenyl or benzyl ( the latter two groups optionally substituted with one to two substituents selected from C 1 - 4 alkyl, alkoxy d 4, halogen, CN, CONH 2, N 0 2, NH 2 and S 0 2 NH 2); and R 3 is C 1-6 alkyl optionally substituted with C 1-4 alkoxy; then R 2 and R 3 do not represent, together with the nitrogen atom to which they are attached, a piperazinyl group, optionally substituted at the 4 (N) position with C 1-4 alkyl optionally substituted with OH, C-M alkoxy or CONH 2; and (b) A represents N; R1 represents CH2Het1 (in which Het1 represents a 6-membered heterocyclic group linked by C, containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a 5-membered heterocyclic group linked by C, containing two or three nitrogen atoms, each of said heterocyclic groups being optionally substituted with C 1-4 alkyl) or benzyl; and R3 is alkyl CM (optionally substituted with one or two substituents selected from OH, C1-4 alkoxy, benzyloxy, NR5aR6a (where R5a and R63 are each independently selected from H and Ct-4 alkyl or, together with the atom of nitrogen to which they are attached, form a pyrrolidinyl, piperidinyl or morpholinyl), phenyl, furanyl or pyridinyl), C3-6 cycloalkyl or 1- (C1-alkyl) piperidinyl; then R12 and R do not represent, together with the nitrogen atom to which they are attached, a 4-piperazine group, optionally substituted with one to two C1-4 alkyl groups, optionally in the form of its 4-N-oxide, and optionally substituted in the 4 (N) position with C1-4 alkyl optionally substituted with one or two substituents selected from OH, NR5aRda, CONR5aR6a (in both cases R5a and R6a are as defined above); these compounds being referred to collectively as "the compounds of the invention". The term "aryl", when used herein, includes aromatic groups with six to ten links, such as phenyl and naphthyl. Each "aryl" group identified herein is optionally substituted with one or more substituents selected from halogen, cyano, nitro, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10b, S02NR11aR11b, N (H) S02R1 a and lower alkyl, the latter group being optionally substituted and / or terminated by one more substituents selected from halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (0) OR7, C (0) ) NR8R9, NR10aR10b, S02NR11aR11b and N (H) S02R11a. The term "Het1", when used herein, includes ring systems of four to twelve links, preferably four to ten links, which may be of aromatic character. Each "Het1" group identified herein is optionally substituted with one or more substituents selected from halogen, cyano, nitro, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10b, S02NR11aR11b, N (H) S02R11a and lower alkyl, the latter group being optionally substituted and / or terminated with one or more substituents selected from halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10b, S02NR11aR11b, N (H) S02R11a. Thus, the term "Het1" includes groups such as azetidinyl, pyrrolidinyl, midazolyl, indolyl, oxadiazolyl, thiadiazoyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl, imidazopyridinyl and piperazinyl. The term "Het2", when used herein, includes ring systems of three to twelve links, preferably four to ten links, which may have aromatic character. Each Het2 group identified herein is optionally substituted with one or more substituents selected from oxo, ethylene ketal, halogen, cyano, nitro, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10b, S02NR11aR11b , N (H) S02R 1a and lower alkyl, the latter group being optionally substituted and / or terminated with one or more substituents selected from halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (O) OR7 , C (O) NR8R9, NR10aR10b, SO2NR11aR11b, N (H) SO2R11a. Thus, the term includes such groups as midazolyl, indolyl, oxadiazolyl, thiadiazolyl, triazoyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, morpholinyl, tetrahydrothiazinyl, pyrazolyl, midazopyridinyl, and azazole groups. diaza-cycloalkyl (C 1 -C 12), such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, aza- or diazacycloheptyl, -cyclooctyl, -cyclononyl, -cyclodecyl, -cyclohexyl and -cyclododecyl.

All the groups Het1 and Het2 can also be in the form of an N-oxide. For the avoidance of doubt, when R12 and R13 together represent Het2, the nitrogen atom to which they are attached is the nitrogen atom that must be present in this ring. The term "lower alkyl", when used herein, includes C 1 -β alkyl. The alkyl groups, which may represent R2, R3, R5, R6, R7, R8, R9, R10, R10a, R10b, Rl1a, R11b, R12, R13, R14 and R15, may be substituted with R1, R12 and R13, aryl and Het (Het1 and Het2), when there is a sufficient number of carbon atoms, may be linear or branched, saturated or unsaturated, cyclic, acyclic or partially cyclic / acyclic, may be interrupted with oxygen, and / or substituted with one more halogen atoms. The terms "alkylHet1" and "alkylaryl" include C1-βHet1 alkyl and C1-6 alkylaryl. Alkyl groups (for example, Ci-β alkyl groups) of alkylHet and alkylaryl can, when there is a sufficient number of carbon atoms, be linear or branched, saturated or unsaturated, and / or can be interrupted with oxygen. When used in this context, the terms "Het1" and "Aryl" are as defined above herein. The halogen groups, with which R 1, R 2, R 3, R 2, R 13, ary, Het 1, Het 2 and the aforementioned alkyl groups may be substituted or terminated, include fluoro, chloro, bromo and iodo. The term "pharmaceutically and veterinarily acceptable derivative" includes salts and solvates. The salts that can be mentioned include: acid addition salts, for example, salts formed with inorganic acids, such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, with carboxylic acids or with organosulfonic acids, base addition salts, metal salts formed with bases, for example, sodium and potassium salts. Pharmaceutically acceptable derivatives also include alkylammonium salts Ci to C4. Preferred compounds of the invention include those in which R12 and R13, together with the nitrogen atom to which they are attached, do not represent an optionally substituted piperazin-4-yl group. Preferred compounds of the invention include those in which: R 1 represents Ci-βHet alkyl, in which Het 1 represents a six-membered aromatic heterocyclic group containing one or more nitrogens; R2 represents linear, branched, cyclic or acyclic lower alkyl; R3 represents linear, branched, cyclic or acyclic lower alkyl, which is optionally substituted or terminated with OR5 (in which R5 is H or straight, branched or cyclic C1-C3 alkyl); R12 and R13 independently represent H; lower alkyl (eg, C 1-5) linear, branched, cyclic or acyclic, said alkyl group being optionally substituted and / or terminated with one or more substituents selected from OR 5 (in which R 5 is H, or linear C 1 -C 3 alkyl) , branched or cyclic), Het1 (where Het1 represents an aromatic heterocyclic group of six 10 11 1 bonds, containing one or more nitrogens) or NR R; Het (where Het represents a six-membered heterocyclic group containing one or two nitrogens); or, together with the nitrogen atom to which they are attached, represents morpholinyl, tetrahydrothiazinyl, aza- or diazacyclo (C3-Cs) alkyl (all of these latter groups being optionally substituted with one or more substituents selected from oxo, ethylene ketal, OR5 ( wherein R5 is H or linear, branched or cyclic C1-C3 alkyl), NR R or lower alkyl (eg, C1-4), or a structural fragment of formula Ia as described above in present, wherein R 14 and R 15 independently represent H, straight, branched, cyclic or acyclic C 1 -C 3 alkyl or C (0) OR 7, where R represents straight or branched C 1 -C 4 alkyl. More preferred compounds of the invention include those in which: R1 represents C1-C3 alkylpyridinyl; R2 represents straight or branched C1-C4 alkyl; R3 represents straight or branched C1-C3 alkyl, optionally terminated with d-2 alkoxy; R12 and R13 independently represent H (with the proviso that both are not H); linear or branched C1-C3 alkyl, said alkyl group being optionally terminated with one or more substituents selected from C entre -2 alco alkoxy, pyridinyl or NR R (in which R and R independently represent H or C1-C3 alkyl) ); piperidinyl (optionally substituted at the 1 (N) position with COOR (in which R represents C1-C4 alkyl)); pyrazinyl or, together with the nitrogen atom to which they are attached, represent morpholinyl, tetrahydro-1,4-thiazinyl, azetidinyl, piperidinyl, 1,4-diazacycloheptyl (all of which are optionally substituted with one or more groups selected from linear or branched C 1 -C 3 alkyl, oxo, ethylene ketal, OH, C 2 alkoxy or NR10R11 (where R10 and R11 independently represent H, straight or branched C1-C3 alkyl)) or a structural fragment of formula IIb or He: Ilb lie wherein R and R each represent H, or one represents H and the other represents linear or branched C 1 -C 3 alkyl or C (0) OR 7, wherein R 7 represents straight or branched C 1 -C 4 alkyl. Especially preferred compounds of the invention include those in which: R 1 represents C 1 -2 pyridin-2-yl alkyl (e.g., methylpyridin-2-yl); R2 represents C2-3 alkyl (for example, ethyl or n-propyl); R3 represents C2-C3 alkyl, optionally terminated with OCH3; R12 and R13 independently represent H (with the proviso that both do not represent H); methyl or ethyl (both optionally being terminated with OCH3, NH2, NH (ethyl), N (methyl) 2 or pyridin-2-yl); 1-ethyloxycarbonylpiperidinyl, pyrazin-2-yl; or together with the nitrogen to which they are together represent morpholinyl, 4-piperidinyl (optionally substituted by C? -2 alquilo alkyl, ethylene ketal, oxo and C? -2 alco alkoxy), 1,4-diazacycloheptyl (optionally substituted by C C1-2 alquilo alkyl), azetidinyl (optionally substituted by OH, N (metil) 2 or NH (ethyl)), tetrahydro-1,4-thiazinyl (optionally substituted by dioxo (in position 1, 1)) or a fragment of the formula lid, lie or llf: lid pe Ilf The most preferred compounds of the invention include the compounds of Examples 1 to 25 described hereinafter. The compounds of the invention may exhibit tautomerism.

All tautomeric forms of the compounds of formulas IA and IB, and mixtures thereof, are included within the scope of the invention. The compounds of the invention may also contain one or more asymmetric carbon atoms and may exhibit optical and / or diastereomeric properties. The diastereoisomers can be separated using conventional techniques, for example, with fractional crystallization or chromatography. The various stereoisomers can be isolated by separation of a racemic compound or other mixture of the compounds using techniques conventional, for example, fractional crystallization or HPLC. The desired optical isomers can be prepared by reaction of the appropriate optically active starting materials under conditions that will not cause racemization or epimerization. In another alternative, the desired optical isomers can be prepared by resolution, or by HPLC of the racemate using an appropriate chiral support, or where appropriate, by fractional crystallization of the diastereomeric salts formed by reaction of the racemate with an appropriate optically active acid or base. All stereoisomers are included within the scope of the invention. Also included within the scope of the invention are the radiolabeled derivatives of the compounds of formulas IA and IB that are suitable for biological studies.

PREPARATION According to another aspect of the invention, methods are provided for the preparation of the compounds of the invention, as illustrated below. The following procedures are illustrative of the general synthetic procedures that can be adopted in order to obtain the compounds of the invention: 1. The compounds of formulas IA and IB can be prepared by reaction of the corresponding compounds of formulas IIIA and IIIB, respectively: wherein Y is a leaving group, such as halogen, preferably chlorine, bromine or iodine and R1, R2, R3 and A are as previously defined for the compounds of formulas IA and IB, with a compound of formula IV: R12R13NH IV wherein R 2 and R 13 are as defined above for the compounds of formulas IA and IB. This reaction can be carried out at or near room temperature, preferably in the presence of an appropriate solvent, such as Ci to Ce alcohol, acetone / water or dichloromethane, using an excess of the compound of formula IV, and optionally, in the presence of another appropriate base, such as triethylamine. In another alternative, the reaction can be carried out at room temperature, in an appropriate solvent, such as tetrahydrofuran, using an excess of the anion of the compound of formula IV, formed by reaction of a compound of formula IV, with an appropriate base (e.g. , sodium hydride), in an appropriate solvent (for example, tetrahydrofuran) at or near room temperature. The compounds of formulas IIIA and 11 i EB, in which A represents N, can be prepared from the corresponding compounds of formulas VA and VB, respectively: VA VB wherein R1, R2 and R3 are as previously defined for the compounds of formulas IIIA and IIIB, using methods known to those skilled in the art to convert an amino group to a SO2Y group (in which Y is as previously defined for compounds of formulas MIA and IIIB). For example, the compounds of formulas IIIA and I i I EB, in which Y is chloro, can be prepared by reaction of a corresponding compound of formulas VA or VB, with approximately a two-fold excess of sodium nitrite in a mixture of hydrochloric acid concentrate and glacial acetic acid, from about -25 ° C to about 0 ° C, followed by treatment with excess liquid sulfur dioxide and an approximately three-fold solution of excess cupric chloride in acetic acid aqueous, from -15 ° C to approximately room temperature. The compounds of formulas VA and VB can be prepared by cyclization of the corresponding compounds of formulas VIA and VIB, respectively: VIA VIB wherein R1, R2 and R3 are as previously defined for the compounds of formulas VA and VB. This cyclization can be carried out under basic, neutral or acid conditions, using methods for the formation of the pyrimidone ring. Preferably, the cyclization is carried out under basic conditions using an alkali metal salt or an alcohol or amine, such as potassium ferc-butoxide or potassium bis (trimethylsilyl) amide, in the presence of an appropriate solvent (for example, an alcohol), optionally in the presence of molecular sieves, for example, at elevated temperature (for example, reflux) (or, if carried out in a closed vessel, at a temperature higher than that of reflux). The skilled artisan will appreciate that, when an alcohol is selected as a solvent, an appropriate alcohol of the formula R OH, or a sterically hindered alcohol, may be used, example, 3-methyI pentan-3-ol, if it is intended to mitigate the alkoxide exchange at position 2 of the pyridin-3-yl substituent. The compounds of formulas VIA and VIB can be prepared by reduction of the corresponding compounds of formulas VIIA and VIIB, respectively: VHA VHB wherein R1, R2 and R3 are as previously defined for the compounds of formulas VIA and VIB, by conventional techniques, such as catalytic hydrogenation or reduction in the presence of SnCl2. The hydrogenation can be carried out using a Raney nickel catalyst in an appropriate solvent, such as ethanol, at a hydrogen pressure of about 150 kPa to 500 kPa, especially 345 kPa, from about 40 ° C to about 50 ° C. The compounds of formulas VIIA and VIIB can be prepared by reaction of the corresponding compounds of formulas VIIIA and VIIIB, respectively: V? IA VfflB wherein R1 and R2 are as previously defined for the compounds of formulas VIIA and VIIB, with a compound of formula IX or a carboxylic acid derivative thereof: IX wherein R is as previously defined for the compounds of formulas VIIA and VIIB. This reaction can be performed with conventional techniques of forming an amide bond, which are well known to those skilled in the art. For example, an acyl halo derivative (eg, chloride) of a compound of formula IX can be reacted with a compound of formula VINA or VIIIB in the presence of an excess of tertiary amine, such as triethylamine or pyridine, optionally in the presence of a appropriate catalyst, such as 4-dimethylaminopyridine, in an appropriate solvent, such as dichloromethane, at a temperature of about 0 ° C to room temperature. Various amino acid coupling methodologies can be used to couple the compound of formula VINA or VIIIB with the compound of formula IX. For example, the acid of formula IX or an appropriate salt thereof (eg, the sodium salt) can be activated with an appropriate activating reagent, for example, a carbodiimide, such as 1,3-dicyclohexylcarbodiimide or hydrochloride of 1- ( 3-dimethylaminopropyl) -3-ethylcarbodiimide, optionally in the presence of the 1-hydroxybenzotriazole hydrate and / or a catalyst, such as 4-diaminomethylpyridine; a halotrisaminophosphonium salt such as bromotris (pi-rrolidinyl) phosphonium hexafluorophosphate; or an appropriate pyridinium salt, such as 2-chloro-1-methyl pyridinium chloride. Any type of coupling reaction can be performed in an appropriate solvent, such as dichloromethane or tetrahydrofuran, optionally in the presence of a tertiary amine, such as N-methylmorpholine or N-ethyldiisopropylamine (for example, when or the compound of formula VINA or VI I IB, or the activating agent is presented in the form of an acid addition salt) from about 0 ° C to about room temperature). In another alternative, the carboxylic acid function of the compounds of formula IX can be activated using an excess of a reagent, such as N, N'-carbonyldiumazole in an appropriate solvent, for example, ethyl, dichloromethane or butan-2-one, from about room temperature to about 80 ° C, followed by the reaction of the intermediate imidazoide, with a compound of formula VINA or VIIIB from about 20 ° C to about 90 ° C. The compounds of formulas IIIA and IIIB, in which A is CH, can be prepared from the corresponding compounds of formulas XA and XB, respectively: XA XB wherein R1, R2 and R3 are as previously defined for the compounds of formulas IIIA and IIIB, for example, using conventional methods for the introduction of a S02Y group into an aromatic ring system, such as the reaction of a compound of formula XA and XB with a compound of formula S02Y and / or a compound of formula YSO3H. When Y is chlorine, an excess of chlorosulfonic acid, optionally with an excess of thionyl chloride, from about 0 ° C to room temperature may be used in an appropriate solvent (for example, dichloromethane). The compounds of formulas XA and XB, in which R1 represents alkylHet1 or alkylaryl can be prepared by alkylation of the corresponding compounds of formulas XIA and XIB, respectively: XIA XIB ?2 . . r-, 3 in which R and R are as previously defined for the compounds of formulas XA and XB, using methods that are well known to those skilled in the art. For example, this reaction can be carried out by reacting a compound of formula XIA or XIB with a compound of formula R aL1, wherein R1a represents alkylHet1 or alkylaryl and L1 is an appropriate leaving group, using conventional techniques, which are well known to those skilled in the art. Preferably, the leaving group is halogen (preferably, chlorine, bromine or iodine) and the alkylation is carried out in the presence of an appropriate base (for example, sodium hydride or potassium bis (trimethylsilyl) amide, in an appropriate solvent (for example, dimethylformamide, toluene or tetrahydrofuran), optionally in the presence of sodium iodide or potassium iodide, from about room temperature to about 50 ° C. Preferably, the alkylation was performed from about 40 ° C to about 50 ° C. Alternatively, the compounds of XVA and XVB formulas can be reacted with a compound of formula R1aOH, in which R1a represents alkylHet or alkylaryl, using the Classical Mitsunobu methodology. The compounds of formulas XI A and XI B can be prepared by cyclization of the corresponding compounds of formulas XIIA and XIIB, respectively: XI I A XI IB wherein R2 and R3 are as previously defined for the compounds of formulas XIA and XIB. The cyclization can be carried out using conditions analogous to those previously described for the preparation of the compounds of formulas VA and VB. The compounds of formulas XI I A and XI IB can be prepared by coupling the corresponding compounds of formulas XIIIA and XIIIB, respectively: XI? A XI? B wherein R2 is as previously defined for the compounds of formulas XIIA and XIIB, with a compound of formula XIV or a carboxylic acid derivative thereof: XIV wherein R is as previously defined for the compounds of formulas XIIA and XIIB, using techniques known to those skilled in the art. For example, the reaction can be carried out using amide bond forming techniques analogous to those described for the preparation of the compounds of formulas VIIA and VIIB. Alternatively, the compounds of formulas XA and XB, as defined hereinabove, can be prepared alternatively by cyclization of the corresponding compounds of formulas XVA and XVB respectively: XVA XVB wherein R1, R2 and R3 are as previously defined for the compounds of formulas XA and XB. This cyclization can be carried out using conditions analogous to those previously described for the preparation of the compounds of formulas VA and VB. The compounds of formulas XVA and XVB can be prepared by reaction of the corresponding compounds of formulas VINA and VIIIB, as defined hereinbefore, with a compound of formula XIV, as defined herein above, or a carboxylic acid derivative thereof. The reaction can be carried out using amide bond forming techniques analogous to those described for the preparation of the compounds of formulas VIIA and VIIB. The compounds of formulas VINA and VIIIB are available using known techniques. For example, compounds of formulas VINA and VIIIB, in which R1 represents alkylHet1 or alkylaryl, can be prepared by alkylation of the corresponding compounds of formulas XIIIA and XIIIB, for example, using methods analogous to those described hereinabove. For example, the compounds of formulas XIIIA and XIIIB can be reacted with a compound of formula R1aL1 as defined hereinbefore, using conventional techniques. Preferably, the leaving group is halogen (preferably, chlorine, bromine or iodine) and the alkylation is carried out in the presence of an appropriate base (eg, cesium carbonate) in an appropriate solvent (eg, dimethylformamide or acetonitrile), optionally in presence of sodium iodide or potassium iodide, from about room temperature to about 80 ° C. 2. The compounds of formulas I A and IB can be prepared by cyclization of the corresponding compounds of formulas XVIA and XVIB, respectively: XVIA XVIB wherein R1, R2, R3, R4 and A are as previously defined for the compounds of formulas IA and IB. This cyclization can be carried out using techniques of pyrimidone ring formation analogous to those described for the preparation of the compounds of formulas VA and VB. The compounds of formulas XVIA and XVIB can be prepared by reaction of the corresponding compounds of formulas VINA and VIIIB, as defined herein above, with a compound of formula XVII or an acid derivative thereof: wherein R 3, R and A are as previously defined for the compounds of formulas XVIA and XVIB. This reaction can be carried out using amide bond formation techniques analogous to those previously described for the preparation of the compounds of formulas VIIA and VIIB. 3. The compounds of formulas IA and IB, in which R1 represents alkyl or alkylaryl, can be prepared by alkylation of the corresponding compounds of formulas XVIIIA and XVIIIB, respectively: XVI HA XVIIIB wherein R2, R3, R4 and A are as previously defined for the compounds of formulas IA and IB, for example, using techniques analogous to those described hereinabove for the preparation of the compounds of formulas XA and XB. The compounds of formulas XVIIIA and XVIIIB can be prepared by analogy with the methods described herein. The compounds of formulas IV, IX, XIIIA and XIIIB, XIV, XVII and the compounds of formulas HNR12R 3 (in which R12 and R13 are as defined hereinabove) and R aL1 and R1aOH (in which R1a and L1 are as defined hereinabove) and derivatives thereof, when not commercially available or not described below, may be obtained either by analogy with the methods described hereinabove or by conventional synthetic procedures, according to standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. Substituents on the aryl and Het groups (Het1 and Het2) in the aforementioned compounds can be introduced, removed and interconverted, using techniques that are well known to those skilled in the art. The person skilled in the art will also know that several standard substituents or interconversions of functional groups and transformations in certain compounds of formulas I A and IB will provide other compounds of formulas IA and IB. For example, the exchange of alkoxide at the 2-position of the 5-phenylene and pyridin-3-yl substituent. In addition, certain compounds of formulas IA and IB, for example, those in which R12 and R13, together with the nitrogen to which they are attached, form an N-alkyl-diazacyclocycle group (C3-C12) alkyl, can be prepared directly from the corresponding compounds of formulas IA and IB, in which R12 and R13 together with the nitrogen to which they are attached, form a diazacycloaikyl group (C3-C-? 2) using standard alkylation procedures. The compounds of the invention can be isolated from their reaction mixtures using conventional techniques. The person skilled in the art will realize during the course of the procedures described above that the functional groups of the intermediates may need protection with protecting groups. The functional groups capable of being protected include oxo, hydroxy, amino and carboxylic acid. Suitable protecting groups for oxo include acetals, ketals (for example, ethylene cetaies) and dithianes. Suitable protecting groups for hydroxy include the trialkylsilyl and diarylalkysilyl groups (e.g., tert-butyldimethylsilyl, urea-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl, Suitable protective groups for amino include butyl-butyloxycarbonyl, 9-phenylrenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protecting groups for carboxylic acid include Ci-β or benzyl alkyl esters. The protection and deprotection of functional groups can take place before or after any of the reaction steps described hereinabove. The protecting groups can be removed according to techniques well known to those skilled in the art.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by JWF McOmie, Plenum Press (1973) and "Protective Groups in Organic Synthesis", 2nd edition, TW Greene & PGM Wutz, Wiley-lnterscience (1991). Those skilled in the art will also realize that in order to obtain the compounds of formulas IA and IB in another alternative form, and sometimes more conveniently, the steps of the individual procedure mentioned hereinabove can be carried out. in another order, and / or the individual reactions can be carried out at a different time in the global route (i.e., substituents can be added to, and / or perform chemical transformations on, intermediates different from those cited above in this , associated with a particular reaction). This will depend among other factors, such as the nature of other functional groups present in a particular substrate and the capacity of the key intermediates and the strategy of the protecting group (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent to be used in these synthetic steps, the need and type of protective groups that are used and the sequence of execution of the synthesis. The pharmaceutically acceptable acid addition salts of the compounds of formulas IA and IB which contain a basic center can be prepared in a conventional manner. For example, a solution of the free base can be treated with the appropriate acid, either neat or in an appropriate solvent, and the resulting salt can be isolated by filtration or by vacuum evaporation of the reaction solvent. The pharmaceutically acceptable basic addition salts can be obtained analogously by treating a solution of a compound of formula I A or IB with the appropriate base. Both types of salts can be formed or interconverted using techniques with ion exchange resins. The person skilled in the art will realize that certain protected derivatives of the compounds of formula I, which can be done before a final deprotection stage, may not possess pharmacological activity as such, but may, in certain cases, be administered via oral or parenteral and then metabolized in the body giving the compounds of the invention, which are pharmacologically active. Said derivatives can therefore be described as "prodrugs". In addition, certain compounds of formula I can act as prodrugs of other compounds of formula I. All protected derivatives and prodrugs of the compounds of formula I are included within the scope of the invention.

MEDICAL USE The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals, including humans. Therefore, they are indicated as pharmaceutical products, as well as for their use in medicines for animals.

According to another aspect of the invention, the compounds of the invention are provided for use as pharmaceuticals and for use as animal medicaments. In particular, it has been found that the compounds of the invention are potent and selective inhibitors of cGMP PDE, such as cGMP PDE5, for example, as demonstrated in the assays described below, and thus are useful in the treatment of disorders in humans, and in animals, in which cGMP PDE inhibitors are indicated, such as cGMP PDE5, and in which inhibition of cGMP PDEs is desired, such as cGMP PDE5. Under the term "treatment", we include both therapeutic (curative) treatment and prophylactic treatment. Thus, according to another aspect of the invention, there is provided the use of the compounds of the invention in the preparation of a medicament for the treatment of a disorder in which a cGMP PDE inhibitor is indicated (e.g., cGMP PDE5). Further provided is the use of the compounds of the invention in the preparation of a medicament for the treatment of a disorder in which inhibition of a cGMP PDE is desired (eg, cGMP PDE5). Thus, the compounds of the invention are expected to be useful for the curative or prophylactic treatment of erectile dysfunction in man (MED), female sexual dysfunction (FSD), preterm birth, dysmenorrhea, benign prostatic hyperplasia (BPH). ), obstruction of the hole of bladder outlet, incontinence, stable angina and unstable variant (Prinzmetal), hypertension, pulmonary hypertension, congestive heart disease, atherosclerosis, cerebral stroke, peripheral vascular disease, reduced blood vessel opening disorders (for example, post-transiuminal coronary angioplasty (post-PCTA)), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or diseases characterized by intestinal motility disorders (e.g. Irritable bowel (IBS)). Other disorders that may be mentioned include preeclampsia, Kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral neuropathy, cerebral stroke, Alzheimer's disease, acute respiratory failure, psoriasis, dermal necrosis, cancer metastases, alopecia, esophagus in corkscrew, anal fissure and hypoxic vasoconstriction. Especially preferred disorders are MED and FSD. Thus, the invention provides a method for the treatment or prevention of a medical disorder for which a cGMP PDE5 inhibitor is indicated, in an animal (e.g., a mammal, including a human), which comprises the administration of a therapeutically effective amount of a compound of the invention to a mammal in need of such treatment.

PHARMACEUTICAL PREPARATIONS The compounds of the invention will normally be administered orally or parenterally, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic or inorganic acid, or basic addition salt, in a dosage form pharmaceutically acceptable. Depending on the disorder and the patient to be treated, as well as the route of administration, the compositions may be administered in varying doses. The compounds of the invention can also be combined with other drugs useful in the inhibition of cGMP PDE, such as cGMP.

PDE5. In human therapy, the compounds of the invention can be administered alone, but will also generally be administered in admixture with an appropriate pharmaceutically acceptable diluent or carrier, selected with respect to the intended route of administration and standard pharmaceutical practice. For example, the compounds of the invention can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, solutions or suspensions, which may contain flavoring or coloring agents, for immediate release applications, delayed or controlled. The compounds of the invention can also be administered by intracavemose injection.

Said tablets may contain excipients, such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants, such as starch (preferably corn starch, potato or tapioca), sodium starch glycolate, croscarmellose sodium and certain complex silicates and binders for granulation, such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylethylcellulose (HPC), sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may also be included. Solid compositions of a similar type can also be used as filling agents in gelatin capsules. Preferred excipients for this include lactose, starch, a cellulose, lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the compounds of the invention may be combined with different sweeteners or flavors, colorants or dyes, with emulsifiers and / or suspending agents and with diluents, such as water, ethanol, propylene glycol and glycerin, and combinations thereof. same. The compounds of the invention can also be administered parenterally, for example, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intranasally, intramuscularly or subcutaneously, or they can be administered by infusion techniques. They are best used in the form of a sterile aqueous solution, which may contain other substances, for example, salts or glucose sufficient for the solution to be isotonic with the blood.

The aqueous solutions should be buffered appropriately (preferably at a pH between 3 and 9) if necessary. The preparation of suitable parenteral formulations under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. For oral and parenteral administration to human patients, the daily dosage level of the compounds of the invention will usually be between 10 and 500 mg / kg (in single or divided doses). Thus, for example, the tablets or capsules of the compound of the invention may contain between 5 mg and 250 mg of the active compound for single administration or two or more at the same time, as required. The doctor will be the one who in any case determines the most appropriate real dose for a specific patient, varying with the age and response of the patient in particular. The above doses are an example of the middle case. Of course there may be specific cases in which higher or lower dosages are required, and they are also within the scope of this invention. The compounds of the invention can also be administered intranasally or by inhalation and are conveniently administered in the form of a dry powder inhaler or as an aerosol spray presentation in a pressurized pack, pump, sprayer or nebulizer using the appropriate propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane, such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A ™ or 1,1,1,3,3,3-heptafluoropropane (HFA 227EA ™), carbon dioxide or other appropriate gas.) In the case of a pressurized aerosol , the dosage unit can be determined by a valve that releases the required amount.The pressurized container, pump, sprayer or nebulizer can contain a solution or suspension of the active compound, for example, using a mixture of ethanol and the propellant as the solvent which can additionally contain a lubricant, for example, sorbitan trioleate Capsules and cartridges (made, for example, of gelatin) for use in an inhaler or insufflator can be formulated to contain a powder mixture of a compound of the invention and a suitable powder base, such as lactose or starch, the aerosol or dry powder formulations are arranged in such a way that each dose or "puff" contains between 1 and 50 mg of a compound of the invention to be administered to the pacie The overall daily dose with an aerosol will be in the range between 1 and 50 mg, which can be administered in a single dose or, more usually, in divided doses throughout the day. In another alternative, the compounds of the invention can be administered in the form of a suppository or pessary, or they can be applied topically in the form of a lotion, solution, cream, ointment or powder. The compounds of the invention can also be administered transdermally, for example, by the use of a dermal patch. They can also be administered via the eye, especially for the treatment of eye diseases. For ophthalmic use, the compounds of the invention can be formulated as micronized suspensions in isotonic, pH-adjusted saline, optionally in combination with a preservative, such as benzylalkonium chloride. In another alternative, they can be formulated in an ointment, such as Vaseline. For topical application to the skin, the compounds of the invention can be formulated as an appropriate ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, petrolatum white, propylene glycol, a polyoxyethylene-polyoxypropylene compound, emulsifying wax and water. In an alternative, they can be formulated as an appropriate lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, poisorbate 60, wax of cetyl esters, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The person skilled in the art will realize that in the treatment of certain disorders (including MED and FSD), the compounds of the invention can be taken as single doses or "as required" (ie, as needed or want). Generally, in humans, the oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example, in the MED, the well-known associated disadvantages are avoided. with intracavernous administration (i.c). A preferred oral dosage regimen in the MED, for a typical man is between 25 and 250 mg of the compound when required. In circumstances, in which the recipient suffers from a swallowing disorder or has difficulty absorbing the drug after oral administration, the drug can be administered parenterally, for example, sublingually or buccally. For veterinary use, the compounds of the invention can be administered as an appropriate formulation acceptable in accordance with normal veterinary practice, with the veterinary surgeon determining the dosage regimen and the most appropriate route of administration for a particular animal. Therefore, according to another aspect of the invention, a pharmaceutical formulation is provided which includes a compound of the invention mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier. In addition to the fact that the compounds of the invention inhibit guanosin 3 ', 5'-cyclic phosphodiesterase monophosphate (cGMP PDE) and in particular, are potent and selective inhibitors of cGMP PDE5, the compounds of the invention also have the advantage of which may be more effective than, less toxic than, have a greater range of activity than, more potent than, produce fewer side effects, are easier to absorb than, or may have other useful pharmacological properties than the compounds known in the prior art. The activities of the compounds of the present invention were determined by the following test methods.

BIOLOGICAL TESTING Inhibitory activity on phosphodiesterases (PDE) The inhibitory activities on PDE were determined in vitro against guanosine 3 ', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) phosphodiesterases by measuring their IC50 values (the concentration of the compound required to inhibit 50% the enzymatic activity). The required PDE enzymes were isolated from several sources, including the human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W.J. Thompson and M.M. Appleman (Biochem., 1971, 10, 311). In particular, cGMP-specific PDE (PDE5) and cAMP PDE inhibited by cGMP (PDE3), were obtained from human cavernous body tissue, human or rabbit platelets; PDE stimulated with cGMP (PDE2) was obtained from the human cavernous body; the calcium / calmodulin-dependent PDE (Ca / CAM) (PDE1) of the human cardiac ventricle; the specific PDE of cAMP (PDE4) of the human skeletal muscle and the PDE of the photoreceptor (PDE6) of the bovine retina.

The tests were carried out using a modification of the "discontinuous" method of W.J. Thompson et al. (Biochem., 1979, 18, 5228). The results of these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP specific PDE5.

Functional activity This was assessed in vitro by determining the ability of a compound of the invention to stimulate sodium nitroprusside-induced relaxation of previously contracted rabbit cavernous body strips, as described by S.A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (supl.), Abstract 153P).

In vivo activity The compounds can be tested in anesthetized dogs to determine their capacity after iv administration, to increase the pressure in the cavernous bodies of the penis induced by intracavemosal injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurol. And Urodyn., 1994, 1_3, 71).

Safety profile The compounds of the invention can be tested by varying the i.v. and p.o. in animals, such as the mouse and the dog, observing any unwanted effect EXAMPLES AND PREPARATIONS The synthesis of the compounds of the invention and intermediates for use herein are illustrated by the following examples and Preparations. Nuclear magnetic resonance (NMR) spectra of 1H were recorded using a Varian Unity 300 or Varian I Nova 400 spectrometer and in all cases they were all concordant with the proposed structures. The chemical shifts (d) are all given in parts per million downfield of tetramethylsilane using conventional abbreviations for the designation of the major peaks; for example, s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; a, wide. Mass spectra (m / z) were recorded using a Fisons Instruments Trio mass spectrometer in the thermospray ionization mode. Ambient temperature includes from 20 to 25 ° C.

SYNTHESIS OF INTERMEDIATES PREPARATION 1 ethyl 3-ethyl-1H-pyrazole-5-carboxylate A solution of sodium ethoxide (21%, w / w, 0.39 mol) was added dropwise to an ice-cooled and stirred solution of diethyl oxalate (58.9 ml, 0.44 mol) in absolute ethanol ( 200 ml) under a nitrogen atmosphere and stirred for 15 minutes. Butan-2-one (39 ml, 0.44 mol) was added dropwise and the reaction mixture was stirred for 18 hours by heating to room temperature and then for 6 hours at 40 ° C. The resulting mixture was cooled to 0 ° C, glacial acetic acid (25 ml, 0.44 mol) was added dropwise and stirred for 30 minutes at 0 ° C. Hydrazine hydrate (20 ml, 0.44 mol) was added dropwise and the reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (300 ml) and water (100 ml). The organic layer was separated and washed with water (2 x 100 ml), dried over Na 2 SO 4 and concentrated under reduced pressure to give the title compound (66.0 g) -d (CDCl 3): 1. 04 (3H, t), 1, 16 (3H, t), 2.70 (2H, q), 4.36 (2H, q), 6.60 (1H, s). LRMS: m / z 169 (M + 1) +.

PREPARATION 2 3-Ethyl-1 H-pyrazole-5-carboxylic acid An aqueous solution of sodium hydroxide (10 M, 100 ml) was added dropwise to a stirred suspension of the title compound of preparation 1 (66.0 g, 0.39 mol) in methanol and heated to reflux for 4 hours. hours. The reaction mixture was cooled and. the solvent was removed under reduced pressure to about 200 ml, diluted with water (200 ml) and washed with toluene (3 x 100 ml). The resulting aqueous layer was acidified to pH 4 with concentrated hydrochloric acid and the white precipitate was filtered and dried by suction to give the title compound as a white solid (34.1 g). d (de-DMSO): 1, 13 (3H, t), 2.56 (2H, q), 6.42 (1 H, s).

PREPARATION 3 4-Nitro-3-n-propyl-1 H-pyrazole-5-carboxylic acid Fuming sulfuric acid (17.8 ml) was added dropwise to ice-cold fuming nitric acid (16.0 ml). The resulting solution was heated to 50 ° C and 3-n-propyl-1H-pyrazole-5-carboxylic acid (16.4 g, 0.106 mol, Chem. Pharm. Bull., 1984, 32, 1568) was added in portions. for 30 minutes while the reaction temperature remained below 60 ° C. The resulting solution was heated for 18 hours at 60 ° C, allowed to cool, then poured into ice. The white precipitate was filtered, washed with water and dried by suction to give the title compound as a white solid (15.4 g), m.p. 170-172 ° C. d (de-DMSO): 0.90 (3H, t), 1.64 (2H, m), 2.83 (2H, m), 14.00 (1H, s). Found: C, 42.35; H, 4.56; N, 21, 07 C7H9N3? 4 requires C, 42.21; H, 4.55; N, 21, 10%.

PREPARATION 4 3-Ethyl-4-nitro-1 H-pyrazole-5-carboxylic acid Obtained from the title compound of preparation 2, using a method analogous to that of preparation 3, as a brown solid (64%). d (de-DMSO): 1, 18 (3H, t), 2.84 (2H, m), 13.72 (1 H, s).

PREPARATION 5 4-nitro-3-n-propyl-1H-pyrazole-5-carboxamide A solution of the title compound of Preparation 3 (15.4 g, 0.08 mol) in thionyl chloride (75 mL) was heated at reflux for 3 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was azeotropically distilled with tetrahydrofuran (2 x 50 ml), then suspended in tetrahydrofuran (50 ml), stirred at 0 ° C and treated with aqueous ammonia for 1 hour. Water (50 ml) was added and the resulting mixture was concentrated under reduced pressure to give a solid. The solid was triturated with water, filtered, dried by suction to give the title compound as a white solid (14.3 g), m.p. 197-199 ° C. d (de-DMSO): 0.90 (3H, t), 1.68 (2H, m), 2.86 (2H, t), 7.68 (1H, s), 8.00 (1H, s) ). Found: C, 42.35; H, 5.07; N, 28.38. C7H? 0N4O3 requires C, 42.42; H, 5.09; N, 28.27%.

PREPARATION 6 3-Ethyl * 4-nitro-1H-pyrazole-5-carboxamide Obtained from the title compound of preparation 4, using a method analogous to that of preparation 5, as a white solid (90%). d (de-DMSO): 1.17 (3H, t), 2.87 (2H, m), 7.40 (1H, s), 7.60 (1H, s), 7.90 (1H , s). LRMS: m / z 185 (M + 1) +.

PREPARATION 7 4-amino-3-n-propyl-1H-pyrazole-5-carboxamide A stirred mixture of the title compound of preparation 5 (10.0 g, 0.05 mol), palladium on carbon 10% > (1.5 g) and ethanol (400 ml), for 18 hours at 50 psi and 50 ° C, then filtered. The filter pad was washed with ethanol (200 ml) and the combined filtrate was evaporated under reduced pressure to give an orange solid, which was recrystallized from ethyl acetate: methanol to give the title compound as a white solid (6.8 g. ), pf 196-201 ° C. d (de-DMSO): 0.88 (3H, t), 1.55 (2H, m), 2.46 (2H, t), 4.40 (2H, s), 7.00 (1H, s), 7.12 (1 H, s), 12.20 (1H, s). Found: C, 48.96; H, 6.98; N, 32.08. C7H? 2N40; 0.25 H20 requires C, 48.68; H, 7.30; N, 32.44%.

PREPARATION 8 4-amino-3-ethyl-1H-pyrazole-5-carboxamide Obtained from the title compound of preparation 6, using a method analogous to that of preparation 7, as a brown solid (80%). d (de-DMSO): 1, 08 (3H, t), 2.45 (2H, q), 4.50 (1H, s), 6.88 (1H, s), 7.10 (1H, s) ), 7.26 (2H, s).

LRMS: m / z 155 (M + 1).

PREPARATION 9 4- (2-n-propoxybenzamido) -3-n-propyl-1H-pyrazole-5-carboxamide A solution of 2-n-propoxybenzoyl chloride (57.6 g, 0.29 mol) in dichloromethane (50 ml) was added dropwise to a solution of the title compound of preparation 7 (35.0 g, 0, 21 mol) in dry pyridine (350 ml) at 0 ° C and stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue azeotropically distilled with toluene (2 x 100 ml). The resulting brown solid was triturated with diethyl ether (100 ml) to give the title compound (83.0 g) as a solid beige. d (CD3OD): 0.92 (3H, t), 1.14 (3H, t), 1.65 (2H, m), 1.94 (2H, m), 2.80 (2H, t), 4.20 (2H, t), 7.08 (1H, m), 7.18 (1H, d), 7.52 (1H, m), 8.04 (1H, d). LRMS: m / z 331 (M + 1) +.

PREPARATION 10 3-Ethyl-4- (2-n-propoxybenzamido) -1H-pyrazole-5-carboxamide Obtained from the title compound of preparation 8 and 2-n-propoxybenzoyl chloride, using a method analogous to that of preparation 9, as a solid beige (68%). d (de-DMSO): 0.93 (3H, t), 1.12 (3H, t), 1.86 (2H, q), 2.71 (2H, m), 4.15 (2H, t), 7.06 (1 H, m), 7.20 (1 H, d), 7.20 (1 H, s), 7.40 (1 H, s), 7 , 50 (1 H, m), 7.92 (1H, d), 10.20 (1 H, s). LRMS: m / z 317 (M + 1) +.

PREPARATION 11 4- (2-ethoxybenzamido) -3-n-propyl-1H-pyrazole-5-carboxamide Obtained from the compound of preparation 7 and 2-ethoxybenzoyl chloride, using a method analogous to that of preparation 9, as a white solid (64%), m.p. 209-211 ° C. d (de-DMSO): 0.82 (3H, t), 1.42 (3H, t), 1.56 (2H, m), 1.75 (2H, t), 4.27 (2H, q ), 7.07 (1 H, m), 7.22 (2 H, m), 8.00 (1 H, d), 10.40 (1 H, s), 12.96 (1 H, s) . Found: C, 60.73; H, 6.41; N, 17.80. Ci6H2oN4O3 requires C, 60.74; H, 6.37; N, 17.71%.

PREPARATION 12 5- (2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyraziro4,3-dlpyrimidin-7-one Potassium tert-butoxide (93.0 g, 0.83 mol) was added portionwise to a stirred solution of the title compound of preparation 9 (83.0 g, 0.25 mol) in propan-2-ol (800 ml) under a nitrogen atmosphere and heated at reflux for 18 hours. The reaction mixture was cooled and water was added (100 ml) obtaining a homogeneous solution, which was acidified to pH 6 with hydrochloric acid (2M). The resulting white precipitate was filtered and dried by suction to give the title compound as a white solid (37.4 g). d (CDCl 3): 1.05 (3H, t), 1.16 (3H, t), 2.00 (4H, m), 3.04 (2H, t), 4.20 (2H, t), 7.07 (1H, d), 7.16 (1H, m), 7.48 (1H, m), 8.52 (1H, d), 11.30 (1H, s), 12.25 (1H , s). LRMS: m / z313 (M + 1) +. Found: C, 65.36; H, 6.49; N, 17.99. C 7 H 20 N 4 O 2 requires C, 65.37; H, 6.45; N, 17.94%.

PREPARATION 13 3-ethyl-5- (2-n-propoxyphenyl) -1,6 ** ihydro-7 H -pyrazir 4,3 ** d 1 -p? imidin-7-one Obtained from the title compound of preparation 10, using a method analogous to that of preparation 12, as a white solid (85%). d (de-DMSO): 0.95 (3H, t), 1.15 (3H, t), 1.72 (2H, m), 2.84 (2H, q), 4.03 (2H, t ), 7.06 (1H, m), 7.15 (1H, d), 7.44 (1H, m), 7.72 (1H, d), 11.83 (1H, s), 13.64 (1H, s). : m / z 299 (M + 1) +.

PREPARATION 14 5- (2-Ethoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyraziro4,3-dlpyrimidin-7-one Obtained from the compound of preparation 11, using a method analogous to that of preparation 12, as a white solid (88%), m.p. 199-201 ° C. d (CDCl 3): 1, 08 (3H, t), 1, 65 (3H, t), 1, 98 (2H, m), 3.04 (2H, t), 4.36 (2H, q), 7.10 (1 H, d), 7.20 (1 H, m), 7.50 (1 H, m), 8.57 (1 H, d), 11, 36 (1 H, s), 11, 88 (1 H, s). Found: C, 64.44; H, 6.19; N, 18.44. C? 6Hi8N402 requires C, 64.41; H, 6.08; N, 18.78%.

PREPARATION 15 5- (2-n-propoxyphenyl) -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo4,3-dlpyrimidin-7-one Sodium hydride (60% dispersion in mineral oil) was slowly added; 704 mg, 17.61 mmol) was added to a solution of the title compound of Preparation 12 (5.0 g, 16 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at room temperature for 1 hour. 2- (Chloromethyl) pyridine (obtained from 2.45 g, 19.21 mole of the hydrochloride salt) was added to the reaction mixture and then stirred at 50 ° C for 18 hours. The mixture was quenched with water (75 ml) and tetrahydrofuran and removed under reduced pressure. He aqueous residue was extracted with ethyl acetate (200 ml), the organic extracts were dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of hexane: ethyl acetate (65:35 to 50:50) to give the title compound as a white solid (2.56 g). d (CDCl 3): 1.00 (3H, t), 1, 15 (3H, t), 1, 70 (2H, m), 2.00 (2H, m), 3.00 (2H, t), 4.20 (2H, t), 5.75 (2H, s), 7.05-7.15 (1 H, m), 7.20 (1 H, m), 7.45 (1 H, m ), 7.65 (1H, m), 8.40 (1H, d), 8.60 (1H, d), 10.90 (1H, s). : m / z 404 (M + 1) +.

PREPARATION 16 3-ethyl-5- (2-n-propoxyphenyl) -2- (pyridin-2-yl) methyl-2,6-dihydro-7 H -pyrazir4,3-dlpyrimidin-7-one The title compound of Preparation 13 (20 g, 67.3 mmol) was suspended in toluene (450 mL) and cooled to 0 ° C. Potassium bis (trimethylsilyl) amide (0.5 M in toluene, 135 ml, 67.5 mmol) was added over 10 minutes and the reaction mixture was warmed to room temperature and stirred for 1 hour. 2- (Chloromethyl) pyridine (obtained from 8.6 g (67.4 mmol) of the hydrochloride salt) was added and the reaction mixture was stirred at 45 ° C for 18 hours. The reaction was quenched with water (200 ml), then partitioned between water (200 ml) and ethyl acetate (1000 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of pentane: ethyl acetate: triethylamine (50: 50: 0.5 to 25: 75: 0.5), then recrystallized from acetate of ethyl giving the title compound as a white solid (12.8 g). d (CDCl 3): 1, 10 (3H, t), 2.00 (2H, m), 3.00 (2H, q), 4.20 (2H, t), 5.70 (2H, s), 7.00-7.15 (3H, m), 7.20 (1H, m), 7.40 (1H, m), 7.60 (1H, m), 8.40 (1H, d), 8.60 (1 H, d), 10.90 (1 H, s). : m / z 390 (M + 1) +.

PREPARATION 17 5- (2 ** ethoxyphenyl) -3-n-prop? -2 ^ pyridin-2-yl) methyl-2,6- * < iihydro-7H-pyrazolf4,3-dlpyrimidin-7-one Obtained from the title compound of preparation 14 and 2- (chloromethyl) pyridine using a method analogous to that of preparation 15, as a white foam (64% o). d (CDCl 3): 1.00 (3H, t), 1, 60 (3H, t), 1.75 (2H, m), 3.00 (2H, t), 4.30 (2H, q), 5.70 (2H, s), 7.05 (2H, m), 7.15 (1 H, m), 7.20 (1 H, m), 7.20 (1 H, m), 7, 45 (1H, m), 7.60 (1H, m), 8.40 (1H, d), 8.60 (1H, d), 10.90 (1H, s). : m / z 390 (M + 1) +.

PREPARATION 18 3-ethyl * -nitro-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide Cesium carbonate (1.414 kg, 4.34 mol) was added to a suspension of the title compound of preparation 6 (800 g, 4.34 mol) in acetonitrile (5 I) and the mixture was heated to 60 °. C. 2- (Chloromethyl) pyridine (obtained from 664.7 g, 5.23 mol of the hydrochloride salt) was added and the reaction was heated at 70 ° C for 7 hours. Water (9.5 L) was added and the reaction mixture was cooled to 10 ° C. Granulation of this mixture gave a precipitate which was filtered and dried to give 3-ethyl-4-nitro-1- (pyridin-2-yl) -methyl-pyrazole-5-carboxamide (367 g). Sodium chloride (1.58 kg) was added to the filtrate and the solution was extracted with ethyl acetate (4 x 1.75 l). The organic layers were combined and approximately 10 l of solvent was removed under reduced pressure. Toluene (5.6 I) was added over 35 minutes to the hot solution (69-76 ° C) and then allowed to cool. The resulting suspension was granulated to < 10 ° C for 30 minutes, filtered, the solid was washed with ethyl acetate: toluene (50:50) (600 ml) and dried (60 ° C) to give the title compound as a light brown solid (624 g). ). d (de-DMSO): 1, 08 (3H, t), 3.02 (2H, q), 5.53 (2H, s), 7.34 (2H, m), 7.65 (1H, s), 7.82 (1 H, m), 7.93 (1 H, s), 8.52 (1 H, d). LRMS: m / z 275 (M) +.

PREPARATION 19 4-nitro-3-n-propyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide 2- (Chloromethyl) pyridine hydrochloride (24.6 g, 150 mmol) was added in portions to a solution of the title compound of preparation 5 (30.0 g, 150 mmol) and cesium carbonate (123.5 g). , 380 mmol) in dimethylformamide (300 ml) and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, the residue was suspended in water and the resulting solid was filtered and suspended by suction. The residue was purified by column chromatography on silica gel using a solvent system of dichloromethane: methanol (98: 2) and repeated using ethyl acetate: pentane (80:20) to give the title compound as a white solid. (16.7 g). d (de-DMSO): 0.85 (3H, t), 1.45 (2H, m), 2.95 (2H, t), 5.50 (2H, s), 7.30 (2H, m ), 7.60 (1H, s), 7.80 (1H, m), 7.90 (1H, s), 8.50 (1H, d).

PREPARATION 20 4-amino-3-ethyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide A mixture of Lindlar catalyst (2 g) and the title compound of preparation 18 (20 g, 72.7 mmol) in ethanol (160 ml) was hydrogenated for 48 hours at 345 kPa (50 psi) and 50 ° C. , then cooled and filtered. The filtrate was combined with an IMS wash (50 ml) of the filter pad and it was concentrated under reduced pressure to a volume of 100 ml. The remaining ethanol was removed by distillation and replaced with ethyl acetate until a temperature of 77 ° C was reached. The cooled mixture was granulated at 4 ° C, filtered and dried to give the title compound as a light brown solid (13.17 g, 73%). d (de-DMSO): 0.90 (3H, t), 2.55 (2H, q), 4.50 (2H, s), 5.30 (2H, s), 6.90 (1H, d) ), 6.95 (1 H, s), 7.10 (1 H, s), 7.30 (1 H, m), 7.75 (1 H, m), 8.50 (1 H, d) . LRMS: m / z 246 (M + 1) + PREPARATION 21 4-amino-3-n-propyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide A mixture of the title compound of preparation 19 (1.0 g, 3.46 mmol) and Raney nickel (1 g) in ethanol (50 ml) was hydrogenated for 18 hours at 345 kPa (50 psi) and 50 ° C. , then cooled and filtered. The filtrate was combined with an ethanol wash (50 ml) of the filter pad and the solvent was removed under reduced pressure to give the title compound as a crystalline solid (830 mg). d (de-DMSO): 0.80 (3H, t), 1.35 (2H, m), 3.30 (2H, t), 4.60 (2H, s), 5.30 (2H, s ), 6.90 (1H, d), 7.00 (1H, s), 7.15 (1H, s), 7.30 (1H, m), 7.75 (1H, m), 8.50 (1H, d). LRMS: m / z 274 (M) +.

PREPARATION 22 4- (2-Ethoxy-benzamido) -3-ethyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide A solution of ethoxybenzoyl chloride (2 g, 10.8 mmol) in dichloromethane (5 ml) was added dropwise to a solution of the title compound of preparation 20 (2 g)., 4 g, 9.72 mmol) and triethylamine (1.8 ml, 12.96 mmol) in dichloromethane (15 ml) at 0 ° C. The resulting mixture was stirred at room temperature for 18 hours, then diluted with water (10 ml). The dichloromethane was removed under reduced pressure, the residue was redissolved in ethyl acetate (20 ml) and extracted with hydrochloric acid (2N, 10 ml). The combined aqueous layers were washed with diethyl ether (20 ml), made alkaline with a solid sodium hydrogencarbonate solution until pH 8 and extracted with dichloromethane (3 x 30 ml). The combined dichloromethane layers were dried over MgSO4, filtered and concentrated under reduced pressure to give the title compound as a white solid (3.65 g, 95% >;). d (CDCl 3): 1, 05 (3H, t), 1, 60 (3H, t), 2.85 (2H, q), 4.35 (2H, q), 5.20-5.30 (1H , sa), 5.50 (2H, s), 6.70 (1H, sa), 6.90 (1H, d), 7.00-7.10 (2H, m), 7.20-7, 25 (1 H, m), 7.40-7.50 (1 H, m), 7.60-7.70 (1 H, m), 8.20 (1 H, d), 8.60 ( 1 H, s), 10.45 (1 H, s). LRMS: m / z 394 (M + 1) +. Analysis: Found C, 63.93; H, 5.82; N, 17.75; C2? H23N503 requires C, 64.10; H, 5.89; N, 17.80%.

PREPARATION 23 5- (2-Ethoxyphenin-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7 H -pyrazir4.3- dlpyrimidin-7-one Potassium fer-butoxide (4.15 g, 37 mmol) was added in portions to a stirred solution of the title compound of Preparation 22 (3.64 g, 9.25 mmol) in ethanol (50 mL) under an atmosphere of nitrogen and heated to reflux for 18 hours. The reaction mixture was cooled and the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (100 ml) and water (50 ml), the layers were separated and the organic layer was washed with water (50 ml), brine (50 ml), dried over MgSO4, filtered and were concentrated under reduced pressure to give the title compound as a white solid (2.8 g). d (CDCl 3): 1, 30 (3H, t), 1, 60 (3H, t), 3.00 (2H, q), 4.30 (2H, q), 5.70 (2H, s), 7.00-7.15 (3H, m), 7.20 (1H, m), 7.40 (1H, m), 7.60 (1H, m), 8.40 (1H, d), 8.60 (1 H, s), 10.90 (1 H, sa). LRMS: m / z 376 (M + 1) + Analysis: found C, 66.79; H, 5.60; N, 18.35; C 21 H 21 N 5 O 2 requires C, 67.18; H, 5.64; N, 18.65%.

PREPARATION 24 4-Ethylpiperidine Prepared by the following procedure described in J. Med. Chem., 1991, 34 (5), 1545.

PREPARATION 25 4-methoxypiperidine Prepared by the following procedure described in Chem.

Soc. Perkin Trans. 2, 1984, 737.

PREPARATION 26 3-azetidinoi Prepared by the following procedure described in J. Med. Chem., 1993, 36 (4), 460.

PREPARATION 27 (1 5S) -3-epito-azabiccof3.1.0lhex-6-tere-butyl-ylcarbamate Prepared by the following procedure described in European Patent No. 0413455.

PREPARATION 28 5-r5- (4-tert-Butyloxycarbonylpiperazin-1-ylsulfonyl) -2-n-propoxyphenin-3-n-propyl-2-fpyridin-2-yl) methyl-2,6-dihydro- 7H-pyraziro4,3-d1pyridin-7-one Obtained from the title compound of preparation 15 and tere-butyl 1-piperazinecarboxylate using a method analogous to that of Example 1 (method B) below, as a white solid (60%). d (CDCl 3): 0.95 (3H, t), 1, 15 (3H, t), 1, 40 (9H, s), 1, 70-1, 80 (2H, m), 1, 95-2 , 10 (2H, m), 2.95-3.10 (6H, m), 3.50 (4H, m), 4.30 (2H, t), 5.70 (2H, s), 7, 00-7.25 (3H, m), 7.60 (1 H, m), 7.80 (1 H, d), 8.60 (1 H, d), 8.80 (1 H, s) 10.60 (1H, s). LRMS: m / z 652 (M + 1) +. Analysis: Found C, 57.91; H, 5.70; N, 16.70; C28H33N7O4S. 0.25CH2Cl2 requires C, 58.01; H, 5.77; N, 16.76%.

PREPARATION 29 5 - (* f5-r3 *** (tert-butyloxycarbonylpaminol-1-ethylaminosulfonyl-2-n-propoxyphenyl) - 3-n-propyl-2- (pyridin-2-yl) ) methyl-2,6-dihydro-7H-pirazoir4,3-d1pyrimidin-7-one Obtained from the title compound of preparation 15 and Ferric-butyl 2-aminoethylcarbamate using a method analogous to that of Example 1 (Method B) below, as a white solid (45%). d (CDCl 3): 0.95 (3H, t), 1, 15 (3H, t), 1, 40 (9H, s), 1, 70-1, 80 (2H, m), 1, 95-2.05 (2H, m), 3.00 (2H, t), 3.15 (2H, m), 3.25 (2H, m), 4.20 (2H, t ), 5.05 (1H, sa), 5.65 (1H, sa), 5.70 (2H, s), 7.10 (2H, m), 7.25 (1H, m), 7 , 65 (1H, m), 7.95 (1H, m), 8.60 (1H, d), 8.80 (1H, s), 10.80 (1H, sa). LRMS: m / z 626 (M + 1) +.

PREPARATION 30 2-Ethoxypyridine-3-carboxylic acid A solution of potassium tert-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was added slowly to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in ethanol (100 ml). ) and the reaction was heated in a closed vessel at 170 ° C for 20 hours. The solvent was removed under reduced pressure, the residue was dissolved in water (200 ml) and acidified to pH 3 with aqueous hydrochloric acid. The aqueous solution was extracted with dichloromethane (4 x 200 ml), the combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the title compound as a white solid (27.4 g). d (CDCl 3): 1.53 (3H, t), 4.69 (2H, q), 7.13 (1H, m), 8.37 (1H, d), 8.48 (1H, d).

PREPARATION 31 2-n-propoxypyridine-3-carboxylic acid Obtained from 2-chloronicotinic acid and 1-propanol, using a method analogous to that of preparation 30 as a brown solid (56%). d (de-DMSO): 0.95 (3H, t), 1, 60-1, 80 (2H, m), 4.30 (2H, t), 7.00 (1H, m), 8.05 (1 H, d), 8.30 (1 H, m), 12.85 (1 H, sa). LRMS: m / z 812 (M + 1) +. Analysis: Found C, 59.05; H, 5.99; N, 7.71; C9HnN03; 0.1 H20 requires: C, 59.07; H, 6.17; N, 7.65%.

PREPARATION 32 2- (2-Methoxyethoxy) pyridin-3-carboxylic acid Obtained from 2-chloronicotinic acid and 2-methoxyethanol, using a method analogous to that of preparation 30 as a brown solid (92%). d (CDCl 3): 3.40 (3H, s), 3.80 (2H, t), 4.70 (2H, t), 7.10 (1H, m), 8.35 (1H, m) , 8.45 (1 H, m). LRMS: m / z 198 (M + 1) +.

PREPARATION 33 2-Ethoxypyridine-3-carboxylic acid ethyl ester A suspension of the title compound of preparation 30 (16.4 g, 98 mmol) and cesium carbonate (32 g, 98 mmol) in dimethylformamide (240 ml) were stirred at room temperature for 2 hours. Ethyl iodide (7.85 mL, 98 mmol) was added and the reaction was stirred for another 24 hours. The solvent was removed under reduced pressure and the residue was partitioned between an aqueous sodium carbonate solution (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give the title compound as a yellow oil (18.0 g). d (CDCl 3): 1.41 (6H, m), 4.36 (2H, q), 4.48 (2H, q), 6.90 (1H, m), 8.12 (1H, d) ), 8.28 (1H, d).

PREPARATION 34 2-n-propoxypyridine-3-carboxylic acid ethyl ester Obtained from the compound of preparation 31, using a method analogous to that of preparation 33 as a yellow oil (99% >). d (CDCl 3): 1.00 (3H, t), 1, 30 (3H, t), 1, 70-1, 80 (2H, m), 4.20-4.35 (4H, m), 6 , 80 (1 H, m), 8.00 (1 H, d), 8.20 (1 H, d).

LRMS: m / z 210 (M + 1) PREPARATION 35 2- (2-Methoxyethoxy) pyridine-3-carboxylic acid ethyl ester Obtained from the compound of preparation 32, using a method analogous to that of preparation 33 as a yellow oil (98%). d (CDCl 3): 1.35 (3H, t), 3.45 (3H, s), 3.75 (2H, t), 4.35 (2H, q), 4.55 (2H, t), 6.90 (1 H, m), 8.15 (1 H, d), 8.25 (1 H, m). LRMS: m / z 226 (M + 1) +. Analysis: Found C, 58.36; H, 6.74; N, 6.04; C 11 H 15 NO 4 requires C, 58.66; H, 6.71; N, 6.22%.

PREPARATION 36 2-Ethoxypyridine-5-nitro-3-carboxylic acid ethyl ester Ammonium nitrate (5.36 g, 66 mmol) was added portionwise to an ice cold solution of the title compound of Preparation 33 (4.66 g, 22.3 mmol) in trifluoroacetic anhydride (50 mL) and the reaction it was stirred for 18 hours at room temperature. The reaction mixture was carefully poured into ice water (200 ml) and the resulting suspension was stirred for 1 hour. The precipitate was filtered, washed with water and dried by suction to give the title compound (3.29 g). d (CDCl 3): 1, 41 (3H, t), 1, 48 (3H, t), 4.41 (2H, q), 4.62 (2H, q), 8.89 (1H, s), 9.16 (1H, s).

PREPARATION 37 5-Nitro-2-n-propoxypyridine-3-carboxylic acid ethyl ester Obtained from the compound of preparation 34, using a method analogous to that of preparation 36 as a cream-colored solid (99%). d (CDCl 3): 1.05 (3H, t), 1.20 (3H, t), 1.80-1.95 (2H, m), 4.40 (2H, q), 4.50 (2H , t), 8.90 (1H, s), 9.15 (1H, s).

PREPARATION 38 Ethyl 2- (2-methoxyethoxy) pyridine-5-nitro-3-carboxylic acid ethyl ester Ammonium nitrate (10.57 g, 0.13 mol) was added in portions to an ice-cold solution of the title compound of preparation 35 (14.80 g, 0.07 mol) in trifluoroacetic anhydride (150 ml) in a large 1 L flask, equipped with an air condenser. The reaction mixture was stirred for 3 hours at room temperature, carefully poured into ice water (120 g) and the resulting solution extracted with dichloromethane (3 x 150 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The resulting orange oil was dried under vacuum to give a solid, which was triturated with diethyl ether and filtered to give the to the title as a white solid. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 97: 3) giving another part of the title compound (11.5). total g). d (CDCl 3): 1.40 (3H, t), 3.40 (3H, s), 3.80 (2H, t), 4.40 (2H, q), 4.70 (2H, t), 8.90 (1 H, s), 9.15 (1 H, s). LRMS: m / z 271 (M + 1). + Analysis: Found C, 48.78; H, 5.13; N, 10.29; C 11 H 14 N 2 O 6 requires C, 48.89; H, 5.22; N, 10.37%.

PREPARATION 39 5-Amino-2-ethoxypyridine-3-carboxylic acid ethyl ester A mixture of the title compound of preparation 36 (5.3 g, 22 mmol) and Raney nickel (2.50 g) in ethanol (150 ml) was hydrogenated for 18 hours at 345 kPa (50 psi) and 50 ° C. , then cooled and filtered. The filter pad was washed with ethanol (150 ml) and the filtrate was concentrated under reduced pressure. The residue was triturated with dichloromethane, the resulting solid was filtered and dried to give the title compound as a brown colored solid (4.56 g). d (CDCl 3): 1.39 (6H, m), 3.41 (2H, s), 4.35 (4H, m), 7.55 (1H, s), 7.78 (1H, s). LRMS: m / z 211 (M + 1) +. Found: C, 57.12; H, 6.79; N, 12.98. C10H14N2O3 requires C, 57.13; H, 6.71; N, 13.33%.

PREPARATION 40 5-R (dimethylamino) sulfonip2-ethoxyp8ridin-3-carboxylic acid ethyl ester A solution of the title compound of preparation 39 (1.5 g, 7.14 mmol) in acetic acid (30 ml) and concentrated hydrochloric acid (30 ml) was cooled to -20 ° C and sodium nitrite (740) was added. mg, 10.7 mmol). The reaction mixture was heated to 0 ° C for 2 hours, then cooled again to -20 ° C. Sulfur dioxide (17 ml) was added followed by a suspension of copper chloride (II) (2.78 g, 20.7 mmol) in water (3 ml) and acetic acid (25 ml). The reaction mixture was warmed to 0 ° C and stirred for 30 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice (25 g) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were dried over MgSO4, filtered, concentrated under reduced pressure and the residue was azeotropically distilled with toluene. The resulting solid was dissolved in ethanol (10 ml), dimethylamine (5.1 ml, 28.54 mmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue was dissolved in dichloromethane (20 ml), washed with water (10 ml), dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (100: 0 to 99: 1) to give the compound of the title as a white solid (1.28 g). d (CDCl 3): 1, 35-1, 60 (6H, m), 2.80 (6H, s), 4.40 (2H, q), 4.60 (2H, q), 8.40 (1 H, s), 8.70 (1 H, s). LRMS: m / z 303 (M + 1) +. Found: C, 47.69; H, 5.99; N, 9.13. C? 2H? 8N205S requires C, 47.67; H, 6.00; N, 9.27%.

PREPARATION 41 5-R (dimethylamino) sulfonin-2-ethoxypyridine-3-carboxylic acid A solution of aqueous sodium hydroxide (15 ml, 1 N) was added dropwise to a solution of the title compound of preparation 40 (1.25 g, 4.13 mmol) in ethanol (15 ml) and the reaction was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was suspended in water (15 ml) and acidified to pH 3 with hydrochloric acid (6N). The resulting white suspension was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with brine (100 ml), dried over MgSO 4, filtered and concentrated under reduced pressure to give a white solid (940 mg ). d (CDCl 3): 1.60 (3H, t), 2.80 (6H, s), 4.80 (2H, 1), 8.80 (2H, s), 10.10-10.30 (1H , sa). LRMS: m / z 275 (M + 1) +. Found: C, 43.56; H, 5.09; N, 10.04. C10H N2O5S requires C, 43.79; H, 5.14; N, 10.21%.

PREPARATION 42 5-R (D-methylamino) sulfonyl-2-ethoxypyridine-3-carbonyl chloride Oxalyl chloride (0.59 ml, 6.7 mmol) was added dropwise to a cooled solution of the title compound of preparation 41 (920 mg, 3.35 mmol) in dichloromethane (15 ml) followed by dimethylformamide ( 1 drop) and the resulting mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, azeotropically distilled with toluene, then triturated with hexane and filtered to give the title compound as a white solid (845 mg). d (CDCl): 1.50 (3H, t), 2.80 (6H, s), 4.60 (2H, q), 8.60 (1H, s), 8.75 (1H, s). LRMS: m / z 291 (M + 1) +. Found: C, 40.93; H, 4.33; N, 9.54. C? OHi3CIN20 S requires C, 41, 03; H, 4.48; N, 9.57%.

PREPARATION 43 4 5-f (N, N-dimethylamino) sulfonip-2-ethoxy-pyridin-3-ylcarboxamid-3-n-propyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide A mixture of the title compound of Preparation 42 (200 mg, 0.68 mmol) and the title compound of Preparation 21 (177 mg, 0.68 mmol) in pyridine (5 mL) was stirred for 18 hours at room temperature. environment in a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 98: 2) to give the title compound as a white solid (235). mg). d (CDC3): 0.80 (3H, t), 1.40 (2H, m), 1.55 (3H, t), 2.70 (6H, s), 2.80 (2H, t), 4.75 (2H, q), 5.20-5.30 (1H, sa), 5.40 (2H, s), 6.60-6.70 (1H, sa), 6.90 (1H , d), 7.20 (1 H, m), 7.60 (1H, m), 8.55 (1 H, m), 8.60 (1 H, s), 8.80 (1H, s ), 10.50 (1H, s). LRMS: m / z 516 (M + 1) +. Found: C, 49.46; H, 5.29; N, 17.16. C 23 H 29 N 7 O 5 S 0.7 CH 2 Cl 2 requires C, 49.50; H, 5.33; N, 17.05%.

PREPARATION 44 2-Ethoxy-pyridine-5-nitro-3-carboxylic acid An aqueous solution of sodium hydroxide (4 ml, 5N) was added dropwise to a solution of the title compound of preparation 36 (5.1 g, 20 mmol) in ethanol (100 ml) and stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, the residue was suspended in water (50 ml) and acidified to pH 3 with hydrochloric acid (6N). This aqueous solution was extracted with ethyl acetate (3 x 100 ml), the combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4, filtered and evaporated under reduced pressure to give a beige solid. The crude product was recrystallized from ethyl acetate: hexane to give the title compound as beige crystals (3.32 g). d (CDCl 3): 1.55 (3H, t), 4.78 (2H, q), 9.17 (1H, s), 9.23 (1H, s).

PREPARATION 45 5-Nitro-2-n-propoxypyridine-3-carboxylic acid An aqueous solution of sodium hydroxide (100 ml, 1 N) was added dropwise to a solution of the title compound of preparation 37 (12 g, 47.8 mmol) in ethanol (100 ml) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was suspended in water (100 ml) and acidified to pH 4 with hydrochloric acid (6N). This solution aqueous was cooled to 0 ° C and a white precipitate formed. After cooling for 2 hours, the solid was filtered and dried to give the title compound as a white solid (7.8 g). d (CDCl 3): 1, 10 (3H, t), 1.95 (2H, m), 4.65 (2H, t), 9.20 (1 H, s).

PREPARATION 46 2- (2-Methoxyethoxy) pyridine-5-nitro-3-carboxylic acid An aqueous solution of sodium hydroxide (40 ml, 1 N) was added dropwise to a solution of the title compound of preparation 38 (4 g, 14.8 mmol) in dioxane (40 ml) and stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, the residue was suspended in water (40 ml) and acidified to pH 3 with hydrochloric acid (6N). The resulting white solid was extracted with dichloromethane (3 x 50 ml), the combined organic layers were dried over MgSO 4, filtered and concentrated under reduced pressure to give the title compound as a beige solid (2.61 g). d (CDCl 3): 3.45 (3H, s), 3.80 (2H, t), 4.80 (2H, t), 9.15 (1H, s), 9.20 (1H, s) . LRMS: m / z 243 (M + 1) +. Found: C, 44.11; H, 4.04; N, 11, 46. C 9 H 10 N 2 O 6 requires C, 44.63; H, 4.16; N, 11, 57%.

PREPARATION 47 4- (2-Ethoxy-5-nityr-pyridin-3-ylcarboxamido) -3-n-propyl-2- (pyridin-2-yl) methyl-pyrazole-5-carboxamide Oxalyl chloride (2.73 ml, 31 mmol) was added dropwise to a suspension of the title compound of preparation 44 (3.31 g, 15.7 mmol) in dichloromethane (50 ml) followed by dimethylformamide (2 ml). drops) and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and azeotropically distilled with hexane to give a white solid. A solution of the acid chloride in dichloromethane (20 ml) was added to a suspension of the title compound of preparation 21 (4, 06 g, 15.7 mmol) and triethylamine (4.37 ml, 31 mmol) in dichloromethane (80 ml) and stirred at room temperature for 20 hours. The solvent was removed under reduced pressure and the residue was partitioned between an aqueous sodium hydrogencarbonate solution (200 ml) and dichloromethane (300 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 300 ml). The combined organic layers were washed with brine (300 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure to give a purple solid. The solid was triturated with diethyl ether and dried by suction to give the title compound as a white solid (6.26 g). d (CDCl 3): 0.85 (3H, t), 1.45 (2H, m), 1.60 (3H, t), 2.90 (2H, t), 4.85 (2H, q), 5.30 (1 H, s), 5.50 (2H, s), 6.70 (1H, s), 6.95 (1 H, d), 7.25 (1 H, m), 7, 65 (1H, m), 8.60 (1 H, d), 9.15 (1 H, s), 9.30 (1 H, s), 10.60 (1 H, s).

LRMS: m / z 454 (M + 1) +. Found: C, 55.42; H, 5.05; N, 21, 49 C 21 H 23 N 7 O 5 requires C, 55.62; H, 5.11; N, 21, 62%.

PREPARATION 48 4- 5-nitro-2-n-propoxy-pyridin-3-ylcarboxamido) -3-n-propyl-2- (2-pyridin-2-yl) methyl-pyrazole-5-carboxamide The title compound of preparation 45 (500 mg, 2.21 mmol), 1-hydroxybenzotriazole hydrate (299 mg, 2.21 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (424 mg, 2.21 mmol) and N-ethyldiusopropylamide (0.77 mL, 4.42 mmol) were added to a stirred solution of the title compound of Preparation 21 (573 mg, 2.21 mmol) in dry dichloromethane (15 g). ml) at 10 ° C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The resulting mixture was washed with water (10 ml), aqueous hydrochloric acid (0.5 N, 10 ml) and saturated sodium hydrogencarbonate (10 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 98: 2) to give the title compound as a white solid (590 mg). d (CDCl 3): 0.80 (3H, t), 1.00 (3H, t), 1.35-1.45 (2H, m), 1.95-2.05 (2H, m), 2 , 85 (2H, t), 4.70 (2H, t), 5.20-5.30 (1H, sa), 5.45 (2H, s), 6.60-6.75 (1H, sa), 6.90 (1H, d), 7.20 (1H, m), 7.65 (1H, m), 8.60 (1H, m), 9.10 (1H, s) 9.30 (1H, s), 10.45 (1H, s). LRMS: m / z 468 (M + 1) +. Found: C, 55.84; H, 5.33; N, 20.68. C22H25N7O5 0.1 CH2Cl2 requires C, 55.78; H, 5.37; N, 20.60%.

PREPARATION 49 4-r2- (2-methoxyethoxy) -5-n-t-pyridin-3-ylcarboxamidol-3-n-propii-2-f2-pyridin-2-yl) methyl-pyrazole-5-carboxamide Obtained from the title compound of preparation 46 and the title compound of preparation 21, using a method analogous to preparation 48, as a white solid (58%). d (CDCl 3): 1.10 (3H, t), 2.90 (2H, q), 3.40 (3H, s), 4.00 (2H, t), 4.90 (2H, t), 5.20-5.35 (1H, sa), 5.50 (2H, s), 6.65-6.75 (1H, sa), 6.90 (1H, d), 7.20 (1H, m), 7.70 (1H, t), 8.60 (1H, d), 9.15 (1H, s), 9.30 (1H, s), 10.50 (1H, s). LRMS: m / z 470 (M + 1). + Found: C, 53.41; H, 4.90; N, 20.65. C2iH23N7? 6, requires C, 53.72; H, 4.94; N, 20.89%.

PREPARATION 50 4-r5-amino-2-ethoxy-pyridin-3-yl-carboxamidol-3-n-propyl-2- (2-pyridin-2-yl) methyl-pyrazole-5-carboxamide A stirred mixture of the title compound of preparation 47 (5 g, 11 mmol) and Raney nickel (2.5 g) in ethanol (150 ml) was hydrogenated for 3 hours at 345 kPa (50 psi) and 50 ° C and then another 72 hours at room temperature. The resulting mixture was filtered through Arbocel and the filtrate was concentrated under reduced pressure to give a pale yellow solid. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 95: 5). The resulting solid was triturated with diethyl ether to give the title compound as a beige solid (4.4 g). d (CDCl 3): 0.78 (3H, t), 1.43 (2H, m), 1.52 (3H, t), 2.82 (2H, t), 3.49 (2H, s), 4.59 (2H, q), 5.30 (1H, s), 5.46 (2H, s), 6.70 (1H, s), 6.93 (1H, d), 7.22 (1H, m), 7.65 (1H, m), 7.78 (1H, s), 7.94 (1H, s), 8.58 (1H, d, 10.53 (1H, s). Found: C, 59.42, H, 5.96, N, 22.98, C2iH25N703 requires C, 59.56, H, 5.95, N, 23.15%.

PREPARATION 51 4-r5-amino-2-n-propoxy-pyridin-3-yl-carboxamidol-3-n-propyl-2- (2-pyridin-2-ylmethyl-pyrazole-5-carboxamide Obtained from the title compound of preparation 48, using a method analogous to preparation 50, as a pale yellow solid (86%). d (CDCl 3): 0.80 (3H, t), 1.00 (3H, t), 1, 40-1, 50 (2H, m), 1, 90-2.00 (2H, m), 2 , 80 (2H, t), 3.50 (2H, s), 4.45 (2H, t), 5.20-5.35 (1H, sa), 5.45 (2H, s), 6 , 60-6.75 (1H, sa), 6.95 (1H, d), 7.20 (1H, m), 7.65 (1H, m), 7.80 (1H, s), 7, 90 (1H, s), 8.60 (1 H, d), 10.45 (1H, s). Found: C, 57.97; H, 6.26; N, 21, 18 C22H27N7O3 0.3CH2Cl2 requires C, 57.85; H, 6.01; N, 21, 18%.

PREPARATION 52 4-r5-Amino-2- (2-methoxyethoxy) -pyridin-3-ylcarboxamido-3-n-propyl-2- (2-pyridin-2-yl) methyl-pyrazole-5-carboxamide Obtained from the title compound of preparation 49, using a method analogous to preparation 39, as a gray solid (100%). d (CDCl 3): 1, 05 (3H, t), 2.80 (2H, q), 3.40 (3H, s), 3.40-3.60 (2H, sa), 3.90 (2H , t), 4.65 (2H, t), 5.30-5.40 (1H, sa), 5.50 (2H, s), 6.60-6.80 (1H, sa), 6, 90 (1H, s), 7.20 (1 H, m), 7.65 (1 H, m), 7.80 (1 H, s), 7.95 (1H, s), 8.60 ( 1 HOUR, d), 10.50 (1 H, s). LRMS: m / z 440 (M + 1) +. Found: C, 56.47; H, 5.82; N, 21, 40 C 21 H 25 N 7 O 4 0.4H 2 O requires C, 56.47; H, 5.82; N, 21, 95%.

PREPARATION 53 5- (5-amino-2 * ^ toxip?> Idin-3-yl) -3-n-propyl-2- (pyridin-2-yl) -methyl-2,6-dihydro-7H - pyrazol-r4,3-d1-pyrimidin-7-one Potassium tert-butoxide (2.32 g, 20 mmol) was carefully added to a suspension of the title compound of preparation 50 (2.11 g, 5 mmoi) and 4 A molecular sieves in ethanol (50 ml) and the The reaction was heated to reflux for 18 hours. The cooled mixture was filtered through Arbocel, the filtrate was concentrated under reduced pressure and the residue was partitioned between aqueous hydrochloric acid (30 ml, 1 N) and ethyl acetate (30 ml). The layers were separated, the aqueous layer was extracted with ethyl acetate (2 x 30 ml) and the combined organic layers were washed with brine (30 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residual brown oil was purified on column chromatography on silica gel, eluting with a gradient system of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a pale yellow solid (1.22 g) . d (CDCl 3): 0.95 (3H, t), 1.50 (3H, t), 1.60 (2H, m), 2.95 (2H, t), 3.60 (2H, s), 4.50 (2H, q), 5.70 (2H, s), 7.05 (1H, d), 7.20 (1H, m), 7.60 (1H, m), 7.80 (1H, s), 8.15 (1H, d), 8.60 (1H, s), 11.05 (1H, s). Found: C, 61, 92; H, 5.69; N, 23.95. C2iH23N7? 2 requires C, 62.21; H, 5.72; N, 24.18%.

PREPARATION 54 5- (5-amino-2-n-propoxypyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) -methyl-2,6-dihydro-7H-pyrazole-r4. 3-d1-pyrimidin-7-one Potassium tert-butoxide (441 mg, 3.9 mmol) was carefully added to a suspension of the title compound of Preparation 51 (430 mg, 0.98 mmol) in 1-propanol (15 mL) and the reaction was heated to a reflux for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in water (10 ml), acidified to pH 5 with hydrochloric acid (2N) and extracted with dichloromethane (3 x 15 ml). The combined organic layers were dried over MgSO 4, filtered and concentrated under reduced pressure. The residual brown oil was purified on column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol (97: 3) to give the title compound as a yellow solid (237 mg). d (CDCl 3): 0.95 (3H, t), 1, 10 (3H, t), 1, 70-1, 80 (2H, m), 1.85-2.00 (2H, m), 2 , 95 (2H, t), 3.60 (1H, s), 4.45 (2H, t), 5.65 (2H, s), 7.05 (1H, d), 7.20-7, 25 (1H, m), 7.60 (1H, t), 7.80 (1H, s), 8.20 (1H, s), 8.60 (1H, d), 11, 10 (1H, s) ). LRMS: m / z 420 (M + 1) +.

PREPARATION 55 5-r5-amino-2- (2-metet) pyridin-3-ip-3-ethyl-2- (pyridin-2-yl) -methyl-2,6-dihydro-7H-pyrazole-r4.3- d1pyrimidin-7-one Potassium tert-butoxide (6.58 g, 33 mmol) was carefully added to a suspension of the title compound of Preparation 52 (2.90 g, 6.60 mmol) in 2-metethanol (70 mL), the mixture heated to reflux for 18 hours and then cooled. The solvent was removed under reduced pressure and the residue was purified by chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (98: 2 to 95: 5) to give the title compound as a white solid (2.20. g). d (CDCl 3): 1.30 (3H, t), 3.00 (2H, q), 3.55 (3H, s), 3.60 (2H, s), 3.80 (2H, t), 4.60 (2H, t), 5.65 (2H, s), 7.05 (1H, d), 7.20 (1H, m), 7.60 (1H, m), 7, 80 (1 H, s), 8.10 (1 H, s), 8.60 (1 H, d), 11, 15 (1 H, s). LRMS: m / z 422 (M + 1) +. Found: C, 59.10; H, 5.44; N, 22.86. C2? H23N703 requires C, 59.09; H, 5.57; N, 22.97%.

PREPARATION 56 5-r5 ** < lorosulfonyl-2- (2-methoxyethoxypyridin-3-ip-3-ethyl-2- (pyridin-2-yl) -methyl-2,6-dihydro-7H-pyrazole-r4.3-d1-pyrimidin-7-one A solution of the title compound of preparation 55 (1.5 g, 7.14 mmol) in acetic acid (30 ml) and concentrated hydrochloric acid (30 ml) was cooled to -20 ° C and sodium nitrite (714 mg, 10.35 mmol) was added. The reaction mixture was heated to 0 ° C for 2 hours, then cooled again to -20 ° C. Sulfur dioxide (20 ml) was added followed by a suspension of copper (II) chloride (2.09 g, 15.52 mmol) in water (3 ml). The reaction mixture was warmed to 0 ° C and stirred for 30 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was poured onto ice (60 g) and the resulting suspension was extracted with dichloromethane (5 x 50 ml). The combined organic layers were dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was stirred in diethyl ether (50 ml) and filtered to give the title compound as a beige solid (2.2 g). d (CDC? 3): 1, 30 (3H, t), 3.10 (2H, q), 3.60 (3H, s), 3.90 (2H, t), 4.85 (2H, t ), 5.70 (2H, s), 7.10 (1H, m), 7.20 (1 H, m), 7.65 (1 H, m), 8.60 (1 H, s), 8.90 (1 H, s), 9.25 (1 H, s), 10.75 (1 H, s). LRMS: m / z 505 (M + 1) +. Found: C, 49.11; H, 4.13; N, 16.02. C21H21CIN6O5S 0.6H2O requires C, 48.90; H, 4.34; N, 16.29%.

PREPARATION 57 4-benzyl-tetrahydro-1,4-thiazine 1.1-dioxide Divinyl sulfone (0.8 mL, 10 mmol) was added to a solution of benzylamine (1.09 mL, 10 mmol) in ethanol (4 mL) and heated to reflux for 2 hours. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (30 ml) and washed with an aqueous solution of sodium hydrogencarbonate (15 ml), dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (100: 0 to 99: 1) to give the title compound as a yellow oil (0.9 g). d (CDCl 3): 3.00 (4H, m), 3.05 (4H, m), 3.65 (2H, s), 7.25-7.40 (5H, m). LRMS: m / z 226 (M + 1) +.

PREPARATION 58 Tetrahydro-1,4-thiazine-1,1-dioxide acetate A stirred mixture of the title compound of preparation 57 (250 mg, 1.1 mmol) and palladium on carbon (30 mg) in acetic acid (5 ml) was hydrogenated for 18 hours at 207 kPa (30 psi) and room temperature. Water (5 ml) was added and the mixture was filtered through Arbocel to remove the catalyst. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (240 mg). d (CDC): 1.85 (3H, s), 2.95 (4H, m), 3.05 (4H, m). LRMS: m / z 226 (M + 1) +.

PREPARATION 59 5- (2-Ethoxy-5- (3-r2,2,2-trifluoroacetyl) ethylamino-1- azetidin-sulfonyl> pyridin-3-yl) -3-n-propyl-2- (pyridine -2-yl) -methyl-2,6-dihydro-7H-pyrazol-r4,3-dl-7-one A solution of the title compound of Preparation 53 (613 mg, 1.51 mmol) in acetic acid (6.25 mL) and concentrated hydrochloric acid (10 mL) was cooled to -20 ° C and sodium nitrite (203 g) was added. mg, 3.03 mmol). The reaction mixture was heated to 0 ° C for 2 hours, then cooled again to -20 ° C. Sulfur dioxide (11 ml) was added followed by a suspension of copper (II) chloride (606 mg, 4.50 mmol) in water (2 ml) and acetic acid (5 ml). The reaction mixture was heated to 0 ° C and stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour. The reaction mixture was poured into ice water (95 ml) and extracted with dichloromethane (3 x 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether and filtered to give a white solid. This solid was dissolved in ethanol (40 ml) and a solution of? - (3-azetidinyl) -? - ethyl-2,2,2-trifluoroacetamide (280 mg, 1.42 mmol); J. Med. Chem., 1993, 36, 9, 808) in ethanol (5 ml) and stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was suspended in a saturated solution of sodium hydrogencarbonate (20 ml) and extracted with ethyl acetate (3 x 30 ml). The combined organic layers were washed with brine (3 x 20 ml), dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (100: 0 to 98: 2). The resulting oil was suspended in diethyl ether and concentrated under reduced pressure (x3) to give the title compound as a white solid (450 mg). d (CDCl 3): 0.95 (3H, t), 1, 30 (3H, t), 1, 50-1, 65 (5H, m), 1, 65-1, 80 (2H, m), 3 , 00 (2H, t), 3.45 (2H, t), 4.10 (3H, m), 4.80 (2H, q), 5.70 (2H, s), 7.10 (1H, d), 7.20 (1 H, m), 7.60 (1 H, m); 8.60 (1 H, m), 8.75 (1 H, s), 9.10 (1 H, s), 10.65 (1H, sa). LRMS: m / z 649 (M + 1) +.

PREPARATION 60 5-f5-r (1 5S) -6-exo-r (tert-butoxycarbonyl) amino1-3-azabicyclo3.1.01hex-3-ylsulfonip-2-ethoxy-pyridin-3-yl -3-n-propyl -2- (pyridin-2-yl) -methyl-2,6-dihydro-7H-pyrrazol-r4,3-d1-pyrimidin-7-one Obtained from the title compound of preparation 53 and tere-butyl (1 5R) -3-azabicyclo [3.1.0] hex-6-ylcarbamate (EP 413 455), by a method analogous to preparation 59, as a white solid (45%). d (CDC): 0.95 (3H, t), 1, 40 (9H, s), 1, 60 (3H, t), 1, 65-1, 80 (4H, m), 2.50 (1 H, s), 3.00 (3H, t), 3.20 (2H, d), 3.70 (2H, d), 4.50-4.65 (1H, sa), 4.75 ( 1H, q), 5.70 (2H, s), 7.10 (1H, d), 7.20 (1H, m), 7.60 (1H, m), 8.60 (1H, m), 8.65 (1H, s), 9.00 (1H, s), 10.65 (1H, sa). LRMS: m / z 651 (M + 1) +. Found: C, 57.61; H, 6.10; N, 16.64. CsiHsßNsOeS 0.1 C6H? 4 requires C, 57,76; H, 6.02; N, 17.00% SYNTHESIS OF THE COMPOUNDS OF FORMULAS IA AND IB EXAMPLE 1 5-f5- (NN-dimethylaminosulfonyl) -2-n-propoxyphenin-3-n-propyl-2- (pyridin-2-ylmethyl-2,6-dihydro-7H-pyrazole-r4,3-dlpyrimidin-7 -one The title compound of preparation 15 (250 mg, 0.60 mmol) was dissolved in chlorosulfonic acid (2 mL, 30 mmol) and thionyl chloride (0.50 mL, 6.90 mmol) was added slowly. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was quenched by pouring on ice and the white precipitate that formed was filtered and dried in vacuo. The resulting solid was suspended in ethanol (10 ml), dimethylamine (0.14 ml, 3.0 mmol) was added and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (30 ml) and washed with a saturated aqueous solution of sodium hydrogencarbonate (15 ml), dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol (98: 2) to give the title compound as a white solid (209 mg). d (CDCla): 0.95 (3H, t), 1, 20 (3H, t), 1.75 (2H, q), 2.05 (2H, q), 2.80 (6H, s), 3.00 (2H, t), 4.25 (2H, t), 5.70 (2H, s), 7.10 (1H, d), 7.35-7.15 (2H, m), 7.60 (1H, m), 7.85 (1H, m), 8.60 (1H, d), 8.80 (1H, s), 10.60 (1H, sa). LRMS: m / z 511 (M + 1) +. Analysis: Found C, 57.57; H, 5.83; N, 15.99; C25H30N6O4S. 0.15CH2Cl2 requires C, 57.72; H, 5.84; N, 16.06%.

EXAMPLES 2 to 11 The compounds of the following tabulated examples of the general formula: were prepared by the method of Example 1 (method A) using the corresponding pyrazolo [4,3-d] pyrimidin-7-one and the appropriate amine. In another alternative, the compounds were prepared using the method of Example 1, with the exception that 1, 2 equivalents of the appropriate amine and 2 equivalents of triethylamine (method B) were used. 15 20 -fifteen twenty EXAMPLE 12 3 *** etií-5 *** (5-r (3 * -ethylamino) -1 *** et? Aminosulfonip-2-n-propoxyphenH) -2- (pyridin-^ il) -methyl-2.6 -dihydro-7H-pyrazole-r4.3-d1-7-one The title compound of Preparation 16 (0.5 g, 1.28 mmol) was added to a cooled mixture of chlorosulfonic acid (1 mL, 15 mmol) and thionyl chloride (0.15 mL, 2 mmol) and the The reaction was stirred for 4 hours, warming to room temperature. The reaction mixture was quenched by pouring on ice and the white precipitate that formed was filtered and dried. The resulting solid was dissolved in a mixture of acetone (15 ml): water (10 ml), a solution of N-ethylethylenediamine (2 ml, 19 mmol) in acetone (5 ml) and the solution was added dropwise over 15 minutes. The reaction mixture was stirred at room temperature during 45 minutes. The acetone was removed under reduced pressure and the aqueous residue was partitioned between dichloromethane (60 ml) and aqueous sodium hydroxide (1 N, 30 ml). The layers were separated and the aqueous layer was neutralized by the addition of solid carbon dioxide. The aqueous layer was then extracted with dichloromethane (3 x 60 ml), the combined organic layers were dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a system in dichloromethane: methanol: ammonia 0.88 (95: 5: 1 to 85: 15: 1) gradient giving the title compound as a white solid (200 mg). d (CDCl 3): 1, 00 (3H, m), 1, 15 (3H, m), 1, 30 (3H, m), 1, 95-2.10 (2H, m), 2.55 (2H , q), 2.75 (2H, m), 3.00-3.10 (4H, m), 4.25 (2H, t), 4.20 (2H, t), 5.70 (2H, s), 7.05-7.20 (2H, m), 7.20 (1H, m), 7.60 (1H, m), 7.95 (1H, m), 8.60 (1H, m), 8.90 (1 H, s), 10.60 (1 H, s). LRMS: m / z 540 (M + 1) +.

EXAMPLE 13 5-r5- (N, N * - methylaminosulfonyl) -2-n-propoxyphenip-3 ** ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazole- r4,3-dlpyrimidin-7-one The title compound of Preparation 16 (2.0 g, 5.13 mmol) was added slowly to chlorosulfonic acid (6 mL, 90 mmol) at 0 ° C and stirred for 18 hours, warming to room temperature. The reaction mixture was quenched by pouring on ice (40 g) and the resulting solution was basified to pH 9.0 by the addition of aqueous sodium hydroxide (5N), maintaining the temperature at 0 ° C. A solution of diethylamine (1.5 g, 20.5 mmol) in acetone (10 ml) was added and the reaction mixture was stirred for 18 hours at room temperature. Water (10 ml) was added and the white precipitate was filtered, washed with acetone: water (1: 1) and dried under vacuum at 50 ° C to give the title compound as a white solid (1.6 g). d (CDCl 3): 1, 00-1, 20 (9H, m), 1, 30 (3H, t), 2.00 (2H, m), 3.00 (2H, q), 3.20-3.35 (4H, m), 4.20 (2H, t), 5.70 (2H, s), 7.10 (2H, t), 7.20 (1H, m ), 7.60 (1H, m), 7.90 (1 H, m), 8.60 (1 H, d), 8.85 (1 H, s), 10.60 (1 H, s) .

EXAMPLE 14 5-r 5 - (3-N, N- * d -methylaminoazetidin-1-ylsulfonyl) -2-n-propoxyphenip-3-n-propyl-2- (py! Din-2-yl) met? -2,6 * lih¡dro-7H-p¡razol-r4,3 * - Tpirímidín-7-ona % palladium on carbon (560 mg) was added to a solution of? / - (1-benzhydryl-3-azetidinyl) -? /,? - dimethylamine (2.95 g, 11 mmol) in methanol ( 65 ml) under a nitrogen atmosphere and stirred at room temperature. Ammonium formate (3.07 g, 48.7 mmol) was added and the reaction was stirred at reflux for 5 hours. After cooling, the mixture was filtered through an Arbocel pad and washed with methanol. The solvent was removed from the filtrate under reduced pressure to give the crude solid? / - (3-azetidinyl) -? /,? / - dimethylamine (1.76 g). The title compound of preparation 15 (0.82 g, 1.62 mmol) was dissolved in chlorosulfonic acid (2 mL, 30 mmol) and thionyl chloride (0.50 mL, 6.90 mmol) was slowly added. The resulting mixture was stirred at room temperature for 8 hours. The resulting mixture was quenched by pouring on ice and the white precipitate that formed was filtered and dried in vacuo. The resulting solid was suspended in ethanol (5 ml), the previously prepared? / - (3-azetidinyl) -? /,? - dimethylamine (1.76 g) was added and the mixture was stirred at room temperature for 18 hours. hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound as a white solid (364 mg). d (CDCla): 0.95 (3H, t), 1, 20 (3H, t), 1, 65-1, 80 (2H, m), 2.00-2.15 (8H, m), 3 , 00 (2H, m), 3.10 (1H, m), 3.60 (2H, m), 3.90 (2H, m), 4.30 (2H, m), 5.70 (2H, s), 7.10 (1 H, d), 7.20-7.30 (2H, m), 7.65 (1 H, m), 7.90 (1 H, m), 8.60 ( 1H, d), 8.85 (1 H, s), 10.65 (1 H, s). LRMS: m / z 566 (M + 1) +. Analysis: Found C, 58.09; H, 6.23; N, 16.85; C28H35N704S 0.75H2O requires C, 58.07; H, 6.35; N, 16.93%.

EXAMPLE 15 5-r2- ^ ToxifenH-5- (2-pyrazinamnosulfonyl) 1-3-ethyl-2 * - (pyridin-2-SI) methylene-2,6-dihydro-7H-p-arazo -r4.3-d1pyrimidin-7-one The title compound of Preparation 23 (240 mg, 0.63 mmol) was added slowly to chlorosulfonic acid (1 mL, 15 mmol) and the reaction was stirred for 18 hours at room temperature. The reaction mixture was quenched by pouring on ice and a white precipitate formed. The resulting mixture was neutralized by the addition of a solution of aqueous sodium hydroxide (5N) while the temperature was maintained at 0 ° C. The white precipitate was filtered, washed with water, then diethyl ether and dried under vacuum. 2-Aminopyrazine (126 mg, 1.32 mmol) was added to a suspension of sodium hydride (40 mg, 80% dispersion in mineral oil, 1.32 mmol) in tetrahydrofuran (3 ml) under a nitrogen atmosphere at room temperature and stirred for 1 hour. The previously obtained white solid was added in portions to this mixture for 2 minutes and stirred for 72 hours at room temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and water (20 ml), the layers were separated and the aqueous layer was acidified with hydrochloric acid (1N, 10 ml) and then extracted with ethyl acetate (40 ml). ml x 2). These latter organic phases were dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a white solid (30 mg). d (CDCl 3): 1.25 (3H, m), 1.60 (3H, t), 3.00 (2H, m), 4.30 (2H, m), 5.70 (2H, s), 7.10 (2H, m), 7.20 (1H, m), 7.60 (1H, m), 8.00 (1H, d), 8.20 (1H, s), 8 , 25 (1H, s), 8.60 (1 H, s), 8.70 (1 H, s), 8.90 (1 H, s), 10.65 (1 H, s). LRMS: m / z 533 (M + 1) +.

EXAMPLE 16 5-f5-R (3-amino) -1-methylaminosulfonin-2-n-propoxyphenyl > -3-n-propyl-2- (pyridin-2-yl) methyl-2,6 * - ihydro-7H-pyrazole-r4.3 ** lpyrimidin-7-one The title compound of preparation 29 (380 mg, 0.60 mmol) was dissolved in dichloromethane (5 ml) and saturated with hydrogen chloride gas while stirring at room temperature. The agitation continued for another 2 hours, then the solvent was removed under reduced pressure. The residue was azeotropically distilled with dichloromethane and dried in vacuo to give the title compound as a white solid (320 mg). d (de-DMSO): 0.80-1.00 (6H, m), 1.55-1.80 (4H, m), 2.80-3.00 (6H, m), 4.10 ( 2H, t), 5.70 (2H, s), 7.20-7.50 (3H, m), 7.85-7.95 (2H, m), 7.95-8.10 (4H, m), 8.60 (1 H, d), 11, 80 (1 H, sa). LRMS: m / z 526 (M + 1) +. Analysis: Found C, 46.05; H, 5.66; N, 14.89; C 25 H 3? N 7 O 4 S 2 HCl 3 H 2 O requires C, 46.01; H, 6.02; N, 15.02%.

EXAMPLE 17 5-r5- (4-Oxo-piperidin-1-ylsulfonyl) -2-n-propoxyphenn-3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-p Razol-r4,3 * < np »rimidin-7-one The title compound of example 5 (440 mg, 0.74 mmol) was dissolved in tetrahydrofuran (5 ml), hydrochloric acid (2N, 2.5 ml) was added and the reaction was stirred at room temperature for 1.5 hours and it was heated at 50 ° C for another 18 hours. The mixture was concentrated under reduced pressure and water (20 ml) was added to the residue. The resulting solution was neutralized by adding solid sodium hydrogencarbonate. The aqueous solution was extracted with ethyl acetate (40 ml), the organic layer was washed with brine (20 ml) and evaporated under reduced pressure. The residue was dissolved in dichloromethane and dried over MgSO, filtered and evaporated under reduced pressure to give the title compound as a white solid (358 mg). d (CDCl 3): 1, 15 (3H, t), 1, 30 (3H, t), 2.00 (2H, m), 2.55 (4H, m), 3.00 (2H, q), 3.45 (4H, m), 4.25 (2H, t), 5.70 (2H, s), 7.10 (1H, d), 7.20 (1H, d), 7.25 ( 1H, m), 7.60 (1 H, m), 7.85 (1 H, m), 8.60 (1 H, d), 8.80 (1 H, s), 10.60 (1 H, s). LRMS: m / z 551 (M + 1) +. Analysis: Found C, 57.96; H, 5.44; N, 14.60; CzzH8NßOsS 0.6H2O requires C, 57.76; H, 5.60; N, 14.97%.

EXAMPLE 18 5- (5-r (1 5S) -6-en o-amino-3-azabicyclo3.1.01hex-3-ylsulfonip-2-n-propoxyphen-3-n-prop? -2 ^ pyridine- 2H) rnetyl-2,6-dihydro-7H-pyrazole-r4.3-dlpyrimidin-7-one The title compound of example 11 (320 mg, 0.48 mmol) was dissolved in dichloromethane (10 ml) and cooled to 0 ° C. Trifluoroacetic acid (2 ml) was added dropwise and the reaction mixture was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was azeotropically distilled with toluene, then with dichloromethane. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol: 0.88 ammonia (95: 5: 1) to give the title compound as a white solid (170 mg). d (CDCl 3): 0.95 (3H, t), 1.15 (3H, t), 1.45 (2H, s), 1.50 (2H, sa), 1.75 (2H, m), 2.00 (2H, m), 2.35 (1H, s), 2.95 (2H, t), 3.10 (2H, d), 3.60 ( 2H, d), 4.20 (2H, t), 5.70 (2H, s), 7.05 (1H, d), 7.15 (1H, d), 7.25 (1H, m), 7.60 (1 H, m), 7.85 (1 H, m), 8.60 (1 H, d), 8.80 (1 H, s), 10.60 (1 H, sa) . LRMS: m / z 564 (M + 1) +. Analysis: Found C, 57.91; H, 5.70; N, 16.70; C28H33N7O4S 0.25CH2Cl2 requires C, 58.01; H, 5.77; N, 16.76%.

EXAMPLE 19 5-r 5 - (N, N ** - dimethylaminosulfonyl) -2 *** ethoxypyridin-3-ip-3-n-propyl-2- (pyridin-2-ipmethyl-2-dihydro-7H-pyrazole -r4,3-d1pyrimidin-7-one Potassium icarb-butoxide (102 mg, 0.91 mmol) was added to a suspension of the title compound of Preparation 43 (235 mg, 0.46 mmol) in ethanol (15 mL) and the reaction mixture was heated in a vessel closed at 100 ° C and stirred for 18 hours. Upon cooling, the solvent was removed under reduced pressure and the residue was suspended in water (10 ml) and extracted with dichloromethane (2 x 10 ml). The combined organic layers were dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (99: 1 to 98: 2) to give the title compound as a brown foam (70 mg). d (CDCl 3): 0.95 (3H, t), 1, 60 (3H, t), 1, 70-1, 85 (2H, m), 2.80 (6H, s), 3.00 (2H , t), 4.80 (2H, q), 5.70 (2H, s), 7.10 (1H, d), 7.20-7.30 (1H, m), 7.60 (1 H, m), 8.60 (1 H, m), 8.70 (1 H, d), 9.05 (1 H, s), 10.65 (1H, s). LRMS: m / z 498 (M + 1) +. Analysis: Found C, 55.30; H, 5.51; N, 18.87; C23H27N 04S. 0.4 CH 3 OH requires C, 55.07; H, 5.65; N, 19.21.% EXAMPLE 20 5- (5-r (3-N, Nd-methylamino) -1-ethylaminosulfonipi-2-n-propoxypyridyl-3-yl) -3-n-propyl-2- (pyridin-2) -H) methyl-2,6 lihydro-7H-pyrazole-r4,3 ** lpyrimidin-7-one A solution of the title compound of Preparation 54 (130 mg, 0.3 mmol) in acetic acid (5 mL) and concentrated hydrochloric acid (5 mL) was cooled to 20 ° C and sodium nitrite (42.8 mg) was added. , 0.62 mmol). The reaction mixture was heated to 0 ° C for 2 hours, then cooled again to -20 ° C. Sulfur dioxide (3 ml) was added followed by a suspension of copper chloride (II) (125 mg, 0.93 mmol) in water (1 ml) and acetic acid (2 ml). The reaction mixture was heated to 0 ° C, stirred for 30 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into ice (10 g) and extracted with dichloromethane (3 x 20 ml). The combined organic layers were dried over MgSO4, filtered, concentrated under reduced pressure and the residue was azeotropically distilled with toluene. The resulting green solid was dissolved in ethanol (5 ml), N, N-dimethylethylenediamine (0.068 ml, 0.62 mmol) was added and the reaction was stirred at room temperature for 18 hours. The solvent was removed at reduced pressure and the residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (97: 3 to 95: 5). This product was suspended in pentane and filtered to give the title compound as a yellow solid (90 mg). d (de-DMSO): 0.85 (3H, t), 0.95 (3H, t), 1, 60-1, 80 (4H, m), 2.05 (6H, s), 2.30 (2H, t), 2.90 (4H, m), 4.20 (2H, t), 5.70 (2H, s), 7.20 (1H, d), 7.30 (1H, m) , 7.80 (1H, m), 8.30 (1H, d), 8.50 (1H, d), 8.65 (1H, s), 11, 80 (1H, sa). LRMS: m / z 555 (M + 1) +. Analysis: Found C, 53.73; H, 6.09; N, 18.58; C 26 H 34 N 8 O 4 S 0.5 CH 2 Cl 2 requires C, 53.30; H, 5.91; N, 18.77%.

EXAMPLE 21 3 * - * ethyl-5-fr5- (3-** ethylamino) -1-ethylaminosulfonip-2-r2-methoxyethoxypyridin-3-yl > -2- (pyridin-2-yl) methyl-2,6 * - ihydro-7H-pyrazole-r4,3-dlpyrimidin-7-one A solution of the title compound of Preparation 56 (150 mg, 0.30 mmol) in dichloromethane (10 mL) was added over 1 hour, to a solution of N-ethylethylenediamine (125 μL, 1.20 mmol) and triethylamine ( 166 μl, 1.20 mmol) in dichloromethane (10 ml) and stirred at room temperature for another hour. The reaction mixture was washed with water (10 ml), dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a solvent system of dichloromethane: methanol: ammonia 0.88 (97: 3: 0.3) giving the compound of the title as a white solid (40 mg). d (CDC): 1, 00 (3H, t), 1, 30 (3H, t), 2.50 (2H, m), 2.70 (2H, t), 3.00 (4H, m), 3.60 (3H, s), 3.85 (2H, t), 4.80 (2H, t), 5.70 (2H, s), 7.10 (1H, d), 7.20 (1 H, m), 7.60 (1 H, m), 8.60 (1 H, d), 8.70 (1 H, d), 9.05 (1 H, s). LRMS: m / z 557 (M + 1) +. Analysis: Found c, 53.60; H, 5.76; N, 19.84; C 25 H 32 N 8 O 5 S requires C, 53.94; H, 5.79; N, 20.13%.

EXAMPLE 22 3-ethyl-5-r5- (4-ethylpiperidin-1-ylsulfonyl) -2- (2-methoxymethyl) pyridin-3-ill-2- (pyridin-2-yl) methyl-2,6- dihydro-7H-pyrazol-r4,3-d1-pyrimidin-7-one Obtained from the title compound of preparation 56 and 4-ethylpiperidine using a method analogous to that of Example 21, as a white solid (20%). d (CDCb): 0.85 (3H, t), 1.10 (1 H, m), 1, 20-1, 40 (7H, m), 1.80 (2H, m), 2.35 ( 2H, t), 3.00-3.10 (2H, m), 3.60 (3H, s), 3.80-3.90 (4H, m), 4.80 (2H, m), 5 , 70 (2H, s), 7.10 (1 H, d), 7.20 (1H, m), 7.60 (1 H, m), 8.75 (1 H, m), 8.60 (1H, s), 9.00 (1 H, s), 10.85 (1 H, s). LRMS: m / z 582 (M + 1) +.

EXAMPLE 23 3-ethyl-5-r2-2-methoxymethyl) -5- (tetrahydro-1,4-thiazin 1,1-dioxidosulfoniDpyridin-3-yl-2- (pyridin-2-yl) metH-2, 6-dihydro-7H-pyrrazol-r4,3-dlpyrimidin-7-one Obtained from the title compound of preparation 56 and the title of the compound of preparation 58 using a method analogous to that of Example 21, as a white solid (13%). d (CDCl 3): 1.30 (3H, t), 3.00-3.10 (2H, m), 3.20 (4H, m), 3.60 (3H, s), 3.80 (4H , m), 3.90 (2H, m), 4.80 (2H, m), 5.70 (2H, s), 7.10 (1H, d), 7.30 (1H, m) , 7.70 (1H, m), 8.60 (1H, d), 8.65 (1H, s), 9.00 (1H, s), 10.80 (1H, s). LRMS: m / z 604 (M + 1) +.

EXAMPLE 24 5- ^ 2 *** ethoxy-5-r (3-N *** ethylamino) -1-azetidinesulfonip-pyridin-3-yl > -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazol-r4,3-d1-pyrimidin-7-one Water (10 ml) was added to a solution of the title compound of preparation 59 (420 mg, 0.65 mmol) in methanol (10 ml). A saturated sodium carbonate solution (5 ml) was added and the reaction mixture was stirred at room temperature for 18 hours. The methanol was removed under reduced pressure and water (30 ml) was further added. The aqueous layer was extracted with ethyl acetate (3 x 30 ml), the combined organic layers were washed with brine (3 x 30 ml), dried over MgSO 4, filtered and concentrated reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane: methanol (100: 0 to 97.5: 2.5) to give an oil. This oil was dissolved in diethyl ether and concentrated under reduced pressure (repeated x3), then recrystallized from: ethyl acetate: hexane to give the title compound as colorless crystals (185 mg). d (CDCl 3): 0.95 (3H, t), 1, 05 (3H, t), 1, 60 (3H, t), 1, 65-1, 80 (2H, m), 2.50-2 , 60 (2H, m), 3.00 (2H, t), 3.60 (3H, m), 4.00-4.10 (2H, m), 4.80 (2H, q), 5, 70 (2H, s), 7.10 (1H, d), 7.20 (1H, m), 7.60 (1H, m), 8.60 (1H, d), 8.70 ( 1H, s), 9.10 (1H, s), 10.65 (1H, s). LRMS: m / z 553 (M + 1) +. Analysis: Found C, 56.41; H, 5.83; N, 20.19; C 26 H 32 N 8 O 4 S requires C, 56.51; H, 5.84; N, 20.28%.

EXAMPLE 25 5-l5-r (1 5S) -6-exo-amino-3-azabicyclo3.1.01hex-3-ylsulfonip2-ethoxy- (pyridin-3-yl -3-n-propyl-2 - (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazole-r4.3- dlpirlmidin-7-one The title compound of preparation 60 (300 mg, 0.46 mmol) was dissolved in ethyl acetate (40 ml) and hydrogen chloride gas was bubbled for 20 minutes while stirring at 0 ° C. The solvent was removed under reduced pressure and the residue was azeotropically distilled with diethyl ether. He The solid was dissolved in water (50 ml) and basified with a saturated sodium carbonate solution. The aqueous solution was then extracted with ethyl acetate (3 x 30 ml) and the combined organic layers were washed with brine (3 x 20 ml), dried over Na2SO, filtered and concentrated under reduced pressure. The residue was dissolved in diethyl ether and concentrated under reduced pressure (repeated x3), then recrystallized from ethyl acetate: hexane to give the title compound as a colorless solid (145 mg). d (CDCl 3): 0.95 (3H, t), 1, 40-1, 65 (7H, m), 1, 65-1, 80 (2H, m), 2.40 (1H, s), 3 , 00 (2H, t), 3.10 (2H, d), 3.60 (2H, d), 4.70-4.80 (2H, q), 5.70 (2H, s), 7, 10 (1H, d), 7.20-7.25 (1H, m), 7.60 (1H, m), 8.60 (1H, d), 8.65 (1H, s), 9.05 (1H, s), 10.65 (1H, s). LRMS: m / z 551 (M + 1) +. Analysis: Found C, 56.18; H, 5.53; N, 19.84; C 26 H 30 N 8 O 4 S 0.5H 2 O requires C, 55.80; H, 5.58; N, 20.02%.

BIOLOGICAL ACTIVITY It was found that the compounds of the invention had in vitro activities as inhibitors of cGMP PDE5 with IC 50 values of less than about 100 nM. The following table illustrates the in vitro activities for a series of compounds of the invention as inhibitors of cGMP PDE5. Example IC50 (nM) 4 26.60 8 16.40 14.00 19. 9.70 8.50 22 10.30

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula IA or of formula IB: IA IB wherein A represents CH or N; R1 represents Het1, alkylHet1, aryl or alkylaryl, all of which are optionally substituted with one or more substituents selected from halogen, cyano, nitro, lower alkyl, OR5, C (0) R6, C (0) OR7, C (0) NR8R9, NR10aR10b and S02NR11aR11b; R2 and R3 independently represent H or lower alkyl, the latter group being optionally substituted and / or terminated by one or more substituents selected from aryl, Het1, halogen, cyano, nitro, OR5, C (O) Rd, C (0) OR7 , C (0) NR8R9, NR10aR10b and S02NR11aR 1b; R4 represents S02NR12R13; R12 and R13 independently represent H; lower alkyl optionally substituted and / or terminated with one or more substituents selected from aryl, Het1, halogen, cyano, nitro, lower alkyl, OR5, C (O) R6, C (O) OR7, C (O) NR8R9, NR? OR? Oa and So2NR11aR11; Het1; or together with the nitrogen to which they are bound form Het or a structural fragment of formula lia: R14 and R15 independently represent H, lower alkyl, C (O) R6, C (O) OR7 or C (O) NR8R9; Het1 represents a heterocyclic group with optionally substituted four to twelve links, group containing at least one nitrogen atom, and optionally, one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; Het2 represents an optionally substituted three to twelve membered heterocyclic group, a group containing at least one nitrogen atom, and optionally, one or more additional heteroatoms selected from nitrogen, oxygen and sulfur; and R5, R6, R7, R8, R9, R10a, R10b, R, R and R independently represent H or lower alkyl; or a pharmaceutically or veterinarily acceptable derivative thereof, with the proviso that when R2 represents C? -6 alkyl and: (a) A represents CH; R1 represents Het1 or CH2Het1 (in both cases Het1 represents a 6-membered heterocyclic group linked by C, containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide or a 5-membered heterocyclic group attached by C which contains one to four heteroatoms selected from nitrogen, oxygen and sulfur, each of said heterocyclic groups being optionally substituted with one or two substituents selected from C 1-4 alkyl, the alkyl group being optionally substituted by C 1-4 alkoxy, halogen or NH 2), phenyl or benzyl (these last two groups being optionally substituted with one or two substituents selected from C 1-4 alkyl, C 1-4 alkoxy, halogen, CN, CONH 2, NO 2, NH 2 and SO 2 NH 2); and R 3 is C 1-6 alkyl optionally substituted with C 4 alkoxy; then R12 and R13 do not represent, together with the nitrogen atom to which they are attached, a piperazinyl group, optionally substituted at the 4 (N) position with C1-4 alkyl optionally substituted with OH, C1-4 alkoxy or CONH2; and (b) A represents N; R1 represents CH2Het1 (in which Het1 represents a 6-membered heterocyclic group linked by C, containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a 5-membered heterocyclic group linked by C, containing two or three nitrogen atoms, each of said heterocyclic groups optionally substituted with C 1-4 alkyl) or benzyl; and R 3 is C 1-4 alkyl (optionally substituted with one or two substituents selected from OH, C 1-4 alkoxy, benzyloxy, NR R (where R and R are each independently selected from H and C 1-4 alkyl or, together with the nitrogen atom to which they are attached, they form a pyrrolidinyl, piperidinyl or morpholinyl group), phenyl, furanyl or pyridinyl), C 3-6 cycloalkyl or 1- (C 1-4 alkyl) piperidinyl; then R12 and R13 do not represent, together with the nitrogen atom to which they are attached, a 4-piperazinyl group, optionally substituted oxide, and optionally substituted at the 4 (N) position with C 1-4 alkyl optionally substituted with one or two substituents selected from OH, NR ^ R63, CONR ^ R63 (in both cases R53 and R63 are as defined above) .

2. A compound according to claim 1 wherein R1 represents alkyld-eHet1, in which Het1 represents a six-membered aromatic heterocyclic group containing one or more nitrogens.

3. A compound according to claim 1 or claim 2 wherein R2 represents linear, branched, cyclic or acyclic lower alkyl.

4. A compound according to any of the preceding claims, wherein R3 represents linear, branched, cyclic or acyclic lower alkyl, which is optionally substituted or terminated with OR5 (in which R5 is H or C1-C3 alkyl) linear, branched or cyclic).

5. A compound according to any of the preceding claims, wherein R12 and R13 independently represent H, linear, branched, cyclic or acyclic lower alkyl, the alkyl group being optionally substituted and / or terminated with one or more substituents selected between OR 5 (in which R 5 is H, or straight, branched or cyclic C 1 -C 3 alkyl), Het 1 (where Het 1 represents an aromatic heterocyclic group of six 10 11 1 bonds containing one or more nitrogens) or NR R; Het (where Het represents a six-membered heterocyclic group containing one or two nitrogens); or together with the nitrogen atom to which they are attached represent morpholinyl, tetrahydrothiazinyl, aza- or diazacycloalkyl (Cß-Cs) (these latter groups being all optionally substituted with one or more substituents selected from oxo, ethylene ketal, OR 5 (in which R 5 is H, or linear C 1 -C 3 alkyl) , branched or cyclic), or a structural fragment of formula Ia as defined in claim 1, in which R 14 and R 5 independently represent H, linear, branched, cyclic or acyclic C 1 -C 3 alkyl or C (O) OR 7 wherein R7 represents linear or branched C? -C alkyl,

6. A formulation comprising a compound as defined in any one of claims 1 to 5 mixed with a pharmaceutically or veterinarily acceptable adjuvant, diluent or vehicle. A formulation according to claim 6, which is a pharmaceutical formulation 8. A formulation according to claim 6, which is a veterinary formulation 9.- The use of a compound as s e has been defined in any one of claims 1 to 5 in the preparation of a medicament for the curative or prophylactic treatment of a medical disorder in a patient for which the inhibition of cGMP PDE5 is desired. 10. The use according to claim 9, wherein the disorder is erectile dysfunction in man, female sexual dysfunction, premature delivery, dysmenorrhea, benign prosthetic hyperplasia (BPH), obstruction of the orifice of the discharge from the bladder, incontinence, stable angina and unstable variant (Prinzmetal), hypertension, pulmonary hypertension, and the unstable variant (Prinzmetal), hypertension, pulmonary hypertension, congestive heart disease, atherosclerosis, cerebral apoplexy, peripheral vascular disease, reduced blood vessel opening disorders, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by disorders of intestinal motility, preeclampsia, Kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral neuropathy, cerebral apoplexy, Alzheimer's disease, respiratory failure acute, psoriasis, dermal necrosis, cancer metastases or alopecia. 11. A process for the preparation of a compound of formula IA or of formula IB, as defined in claim 1, comprising: (a) the reaction of the corresponding compound of formula IIIA or formula IIIB, respectively: wherein Y is a leaving group and R1, R2, R3 and A are as defined in claim 1, with a compound of formula IV: R12R13NH IV wherein R12 and R13 are as defined in claim 1; (b) the delation of the corresponding compound of formula XVIA or of formula XVIB, respectively: XVIA XVIB wherein R1, R2, R3, R4 and A are as defined in claim 1; (c) for the compounds of formulas IA and IB in which R1 represents alkylHet1 or alkylaryl, the alkylation of the corresponding compound of formula XVIIIA or of formula XVIIIB, respectively: XVIIIA XVIIIB wherein R2, R3, R4 and A are as defined in claim 1; (d) the conversion, removal or introduction of a substituent on an aryl, a group Het1, or a Het2, or in the phenyl / pyridinyl or pyrazolo unit, of a compound of formula IA or IB; (e) the conversion of one R3 group to another by alkoxide exchange; (f) for compounds of formula IA or IB in which R12 and R13, together with the nitrogen atom to which they are attached, form an N-alkyldiazacyclo-C3-C12 alkyl group, the alkylation of the corresponding compound of formula IA or IB, in which R12 and R13, together with the nitrogen atom to which they are attached, form a diazacyclo-C3-C12 alkyl group: or (g) the deprotection of a protected derivative of a compound of formula IA or of formula IB. 12. A compound of formula IIIA, or of formula IIIB, as defined in claim 11. 13. A compound of formula XVIA, or of formula XVIB, as defined in claim 11. 14. A composed of formula XVIIIA, or of formula XVIIIB, as defined in claim 11.