MXPA00010388A - Pyrazolopyrimidinone cgmp pde5 inhibitors for the treatment of sexual dysfunction - Google Patents

Abstract

Compounds of formulae (IA) and (IB) wherein R1 is C1 to C3 alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl;wherein said phenyl group is optionally substituted by one or more substitutents selected from C1 to C4 alkoxy;halo;CN;CF3;OCF3 or C1 to C4 alkyl wherein said C1 to C4 alkyl group is optionally substituted by C1 to C4 haloalkyl or haloalkoxy either of which is substituted by one or more halo atoms;R2 is C1 to C6 alkyl and R13 is OR3 or NR5R6, or pharmaceutically or veterinarily acceptable salts thereof, or pharmaceutically or veterinarily acceptable solvates of either entity are potent and selective inhibitors of type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE5) and have utility in the treatment of, inter alia, male erectile dysfunction (MED) and female sexual dysfunction (FSD).

Description

PIRAZ0L0PIRIMIDIN0NAS OF GMPc PDE5 INHIBITORS FOR THE TREATMENT OF SEXUAL DYSFUNCTION DESCRIPTIVE MEMORY This invention relates to a series of prazrazolo [4,3-d] pyrimidin-7-ones that inhibit guanosine 3 ', 5'-cyclic phosphodiesterase monophosphate (cGMP PDE). Most notably, the compounds of the invention are potent and selective inhibitors of guanosine 3 ', 5'-cyclic phosphodiesterase monophosphate type 5 (cGMP PDE5) and, therefore, have utility in a variety of therapeutic areas. In particular, the compounds are valuable in the treatment of erectile dysfunction in males (MED) and of sexual dysfunction in females (FSD) but, clearly, they will also be useful for the treatment of other medical conditions for which an inhibitor is indicated powerful and selective GMPc PDE5. Such conditions include premature delivery, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outflow tracts, incontinence, stable, unstable and variable angina (Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduction of permeability of blood vessels, for example, after percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, cerebrovascular accidents, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterized by disorders of bowel motility, for example, irritable bowel syndrome (IBS). Other conditions that may be mentioned include pre-eclampsia, Kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral neuropathy, cerebrovascular accidents, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, esophagus cracked, anal fissure and hypoxic vasoconstriction. Particularly preferred conditions include MED and FSD.

Therefore the invention provides compounds of formulas (IA) and (IB): or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, wherein R1 is C1 to C3 alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted with one or more substituents selected from C 1 to C 4 alkoxy; halogen; CN; CF3, OCF3 or Ci to C4 alkyl, wherein said C-i to C4 alkyl group is optionally substituted with halogen C1 to C or halogenalkoxy C1 to C4, either of which is substituted with one or more halogen atoms; R2 is C 1 to C 1 alkyl, R 13 is OR 3 or NR 5 R 6; R 3 is C 1 to C 1 alkyl optionally substituted with one or two substituents selected from C 3 to C 5 cycloalkyl, OH, C 1 to C 4 alkoxy, benzyloxy, NR 5 R 6, phenyl, furanyl and pyridinyl; C3 cycloalkyl to Ce; 1- (C 1 to C 4 alkyl) piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; and wherein C 1 to C 1 and C 1 to C 4 alkoxy groups may be optionally terminated with a halogenoalkyl group such as CF 3; R4 is SON2NR7R8; each of R5 and R6 is independently selected from H and Ci to C4 alkyl optionally substituted with C3 to C5 cycloalkyl or Ci to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl group or morpholinyl; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-plperazinyl group optionally substituted with one or two C-to C4 alkyl groups and optionally in the form of their 4-N-oxido; R10 is H; C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R ?, phenyl optionally substituted by C1 to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 alkenyl to Ce; pyridinyl or pyrimidinyl; Het is a 6-membered heterocyclic group attached to C that contains one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a 5-membered heterocyclic group attached to C containing two or three nitrogen atoms, wherein any of said heterocyclic groups is optionally substituted with Ci to C4 alkyl, Ci to C4 alkoxy or NHR15 wherein R15 is H, C1 to C4 alkyl or C1 to C4 alkanoyl. In the above definition, unless otherwise indicated, alkyl, alkoxy and alkenyl groups having three or more carbon atoms, and alkanoyl groups having four or more carbon atoms, may be straight chain or chain branched The term halogen includes Cl, Br, F and I. Halogenoalkyl and halogenoalkoxy are preferably CF3 and O CF3 respectively. The compounds of the formulas (IA) and (IB) may contain one or more chiral centers and, therefore, exist in the form of stereoisomers, that is, as enantiomers or diastereomers, as well as mixtures thereof. The invention includes the two individual stereoisomers of the compounds of the formulas (IA) and (IB) and any mixture thereof. The separation of the diastereoisomers can be achieved by conventional techniques, for example, by fractional crystallization or chromatography (including CLAR) of a diastereomeric mixture of a compound of formula (IA) or (IB) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (IA) or (IB) can prepared from a corresponding optically pure intermediate or by resolution, by CLAR of the racemate using a suitable chiral support or, where appropriate, by fractional crystallization of the diastereomeric salts formed by the reaction of the racemate with a suitable active or base acid. The compounds of formulas (IA) and (IB) can also exist in tautomeric forms and the invention includes both mixtures thereof and individual tautomers. The invention also includes radiolabeled derivatives of the compounds of formulas (IA) and (IB) that are suitable for biological studies. The pharmaceutically or veterinarily acceptable salts of the compounds of formulas (IA) or (IB) containing a basic center are, for example, addition salts of non-toxic acids formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids. , with carboxylic acids or with organosulfonic acids. The compounds of the formulas (IA) and (IB) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular, non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts. A preferred group of compounds of the formulas (IA) or (IB) is that in which R1 is Ci to C2 alkyl optionally substituted with Het; 2- (morpholin-4-yl) ethyl or benzyl; R2 is C2 to C4 alkyl; R13 is OR3 or NR5R6; R3 is Ci to C4 alkyl optionally substituted with one to two substituents selected from cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR5R6, phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl; cyclobutyl; 1-methylpiperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; each of R 5 and R 6 is independently selected from H and C 1 to C 2 alkyl optionally substituted by cyclopropyl or methoxy, or together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl or morpholinyl group; R7 and R ?, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally substituted with one or two methyl groups and optionally in the form of its 4-N-oxide; R 10 is H, C 1 to C 3 alkyl optionally substituted with one or two substituents selected from OH, NR 5 R 6, CONR 5 R 6, phenyl optionally substituted by methoxy, benzodioxol-5-yl and benzodioxan-2-yl; allyl; pyridin-2-yl; pyridin-4-yl or pyrimidin-2-lll; and Het is selected from pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypyridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl. A preferred group of compounds of the formulas (IA) and (IB) is that in which R1 is C 1 to C 2 alkyl optionally substituted with Het; 2- (morpholin-4-yl) ethyl or benzyl; R2 is C2 to C4 alkyl; R13 is OR3, R3 is C1 to C4 alkyl optionally monosubstituted with cyclopropyl, cyclobutyl, OH. methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl; cyclobutyl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally in the form of its 4-N-oxide; R10 is C1 to C3 alkyl optionally monosubstituted with OH; and Het select between pyridin-2-yl; 1 -oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypridridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl. Particularly preferred individual compounds of the invention include 3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin -2-yl) methyl-2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one; 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro- 7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl- 2,6-D-Hydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; (+) - 3-Ethyl-5- [5- (4-ethyl-piperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2-methyl -2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylp? Perazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyl-methoxy) pyridin-3-yl] -2- (6-methylpyridin) -2-yl) methyl-2,6-dihydro-7 H-pyrrazolo [4,3-d] pyrimidin-7-one; 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (6-methoxypyridin-2-yl) methyl-2,6- dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-Butoxy-5- (4-ethyl-piperazin-1-ylsulfonyl) pyridn-3-yl] -2,3-diethyl-2,6- dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (pyridin-2-yl) ethyl] -2,6-dihydro-7H -pyrazolo [4,3-d] pyrimidin-7-one. According to another aspect of the present invention, there are provided compounds of the formulas (IA) and (IB) as defined hereinabove, but in which R 1 is unsubstituted C 1 -alkyl; the optional substituent on the C 1 -alkyl group of R 1 is not a substituted phenyl group or a heterocyclic group attached to N; the optional substituent on the C2 or C3 alkyl group of R1 is not phenyl or Het; or where R13 is not NR5R6; or wherein the alkyl group of R3 is not C5 or Ce; or wherein the optional substituent on R3 is not C3 to C5 cycloalkyl; or wherein neither the alkyl substituents nor the optional alkoxyl substituents on R3 are terminated with a halogenoalkyl group; or wherein the C1 to C4 alkyl groups of R5 and R6 are not substituted by C3 to C5 cycloalkyl or C1 to C4 alkoxy; or wherein the C 1 to C 4 alkyl groups of R 5 and R 6, together with the nitrogen group to which they are attached, do not form an azetidinyl group; or where Het is not an alkoxy C-i to C4 or a group HNR 5 In another aspect, the present invention provides processes for the preparation of compounds of the formulas (IA) and (IB), their pharmaceutically and veterinarily acceptable salts and pharmaceutically and veterinarily acceptable solvates of any entity, as illustrated below. Those skilled in the art will appreciate that, within certain the described procedures, the order of the synthesis stages used can be varied and this will depend, among other things, of factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediaries and the strategy of the protective group (if present) to adopt. Clearly, such factors will also influence the choice of reagent for use in said synthetic steps. Illustrative of a protecting group strategy is the route for the 2 '- (2-hydroxyethoxy) analogue (example 33), whose precursor (example 32) contains benzyl as a protective group for alcohol. It will also be appreciated that various interconversions and transformations of various substituents or conventional functional groups within certain compounds of the formulas (IA) and (IB), will provide other compounds of the formulas (IA) and (IB). Examples include alkoxide exchanges at position 2 of the 5- (pyridin-3-yl) substituent (see the conversations of example 1 in examples 4B, 9, 11, 13, 23, 24, 32 and 64 of the example 2 in example 14, example 20 in example 21, example 26 in examples 29, 65, 66, 67 and 68, example 35 in example 36, example 38 in examples 39 and 40, and of example 45 in example 46), exchange of amine in position 2 of the substituent 5- (pyridin-3-ylo) (see conversions of example 78 in examples 148 and 154) and N-oxidation of piperazine and / or pyridine (see the conversions of example 1 in example 70, example 28 in example 71 and example 4 in examples 72 and 73). The following procedures are illustrative of the general synthetic procedures that can be adopted to obtain the compounds of the invention. 1. A compound of formula (IA) or (IB) can be prepared from a compound of formula (NA) or (IIB), respectively: where Y is halogen, preferably chlorine, and R1, R2 and R13 are as previously defined for formulas (IA) and (IB), by reaction with a compound of the formula (III): R7R8NH (lll) wherein R7 and R8 are as previously defined for formulas (IA) and (IB). The reaction is generally carried out at a temperature from about 0 ° C to about room temperature, preferably in the presence of an appropriate solvent such as a Ci to C3 alkanol or dichloromethane, using an excess of (III) or another suitable base such as triethylamine, to remove the acid by-product (HY). Conveniently, this reaction lends itself to the "synthesis of high-speed analogs" (HSAS), as illustrated by examples 203 to 212 in which a particular compound of formula (IIB) is coupled to a series of readily available amines of formula (III). A compound of formula (HA) or (IIB) can be prepared from a compound of formula (IVA) or (IVB), respectively: wherein R1, R2 and R13 are as previously defined for the formulas (HA) and (IIB), by the application of known procedures, to convert an amino group to a group S02Y, where Y is also as previously defined for the formulas (HA) and (HB). For example, when Y is chlorine, by the action of approximately a two-fold excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid, at a temperature of about -25 ° C to about 0 ° C, followed by treatment with excess liquid sulfur dioxide and a solution of approximately three times excess of cupric chloride in aqueous acetic acid, at a temperature of about -15 ° C to about room temperature. When R13 contains a primary or secondary amino group, protection of said amino group with a stable acid group such as acetyl or benzyl will generally be advantageous. A compound of formula (IVA) or (IVB) can be prepared by cyclizing a compound of formula (VA) or (VB) respectively: wherein R1, R2 and R13 are as previously defined for the formulas (IVA) and (IVB). Preferably, the cyclization is mediated by a base, using an alkali metal salt of a sterically hindered alcohol or amine. For example, the required cyclization can be performed using an excess of about 1.5 to 5, preferably 3 to 5 times, of potassium t-butoxide or potassium bis (trimethylsilyl) amide, optionally in the presence of molecular sieves, in a solvent suitable for reflux temperature of the reaction mixture, or, optionally, in a sealed container at about 100 ° C When R13 is OR3 and an alcohol is selected as the solvent, the appropriate alcohol of formula R3OH should be used to avoid the potential problems associated with the alkoxide exchange at position 2 of the pyridine ring. A compound of formula (VA) or (VB) can be prepared by reducing a compound of formula (VIA) or (VI B), respectively: (VIA) (VIB) wherein R1, R2 and R13 are as previously defined for the formulas (VA) and (VB), by catalytic transfer hydrogenation methods or conventional catalytic methods. Typically, hydrogenation is achieved using a Raney nickel catalyst or a palladium catalyst such as 10% Pd on carbon, in a suitable solvent such as ethanol, at a hydrogen pressure of about 345 kPa (3.515 kg / cm2) at approximately 414 kPa (psi), at a temperature from about room temperature to about 60 ° C, preferably about 40 ° C to about 50 ° C A compound of formula (VIA) or (VIB) can be prepared by the reaction of a compound of the formula (VIIA) or (VIIB), respectively: (VIIA) (VIB) wherein R1 and R2 are as previously defined for the formulas (VIA) and (VIB), with a compound of the formula (HIV): (VIII) wherein R13 is also as previously defined for the formulas (VIA) and (VIB). Again, as in the case of (IVA) and (IVB), a conventional amine protecting group strategy is preferred for (VIII) when R13 contains a primary or secondary amino group.

The coupling reaction can be achieved using conventional amide bond formation techniques, for example, by the acyl chloride derivative of (HIV), in the presence of an up to about five times excess of a tertiary amine, such as triethylamine or pyridine , to act as a scavenger for the acid by-product (HY), optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at a temperature from about 0 ° C to about room temperature. For reasons of convenience, pyridine can also be used as the solvent. In particular, any one of a multitude of amino acid coupling variations can be used. For example, to the acid of formula (HIV) or a suitable salt (eg, sodium salt) thereof can be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminoprop-1-yl) carbodiimide, optionally in the presence of 1-hydroxybenzotriazole hydrate and / or a catalyst such as 4-dimethylaminopyridine, or by the use of a halotrisaminophosphonium salt such as bromotris (pyrrolidino) phosphonium hexafluorophosphate, or by the use of a salt of suitable pyridinyl such as 2-chloro-1-methylpyridinium iodide. Any type of coupling is carried out in a suitable solvent, such as dichloromethane or tetrahydrofuran, optionally in the presence of a tertiary amine, such as N-methylmorpholine or N-ethyldiisopropylamine (for example, when the compound of formula (VIIA), (VIIB) , or the activation reagent, is present in the form of an acid addition salt), at a temperaturefrom about 0 ° C to about room temperature. Preferably, 1 to 2 molecular equivalents of the activation reagent and 1 to 3 molecular equivalents of any tertiary amine present are employed. In another variation, the function of the carboxylic acid of (HIV) may be activated first using an excess of up to about 5% reactant, such as N, N-carbonyldiumazole, in a suitable solvent, for example, ethyl acetate or butan-2-one, at a temperature from about room temperature to about 80 ° C, followed by the reaction of the intermediate imidazolide with (VI IA) or (VIIB) at a temperature of about 20 ° C to about 90 ° C An alternative synthetic route, generally applicable, to obtain the compounds of the formulas (IA) and (IB) involves the incorporation of the R4 substituent in one of the first phases of the synthesis. Thus, a compound of formula (IA) or (IB) can be prepared by cyclization of a compound of formula (IXA) or (IXB) respectively: (IXA) (IXB) wherein R1, R2, R13 and R4 are as previously defined for formulas (IA) and (IB), by analogy with the previously described cyclization of the compounds of formulas (VA) and (VB). The alternative reaction conditions are to carry out the reaction with about 1.2 to 4 molecular equivalents of a sterically hindered base in a sealed container, at a temperature of about 100 ° C to about 120 ° C or, instead of an alcohol of formula R3OH, using a sterically hindered alcohol, for example, 3-methylpentan-3-ol, as a solvent, with about 1.5 to 4.5 molecular equivalents of a sterically hindered base, such as potassium t-butoxide or KHMDS and, optionally, in a sealed container at a temperature of about 120 ° C to about 150 ° C. A compound of formula (IXA) or (IXB) can be prepared by the reaction of a compound of formula (VIIA) or (VIIB) respectively, wherein R1 and R2 are as previously defined for formulas (IXA) and ( IXB), with a compound of the formula (X): wherein R13 and R14 are also as previously defined for the formulas (IXA) and (IXB), by analogy with the reactions of (VHA) or (VIIB) with the nicotinic acid derivatives of the formula (HIV) already described. The compounds having the general formula (X) can be prepared directly from compounds having the general formula (VIII), by reduction and subsequent conversion with R 4 as previously detailed in this document. 3. As mentioned above, certain compounds of the formulas (IA) and (IB) can be interconverted by the induction of exchange or displacement of the alkoxide at the 2-position of the 5- (pyridin-3-yl) substituent. (i) When R13 or OR3, this can be achieved by treating the appropriate alcohol with an alkali metal salt of an alcohol or sterically hindered amine, to generate the required alkoxide anion which then reacts with the substrate. Typically, in a two-step process, a mixture of about 5 to about 8 molecular equivalents of potassium bis (trimethylsilyl) amide and the alcohol required as the solvent is heated to a temperature of about 80 ° C to about 100 ° C for about 0.5 to 1 hour, followed by the addition of the compound of formula (IA) or (IB) and the heating of the reaction mixture at a temperature of from about 100 ° C to about 120 ° C. Alternatively, in a one-stage process, the substrate can be treated directly, in the alcohol required as the solvent, with from about 1.2 to about 6, preferably from about 4 to about 6 molecular equivalents of, for example, potassium bis (trimethylsilyl) amide or potassium t-butoxide, at a temperature of about 80 ° C to about 130 ° C. An additional variation uses the alcohol required as solvent, saturated with ammonia, at about 100 ° C in a sealed container, (ii) When R13 is NR6, the substrate can be treated with an excess of R5R6NH, or with an acid addition salt thereof, in the presence of an excess of a sterically hindered amine, in a suitable solvent. Typically, R5R6NH is used as the free base with an approximately 3-fold excess (relative to the substrate) of potassium bis (trimethylsilyl) amide (KHMDS) in dimethylformamide (DMF) as the solvent, at about 100 ° C. Alternatively, an excess of R5R6NH may be used as the solvent and the reaction may be carried out in the presence of an excess of about 50% copper (II) sulfate, at a temperature up to the reflux temperature of the reaction medium. When the desired amino substituent of the compound of the formula (IA) or (IB) is -NR5R6 and one of R5 or R6 is H, then the exchange reaction can be carried out by heating under reflux with the appropriate amine, and copper sulfate ( ll) penta- or hepta-hydrate or KHDMS in DMF. Typically, to exchange the OR3 group for alternative amines of the formula NHR5R6, such as the compounds in which R5 or R6 are selected from aliphatic or cyclic amines, optionally containing oxygen, then the reaction is preferably carried out by treatment with the amine and about 3 equivalents of potassium bis (trimethylsilyl) amide in DMF, for about 18 hours at 100 ° C. 4. Obviously, for certain compounds of formulas (IA) and (IB) in which R13 or OR3, taking advantage of the cyclolation and alkoxide exchange methodology described above, it can be particularly advantageous to generate a compound of formula (IA) or (IB) from a compound of formula (IXA) or (IXB), respectively, wherein the 2-alkoxy group of the substituent 5- (pyridin-3-yl) in the first compound is different from the latter, directly in " a reaction of a container ". When the alcohol is used to provide the new group 2-alkoxy is too scarce or expensive to be used as a reaction solvent, then it will be convenient to use a suitable alternative such as 1,4-dioxane. 5. An additional synthetic route, generally applicable, to obtain the compounds of the formula (IA) and (IB), involves the incorporation of the substituent R1 in the final stage of the synthesis. Thus, a compound of the formula (IA) or (IB) can be prepared by the alkylation of a compound of the formula (IA) or (IB), wherein R1 is hydrogen and R2, R13 and R4 are as defined previously for formulas (lA) or (IB), using one or more of a plethora of well-known procedures, such as: (i) the reaction with a compound of formula R1X, wherein R1 is as previously defined for the formulas (IA) and (IB) and X is a group suitable projection, for example, halo (preferably chlorine, bromine or iodine), C 1 -C 4 alkanesulfonyloxy, trifluoromethanesulfonyloxy or arylsulfonyloxy (such as benzenesulfonyloxy or p-toluenesulfonyloxy), in the presence of an appropriate base, optionally in the presence of sodium iodide or potassium iodide , at a temperature of about -70 ° C to about 100 ° C. Preferably, the alkylation is carried out at a temperature from about room temperature to about 80 ° C. Suitable base-solvent combinations may be selected from: (a) sodium, potassium or cesium carbonate, sodium or potassium bicarbonate or a tertiary amine such as triethylamine or pyridine, together with a Ci to C4 alkanol, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, acetonitrile, pyridine, dimethylformamide or N, N-dimethylacetamide; (b) sodium or potassium hydroxide, or a sodium or potassium C 1 to C 4 alkoxide, water or mixtures thereof; (c) lithium, sodium or potassium hydride, lithium, sodium or potassium bis (trimethylsilyl) amide, lithium diisopropylamide or butyllithium, together with toluene, ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxane; or (d) under conditions of phase transfer catalysis, a halide or tetraalkylammonium hydroxide, together with a mixture of an aqueous solution of sodium or potassium hydroxide and dichloromethane, 1,2-dichloroethane or chloroform; (i) reaction with a compound of formula R1OH, wherein R1 is as previously defined for formulas (IA) and (IB), using the Classical Mitsunobu methodology. Typical reaction conditions involve the treatment of the substrate with the alkanol, in the presence of a triarylphosphine and dialkyl azodicarboxylate (Ci to C4), in a suitable solvent such as tetrahydrofuran or 1,4-dioxane, at a temperature of about - 5 ° C at about room temperature. Typically, an excess of about 10% sodium hydride is added to a solution of the substrate in a suitable solvent, for example, anhydrous tetrahydrofuran, and the resulting anion is treated with an excess of about 10% of the required R1X. A compound of formula (IA) or (IB) wherein R 1 is hydrogen and R2, R3 and R4 are as previously defined for the formulas (IA) and (IB), can be obtained from a compound of the formula (IXA) or (IXB), respectively, where R1 is hydrogen and R2, R13 and R4 are as previously defined for formulas (IXA) and (IXB), under the same conditions as those used for the conversion of a compound of the formula (IXA) or (IXB) into a compound of the formula (IA) or (IB), respectively, when R1 is other than hydrogen, followed by acidification of the reaction mixture at a pH of about 6. The amines of the formula (III), the 4-aminopyrazole-5-carboxamides of the formulas (VIIA) and (HBV) and the carboxylic acids of the formulas (HIV) and ( X), the nitriles of the formula (XIII) and the esters of the formula (XVI), when they can not be purchased on the market or as described below, can be obtained by analogy with the procedures described in the section of preparations or by conventional synthetic methods, according to conventional textbooks on organic chemistry or the above literature, from readily available starting materials and using appropriate reagents and reaction conditions. In addition, those skilled in the art will be aware of the variations and alternatives to the procedures described below in the examples and preparations sections, which allow obtaining the compounds defined by the formulas (IA) and (IB). The pharmaceutically acceptable acid addition salts of the compounds of the formulas (IA) and (IB) which contain a basic center can also be prepared in a conventional manner. For example, a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt is isolated by filtration or by vacuum evaporation of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of the formula (IA) or (IB) with the appropriate base. The two types of salt can be formed or interconverted using ion exchange resin techniques. The biological activities of the compounds of the present invention were determined by the following test procedures.

Inhibitory activity of phosphodiesterase (PDE) The inhibitory activities of PDE in vitro against guanosine 3 ', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) were determined by measuring their values of CI or (the concentration of compound required for 50% inhibition of enzyme activity.) The required PDE enzymes were isolated from a variety of sources, including human cavernous bodies, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the procedure of WJ 10 Thompson and MM Appleman (Biochem., 1971, 10, 311) .In particular, PDE specific for cGMP (PDE5) and cAMP PDE inhibited by cGMP (PDE3) were obtained from human cavernous body tissue, human platelets or rabbit platelets, cGMP-stimulated PDE (PED2) was obtained from human cavernous bodies, calcium / calmodulin-dependent PDE (Ca / CAM) (1DE1) from human cardiac ventricle; and cAMP-specific PDE (PDE4) of human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina. The tests were performed using a modification of the "discontinuous" procedure 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 tested in vitro by determining the ability of a compound of the invention to increase the relaxation induced by sodium nitrocyanide from tissue strips of contracted rabbit cavernous bodies, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, US (supl.), Abstract 153P).

In vivo activity The compounds were investigated in anesthetized dogs to determine their capacity, after iv administration, to enhance the pressure elevations in the corpora cavernosa of the penis, induced by intracavernous injection of sodium nitroprusside, using a procedure based on that described by Trigo-Rocha et al. (Neurourol. And Urodyn., 1994, 13, 71). In human therapy, the compounds of the formulas (IA) and (IB), their pharmaceutically acceptable salts and the pharmaceutically acceptable solvates of any entity, can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with respect to the desired administration route and conventional pharmaceutical practice. Preferably, they are administered orally in the form of tablets containing excipients such as starch or lactose, in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing agents flavors or colorants. They can also be injected parenterally, for example, intracavernous, intravenous, intramuscular or subcutaneous. For parenteral administration, it is best to use them in the form of a sterile aqueous solution which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with the blood. For buccal or sublingual administration, they can be administered in the form of tablets or lozenges that can be formulated in a conventional manner. The compounds can also be administered intranasally or formulated for dermal application. For oral, parenteral, buccal and sublingual administration to patients, the daily dosage level of the compounds of the formulas (IA) and (IB) and their pharmaceutically acceptable salts and solvates, may be from 10 to 500 mg (in one single dose or in divided doses). Thus, for example, the tablets or capsules may contain from 5 to 250 mg of active compound for single administration, or two or more at a time, as appropriate. In any case, the doctor will determine the most appropriate actual dose for an individual patient, and this will vary with the age, weight and response of the particular patient. The above doses are exemplary of the average case; Of course, there may be individual cases where larger or smaller dosage intervals are required, and such ranges are within the scope of the invention. The skilled person will also appreciate that in the treatment of certain conditions (including MED and FSD), the compounds of the invention can be taken as a single dose on a "when necessary" basis (that is, when necessary or desired). Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example, in the MED, avoiding the well-known drawbacks associated with intracavernosal administration (i.c). A preferred oral dosage regimen in the MED for a typical man is 25 to 250 mg of compound when required. In the circumstances in which the recipient suffers from a disorder that prevents swallowing or that impedes the absorption of the drug after oral administration, the drug can be administered parenterally, sublingually or buccally. For veterinary use, a compound of formula (Ia) or (IB), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of any entity, is administered as a formulation suitably acceptable in accordance with normal veterinary practice, and the veterinarian will determine the dosage regimen and the most appropriate route of administration for a particular animal. Thus, the invention provides a pharmaceutical composition comprising a compound of formula (IA) or (IB), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, together with a pharmaceutically acceptable diluent or carrier. In addition, it provides a veterinary formulation that comprises a compound of formula (IA) or (IB), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate thereof, or a veterinarily acceptable solvate of any entity, together with a veterinarily acceptable diluent or carrier. The invention also provides a compound of formula (IA) or (IB), a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament. In addition, it provides a compound of formula (IA) or (IB), a veterinarily acceptable salt thereof, a veterinarily acceptable solvate of any entity, or a veterinary formulation containing any of the foregoing, for use as an animal medicament. In still another aspect, the invention provides the use of a compound of formula (IA) or (IB), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any kind, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which an inhibitor of cGMP PDE5 is indicated. In addition, there is provided the use of a compound of formula (IA) or (IB) or a suitable salt or solvate thereof, in the manufacture of a medicament for the treatment of a medical condition in which the inhibition of a cGMP is desirable. PDE5. It also provides the use of a compound of the formula (IA) or (I), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of any entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated. In addition, the invention provides the use of a compound of the formula (IA) or (IB), of a pharmaceutically acceptable salt thereof, or of a pharmaceutically acceptable solvate containing any amount, for the manufacture of a human medicament for the treatment or prophylactic treatment of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outflow tracts, incontinence, stable angina, unstable variable (Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, blood vessels patency reduction conditions (for example, after a transluminal coronary angioplasty (post-PTCA), asthma chronic, bronchitis, allergic asthma, allergic rhinitis, glaucoma and diseases characterized by motilide disorders d of the intestine (for example, irritable bowel syndrome (IBS)). Other conditions that may be mentioned include pre-eclampsia, Kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral neuropathy, cerebrovascular accidents, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, esophagus cracked, anal fissure and vasoconstriction hypoxic Particularly preferred conditions include MED and FSD. In addition, it provides the use of a compound of the formula (IA) or (IB), a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate containing any entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outflow tracts, incontinence, stable, unstable and variable angina (Prinzmetal) , hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, blood vessel patency reduction conditions (eg, post-PTCA), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by bowel motility disorders (eg, IBS). Other conditions that may be mentioned include pre-eclampsia, Kawasaki syndrome, nitrate tolerance, multiple sclerosis, diabetic peripheral neuropathy, cerebrovascular accidents, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, esophagus cracked, anal fissure and hypoxic vasoconstriction. Particularly preferred conditions include MED and FSD. In addition, the invention provides a method for the treatment or prevention of a medical condition for which a cGMP PDE inhibitor is indicated, in a mammal (including a human), which comprises administering to said mammal a therapeutically effective amount of a compound of the formula (IA) or (IB), a pharmaceutically or veterinarily acceptable salt thereof, a pharmaceutically or veterinarily acceptable solvate of any entity, or a pharmaceutical composition or veterinary formulation that contains any of the above. In addition, the invention provides a method of treatment or prevention of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outflow tracts , incontinence, stable angina, unstable and variable (Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, diseases of reduced blood vessel permeability (eg, post-PTCA), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by disorders of bowel motility in a mammal (including a human), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), a pharmaceutically or veterinarily acceptable salt thereof, a pharmaceutically or veterinarily acceptable solvate of any entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing. The invention also includes any new described intermediate in this document, for example, those of the formulas (HA), (IIB), (VAT), (IVB), (IXA), (IXB), (VA) and (VB). The syntheses of the compounds of the invention and intermediates for use in this document are illustrated by the following examples and preparations. The 1H nuclear magnetic resonance (NMR) spectra were recorded using a Varian Unity 300 or Varian Inova 400 spectrometer and in all cases coincided with the proposed structures. The characteristic chemical shifts (?) Are provided 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. The mass spectra (m / z) were recorded using a Fisons Instruments Trxo mass spectrometer in the heat-ionization ionization mode. Ambient temperature means 20 to 25 ° C.

EXAMPLE 1 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo | .3-d1pyrimidin-7-one Alternative A A dispersion of 60% sodium hydride in mineral oil (14.3 mg, 0.36 mmol) was added to a stirred suspension of the compound of title of preparation 44 (150 mg, 0.325 mmol) in anhydrous tetrahydrofuran (5 ml) under nitrogen. After 1 hour, a solution of 2- (chloromethyl) pyridine (45.5 mg, 0.36 mmol) in tetrahydrofuran (1 ml) was added, the reaction mixture was heated at 40 ° C for 16 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (15 ml) and water (5 ml). The organic phase was separated, combined with a dichloromethane extract (20 ml) of the aqueous phase, dried (gS04) and evaporated under reduced pressure. The residual yellow foam was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent, followed by HPLC using a 5 μm Spherisorb silica column with water: acetonitrile: diethylamine (50:50). : 0.1) as eluyende, at a rate of 1 ml / min, to give the title compound (30 mg, 17%) in the form of a white foam,? (CDCl 3): 1.03, (3H, t), 1.30 (3H, t), 1, 57 (3H, t), 2.40 (2H, q), 2.53 (4H, m), 3.05 (2H q), 3.12 ( 4H, m), 4.75 (2H, q), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.64 (1H, m), 8.56 (1H, d), 8.64 ( 1H, s), 9.04 (1 H, s), 10.65 (1 H, s). LRMS: m / z 553 (M + 1) +.

Alternative B A mixture of the title compound of preparation 45B (17.4 g, 30.5 mmol) and potassium bis (trimethylsilyl) αmidide (7.28 g, 36.5 mmol) in ethanol (155 ml) was heated to 120 ° C in a sealed container for 10 hours, allowed to cool and evaporated under reduced pressure. The residue was suspended in Water (200 ml), the suspension was extracted with dichloromethane (2 x 300 ml) and the combined extracts were dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent, to give a clear yellow foam (11.2 g, 66%) which was crystallized from diisopropyl ether-methanol to produce the composed of the title in the form of a crystalline solid. Found: C: 55.58; H, 5.90; N, 19.58. C26H32N8O4S; 0.50 H20 requires C, 55.60; H, 5.92; N, 19.95%.

EXAMPLE 2 5- [2-Ethoxy-5- (4-methyl-piperazin-1-ylsulfonyl) -pyridin-3-ill-3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo | 3-d1-pyrimidin-7-one 1-Methylpiperazine (0.2 ml, 1.8 mmol) was added dropwise to a stirred suspension of the title compound of preparation 63 (450 mg, 0.92 mmol) in ethanol (40 ml), the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution (30 ml) and ethyl acetate (90 ml), then the organic phase was separated, washed with brine (2 x 20 ml), dried (Na 2 S 4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel, using a gradient elution of dichloromethane: methanol (100: 0 to 96: 4), followed by recrystallization from hexane-ethyl acetate to provide the title compound (340 mg, 67%) as a white solid. Found: C, 55.90; H, 5.85; N, 20.04. C26H32N8O4S; 0.50 H20 requires C, 55.60, H, 5.92; N, 19.95%. ? (CDCl 3): 0.94 (3H, t), 1.58 (3H, t), 1.74 (2H, m), 2.27 (3H, s), 2.40 (4H, m), 2.99 (2H, t), 3.14 (4H, m), 4.69 (2H, q), 5.68 (2H, s), 7.09 (1H, d), 7.23 (1H, m), 7.63 (1H, m), 8.58 (1H, d), 8.63 (1H , s), 9.03 (1H, s), 10.64 (1H, s). LRMS: m / z 552 (M) +.

EXAMPLE 3 3-Ethyl-5- [2-methoxy-ethoxy) -5- (4-methyl-piperazin-1-ylsulfonyl) pyridin-3-yl] -2- (pyridin-2-yl) ) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Triethylamine (83 μL, 0.59 mmol) and 1-methylpiperazine (36 mg, 0.356 mmol) were added to a stirred and ice-cooled suspension of the title compound of Preparation 64 (150 mg, 0.30 mmol) in dichloromethane (10 mL). ) and the rean mixture was stirred for 2 hours at room temperature. The resulting mixture was washed with water (5 ml), dried (gSÜ4) and evaporated under reduced pressure to give a beige solid which was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol ( 98: 2 to 95: 5), followed by trituration with ether, to yield the title compound (145 mg, 85%) as a white solid. Found: C, 54.53, H, 5.69; N, 19.38. C2eH32N805S requires C, 54.92; H, 5.67; N, 19.71%. ? (CDCI3): 1.30 (3H, t), 2.28 (3H, s), 2.50 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 3.57 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.68 (2H, S), 7.09 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.58 (1H, d), 8.62 (1H, s), 8.97 (1H, s), 10.81 (1H, s). LRMS: m / z 569 (M + 1) +.

EXAMPLE 4 3-Ethyl-5- [5- (4-ethy1-piperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-α-2- (pyridine- 2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyridimidin-7-one Alternative A Potassium t-butoxide (56 mg, 0.50 mmol) was added to a stirred solution of the title compound of preparation 45 A (200 mg, 0.35 mmol) in 2-methoxyethanol (10 mL), the rean mixture was stirred refluxed for 2 hours and then allowed to cool. A saturated aqueous solution of ammonium chloride (1 ml) was added, followed by water (5 ml) and the mixture was extracted with ethyl acetate (2 x 10 ml). The combined extracts were dried (MgSO) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to produce the title compound (11 mg, 5%) as a solid,? (CDCl 3): 1.03 (3H, t), 1.30 (3H, t), 2.41 (2H, q), 2.54 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 3.56 (3H, s), 3.87 (2H, t), 4.78 (2H, t), 5.69 (2H, s), 7.10 (1H, d), 7.21 (1H, m), 7.61 (1H, m), 8.56 (1H , d), 8.62 (1H, s), 8.95 (1H, s), 10.82 (1H, s). LRMS: m / z 583 (M) +.

Alternative B A mixture of potassium bis (trimethylsilyl) amide (16.58 g, 83 mol) and 2-methoxyethanol (250 ml) was stirred at 90 ° C for 30 minutes and then allowed to cool. Then the title compound of Example 1 (9.21 g, 16.7 mmol) was added and the rean mixture was stirred at 110 ° C for 6 hours. The resulting mixture, when cooled, was evaporated under reduced pressure, the residue was dissolved in water (300 ml) and the solution was neutralized to pH 7 with 2 M hydrochloric acid and then extracted with ethyl acetate (3 x 200 ml. ). The combined extracts were washed with brine (3 x 200 ml), dried (Na 2 S 4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent, followed by trituration with ether, crystallization from ethyl acetate and recrystallization from acetone, to produce a solvate (with acetone). of the title compound (7.7 g, 79%) as colorless crystals, mp 171.5-173 ° C. Found: C55.59; H, 5.94; N, 18.78. C27H34N8? 5S; 0.125 C3H60 requires C, 55.72; H, 5.94; N, 19.00%. The product was suspended in water (200 ml), enough 2 M hydrochloric acid was added to get the solution and then the solution was washed with ether (3 x 50 ml) and neutralized with saturated aqueous sodium bicarbonate solution. The resulting precipitate was collected, washed with water and dried at 80 ° C to yield a hemihydrate of the title compound (5.99 g, 61.6%) as a white solid, m.p. 139-140 ° C. Found: C, 54.74; H, . 92; N, 18.86. C27H34N8O5S, 0.50 H20 requires C, 54.81; H, 5.96; N, 18.94%.

EXAMPLE 5 3-Ethyl-5-. { 2-methoxyethoxy) -5- [4- (prop-1-yl) piperazin-1-ylsulfonyl-pyridin-3-H} -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidn-7-one Obtained as a yellow foam (88%) from the title compound of preparation 64 and 1- (prop-1-yl) piperazine dibromhydrate, using the procedure of Example 3. Found: C, 56.12; H, 6.06; N, 18.62. C ^ HseNsOsS requires C, 56.36; H, 6.08; N, 18.78%. ? (CDCl 3): 0.86 (3H, t), 1.30 (3H, t), 1.43 (2H, m), 2.30 (2H, t), 2.53 (4H, m), 3.04 (2H, q), 3.12 (4H, m), 3.57 (3H, s), 3.88 (2H, t), 4.78 (2H, t), 5.68 (2H, s), 7.10 (1H, d), 7.23 (1H, m), 7.62 (1H , m), 8.58 (1 H, d), 8.62 (1 H, s), 8.97 (1 H, s), 10.81 (1 H, s). LRMS: m / z 597 (M + 1 f.

) EXAMPLE 6 3-Ethyl-5- 2- (2-methoxyethoxy) -5- [4- (prop-2-yl) piperazin-1-α-sulfonyl-pyridin-3-yl > -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white powder (78%) from the title compound of preparation 64 and 1- (prop-2-ll) piperazine, using the procedure of Example 3. Found: C, 55.95; H, 6.06; N, 18.46. CüsHseN? OsS requires C, 56.36; H, 6.08; N, 18.78%. ? (CDCI3): 1.00 (6H, 2xd), 1. 30 (3H, t), 2.61 (4H, m), 2.68 (1H, m), 3.02 (2H, q), 3.12 (4H, m), 3.57 (3H, s), 3.86 (2H, t), 4.79 (2H, t), 5.68 (2H, s), 7.10 (1 H, d), 7.22 (1H, m), 7.62 (1 H, m), 8.58 (1H, d), 8.62 (1 H, s) , 8.97 (1 H, s), 10.71 (1 H, s). LRMS: m / z 597 (M + 1) +.

EXAMPLE 7 5-. { 5- 4- (2-Aminoethyl) piperazin-1-ylsulfonyl-2- (2-methoxyethoxy) pyridin-3-yl} -3- ethyl-2- (pyridin-2-yl) methyl-2,6-d -hydro-7H-pyrrazolo [4.3-dlpyrimin-7-one] A solution of the title compound of preparation 64 (100 mg, 0.198 mmol) in dichloromethane (10 ml) was added dropwise over 1 hour to a stirred solution of 1- (2-aminoethyl) piperazine (102 mg, 0.79 mmol) ) in dichloromethane (10 ml) and the reaction mixture was stirred for a further 1 hour at room temperature. The resulting mixture was washed with water (10 ml), dried (MgSO 4) and evaporated under reduced pressure to give a beige solid, which was purified by column chromatography on silica gel, using an elution gradient of dichloromethane. : methanol: ammonia 0.88 (90: 10: 0 to 90: 10: 1), to yield the title compound (104 mg, 88%) as a white foam,? (CDCI3): 1.29 (3H, t), 2.43 (2H, t), 2.54 (4H, m), 2.74 (2H, t), 3.04 (2H, q), 3.12 (4H, m), 3.56 (3H, s), 3.88 (2H, t), 4.79 (2H, t), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.56 (1H, d) ), 8.62 (1H, s), 8.99 (1H, s). LRMS: m / z 598 (M + 1) +.

EXAMPLE 8 5- [5- (4-Ethylpiperazin-1-sulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-3-n-propyl-2- (pyridn-2-yl) ) methyl-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7-one] Potassium t-butoxide (104 mg, 0.97 mmol) was added to a stirred suspension of the title compound of Preparation 53 (380 mg, 0.618 mmol) in 3-methylpentan-3-ol (30 mL) and the mixture of The reaction was heated to reflux for 1 hour and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual yellow gum was partitioned between dichloromethane (20 ml) and saturated aqueous sodium bicarbonate solution (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and the combined extracts were dried (g SÜ4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to give the title compound (75 mg, 13%) as a white foam. ,? (CDCl 3): 0.93 (3H, t), 1.04 (3H, t), 1.73 (2H, m), 2.41 (2H, q), 2.54 (4H, m), 2.97 (2H, t), 3.13 (4H, m), 3.56 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.68 (2H, s), 7.08 (1H, d), 7.21 (1H, m), 7.61 (1H , m), 8.54 (1H, d), 8.62 (1H, s), 8.97 (1H, s), 10.80 (1H, s). LRMS: m / z 597 (M + 1) +.

EXAMPLE 9 5- [2- (2-Ethoxyethoxy) -5- (4-tylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro- 7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of potassium bis (trimethylsilyl) amide (434 mg, 2. 2 mmol) and 2-ethoxyethanol (2 ml) was heated at 90 ° C for 30 minutes and then allowed to cool. A solution of the title compound of Example 1 (153 mg, 0.27 mmol) in 2-ethoxyethanol (2 ml) was added and the reaction mixture was stirred at 110 ° C for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual brown oil was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, to yield the title compound (110 mg, 68%) in shape of a yellow foam,? (CDCI3): 1.04 (3H, t), 1.31 (6H, m), 2.41 (2H, q), 2.54 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 3.72 (2H, q), 3.90 (2H, t), 4.78 (2H, t), 5.67 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1H , d), 8.62 (1 H, s), 8.99 (1 H, s), 10.78 (1 H, s). LRMS: m / z 597 (M + 1f.

EXAMPLE 10 5- [2- (2-Ethoxyethoxy) -5- (4-etl-piperazin-1-ylsulfonyl) pyridin-3-yl-3-n-propyl-2- (pyridin-2-yl ) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of potassium t-butoxide (110 mg, 0.98 mmol), the title compound of Preparation 54 (400 mg, 0.63 mmol) and 3-methylpentan-3-ol (5 mL) was stirred at 150 ° C for 3 hours. hours and then left to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (5 ml) and ethyl acetate (5 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol: aqueous ammonia 0.88 (99: 1: 0.5 to 98: 2: 0.5), to yield the title compound (74 mg, 12%) in the form of a white foam. Found: C, 56.92; H, 6.33; N, 17.80. C? Hs? N? OüS requires C, 57.21; H, 5.96, N, 18.41%. ? (CDCl 3): 0.94 (3H, t), 1.03 (3H, t), 1.30 (3H, t), 1.72 (2H, m), 2.41 (2H, q), 2.54 (4H, m), 3.14 (4H, m), 3.72 (2H, q), 3.90 (2H, t), 4.78 (2H, t), 5.67 (2H, s), 7.09 (1H, d), 7.22 (1H, m), 7.62 (1 H, m), 8.57 (1H, d), 8.62 (1H, s), 8.98 (1H, s), 10.77 (1H, s).

EXAMPLE 11 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxyprop-1-oxo-pyridin-3-ill-2- (pyridin-2-yl) methyl-2.6 -dihydro-7H-pyrrazolo [4.3-d1pyrimidin-7-one] A mixture of the title compound of Example 1 (200 mg, 0.36 mmol), potassium bis (trimethylsilyl) amide (361 mg, 1.81 mmol) and 3-methoxypropan-1-ol (1.5 mL) was heated at 90 ° C for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (97: 3 to 95: 5), to give the title compound ( 81 mg, 38%) in the form of a foam. Found: C, 55.36; H, 6.11; N, 18.18. CajHseN? OjS, 0.50 H20 requires C, 55.52; H, 6.16; N, 18.50%. ? (CDCI3): 1.01 (3H, t), 1.29 (3H, t), 2.19 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 3.02 (2H, q), 3.12 (4H, m), 3.39 (3H, s), 3.65 (2H, t), 4.76 (2H, t), 5.68 (2H, s), 7.09 (1H, d), 7.21 (1H, m), 7.62 (1H, m ), 8.56 (1H, d), 8.62 (1H, s), 8.93 (1H, s), 10.84 (1H, s). LRMS m / z 597 (M + 1) +.

EXAMPLE 12 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (3-methoxyprop-1-oxy) pyridin-3-yl-3-n-propyl-2- (pyridin-2-yl ) methyl-2,6-dihydro-7H-pyrrazolo [4.3-dlpyrimidin-7-one] Obtained as a foam (26%) from the title compound of preparation 55, using the procedure of Example 10.

Found: C, 56.86; H, 6.47; N, 17.78. C29H38N8O5S requires C, 57.04; H, 6.27; N, 18.35%. ? (CDCl 3): 0.93 (3H, t), 1.02 (3H, t), 1.72 (2H, m), 2.20 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 2.97 (2H, t), 3.12 (4H, m), 3.40 (3H, s), 3.65 (2H, t), 4.77 (2H, t), 5.67 (2H, s), 7.08 (1H, d), 7.21 (1H , m), 7.61 (1H, m), 8.58 (1H, d), 8.62 (1 H, s), 8.94 (1H, s), 10.83 (1 H, s). LRMS m / z 611 (M + 1) +.

EXAMPLE 13 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methoxyprop-2 (S) -oxy) pyridin-3-yl] -2- ( pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyridimidin-7-one Obtained as a foam (33%) from the title compound of Example 1 and 1-methoxypropan-2 (S) -ol (J. Chem. Soc, Perkin Trans. I, 1996, 1467), using the procedure of Example 9, but with ether: methanol: aqueous ammonia 0.88 (97: 3: 1) as the chromatographic eluent. Found: C, 55.91; H, 6.17; N, 18.10. C-? Hs? N? OsS; 0.50 H20 requires C, 55.52; H, 6.16; N, 18.50%. ? (CDCI3): 1 04 (3H, t), 1.30 (3H, t), 1.52 (3H, d), 2.42 (2H, q), 2.56 (4H, m), 3.04 (2H, q), 3.14 (4H , m), 3.55 (3H, s), 3.66 (1 H, dd), 3.74 (1 H, dd), 5.60 (1 H, m), 5.68 (2H, s), 7.08 (1H, d), 7.21 (1 H, m), 7.62 (1 H, m), 8.57 (1 H, d), 8.61 (1 H, s), 8.89 (1 H, s), 10.85 (1 H, s). LRMS m / z 597 (M + 1f.

EXAMPLE 14 5- [2- (2-Methoxyethoxy) -5- (4-methylpiperazin-1-Hsulfonyl) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl-2.6- dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of potassium bis (tr? Methylsilyl) amide (460 mg, 2.3 mmol) and 2-methoxyethanol (40 ml) was stirred at 90 ° C for 30 minutes and then allowed to cool. The title compound of Example 2 (270 mg, 0.46 mmol) was added and the reaction mixture was stirred at 110 ° C for 5 hours, allowed to cool and evaporated under reduced pressure. The residue was suspended in After water (20 ml), the pH was adjusted to 7 with hydrochloric acid and the resulting solution was extracted with ethyl acetate (3 x 30 ml). The combined extracts were washed with brine (3 x 20 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 a). 96: 4), followed by crystallization from hexane-ethyl acetate, to give the title compound (200 mg, 75%) as a white solid. Found C, 54.83; H, 5.83; N, 18.90. C27H34N8O5S; 0.50 H20 requires C, 54.81; H, 5.96; N, 18.94%. ? (CDCl 3): 0.94 (3H, t), 1.74 (2H, m), 2.28 (3H, s), 2.50 (4H, m), 2.98 (2H, t), 3.15 (4H, m), 3.57 (3H, s), 3.87 (2H, t), 4.80 (2H, t), 5.68 (2H, s) 7.08 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.57 (1H, d), 8.64 (1H, s), 8.96 (1H, s), 10.80 (1H, s ). LRMS m / z 583 (M + 1) +.

EXAMPLE 15 5- [2-. { 1,3-Dimethoxyprop-2-oxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) nr? ethyl-2,6-dihydro-7H-pyrrazolo [4.3-dlpyrimidin-7-one] A mixture of the title compound of preparation 72 (70 mg, 0.10 mmol), potassium t-butoxide (23 mg, 0.20 mmol) and 3-methylpentan-3-ol (3 mL) was stirred under reflux for 4 hours, then it was cooled and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (98: 2) as eluent, to give the title compound (6 mg, 9%) as an off-white solid,? (CDCl 3): 0.93 (3H, t), 1.03 (3H, t), 1.72 (2H, m), 2.42 (2H, q), 2.55 (4H, m), 2.98 (2H, t), 3.16 (4H, m), 3.50 (6H, s), 3.77 (2H, m), 3.86 (2H, m), 5.68 (3H, m), 7.08 (1H, d), 7.21 (1H, m), 7.62 (1H, m ), 8.57 (1H, d), 8.61 (1H, s), 8.84 (1H, s), 10.87 (1H, s). LRMS m / z 641 (M + 1) +.

EXAMPLE 16 3-Ethyl-5-f5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl-1- (pyridin-2-yl) methyl -1.6-d-Hydro-7H-pyrazolo [4.3-d1-pyrimidin-7-one] Obtained as a white solid (50%) from the title compound of preparation 65, using the procedure of Example 10. Found: C, 55.45, H, 5.91; N, 18.94. C27H3 N805S: C, 55.66; H, 5.88; N, 19.23%. ? (CDCl 3): 1.02 (3H, t), 1.40 (3H, t), 2.42 (2H, q), 2.56 (4H, m), 3.00 (2H, q), 3.16 (4H, m), 3.55 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.95 (2H, s), 7.01 (1H, d) ), 7.17 (1H, m), 7.60 (1H, m), 8.57 (1H, d), 8.62 (1H, s), 9.02 (1H, s), 11.04 (1H, s). LRMS m / z 583 (M + 1) +.

EXAMPLE 17 3-Ethyl-5- [5- (4-etllperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) -lox) pi? Din- 3- ill-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Obtained as a solid (29%) from the title compound of Preparation 56, using the procedure of Example 10. Found: C, 55.85, H, 5.98; N, 17.86. C28H34N8O5S; 0.20 H 0; 0.10 CH2Cl2 requires C, 55.24; H, 5.73; N, 18.41%. ? (CDCl 3): 1.02 (3H, t), 1.28 (3H, t), 2.40 (4H, m), 2.55 (4H, m), 3.02 (2H, q), 3.13 (4H, m), 4.00 (2H, m), 4.16 (2H, m), 5.68 (2H, s), 5.86 (1H, m), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.56 (1 H, d), 8.63 (1 H, s), 8.98 (1 H, s), 10.42 (1 H, s). LRMS: m / z 594 (M) +. [?] D25 -13.8 ° (c = 0.10, CH3OH).

EXAMPLE 18 3-Ethyl-5- [5- (4-tylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7-one] Obtained as a solid (24%) from the title compound of preparation 75, using the procedure of Example 10.

Found: C, 55.32, H, 5.82; N, 17.70. C28H34N8? 5S; H20; requires C, 54.88; H, 5.92; N, 18.29%. ? (CDCl 3): 1.02 (3H, t), 1.28 (3H, t), 2.40 (4H, m), 2.55 (4H, m), 3.02 (2H, q), 3.13 (4H, m), 4.00 (2H, m), 4.16 (2H, m), 5.68 (2H, s), 5.86 (1H, m), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.56 ( 1 H, d), 8.63 (1 H, s), 8.98 (1 H, s), 10.42 (1 H, s). LRMS: m / z 595 (M + 1) +. [?] D25 + 14.0 ° (c = 0.14, CH3OH).

EXAMPLE 19 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrodan-4-yloxy) pyridin-3-yl-3-n-propyl-2- (p. Ridin-2-yl) methyl-2,6-dihydro-7H-pyrazolof4.3-d] pyrimidin-7-one Obtained as a white solid (30%) from the title compound of preparation 76, using the procedure of example 10.? (CDCb): 0.94 (3H, t), 1.03 (3H, t), 1.73 (2H, m), 2.01 (2H, m), 2.22 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 2.98 (2H, t), 3.12 (4H, m), 3.66 (2H, m), 4.06 (2H, m), 5.60 (1H, m), 5.69 (2H, s), 7.10 (1H, d), 7.22 (1 H, m), 7.63 (1 H, m), 8.57 (1 H, d), 8.61 (1 H, s), 9.01 (1 H, s), 10.55 (1 H, s). LRMS: m / z 623 (M + 1) +.

EXAMPLE 20 3-Ethyl-5- [5- (4-methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl] -2- (pyridin-3-ill-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one T-Butoxide (540 mg, 4.8 mmol) was added to a stirred solution of the title compound of Preparation 52 (683 mg, 1.2 mmol) in n-propanol (10 mL), the reaction mixture was stirred at reflux for 18 h. hours and then left to cool. The resulting mixture was evaporated under reduced pressure and the residual oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to yield the title compound (290 mg , 44%) in the form of a foam. Found: C, 56.32, H, 6.04; N, 19.36. C26H32N8? 4S requires C, 56.50; H, 5.83; N, 20.27%. ? (CDCI3): 1.02 (3H, t), 1.30 (3H, t), 1.98 (2H, m), 2.38 (3H, s), 2.50 (4H, m), 3.04 (2H, q), 3.13 (4H, m), 4.64 (2H, t), 5.69 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.30 (1H, m), 8.58 (1H, d), 8.63 (1H , s), 9.04 (1 H, s), 10.66 (1 H, s). LRMS: m / z 553 (M + 1) +.

EXAMPLE 21 3-Ethyl-5- [5- (4-methyl-piperazin-1-ylsulfonyl) -2- (prop-2-oxi) pyridin-3-yl-2- (pyridin-2- il) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Potassium t-butoxide (290 mg, 2.60 mmol) was added to a stirred solution of the title compound of Example 20 (239 mg, 0.43 g. mmoles) in propan-2-ol (7 ml) under nitrogen, the reaction mixture was heated to reflux for 48 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (20 ml) and ethyl acetate (20 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5), to yield the title compound (84 mg, 35%) as a foam ,? (CDCb): 1.28 (3H, t), 1.56 (6H, 2xd), 2.28 (3H, s), 2.50 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 5.68 (3H, m), 7.09 (1 H, d), 7.22 (1 H, m), 7.62 (1 H, m), 8.57 (1 H, s), 8.62 (1 H, s), 9.02 (1 H, s), 10.68 (1 H, s). LRMS: m / z 553 (M + 1) +.

EXAMPLE 22 3-Ethyl-5- [5- (4-ethyl piperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-yl-2- ( pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7-one] A mixture of the title compound of preparation 45A (200 mg, 0.35 mmol), 60% sodium hydride dispersion in mineral oil (400 mg, 10 mmol) and propan-2-ol (20 ml) was stirred at reflux for 18 hours and then it was allowed to cool. A saturated aqueous solution of ammonium chloride (20 ml) was added, the resulting mixture was extracted with ethyl acetate (3 x 50 ml), then the combined extracts were washed with aqueous sodium bicarbonate (150 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound (11 mg, 6%) as a foam. ? (CDCb): 1.04 (3H, t), 1.30 (3H, t), 1.56 (6H, 2xd), 2.1 (2H, q), 2.55 (4H, m), 3.04 (2H, q), 3.13 (4H, m), 5.68 (3H, m), 7.10 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.57 (1H, d), 8.62 (1H, s), 9.02 (1 H, s), 10.68 (1H, s). LRMS: m / z 567 (M + 1) +.

EXAMPLE 23 5- [2-n-Butoxy-5-? 4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d1pyrimidin-7-one A mixture of the title compound of example 1 (200 mg, 0.36 mmol), potassium bis (trimethylsilyl) amide (360 mg, 1.81 mmol) and n-butanol (5 ml) was stirred at 100 ° C for 18 hours and then it was allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (5 ml) and dichloromethane (5 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (2 x 10 ml), then the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel, using dichloromethane: methanol (97.5: 2.5) as eluent, to give the title compound (145 mg, 69%) as a white solid.

Found: C, 57.43; H, 6.29; N, 18.82. C28H36N8? 4S; 0.20 H20 requires C, 57.56; H, 6.28; N, 19.18%. ? (CDCl 3): 1.03 (6H, 2xt), 1.30 (3H, t), 1.55 (2H, m), 1.94 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.13 (4H, m), 4.67 (2H, t), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.56 (1 H, d), 8.62 (1 H, s), 9.01 (1 H, s), 10.64 (1 H, s). LRMS: m / z 581 (M + 1) +.

EXAMPLE 24 5- [2-i-Butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-ethyl-2-pyridin-2-yl) methyl-2. 7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (67%) from the title compound of Example 1 and i-butanol, using the procedure of Example 23. Found: C, 57.25; H, 6.24; N, 18.84. C28H36N804S; 0.20 H20 requires C, 57.56; H, 6.28; N, 19.18%. ? (CDCb): 1.03 (3H, t), 1.12 (6H, d), 1.30 (3H, t), 2.30 (1H, m), 2.40 (2H, q), 2.55 (4H, m), 3.04 (2H , q), 3.13 (4H, m), 4.45 (2H, d), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.58 ( 1 H, d), 8.62 (1 H, s), 9.02 (1 H, s), 10.63 (1 H, s). LRMS: m / z 581 (M + 1) +.

EXAMPLE 25 5- [2-Cyclobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-y-3-ethyl-2- (pyridin-2-yhmethyl) 2.6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of the title compound of the preparation 45A (200 mg, 0.35 mmol), cyclobutanol (144 mg, 2 mmol), potassium t-butoxide (80 mg, 0.70 mmol) and 1,4-dioxane (5 mL), was heated to reflux for 24 hours and then let cool. The resulting mixture was poured into a stirred aqueous solution of sodium bicarbonate (20 ml) and this mixture was extracted with ethyl acetate (3 x 20 ml). The combined extracts were dried (MgSO 4) and evaporated under reduced pressure, and then the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4), provide the title compound (9 mg, 4%) as a solid,? (CDCb): 1.03 (3H, t), 1.29 (3H, t), 1.78 (2H, m), 1.98 (2H, m), 2.35 (2H, m), 2.55 (6H, m), 3.04 (2H, q), 3.12 (4H,), 5.48 (1H, m), 5.68 (2H, s), 7.10 (1H, d), 7.23 (1H, m), 7.63 (1H, m), 8.56 (1H , d), 8.60 (1 H, s), 9.01 (1 H, s), 10.67 (1H, s). LRMS: m / z 579 (M + 1) +.

EXAMPLE 26 5-f2-Ethoxy-5- (4-ethylpip? Razin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H -pyrazolo [4.3-d1pyrimidin-7-one] Potassium t-butoxide (2.38 g, 21.2 mmol) was added to a solution of the title compound of Preparation 77 (3.1 g, 5.3 mmol) in absolute ethanol (95 mL), the reaction mixture was heated to 100 ° C in 100 ° C. a sealed container for 40 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressureThe residue was dissolved in water (20 ml) and the aqueous solution was acidified to pH 5 with 2 M hydrochloric acid. The aqueous suspension thus obtained was extracted with dichloromethane (3 x 30 ml) and the combined extracts were dried (MgSO4). and evaporated under reduced pressure. The residual brown foam was purified by silica gel column chromatography, using an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound (1.39 g, 46%) as a foam. ,? (CDCb): 0.93 (3H, t), 1.02 (3H, t), 1.58 (3H, t), 1.74 (2H,), 2.40 (2H, q), 2.54 (4H, m), 2.98 (2H, t ), 3.13 (4H,), 4.75 (2H, q), 5.68 (2H, s), 7.09 (1H, d), 7.23 (1H, m), 7.63 (1H, m), 8.58 (1H, d), 8.63 (1 H, s), 9.02 (1 H, s), 10.64 (1 H, s).

EXAMPLE 27 Trichlorohydrate of 5-. { 5- [4- (3-dimethylaminoprop-1-yl) piperazin-1-ylsulfonyl-1-2-ethoxypyridin-3-yl} -n-propyl-2- (pyridin-2-ylmethyl-2,6-dihydro-7H-pyrazolo [4.3- d] pyrimidin-7-one) A solution of freshly distilled 1- (3-dimethylalanoprop-1-yl) plperazine (J. Chem. Soc. (C), 1971, 132: 160 mg, 0.93 mmol) in ethanol (2 ml) was added. To a stirred solution of the title compound of Preparation 63 (230 mg, 0.467 mmol) in ethanol (10 mL), the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was suspended in aqueous sodium bicarbonate solution (30 ml), the suspension was extracted with acetate (3 x 30 ml) and the combined extracts were washed with brine (2 x 30 ml), dried (Na2SO4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 90:10) and then the product was dissolved in the minimum volume of ethyl acetate. A saturated solution of ethereal hydrogen chloride was added and the resulting white precipitate was collected, triturated with ether and dried under suction to yield the title compound (140 mg, 37%) as a white solid. Found: C, 44.45; H, 6.34; N, 15.38. C38H4? Ng04S; 3 HCl; 4 H20 requires C, 44.45; H, 6.51; N, 15.66%. ? (DMSOde): 0.86 (3H, t), 1.34 (3H, t), 1.64 (2H, m), 2.12 (2H, m), 2.72 (6H, 2x), 2.95 (2H, t), 3.00 (2H, m), 3.12 (2H, t), 3.18 (2H, m), 3.56 (2H, m), 3.84 (2H, m), 4.50 (2H, q), 5.75 (2H, s), 7.27 (1H, d), 7.42 (1H, m), 7.90 (1H, m), 8.28 (1H, s), 8.57 ( 1H, d), 8.73 (1H, s), 10.63 (1H, s), 11.47 (1H, s), 11.96 (1H, s). LRMS: m / z 624 (M + 1) \ EXAMPLE 28 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl] -3-n-propyl-2- (pyridin-2-H) methyl-2,6-dihydro -7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a colorless solid (40%) from the title compound of preparation 80, using the procedure of Example 20. Found: C, 57.16; H, 6.15; N, 18.85. C28H36N8? S requires C, 57.03; H, 6.32; N, 19.00%. ? (CDCb): 0.94 (3H, t), 1.02 (3H, t), 1.13 (3H, t), 1.74 (2H, m), 1.98 (2H, m), 2.40 (2H, q), 2.54 (4H, ), 2.98 (2H, t), 3.12 (4H, m), 4.62 (2H, t), 5.66 (2H, s), 7.09 (1H, d), 7.21 (1H, m), 7.62 (1H , m), 8.57 (1 H, d), 8.62 (1 H, s), 9.02 (1H, s), 10.63 (1H, s). LRMS: m / z 582 (M + 1) +.

EXAMPLE 29 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-ill-3-n-propyl-2- (pyridin-2-yl) methyl -2.6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Obtained as a solid (48%) from the title compound of Example 26 and propan-2-ol, using the procedure of Example 21.? (CDCb): 0.94 (3H, t), 1.03 (3H, t), 1.57 (6H, d), 1.74 (2H, m), 2.41 (2H, q), 2.56 (4H, m), 2.98 (2H, t), 3.12 (4H, m), 5.68 (3H, m), 7.08 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.57 (1 H, d), 8.63 (1H, s), 9.02 (1 H, s), 10.67 (1 H, s). LRMS: m / z 581 (M + 1) +.

EXAMPLE 30 5-. { 2-Ethoxy-5- [4- (2-hydroxyethyl) piperazin-1-ylsulfonylpyridin-3-yl} -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolof4.3-dlpyrimidin-7-one Obtained as a white solid (49%) from the title compound of preparation 63 and 1- (2-hydroxyethyl) piperazine, using the procedure of example 2. Found: C, 55.48 H, 5.93; N, 18.85. G27H34N8O5S; 0.10 C H802 requires C, 55.64; H, 5.93; N, 18.94%. ? (CDCl 3): 0.95 (3H, t), 1.59 (3H, t), 1.75 (2H, m), 2.28 (1H, s), 2.58 (2H, m), 2.65 (4H, m), 3.00 (2H , t), 3.16 (4H, m), 3.60 (2H, t), 4.76 (2H, q), 5.68 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.62 (1 H, d), 8.58 (1 H, d), 8.64 (1H, s), 9.04 (1 H, s), 10.66 (1H, s). LRMS: m / z 583 (M + 1) +.

EXAMPLE 31 5-. { 2-Ethoxy-5- [4- (3-hydroxprop-1-yl) p-piperazin-1-ylsulfonyl-1-pyridin-3-yl} -3-n-propyl-2- (pyridin-2-yl) -methyl-2,6-dihydro-7H-pyrazolo [43.3-dlpyrimidin-7-one] Obtained as a white solid (52%) from the title compound of preparation 63 and 1- (3-h? Droxiprop-1-yl) piperazine, using the title procedure example 2. Found: C, 56.27; H, 6.13; N, 18.38. C28H3eN805S requires C, 56.36; H, 6.08; N, 18.78%. ? (CDCb): 0.94 (3H, t), 1.60 (3H, t), 1.72 (4H, m), 2.63 (6H, m), 2.98 (2H, t), 3.12 (4H, m), 3.72 (2H, t), 4.15 (1 H, s), 4.77 (2 H, q), 5.69 (2 H, s), 7.08 (1 H, m), 7.23 (1 H, m), 7.63 (1 H, m), 8.58 ( 1 H, d), 8.61 (1 H, s), 9.01 (1 H, s), 10.67 (1 H, s). LRMS: m / z 596 (M + 1) +.

EXAMPLE 32 5- [2- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-ethyl-2- (pyridin-2-yl) methyl- 2.6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a yellow oil (57%) from the title compound of example 1 and 2-benzyloxyethanol, using the procedure example 11.? (CDCb): 1.02 (3H, t), 1.32 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 3.04 (2H, q), 3.13 (4H, m), 3.94 (2H, t), 4.76 (2H, s), 4.80 (2H, t), 5.69 (2H, s), 7.11 (1H, d), 7.20-7.37 (4H, m), 7.41 (2H, m), 7.64 (1H , d), 8.60 (2H, s), 8.98 (1 H, s), 10.80 (1 H, s). LRMS: m / z 659 (M + 1) +.

EXAMPLE 33 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl-2-. {2-hydroxyethoxy) pyridin-3-ill-2- (pyridin-2-yl) methyl-2,6-dihydro- 7H-pyrazolo [4.3-dlpyrimidin-7-one] Ammonium formate (62 mg, 0.99 mmol) was added to a mixture of the title compound of example 32 (130 mg, 0.197 mmol), 10% palladium on carbon (15 mg) and acetone (9 ml) and the reaction mixture. it was stirred under reflux for 14 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 90:10), to give the title compound (18 mg, 16%) in the form of a solid,? (CD3OD): 1.06 (3H, t), 1.28 (3H, t), 2.44 (2H, q), 2.58 (4H, m), 3.06 (2H, q), 3.14 (4H, m), 3.97 (2H, t), 4.68 (2H, t), 5.75 (2H, s), 7.20 (1H, d), 7.36 (1H, m), 7.80 (1H, m), 8.54 (2H, m), 8.68 (1H , s). LRMS: m / z 569 (M + 1) +.

EXAMPLE 34 5- [2- (2-Benzyloxyethoxy) -5- (4-tylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-n-propyl-2- (pyridin-2-yl) methyl- 2.6-dihydro-7H-pyrrazolo [4.3-dlpyrimidin-7-one A stirred mixture of the title compound of Preparation 84 (500 mg, 0.72 mmol), potassium bis (trimethylsilyl) amide (347 mg, 3.09 mmol) and 3-methylpentan-3-ol (8 mL) was heated to reflux for 3 hours. hours and then it was allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (10 ml) and dichloromethane (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by two column chromatography operations on silica gel, using first dichloromethane: methanol: 0.88 aqueous ammonia (90: 10: 1) and then a gradient of ethyl acetate: methanol (100: 0 a). 80:20) as eluents, to produce the title compound in the form of an oil,? (CDCb): 0.92 (3H, t), 1.02 (3H, t), 1.73 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 2.99 (2H, t), 3.10 (4H, m), 3.84 (2H, t), 4.58 (2H, s), 4.78 (2H, t), 5.68 (2H, s), 7.09 (1H, d), 7.18-7.42 (6H, m), 7.62 (1H , m), 8.55 (1H, d), 8.61 (1H, s), 8.97 (1H, s), 10.81 (1H, s). LRMS: m / z 673 (M + 1) +.

EXAMPLE 35 2-Benzyl-5-f2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-etl-2,6-dihydro-7H- pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white foam (27%) from the title compound of preparation 87, using the procedure of example 10.? (CDCb): 0.90 (3H, t), 1.03 (3H, t), 1.28 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 2.94 (2H, q), 3.12 (4H, m), 4.75 (2H, q), 5.58 (2H, s), 7.22 (2H, m), 7. 31 (3H, m), 8.62 (1H, s), 9.01 (1H, s), 10.65 (1H, s). LRMS: m / z 552 (M + 1) +.

EXAMPLE 36 2-Benzyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-Hl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin- 7-one Obtained in the form of a cream colored foam (80%) from the title compound of example 35 and 2-methoxyethanol, using the procedure of example 9. Found: C, 57.05; H, 6.19; N, 16.15. C28H35N7? 5S; 0.10 CH2Cl2 requires C, 57.19; H, 6.01; N, 16.61%. ? (CDCb): 1.02 (3H, t), 1.27 (3H, t), 2.40 (2H, q), 2.55 (4H, m), 2.94 (2H, q), 3.13 (4H, m), 3.57 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.56 (2H, s), 7.22 (2H, m), 7.32 (3H, m), 8.61 (1H, s), 8.96 (1H, s), 10.80 (1 H, s) EXAMPLE 37 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (1-methylimidazol-2-yl) methyl-2, 6-Hydro-7H-pyrazolo [4.3-dlpyrirnidin-7-one] Obtained in the form of a foam (33%) from the compound of preparation 90, using the procedure of example 10.? (CDCb): 1.05 (3H, t), 1.34 (3H, t), 2.41 (2H, q), 2.54 (4H, m), 3.13 (4H, m), 3.19 (2H, q), 3.57 (3H, s), 3.79 ( 3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.65 (2H, s), 6.84 (1 H, s), 7.00 (1H, s), 8.62 (1 H, s), 8.94 (1H, s), 10.83 (1 H, s). LRMS: m / z 586 (M + 1) +.

EXAMPLE 38 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonihpyridin-3-ill-2- (1-methylimidazol-2-yl) methyl-3-n-propyl-2,6-dihdrone -7H-pyrazole [4.3-dlpyrimidin-7-one] A mixture of the title compounds of preparation 28 (232 mg, 0.58 mmol) and preparation 92 (152 mg, 0.58 mmol), triethylamine (403 μL, 2.9 mmol) and dichloromethane (8 mL), was stirred at room temperature for 18 hours. Brine (20 ml) was added and the resulting mixture was extracted with dichloromethane (2 x 20 ml), then the combined extracts were dried (MgSO 4) and evaporated under reduced pressure. A stirred solution of this potassium bis (trimethylsilyl) amide intermediate (305 mg, 1.53 mmol) in ethanol (10 ml) was heated at 100 ° C for 14 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol, (95: 5) as eluent, to give the title compound (163 mg, 49%) as of a yellow oil,? (CDCb): 0.96 (3H, t), 1.01 (3H, t), 1.57 (3H, t), 1.72 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 3.13 (6H, m), 3.77 (3H, s), 4.75 (2H, q), 5.67 (2H, s), 6.85 (1H, s), 7.00 (1 H, s), 8.63 (1H, s), 9.00 (1 H, s), 10.65 (1H, s). LRMS: m / z 570 (M + 1) +.

EXAMPLE 39 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- (1-methylimidazol-2-yl) methyl-3-n-propyl -2.6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a solid (61%) from the title compound of Example 38 and 2-methoxyethanol, using the procedure of Example 9.? (CDCb): 0.97 (3H, t), 1.02 (3H, t), 1.74 (2H, m), 2.41 (2H, q), 2.55 (4H, m), 3.14 (6H, m), 3.57 (3H, s), 3.76 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.66 (2H, s), 6.86 (1 H, s), 7.00 (1 H, s), 8.62 (1H , s), 8.94 (1H, s), 10.82 (1H, s). LRMS: m / z 600 (M + 1) +.

EXAMPLE 40 5-f2-n-Butoxy-5- (4-ethy1-piperazin-1-ylsulfonyl) pyridin-3-yl1-2- (1-methylimidazol-2-yl) methyl-3-n-propyl- 2.6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Obtained in the form of a cream colored foam (76%) from the title compound of Example 38 and n-butanol, using the procedure of Example 9. Found: C, 54.83; H, 6.74; N, 20.08. C28H39Ng0 S; H20 requires C, 54.62; H, 6.71; N, 20.47%. ? (CDCl 3): 0.93 (3H, t), 1.00 (6H, m), 1.54 (2H, m), 1.77 (2H, m), 1.92 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 3.12 (6H, m), 3.76 (3H, s), 4.66 (2H, t), 5.67 (2H, s), 6.85 (1H, s), 6.98 (1H, s), 8.62 (1H, s) ), 8.97 (1 H, s), 10.64 (1 H, s). LRMS: m / z 599 (M + 1) +.

EXAMPLE 41 5- [5- (4-Ethyl-piperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-yl-3-n-propyl-2- (pyridazin- 3-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Preparation 98 (230 mg, 0.38 mmol), potassium t-butoxide (258 mg, 2.3 mmol) and propan-2-ol (10 mL) was heated in a sealed container at 100 ° C. for 24 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure, then the residue was purified by two column chromatography operations on silica gel, first using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) and then a ethyl acetate: methanol elution gradient (90:10 to 80:20), to yield the title compound (42 mg, 19%), to yield the title compound (42 mg, 19%) as a orange gum,? (CDCb): 0.93 (3H, t), 1.01 (3H, t), 1.55 (6H, d), 1.75 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 3.02 (2H, t), 3.12 (4H, m), 5.67 (1H, m), 5.88 (2H, s), 7.47 (2H, m), 8.60 (1H, s), 8.98 (1H, s), 9.16 (1H, s) ), 10.70 (1H, s). LRMS: m / z 582 (M + 1) +.

EXAMPLE 42 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-y-3-n-propyl-2- ( pyrimidin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a yellow foam (14%) from the title compound of preparation 102b, using the procedure of Example 10.? (CDCb): 0.99 (3H, t), 1.03 (3H, t), 1.81 (2H, m), 2.42 (2H, q), 2.55 (4H, m), 2.97 (2H, t), 3.14 (4H, m), 3.54 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.80 (2H, s), 7.22 (1H, m), 8.62 (1H, s), 8.70 (2H, d), 8.99 (1 H, s), 10.72 (1 H, s). LRMS: m / z 597 (M + 1) +.

EXAMPLE 43a 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-n-propyl-1-? Pyrirr? Idin-2-yl) methyl-1.6- Hydro-7H-p -razolof4.3-dlpyrimidin-7-one and EXAMPLE 43b 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-2-n-propyl) 2- (pyrimidin-2-yl) methyl-2,5-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of the title compounds of Preparation 103a and Preparation 103b (390 mg, 0.66 mmol), potassium t-butoxide (224 mg, 2.0 mmol), 4A molecular sieves and ethanol (10 mL) was heated in a sealed container for 18 hours at 100 ° C, then let cool and filtered. The filtrate was evaporated under reduced pressure and the residual n oil was suspended in dichloromethane (25 ml). This mixture was washed with water (5 ml), dried (MgSO 4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (99: 1). to 95: 5) to give an orange foam. This product was further purified by HPLC using a Magellan C-is column and methanol: water: diethylamine (50: 50: 0.1) as eluent, at a rate of 20 ml / min, to produce the first title compound (isomer-1) 20 mg) in the form of a white solid. ? (CDCb): 1.04 (6H, m), 1.58 (3H, t), 1.88 (2H, m), 2.42 (2H, q), 2.57 (4H,), 2.98 (2H, t), 3.14 (4H, m ), 4.75 (2H, q), 6.07 (2H, s), 7.18 (1H, m), 8.64 (3H, m), 9.10 (1 H, s), 10.75 (1 H, s). LRMS: m / z 568 (M + 1) +; followed by the second title compound (isomer-2; 20 mg) as a white solid,? (CDCl 3): 1.02 (6H, m), 1.58 (3H, t), 1.82 (2H, m), 2.42 (2H, q), 2.55 (4H, m), 2.98 (2H, t), 3.15 (4H, m), 4.74 (2H, q), 5.80 (2H, s), 7.23 (1H, m), 8.63 (1H, s), 8.70 (2H, m), 9.03 (1H, s), 10.56 (1 H, s). LRMS: m / z 568 (M + 1) +.

EXAMPLE 44 5- [2-Ethoxy-5- (4-etl-piperazin-1-ylsulfonyl) pyridin-3-yl-3-n-propyl-1- (pyridn-2) - il) methyl-1,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of the title compound of preparation 105 (304 mg, 0.52 mmole), potassium t-butoxide (175 mg, 1.56 mmole) and Ethanol (10 ml) was heated at 100 ° C in a sealed container for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual n oil was partitioned between dichloromethane (15 ml) and water (5 ml). The phases were separated and then the organic phase was dried (MgSO 4) and evaporated under reduced pressure to give a n foam which was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent, provide the title compound (230 mg, 78%) as a white foam. Found: C, 56.93; H 6.03; N, 19.42. C27H34N80 S requires C, 57.22; H 6.04; N, 19.77%. ? (CDCb): 1.01 (3H, t), 1.59 (6H, m), 1.86 (2H, m), 2.42 (2H, q), 2.57 (4H, m), 2.97 (2H, t), 3.16 (4H, m), 4.74 (2H, q), 5.94 (2H, s), 7.02 (1H, d), 7.18 (1H, m), 7.60 (1H, m), 8.57 (1H, d), 8.63 (1H , s), 9.10 (1 H, s), 10.85 (1H, s). LRMS: m / z 567 (M + 1) +.

EXAMPLE 45 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-ethyl-1 - (1-methylimidazol-2-yl) methyl-1,6-dihydro -7H-pyrazolo [4.3-d] pyrirnidin-7-one Obtained as a light yellow solid (60%) from the compound the title of preparation 107, using the procedure of Example 44.? (CDCb): 1.02 (3H, t), 1.38 (3H, t), 1.59 (3H, t), 2.41 (2H, q), 2.56 (4H, m), 2.97 (2H, q), 3.15 (4H, m), 3.78 (3H, s), 4.75 (2H, q), 5.89 (2H, s), 6.85 (1H, s), 7.00 (1H, s), 8.64 (1H, s), 9.07 (1H, s) ), 10.87 (1H, s). LRMS: m / z 556 (M + 1) \ EXAMPLE 46 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl-1- (1-methylimidazol-2-yl) methyl-1,6-dih Dro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of the title compound of Example 45 (150 mg, 0.27 mmol), potassium t-butoxide (126 mg, 1.1 mmol) and 2-methoxyethanol (6 mL) was heated to reflux for 48 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol: aqueous ammonia 0.88 (90: 10: 1) as eluent. The product was triturated with diisopropyl ether, the mixture was filtered and the filtrate was evaporated under reduced pressure to yield the title compound (43 mg, 27%) as a foam,? (CDCl 3): 1.10 (3H, t), 1.36 (3H, t), 2.52 (2H, q), 2.65 (4H, m), 2.96 (2H, q), 3.22 (4H, m), 3.56 (3H, s), 3.75 (3H, s), 3.86 (2H, t), 4.78 (2H, s), 5.92 (2H, s), 6.85 (1H, s), 7.01 (1H, s), 8.63 (1H, s) ), 8.99 (1H, s), 11.10 (1H, s). LRMS: m / z 585 (M + 1) +.

EXAMPLE 47 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-1 - (1-methylimidazol-2-yl) methyl-3 -n-propyl-1,6-dihydro-7H-pyrazolo [4.3-1pyrimidin-7- ona Obtained as a solid (11%) from the title compound of preparation 109, using the procedure of Example 10. Found: C, 52.43; H, 6.11; N, 20.12. C27H37N905S; H20 requires C, 52.50; H, 6.36; N, 20.41%. ? (CDCb): 0.98 (3H, t), 1.03 (3H, t), 1.81 (2H, m), 2.41 (2H, q), 2.55 (4H, m), 2.90 (2H, t), 3.15 (4H, m), 3.58 (3H, s), 3.75 (3H, s), 3.86 (2H, t), 4.78 (2H, t), 5.92 (2H, s), 6.85 (1H, s), 7.00 (1H, s ), 8.63 (1H, s), 9.00 (1H, s), 11.07 (1H, s). LRMS: m / z 600 (M + 1) +.

EXAMPLE 48 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-m-toxy-toxy) pyridin-3-yl] -3-n-propyl-1- (pyrimidin-2-yl) methyl-1,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Obtained as a yellow foam (5%) from the title compound of preparation 102a, using the procedure of Example 10.? (CDCb): 1.02 (6H, m), 1.86 (2H, m), 2.42 (2H, q), 2.56 (4H, m), 2. 97 (2H, t), 3.17 (4H, m), 3.54 (3H, s), 3.83 (2H, t), 4.77 (2H, t), 6.09 (2H, s), 7. 16 (1H, s), 8.65 (3H, m), 9.03 (1H, s), 11.00 (1H, s). LRMS: m / z 598 (M + 1) +.

EXAMPLE 49 5- 2-Ethoxy-5- [4- (pyrrolidin-1-ylcarbonimethyl) piperazin-1-ylsulfonylpyridin-3-yl} -3-n-propyl-2- (pyridin-2-yl) methyl-2.? - dihydro-7H-pyrazolo [4.3-dlpyridin-7- ona] A mixture of the title compound of Preparation 63 (350 mg, 0.715 mmol), 1- (pyrrolidin-1-ylcarbonylmethyl) piperazine (150 mg, 0.715 mmol) and ethanol (40 mL) was stirred at room temperature for 18 hours and then under reduced pressure. The residue was suspended in aqueous sodium bicarbonate solution (30 ml) and the suspension was extracted with ethyl acetate (3 x 30 ml). The combined extracts were washed with brine (3 x 20 ml), dried (Na 2 SO) and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give an oil, which was triturated with ether to yield the title compound (240 mg, 52%) in the form of a colorless foam. Found: C, 56.79; H, 6.30; N, 18.49. C3? H38N9? 5S; 0.50 H20; 0.25 C4H10O requires C, 56.75; H, 6.32; N, 18.61%. ? (CDCb): 0.94 (3H, t), 1.60 (3H, t), 1.66-1.86 (4H, m), 1.92 (2H, m), 2.68 (4H, m), 2.98 (2H, t), 3.14 ( 2H, s), 3.18 (4H, m), 3.32-3.46 (4H, m), 4.75 (2H, q), 5.70 (2H, s), 7.18 (1H, d), 7.22 (1H, m) , 7.62 (1 H, s), 8.58 (1H, d), 8.63 (1H, s), 9.00 (1H, s), 10.66 (1H, s). LRMS: m / z 650 (M + 1) +.

EXAMPLE 50 5- [2-Ethoxy-5- (4-allyl-2 (S). 5 (R) -dimethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-n-propyl- 2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolof4.3-d] pyrimidin-7-one A solution of (-) - 1-allyl-2 (R), 5 (S) -dimethylpiperazine (document WO 93/15062; 502 mg, 3.2 mmol) in ethanol (4 ml) was added dropwise to a stirred suspension of the title compound of preparation 63 (800 mg, 1.6 mmol) in ethanol and the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between aqueous sodium carbonate solution (20 ml) and ethyl acetate (20 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 20 ml). The combined organic solutions were washed with brine (20 ml), dried (Na2SO4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 98: 2), followed by trituration with ether, to yield the title compound (550 mg, 57%) in the form of a colorless foam. Found: C, 59.07; H, 6.37; N, 18.18. C3oH38N804S requires C, 59.39; H, 6.31; N, 18.47%. ? (CDCb): 0.95 (3H, t), 0.99 (3H, d), 1.24 (3H, d), 1.58 (3H, t), 1.72 (2H, m), 2.27 (1H, dd), 2.73 (1H, dd), 2.92 (1 H, m), 3.00 (4H, m), 3.20 (1H, dd), 3.48 (1H, dd), 3.85 (1 H, m), 4.75 (2H, q), 5.22 ( 2H, m), 5.68 (2H, s), 5.74 (1H, m), 7.09 (1H, d), 7.22 (1H, m), 7.62 (1H, m), 8.58 (1H, d) , 8.67 (1 H, s), 9.08 (1H, s), 10.69 (1H, s). LRMS: m / z 607 (M + 1) +.

EXAMPLE 50a 3-Ethyl-5- [5- (4-ethylpiperazine-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyl-octyl) pyridin-3-yl-2-1 (1-methylimidazol-2-H) -nr? Etl-2,6-dihydro-7H-pyrazole [4.3-d] pyrimidin-7-one Obtained as a white foam (82%), from the title compounds of preparations 165 and 170, following a procedure similar to that described in example 11. Found: C, 52.14; H, 6.15; N, 19.73. C27H37N905S; 1.5 H20 requires C, 51.74; H, 6.43; N, 20.11%. ? (CDCb): 1.02 (3H, t), 1.32 (3H, t), 1.50 (3H, d), 2.40 (2H, q), 2.56 (4H, m), 3.04-3.22 (6H, m), 3.54 ( 3H, s), 3.62-3.80 (5H, m), 5.59 (1H, m), 5.66 (2H, s), 6.83 (1H, s), 6.99 (1 H, s), 8.60 (1 H, s) , 8.84 (1 H, s), 10.87 (1 H, s). LRMS: m / z 600 (M + 1) +.

EXAMPLE 51 TO 60 A group of analogues was obtained based on the structural formula identified above, in which the substituent R10 is varied, by the technique of synthesis of high-speed analogues (HSAS) as described below. A 0.4 M solution of triethylamine in dichloromethane (100 μl, 40 μmol) was added to each well of a 96 well plate containing the required series of 1-substituted piperazines (10 μmol). A 0.1 M solution of the title compound of preparation 63 in dichloromethane (100 μL, 10 μmol) was added to each well, and then the plates were covered and stirred at room temperature for 18 hours. The reaction mixtures were filtered through a 96-well filtration block, which was washed with dichloromethane (1 ml), and then the filtrates were evaporated under reduced pressure. The residues were dissolved in dimethylsulfoxide (1 ml) and purified by HPLC using a 5? Column. Hypersil C18 (10 x 0.46 cm) with a flow rate of 4 ml / min and an elution gradient of 0.1% trifluoroacetic acid in water: acetonitrile.

In this manner, the following compounds were obtained: : point of union of R11 EXAMPLE 61 3-Ethyl-5- [2- (2-methoxyethoxy) -5- (3,4,5-trimethylpiperazin-1-ylsulfonihpyridin-3-yl) -2- (pyridin-2-yl) methyl-2,6-dihydro -7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (170 mg, 47%) from the title compound of preparation 64 and 1, 2,6-trimethylpiperazine (J. Med. Chem., 1968, 11, 592), using the procedure from example 50. Found: C, 55.78; H, 6.02; N, 18.42. C28H36N805S; 0.50 H20 requires C, 55.22; H. 6.16; N, 18.58%. ? (CDCb): 1.09 (6H, d), 1.31 (3H, t), 2.01 (5H, m), 2.36 (2H, m), 3.04 (2H, q), 3.60 (5H, m), 3.88 (2H, t), 4.79 (2H, t), 5.68 (2H, s), 7.12 (1H, d), 7.22 (1H, m), 7.64 (1H, m), 8.58 (1H, d), 8.62 (1H, s), 8.95 (1H, s), 10.79 (1 H, s). LRMS: m / z 597 (M + 1) +.

EXAMPLE 62 3-Ethyl-5-f2- (2-methoxyethoxy) -5-piperazin-1-ylsulfonyl) pyridin-3-ill-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3 -d] pyrimidin-7-one A solution of the title compound of preparation 64 (200 mg, 0.40 mmol) in dichloromethane (10 ml) was added dropwise to a stirred solution of piperazine (136 mg, 1.58 mmol) and triethylamine (100 μl, 0.79 g). mmoles) in dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 1 hour, then washed with water (10 ml), dried (MgSO 4) and evaporated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (98: 2 to 92: 8), followed by trituration with dichloromethane, to give the title compound (189 mg, 86%) as of a white foam. Found: C, 52.75; H, 5.43; N, 19.18. C25H3oN8? 5S; 0.75 H20 requires C, 52.85; H, 5.59; N, 19.72%. ? (CDCI3): 1.30 (3H, t), 2.94-3.13 (10H, m), 3.58 (3H, s), 3.88 (2H, s), 4.79 (2H, t), 5.68 (2H, s), 7.10 ( 1 H, d), 7.22 (1 H, m), 7.62 (1 H, m), 8.58 (1 H, d), 8.62 (1 H, s), 8.98 (1 H, s), 10.82 (1 H, s ). LRMS: m / z 555 (M + 1) +.

EXAMPLE 63 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl-2-rnetoxypyridin-3-yl) -2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo [4.3- dlpyrimidin-7-one A stirred mixture of the title compound of example 1 (350 mg, 0.63 mmol), potassium bis (trimethylsilyl) amide (630 mg, 3.15 mmol) and n-propanethiol (5 ml) was heated at 110 ° C in a sealed container for 48 hours, then allowed to cool and evaporated under pressure reduced. The residue was made azeotropic with dichloromethane: methanol (95: 5) and then partitioned between water (10 ml) and dichloromethane (15 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 15 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. This residue was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent, to produce the title (170 mg, 50%) as a yellow solid. Found: C, 54.50; H, 5.64; N, 19.93. C25H3oN804S; 0.75 H20 requires C, 54.38; H, 5.75; N, 20.29%. ? (CDCl 3): 1.02 (3H, t), 1.32 (3H, t), 2.40 (2H, q), 2.55 (4H, m), 3.06 (2H, q), 3.14 (4H, m), 4.26 (3H, s), 5.68 (2H, s), 7.14 (1 H, d), 7.22 (1 H, m), 7.64 (1 H,), 8.58 (1H, d), 8.66 (1 H, s), 9.05 ( 1 H, s), 10.59 (1 H, s). LRMS: m / z 540 (M + 2) +.

EXAMPLE 64 5- [2-Benzyloxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H- pyrazolo [4.3-d] p¡r¡m¡din-7-ona Potassium bis (trimethylsilyl) amide (360 mg, 1.81 mmol) was added to a stirred solution of the title compound of Example 1 (200 mg, 0.36 mmol) in benzyl alcohol (5 ml) at 100 ° C and the reaction mixture it was stirred for 14 hours and then allowed to cool. The resulting mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and the combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure. The residual benzyl alcohol was removed by Kugelrohr distillation, then the crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (97.2: 2.5) as eluent, to give the title compound (86 mg, 39% ) in the form of a white solid. Found: C, 59.92; H, 5.64; N, 17.60. C3? H34N804S; 0.40 H20 requires C, 59.87; H, 5.64; N, 18.02%. ? (CDCb): 1.05 (3H, t), 1.29 (3H, t), 2.41 (2H, q), 2.56 (4H, m), 3.05 (2H, q), 3.15 (4H, m), 5.68 (2H, s), 5.75 (2H, s), 7.10 (1H, d), 7.24 (1H, m), 7.42 (3H, m), 7.52 (2H, m), 7.64 (1H, m), 8.58 (1 H, d), 8.65 (1 H, s), 9.02 (1H, s), 10.58 (1 H, s). LRMS: m / z 615 (M + 1) +.

EXAMPLE 65 5- [5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (furan-3-methoxy) pyridin-3-yl-3-n-propyl- 2- ( pyridin-2-ylmethyl-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7-one] Potassium bis (trimethylsilyl) amide (176 mg, 0.88 mmol) was added to a stirred suspension of the title compound of Example 26 (100 mg, 0.17 mmol) in 3-hydroxymethylfuran (4 mL) and the reaction mixture was heated to a reflux for 24 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, to yield the title compound (33 mg, 31%) as a a light yellow foam,? (CDCb): 0.93 (3H, t), 1.04 (3H, t), 1.72 (2H, m), 2.41 (2H, q), 2.55 (4H, m), 2.99 (2H, t), 3.14 (4H, m), 5.63 (2H, s), 5.68 (2H, s), 6.60 (1H, s), 7.09 (1H, d), 7.22 (1H, m), 7.44 (1H, s), 7.64 (2H , m), 8.57 (1 H, d), 8.68 (1 H, s), 9.02 (1 H, s), 10.53 (1 H, s). LRMS: m / z 619 (M + 1) +.

EXAMPLE 66 5- [5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (pyridin-2-ylmethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-ylmethyl) 2.6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A stirred mixture of potassium bis (trimethylsilyl) amide (260 mg, 1. 32 mmoles) and 2-hydroxymethylpyridine (5 ml) was heated at 100 ° C for one hour, then the title compound of example 26 (150 mg, 0.2 mmol) was added and the reaction mixture was stirred at 100 ° C for 14 hours. The resulting cold mixture was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2 x 10 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure, and then the residual yellow oil was purified by column chromatography on silica gel, using dichloromethane: ethyl acetate: methanol (47.5: 47.5: 5) as eluent , to produce the title compound (35 mg, 21%) as a white solid,? (CDCb): 0.94 (3H, t), 1.03 (3H, t), 1.73 (2H, m), 2.40 (2H, q), 2.55 (4H,), 2.98 (2H, t), 3.14 (4H, m ), 5.69 (2H, s), 5.92 (2H, s), 7.07 (1 H, d), 7.21 (1 H, m), 7. 33 (2H, m), 7.62 (1 H, m), 7.76 (1 H, m), 8.58 (2H, m), 8.81 (1 H, s), 8.85 (1 H, d), 12.80 (1H, s). LRMS: m / z 630 (M + 1) +.EXAMPLE 67 5-r2- (2-Dimethylaminoethoxy) -5- (4-etiylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-n-propyl-2- (pyridin-2-yl ) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A mixture of the title compound of example 26 (200 mg, 0. 35 mmol), potassium bis (trimethylsilyl) amide (352 mg, 1.76 mmol) and 2-dimethylaminoethanol (1.5 ml), was stirred at 90 ° C for 18 hours and then allowed to cool. Water (5 ml) was added, the mixture was extracted with ethyl acetate (3 x 5 ml) and the combined extracts were dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (95: 5 to 90:10), to give the title compound (147 mg, 68%) as a foam whitish Found: C, 56.35; H, 6.37; N, 20.12%. C26H3gN9? 4S; 0.5 H20 requires C, 56.29; H, 6.52; N, 20.37%. ? (CDCb): 0.94 (3H, t), 1.04 (3H, t), 1.72 (2H, m), 2.43 (8H, m), 2.56 (4H, m), 2.74 (2H, t), 2.95 (2H, t), 3.15 (4H, m), 4.80 (2H, t). 5.67 (2H, s), 7.07 (1H, d), 7.21 (1H, m), 7.61 (1H, m), 8.56 (1H, d), 8.62 (1H, s), 8.75 (1H , s), 12.23 (1H, s). LRMS: m / z 610 (M + 1) +.

EXAMPLE 68 5-. { 5- (4-Ethyl-piperazin-1-ylsulfonyl) -2- [2- (morpholin-4-yl) -ethoxylpyridin-3-yl} -3-n-propyl-2- (pyridin-2-H) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of potassium bimes (trimethylsilyl) amide (180 mg, 0.80 mmol) and 4- (2-hydroxyethyl) morpholine (4 ml) was stirred at 100 ° C for 1 hour, then the compound of title of Example 26 (100 mg, 0.17 mmol) and the reaction mixture was stirred at 110 ° C for 18 hours. The resulting cold mixture was partitioned between water (10 ml) and dichloromethane (20 ml), the phases were separated and the organic phase was washed with water (10 ml), dried (MgSO 4) and evaporated under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol (90:10 to 80:20), to yield the title compound (33 mg, 30%) in shape of a white solid,? (CDCb): 0.95 (3H, t), 1.04 (3H, t), 1.74 (2H,), 2.42 (2H, q), 2.56 (4H, m), 2.64 (4H, m), 2.90 (2H, t ), 2.99 (2H, t), 3.15 (4H, m), 3.80 (4H, m), 4.75 (2H, t), 5.68 (2H, s), 7.12 (1H, d), 7.25 (1H, m ), 7.63 (1 H, m), 8.58 (1H, d), 8.62 (1 H, s), 8.92 (1H, s), 11.16 (1H, s). LRMS: m / z 652 (M + 1) +.

EXAMPLE 69 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (1-methylpipyridin-4-yloxy) pyridin-3-yl-3-n-propyl-2- (pyridin-2-yl ) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Cesium t-butoxide (76 mg, 0.37 mmol) was added to a stirred solution of the title compound of Preparation 119 (160 mg, 0.24 mmol) in 3-methylpentan-3-ol (5 mL), the reaction mixture it was stirred at 120 ° C for 3 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between dichloromethane (10 ml) and water (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The yellow residual oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (95: 5 to 92.5: 7), to give the title compound as a yellow foam,? (CDCb): 0.94 (3H, t), 1.03 (3H, t), 1.74 (2H, m), 2.10 (2H, m), 2.22 (2H, m), 2.42 (5H, m), 2.58 (6H, m), 2.78 (2H, m), 2.99 (2H, t), 3.13 (4H, m), 5.59 (1H, m), 5.67 (2H, s), 7.10 (1H, d), 7.22 (1H, m), 7.63 (1 H, m), 8.57 (1 H, m), 8.61 (1 H, s), 9.00 (1 H, s), 10.63 (1 H, s). LRMS: m / z 636 (M + 1) +.

EXAMPLE 70 5- [2-Ethoxy-5- (4-butyl-4-oxidopiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-2- (pyridin-2-methyl-2,6-dihydro-7H -pyrazolof4.3-d] pyrimidin-7-one A mixture of the title compound of example 1 (180 mg, 0.32 mmol), 3-chlorobenzoic acid (13 mg, 0.08 mmol) and dichloromethane (10 ml) was stirred at room temperature for 20 minutes, 3-chloroperoxybenzoic acid was added ( 112 mg, 0.32 mmole), the reaction mixture was stirred for a further 18 hours and then partitioned between dichloromethane (20 ml) and aqueous sodium bicarbonate solution (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 20 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (80:20) as eluent, to yield the title compound (82 mg, 45%) as a white powder. Found: C, 52.73; H, 5.67; N, 17.69. C26H32N? 05S; 0.50 CH2Cl2 requires C, 52.08; H, 5.44; N, 18.34%. ? (CDCb): 1.30 (3H, t), 1.40 (3H, t), 1.58 (3H, t), 3.02 (2H, q), 3.20 (2H, m), 3.32 (4H, m), 3.48 (2H, m), 3.72 (2H, m), 4.76 (2H, q), 5.68 (2H, s), 7.08 (1H, d), 7.22 (1H, m), 7.63 (1H, m), 8.58 (1H, d) ), 8.65 (1H, s), 9.03 (1H, s), 10.70 (1H, s).

EXAMPLE 71 5- [5- (4-Ethyl-4-oxidopiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl-2.6 -dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one 3-Chloroperoxybenzoic acid (93 mg, 0.27 mmol) was added to a stirred solution of the title compound of Example 28 (155 mg, 0.27 mmol) in dichloromethane (2 mL), the reaction mixture was stirred at room temperature for 2 hours , and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 aqueous ammonia (90: 10: 1) as eluent, to yield the title compound (40 mg, 25%) as a solid, ? (CDCb): 0.93 (3H, t), 1.14 (3H, t), 1.41 (3H, t), 1.72 (2H, m), 2.00 (2H, m), 2.97 (2H, t), 3.15 (2H, m), 3.31 (4H, m), 3.50 (2H, m), 3.70 (2H, m), 4.65 (2H, t), 5.68 (2H, s), 7.06 (1H, d), 7.24 (1H, m), 7.64 (1 H, m), 8.58 (1 H, d), 8.66 (1 H, s), 9.06 (1 H, s), 10.67 (1 H, s). LRMS: m / z 598 (M + 1) +.

EXAMPLE 72 3-Ethyl-5- [5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yi-2- (pyridin-2-yl) ) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyridin-7-one and EXAMPLE 73 3-Ethyl-5- [5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- (1-oxidopyridin-2-H) methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] 3-Chlorobenzoic acid (15 mg, 0.096 mmol) was added to a stirred solution of the title compound compound of Example 4 (223 mg, 0.38 mmol) in dichloromethane (3 mL) and the mixture was stirred at room temperature for 30 minutes. . Then 3-chloroperoxybenzoic acid was added (132 mg, 0.38 mmol), the reaction mixture was stirred at room temperature for 14 hours and then partitioned between dichloromethane (5 ml) and aqueous sodium bicarbonate solution (5 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (3 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient elution of dichloromethane: methanol (90:10 to 80:20), to give the first title compound (78 mg, 34%) as a solid.

Found: C, 51.77; H, 5.82; N, 17.33. C27H34N806S; 1.75 H20 requires C, 51. 46; H, 6.00; N, 17.78%. ? (CDCb): 1.28 (3H, t), 1.42 (3H, t), 3.02 (2H, q), 3. 18 (2H, m), 3.30 (4H, m), 3.50 (2H, m), 3.56 (3H, s), 3.72 (2H, m), 3.88 (2H, t), 4.80 (2H, t), 5.68 (2H, s), 7.08 (1H, d), 7.22 (1H, m), 7.64 (1H, m), 8.58 (1H, d), 8.68 (1H , s), 8.99 (1H, s), 10.84 (1 H, s); followed by the second title compound (50 mg, 22%) as a solid. Found: C, 50.15; H, 5.81; N, 16.85. C27H34N806S; 2.0 H20 requires C, 49.84; H, 5.89; N, 17.22%. ? (CDCb): 1.32 (3H, t), 1.42 (3H, t), 3.05 (2H, q), 3.18 (2H, m), 3.32 (4H, m), 3.53 (5H, m), 3.72 (2H, m), 3.86 (2H, t), 4.80 (2H, t), 5.81 (2H, s), 6.78 (1H, d), 7.22 (2H, m), 8.29 (1H, d), 8.66 (1H, s), 8.99 (1H, s), 10.90 (1H, s).

EXAMPLE 74 5- [2-Ethoxy-6- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2- (2-morpholin-4-yl) ethyl-3-n-propyl-2,6- dihydro-7H-pyrazolo [4,3-dlpyrimidin-7-one] Potassium t-butoxide (110 mg, 0.99 mmol) was added to a stirred solution of the title compound of Preparation 120 (400 mg, 0.66 mmol) in 3-methylpentan-3-ol (20 mL) and the reaction mixture was stirred. it was refluxed for 3 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue was suspended in water (10 ml) and the suspension was extracted with dichloromethane (3 x 10 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure, then the residual yellow oil was purified by column chromatography on silica gel, using dichloromethane: methanol (97.5: 2.5) as eluent, to yield the title compound ( 65 mg, 17%) in the form of a white foam. Found: C, 54.51; H, 6.95; N, 18.18. C2 H40N8O5S; 0.15 CH2CI2 requires C, 54.51; H, 6.92; N, 18.14%. ? (CDCb): 1.04 (6H, m), 1.58 (3H, t), 1.88 (2H, m), 2.41 (2H, q), 2.54 (8H, m), 2.99 (4H, m), 3.15 (4H, m), 3.68 (4H, m), 4.40 (2H, t), 4.75 (2H, q), 8.62 (1H, s), 9.04 (1H, s), 10.61 (1H, s). LRMS: m / z 589 (M + 1) +.

EXAMPLE 75 5- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- < 2- morpholin-4-yl) ethyl-3-n-propyl-2,6-dihydro-7H-pyrrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (24%) from the title compound of example 74 and 2-methoxyethanol, using the procedure of example 66. Found: C, 53.81; H, 6.93; N, 16.89. C28H42N8? 6S; 0.30 C4H802; 0.20 H20 requires C, 54.06; H, 6.96; N, 17.27%. ? (CDCb): 1.04 (6H, m), 1.87 (2H, m), 2.42 (2H, q), 2.55 (8H, m), 2.99 (4H, m), 3.16 (4H, m), 3.56 (3H, s), 3.69 (4H, m), 3.88 (2H, t), 4.40 (2H, t), 4.79 (2H, t), 8.63 (1H, s), 8.98 (1 H, s), 10.78 (1H, s). LRMS: m / z 619 (M + 1) +.

EXAMPLE 76 3-t-Butyl-5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl) -1- (pyridin-2-yl) methyl -1.6-dihydro-7H-pyrazolof4.3-dlpyrimidin-7-one A stirred mixture of the title compound of preparation 121 (150 mg, 0.25 mmol), potassium t-butoxide (71 mg, 0.625 mmol) and Ethanol (10 ml) was heated at 100 ° C for 18 hours in a sealed container and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (10 ml) and ethyl acetate (15 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 15 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (100: 0 to 95: 5) as eluent, to give the title compound (140 mg, 97%) as a white solid. Found: C, 56.30; H, 6.39; N, 18.43. C28H36N? 04S; H20 requires C, 56.17; H, 6.40; N, 18.72%. ? (CDCb): 1.04 (3H, t), 1.56 (12H, m), 2.42 (2H, q), 2.56 (4H, m), 3.16 (4H, m), 4.76 (2H, q), 5.95 (2H, s), 6.94 (1 H, d), 7.18 (1 H, m), 7.60 (1 H, m), 8.58 (1 H, d), 8.64 (1 H, s), 9.08 (1 H, s), 10.82 (1 H, s). LRMS: m / z 581 (M + 1) +.

EXAMPLE 77 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-1- (2-morpholin-4-yl) ethyl-3- n-propyl-1.6 -dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (68%) from the title compound of preparation 122, using the procedure of Example 74. Found: C, 54.59; H, 6.91; N, 18.08. C27H40N8O5S; 0.15 CH2Cl2 requires C, 54.59; H, 6.89; N, 18.08%. ? (CDCb): 1.01 (6H, m), 1.60 (3H, t), 1.84 (2H, m), 2.42 (2H, q), 2.53 (8H, m), 2.86 (2H, t), 2.94 (2H, t), 3.15 (4H, m), 3.62 (4H, m), 4.72 (4H, m), 8.63 (1 H, s), 9.09 (1H, s), 10.81 (1 H, s). LRMS: m / z 589 (M + 1) +.

EXAMPLE 78 5-f2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-etl-2-methyl-2,6-dihydro-7H -pyrazolo [4.3-dlpyrimidin-7-one] A mixture of the title compound of Preparation 152 (25.9 g, 52.5 mmol) and potassium bis (trimethylsilyl) amide (22.0 g, 110.0 mmol) in ethanol (1500 mL) was heated at 120 ° C for 18 hours in a sealed container. The cooled solution was concentrated under reduced pressure and pre-adsorbed on silica gel. The crude product was purified by column chromatography on silica gel using an elution vessel of ethyl acetate: diethylamine (97: 3 to 95: 5) and triturated with ether to yield the title compound (11.0 g, 44% ) in the form of a white solid,? (CDCb): 1.03 (3H, t), 1.40 (3H, t), 1.5 (3H, t), 2.41 (2H, q), 2.57 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 4.09 (3H, s), 4.75 (2H, q), 8.62 (1 H, s), 9.04 (1 H, s), 10.64 (1 H, s). LRMS: m / z 476 (M + 1) +.

EXAMPLE 79 5- [2-Ethoxy-5- (4-methyl-piperazin-1-ylsulfonyl) pyridin-3-y-2-methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo [ 4.3-dlpyrimidin-7-one The title compound of Preparation 151 (500 mg, 1.0 mmol) was added to a solution of potassium bis (trimethylsilyl) amide (610 mg, 3.06 mmol) in ethanol (20 mL) and the reaction was heated to 110 ° C. for 18 hours in a sealed container. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in water and neutralized with hydrochloric acid. This aqueous suspension was extracted with dichloromethane (3 x 30 ml), the combined organic extracts were washed with brine (3 x 30 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 97.5: 2.5) and triturated with ether, to yield the title compound (207 mg, 44%) in the form of a whitish solid,? (CDCb): 1.03 (3H, t), 1.59 (3H, t), 1.83 (2H, m), 2.29 (3H, s), 2. 53 (4H, m), 3.00 (2H, t), 3.16 (4H, m), 4.10 (3H, s), 4.75 (2H, q), 8.63 (1H, s), 9.06 (1 H, s), 10.65 (1 H, s). LRMS: m / z 476 (M + 1) +.

EXAMPLES 80 TO 84 The compounds of the general formula: were prepared from the appropriate pyrazole-5-carboxamides, ie, preparations 153, 154, 156, 157 and 155, respectively, following procedures similar to those described in example 79. Examples 80 to 84, R1 is methyl and R13 is -OR3. 1 = 1.5 equivalents of potassium bis (trimethylsilyl) 2 were used = dichloromethane: methanol: 0.88 ammonia (96: 4: 0.4) was used as the chromatographic eluent.

EXAMPLE 85 2-Ethyl-5-f5- (4-ethylpiperazin-1-ylsulfonyl) -2-methoxy-pyridin-3-ill-2-methyl-2,6-dihydro-7H-pyrazolo [4.3- dlpyrimidin-7-one A mixture of the title compound example 8 (100 mg, 0.21 mmol) and copper (II) sulfate heptahydrate (75 mg, 0.3 mmol) in saturated methanolic ammonia (20 ml), was heated at 100 ° C for 4 hours in a sealed container. The cooled mixture was evaporated under reduced pressure and the residue was suspended in aqueous sodium carbonate solution (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml 9, dried (Na 2 SO 4) and evaporated under reduced pressure to give a green solid The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and recrystallized from hexane / ethyl acetate / methanol to give the title compound (23 mg, 24%) as of a white solid. Found: C, 51.22; H, 5.81; N, 20.61. C20H27N7O4S; 0.5 H20 requires C, 51.0'5; H, 6.00; N, 20.84%. ? (CDCb): 1.07 (3H, t), 1.40 (3H, t), 2.40-2.65 (6H, m), 3.04 (2H, q), 3.19 (4H, m), 4.09 (3H, s), 4.24 ( 3H, s), 8.65 (1H, s), 9.05 (1H, s), 10.58 (1 H, s). LRMS: m / z 462 (M + 1) +.

EXAMPLE 86 2-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1 (R) -methyl-n-propoxy) pyridin-3-yl] -2-methyl-2,6-dihydro- 7H-pyrazolo [4.3-d] pyrimidin-7-one The title compound of Example 78 (400 mg, 0.84 mmol) was added to a mixture of potassium bis (trimethylsilyl) amide (8.40 mg, 4.2 mmol) in (R) -2-butanol (4 mL) and the reaction was stirred at 110 ° C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was suspended in water (10 ml) and neutralized using 2N hydrochloric acid. This aqueous suspension was extracted with ethyl acetate (3 x 30 ml), the The combined organic extracts were washed with sodium hydroxide solution (20 ml) and brine (2 x 30 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 97.5: 2.5 and the product was suspended in ether and evaporated under reduced pressure.This solid was recrystallized from hexane / ethyl acetate to yield the title compound (7 mg, 17%) as a white solid. [<X] D = -20.88 ° (= 0.083, dichloromethane) Found: C, 54.65; H, 6.63 N, 19.25, C23H33N704S, 0.5 H20 requires C, 53.89, H, 6.69, N, 19.13%.? (CDCb): 1.06 (6H, m), 1.40 (3H, t), 1.50 (3H, d), 1.86 (1H, m), 1.99 (1H, m), 2.42 (2H, q), 2.58 (4H, m), 3.04 (2H, q), 3.16 (4H, m), 4.09 (3H, s), 5.56 ( 1H, m), 8.62 (1H, s), 9.05 (1H, s), 10.70 (1H, s), LRMS: m / z 504 (M + 1) +.

EXAMPLES 87 TO 97 The compounds of the general formula wherein R 1 is methyl and R 13 is -OR 3: were prepared from the appropriate alcohols and pyrazolo [4,3-d] p? m? d? n-7-ones, following procedures similar to those described in Example 86. 1 = dichloromethane: methanol: 0.88 ammonia (100: 0: 0.5 to 99.5: 1: 1.5) was used as the chromatographic eluant and the compound isolated without crystallization. 2 = dichloromethane: methanol: 0.88 ammonia (100: 0: 0.5 to 99.5: 1: 1.5) was used as the chromatographic eluant and the compound was triturated with ether. 3 = isolated without crystallization.

EXAMPLE 98 2-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2- (R) -methoxy-1- (R) -methyl-propoxy) pyridin-3-ill-2- methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] (R, R) -2,3-Butanediyl (7.78 ml, 85 mmol) was added dropwise to an ice-cold solution of sodium hydride (3.79 g, 60% dispersion in mineral oil, 93.5 mmol) in ether ( 800 ml) and the solution was stirred at room temperature for 30 minutes. Iodide was added dropwise from methyl (5.6 ml, 89.3 mmol) and the reaction was stirred at reflux for 48 hours. 1,3-Dimethyl-3,4,5,6-tetrahydro-2 (IH) -pyrimidinone (10.24 mL, 85 mmol) was added and stirring was continued for a further 90 minutes under reflux. The cooled reaction was washed with aqueous ammonium chloride solution (500 ml), dried (MgSO 4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ether pentane (10:90 to 50:50) to give a light yellow oil. The title compound of Example 78 (100 mg, 0.2 mmol, and potassium bis (trimethylsilyl) amide (121 mg, 0.61 mmol) in the intermediate alcohol (1 mL) was heated at 110 ° C for 30 hours, and then The reaction was cooled and concentrated under reduced pressure.The residual brown solid was purified by column chromatography on silica gel using diethylamine: ethyl acetate (5:95) as eluent and repeated using ethyl methanoacetate (5:95). ) as eluent The product was triturated with ether to yield the title compound (7 mg, 6%) as a white solid,? (CDCb): 1.03 (3H, t), 1.25 (3H, d), 1.40 (3H, t), 1.48 (3H, d), 2.41 (2H, q), 2.55 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.52 (3H, s), 3.70 ( 1 H, m), 4.09 (3H, s), 5.39 (1 H, m), 8.60 (1H, s), LRMS: m / z 534 (M + 1) +.

EXAMPLE 99 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (pyridin-2-yl) methoxypyridin-3-ill-2-methyl-2,6-dihydro- 7H-pyrazolo [4.3-dlpyrimidin-7-one] A mixture of the title procedure of Example 78 (100 mg, 0.2 mmol), potassium bis (trimethylsilyl) amide (210 mg, 1.1 mmol) in pyridine-2-methanol (1 mL) was heated to 110 ° C for 18 hours. The cooled mixture was partitioned between ethyl acetate (10 ml) and water (10 ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 x 5 ml) and dichloromethane (10 ml), the combined organic solutions were dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using methanol: ethyl acetate (10:90) as the eluent, and triturated with ether, to yield the title compound (49 mg, 43%) as a solid,? (CDCb): 1.02 (3H, t), 1.40 (3H, t), 2.40 (2H, q), 2.55 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 4.10 (3H, s), 5.90 (2H, s), 7.32 ( 2H, m), 7.76 (1 H, m), 8.58 (1H, s), 8.82, (2H, m), 12.72 (1 H, s). LRMS: m / z 539 (M + 1) +.

EXAMPLE 100 5- [2-Cyclobutylmethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7- ona Obtained (69%) from the compound the title of example 78 and chlorobutanemethanol, following a procedure similar to that described in example 99. Found: C, 55.71; H, 6.44; N, 18.83. C24H33N70 S requires C, 55.90; H, 6.45; N, 19.01%. ? (CDCb): 1.03 (3H, t), 1.40 (3H, t), 1.98 (4H, m), 2.26 (2H, m), 2.42 (2H, q), 2.57 (4H, m), 3.02 (3H, m), 3.15 (4H, m), 4.10 (3H, s), 4.62 (2H, d), 8.62 (1 H, s), 9.04 (1 H, sm), 10.61 (1 H, s). LRMS: m / z 516 (M + 1) +.

EXAMPLE 101 5- [2-n-Butoxyl-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-2-methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin] -7-ona A mixture of the title compound of Example 90 (104 mg, 0.02 mmol) and potassium bis (trimethylsilyl) amide (200 mg, 1.0 mmol) in n-butanol (5 mL) was stirred at reflux for 5 days. The cooled mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate (20 ml) and the mixture was neutralized using 1 M hydrochloric acid. The layers were separated, the organic phase was washed with brine (10 ml), dried (MgSO) and evaporated under reduced pressure. The crude product was triturated with ether and the resulting solid was filtered and further purified by column chromatography on silica gel, using a gradient of dichloromethane: methanol: 0.88 ammonia (100: 0.5 to 99: 1: 05) to afford the compound of the title (86 mg, 82%) in the form of a solid,? (CDCb): 1.02 (9H, m), 1.57 (2H, m), 1.82 (2H, m), 1.95 (2H, m), 2.42 (2H, q), 2.58 (4H,), 2.99 (2H, t), 3.15 (4H, m), 4.08 (3H, s), 4.68 (2H, t), 8.62 (1 H, s), 9.02 (1 H, s), 10.62 (1 H, s) . LRMS: m / z 518 (M + 1) \ EXAMPLE 102 3-Ethyl-5-r2- (2-methoxy-1-methylethoxy) -5- (4-n-propylpiperazin-1-ylsulfonyl) -pyridin-3-in-2-methyl-2,6- dihydro-7H-pyrazolo (4,3-dlpyrimidin-7-one (U-isomer) EXAMPLE 103 3-Ethyl-5-r2- (2-methoxy-1-methylethoxy) -5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yn-2-methyl-2,6-dih Dro-7H-pyrazolo (4.3-d1-pyridin-7-one (isomer 2) Potassium bis (trimethylsilyl) amide (325 mg, 1.63 mmol) was added to a solution of the title compound of Example 119 (200 mg, 0.41 mmol) in 1-methoxy-2-propanol (6 mL) and the reaction was stirred at reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent to yield 193 mg of a colorless oil. This product was further purified by HPLC using an AD250 column, using hexane: isopropanol: diethylamine (70: 30: 0.3) as eluent, to yield the title compound of example 102 (58 mg, 26%, 99.5% ee). ? (CDCb): 0.86 (3H, t), 1.40 (5H, m), 1.50 (3H, d), 2.32 (2H, t), 2.56 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.55 (3H, s), 3.66 (1 H, m), 3.76 (1H, m), 4.08 (3H, s), 5.61 (1H, m), 8.61 (1H, s), 8.92 (1H, s), 10.82 (1H, s). LRMS: m / z 534 (M + 1) +, and the title compound of Example 103 (47 mg, 21%, 98.7%). ? (CDCb): 0.86 (3H, t), 1.41 (5H, m), 1.50 (3H, d), 2.32 (2H, t), 2.56 (4H, m), 3.04 (2H, q), 3.14 (4H, m), 3.55 (3H, s), 3.66 (1H, m), 3.76 (1H, m), 4.08 (3H, s), 5.61 (1H, m) , 8.60 (1H, s), 8.92 (1H, s), 10.82 (1H, s) LRMS: m / z 534 (M + 1) +.

EXAMPLE 104 (+) - 5-r 2 - (2-Methoxy-1-methylethoxy) -5- (4-methyl-piperazin-1-ylsulfonyl) pyridyl-3-yl-methyl-3 -n-propyl-2,6-dihydro-7H-pyrazol-4,3-d] pyrirnidin-7-one (isomer D and EXAMPLE 105 (-) - 5-f2- (2-Methoxy-1-methylethoxy) -5 - (4-Methypiperazin-1-ylsulfonyl) -pyridin-3-yl-1-methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo (4.3-d) pyrimidin-7-one (isomer) 2) The title compound of Example 79 (198 mg, 0.42 mmol) was added to a solution of potassium bis (trimethylsilyl) amide (415 mg, 2.1 mmol) in 1-methoxy-2-propanol (5 mL) and the The reaction was heated at 110 ° C for 72 hours. The cooled mixture was evaporated under reduced pressure, the residue was dissolved in water and neutralized using 2M hydrochloric acid. This aqueous solution was extracted with ethyl acetate (3 x 30 ml), the extracts The combined organics were washed with brine (3 x 20 ml), dried (Na2SO4) and washed under reduced pressure. The residual yellow oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and evaporated in ether to give a white solid. The racemic product was purified by chiral HPLC using an AD250 column and hexane: isopropanol: trifluoroacetic acid (80: 20: 0.5) as eluent. The first enantiomer was redissolved in water, basified using aqueous sodium carbonate solution and this mixture was extracted with ethyl acetate.

Ethyl acetate (3 x 20 ml). The organic extracts were washed with brine (2 x 20 ml), dried (Na 2 SO) and evaporated under reduced pressure. This product was then further purified by column chromatography on silica gel, using an elution gradient of dichloromethane. methanol (100: 0 to 97: 3) and an ether was evaporated, to yield the title compound of the example 104 (39 mg, 18%, 98.1 ee) as a colorless solid. [?] D = + 30.31 ° (c = 0.067, dichloromethane) Found: C, 53.32; H, 6.49; N, 18.48. C23H33N7? 5S requires C, 53.16; H, 6.40; N, 18.87%. ? (CDCb): 1.02 (3H, t), 1.50 (3H, d), 1.82 (2H, m), 2.53 (4H, m), 2.98 (3H, s), 2.53 (4H, m), 2.98 (2H, t), 3.16 (4H, m), 3.55 (3H, s), 3.66 (1H, m), 3.76 (1H, m), 4.07 (3H, s), 5.61 (1H, m). 8.61 (1 H, s), 8.92 (1H, s), 10.82 (1H, s). LRMS: m / z 520 (M + 1) +. The title compound of Example 105 was isolated using the same procedure as in Example 104 (26 mg, 12%, 94.0% ee). [?] D = -30.31 ° (c = 0.067, dichloromethane). ? (CDCb): 1.02 (3H, t), 1.51 (3H, d), 1.82 (2H, m), 2. 29 (3H, s), 2.53 (4H, m), 2.98 (2H, t), 3.14 (4H, m), 3.55 (3H, s), 3.65 (1 H, m), 3.77 (1 H, m) , 4.08 (3H, s), 5.61 (1 H, m), 8.61 (1 H, s), 8.92 (1H, s), 10.82 (1H, s). LRMS: m / z 520 (M + 1) +.

EXAMPLE 106 (+) - 5- [5- (4-Ethyl-piperzin-1-ylsulfonyl) -2- (2-methoxy-1-methyl-ethoxy) -pyridin-3-yl-2-methyl-3-n- propyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one and EXAMPLE 107 (-) - 5- [5- (4-Ethyl-pyrzin-1-ylsulfonyl) -2- (2-methoxy 1-methylethoxy) pyridin-3-yl-2-methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyridin-7-one] Potassium bis (trimethylsilyl) amide (1.47 g, 7.4 mmol) was added to a solution of the title compound of Example 80 (720 mg, 1.5 mmol) in 1-methoxy-2-propanol (10 mL) and the reaction it was stirred at reflux for 72 hours. The cooled mixture was evaporated under reduced pressure and the residual brown rubber it was purified by column chromatography on silica gel, using ethyl acetate: diethylamine (97: 3) as eluent. This reblemic mixture was purified by chiral HPLC using an AD250 column and hexane: isopropanol: diethylamine (70: 30: 0.3) as eluent, to give each enantiomer. The first enantiomer was partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (10 ml), the phases were separated and the organic layer was dried (Na2SO4) and evaporated under reduced pressure. The product was further purified by column chromatography on silica gel, using ethyl acetate: methanol (95: 5) as eluent, to yield the title compound of example 106 (130 mg, 16%, 99.76% ee) of a white foam. [?] D = + 15.65 ° (c = 0.093, methanol). Found: C, 53.47; H, 6.66; N, 17.92. C24H35N7? 5S; 0.3 H20 requires C, 53.48; H, 6.66; N, 18.19%. ? (CDCb): 1.02 (6H, m), 1.52 (3H, t), 1.82 (2H, m), 2.42 (2H, q), 2.57 (4H, m), 2.98 (2H, t), 3.14 (4H, m), 3.55 (3H, s), 3.65 (1 H, m), 3.76 (1 H, m), 4.08 (3H, s), 5.60 (1 H, s), 8.61 (1 H, s), 8.90 (1H, s), 10.81 (1 H, s). LRMS: m / z 534 (M + 1) +. The title compound of Example 107 was obtained (94 mg, 12%, 97.2% ee) as a white foam, using the same procedure in Example 106. [?] D = -14.52 ° (c = 0.10, methanol ). Found: C, 53.66; H, 6.73; N, 17.89. C2 H35N705S; 0.25 H20 requires C, 53.57; H, 6.65; N, 18.22%. ? (CDCb): 1.03 (6H, m), 1.50 (3H, d), 1.82 (2H, m), 2.42 (2H, q), 2.57 (4H,), 2.98 (2H, m), 3.17 (4H, m ), 3.55 (3H, s), 3.65 (1H, m), 3.75 (1H, m), 4.08 (3H, s), 5.60 (1H, m), 8.60 (1H, s), 8.91 (1H , s), 10.81 (1H, s). LRMS: m / z 534 (M + 1) +.

EXAMPLE 108 3-Ethyl-5-f5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-n-propoxy) pyridin-3-yl-2-methyl-2,6-dihydro-7H- pyrazolo [4.3-d] pyrimidin-7-one (isomer 1) Y EXAMPLE 109 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-n-propoxy) pyridin-3-Hl-2-methyl-2,6-dihydro-7H-pyrazolo [ 4.3-dlpyrimidin-7-one (isomer 2) The title compounds were prepared from the title compound of Example 78 and 2-methoxy-1-propanol, following a procedure similar to that described in Examples 104 and 105. The racemate was further purified by HPLC using an AD250 column and hexane : ethanol: diethylamine (60: 40: 1) as eluent, to give isomer 1. This product was repurified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and triturated with ether to yield the title compound of the example 108 (8 mg, 2%, 82% ee) as a white solid,? (CDCb): 1.19-1.36 (6H, m), 1.40 (3H, t), 2.68-3.10 (8H, m), 3.32-3.59 (7H, m), 3.92 (1H, m), 4.09 (3H, s), 4.47 (1H, m), 4.72 (1 H, m), 8.62 (1 H, s), 8.97 (1 H, s), 10.90 (1 H, s). LRMS: m / z 520 (M + 1) +. The title compound of Example 109 was isolated (5 mg, 1%, 93% ee) as a white solid, using the same procedure as that described in Example 108.? (CDCb): 1.26 (3H, t), 1.32 (3H, d), 1.40 (3H, t), 2.80-3.10 (8H, m), 3.38-3.60 (7H, m), 3.92 (1H, m) , 4.09 (3H, s), 4.48 (1 H, m), 4.72 (1H, m), 8.61 (1H, s), 8.98 (1H, s), 10.89 (1H, s). LRMS: m / z 520 (M + 1) +.

EXAMPLE 110 3-Ethyl-5-f5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxy-1-methyl-n-propoxy) pyridyl-3-yl-2-methyl -2.6-dihydro-7H-pyrazole [4.3-d1pyrimidin-7-one Y EXAMPLE 111 3-Ethyl-5-f5- (4-ethyl piperazin-1-ylsulfonyl) -2- (3-methoxy-1-methyl-n-propoxy) pyridin-3-ill-2-methyl -2.6-dihydro-7H-pyrazole [4.3-dlpyrimidin-7-one (isomers 1 and 2) A mixture of the title compound of Example 78 (330 mg, 0.70 mmol) and potassium bls (trimethylsilyl) amide (693 mg, 3.47 mmol) in the title compound of Preparation 162 (2.5 mL) was heated to 110 ° C for 16 hours. The cooled reaction was suspended in ethyl acetate (25 ml), washed with saturated ammonium chloride solution (5 ml) and then with saturated sodium bicarbonate solution (10 ml), dried (MgSO 4) and evaporated under reduced pressure. . The residue was purified by chromatography on column over silica gel using methanol: dichloromethane (5:95) as eluent and repeated using diethylamine: ethyl acetate (10:90) as eluent to give a gum. This racemate was purified by HPLC using a column AD250 5 and hexane: ethanol: diethylamine (85: 15: 1) as eluent to yield the title compound of example 110 (25 mg, 6.7%, 98.9% ee). ? (CDCb): 1.04 (3H, t), 1.39 (3H, t), 1.49 (3H, d), 2.04 (1H, m), 2.24 (1H, m), 2.42 (2H, q), 2.56 (4H, m), 3.01 (2H, m), 3.16 (4H, m), 3.33 (3H, s), 3.57 (1H, m), 3.68 (1H, m), 4.06 (3H, s), 5.75 (1H, m ), 8.61 (1H, s), 8.88 (1H, s), 10.99 (1H, s). LRMS: m / z 534 (M + 1) +. And the title compound of example 111 (29 mg, 7.8%, 99.7% ee). ? (CDCb): 1.03 (3H, t), 1.40 (3H, t), 1.48 (3H, d), 2.04 (1H, m), 2.24 (1H,), 2.42 (2H, q), 2.58 (4H, m ), 3.02 (2H, q), 3.16 (4H, m), 3.34 (3H, s), 3.57 (1H, m), 3.66 (1H, m), 4.08 (3H, s), 5.74 (1H , m), 8.60 (1 H, s), 8.98 (1H, s), . 10.98 (1H, s). LRMS: m / z 534 (M + 1) +.

EXAMPLE 112 (+) - 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-ethoxy-1-methylethoxy) pyridin-3-ill-2-methyl-2.6 -dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one (isomer 1) Y EXAMPLE 113 (-) - 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-ethoxy-1-methylethoxy) pyridin-3-yl-2-methyl-2,6-dihydro- 7H-pyrazolo [4.3-d] pyrimidin-7-one (isomer 2) The racemate was prepared (70%) from the title compound of Example 78 and 1-ethoxy-2-propanol, following the procedure described for Examples 104 and 105. This racemate was purified by chiral HPLC using a column AD250 and hexane: isopropanol: diethylamine (70: 30: 0.3) as eluent, to give the enantiomer 1. This product was further purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluant, and evaporated with ether, to give the title compound of Example 112 (52 mg, 15%, 99.5% ee) as a foam. [CX] D = + 18.60 ° (c = 0.067, dichloromethane) Found: C, 53.20; H, 6.70; N, 17.78. C24H35N705S; 0.5 H20 requires C, 53.12; H, 6.69; N, 18.07%. ? (CDCb): 1.04 5 (3H, t), 1.25 (3H, t), 1.40 (3H, t), 1.52 (3H, d), 2.42 (2H, q), 2.57 (4H, m), 3.02 (2H , q), 3.15 (4H, m), 3.60-3.82 (4H, m), 4.08 (3H, s), 5.60 (1H, m), 8.61 (1H, s), 8.94 (1H, s), 10.81 (1 H, s). The title compound of Example 113 was isolated (11 mg, 3%, 99.5% ee) following the same procedure as that described in Example 10 112. [?] D = -19.43 ° (c = 0.070, dichloromethane). Found: C, 53.34; H, 6.66; N, 17.86. C24H35N7? 5S; 0.5 H20 requires C, 53.12; H, 6.69; N, 18.07. ? (CDCb): 1.04 (3H, t), 1.25 (3H, t), 1.40 (3H, t), 1.52 (3H, d), 2.42 (2H, q), 2.57 (4H, m), 3.03 (2H, q), 3.16 (4H, m), 3.60-3.82 (4H, m), 4.09 (3H, s), 5.60 (1H, m), 8.62 (1 H, s), 8.92 (1 H, s), 10.82 (1 H, s). LRMS: m / z 534 (M + 1) +.

EXAMPLE 114 (+) - 3-Ethyl-5- [5- (4-ethyl-piperazin-1-ylsulfonyl) -2- (1-methoxy-methylene-propoxy) pyridin-3-ill-2-methyl l-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Y EXAMPLE 115 (-) - 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methoxymethyl-n-propoxy) pyridin-3-yl-2-methyl-2,6-dihydro- 7H-pyrazolo [4.3-djpyrimidin-7-one (isomer 1 and 2) The title compounds of Examples 114 and 115 were obtained (11%, 93% ee) and (6.7%, 97% ee), respectively, from the title compounds of Example 78 and 1-methoxy-2-butanol, using the procedure described in Examples 108 and 109. [OJD + 37.04 ° (c = 0.097, dichloromethane). Found: C, 53.36; H, 6.73; N, 17.84. C24H35N705S; 0.5 H20 requires C, 53.12; H, 6.69; N, 18.07%. ? (CDCb): 1.03 (6H, m), 1.39 (3H, t), 1.92 (2H, m), 2.42 (2H, q), 2.57 (4H, m), 3.02 (2H, q), 3.16 (4H, m), 3.51 (3H, s), 3.66 (1H, m ), 3.77 (1H, m), 4.08 (3H, s), 5.57 (1 H, m), 8.60 (1H, s), 8.88 (1 H, s), 10.84 (1H, s). LRMS: m / z 534 (M + 1 f; y? D = -40.08 ° (c = 0.093, dichloromethane) Found: C, 53.44; H, 6.75; N, 17.76, C24H35N7? 5S; 0.5 H20 requires C, 53.12; H, 6.69; N, 18.07%.? (CDCb): 1.03 (6H, m), 1.40 (3H, t), 1.92 (2H,), 2.42 (2H, q), 2.57 (4H, m), 3.02 (2H, q), 3.16 (4H, m), 3.51 (3H, s), 3.68 (1H, m), 3.78 (1H, m), 4.10 (3H, s), 5.57 (1H, m), 8.61 ( 1 H, m), 8.89 (1 H, s), 10.83 (1 H, s).

EXAMPLE 116 (-) - 3-Ethyl-5- (4-ethylpiperazin-1-ylsulfonyl) -2- [1- (pyridin-2-yl) ethoxylpyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one (isomer 1) AND EXAMPLE 117 (+) - 3-Ethyl-5-. { 5- (4-ethylpiperazin-1-ylsulfonyl) -2-f1- (pyridin-2-yl) ethoxylpyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo | 4.3-dlpyrimidin-7-one (isomer 2) The title compounds of Examples 116 and 117 were obtained in the form of solids, (4%, 99% ee) and (2%, 99.0% ee) respectively, from the title compound of Example 78 and 1- (pyridine -2-) ethanol (Helv. Chim. Acta. 1955, 38, 1114), following a procedure similar to that described in Examples 112 and 113, with the exception that hexane: isopropanol: diethylamine (70:30) : 1) as eluent for HPLC. [?] or = -90.11 ° (c = 0.033, dichloromethane)? (CDCb): 1.02 (3H, t), 1.40 (3H, t), 1.80 (3H, d), 2.41 (2H, q), 2.54 (4H, m), 3.00-3.17 (6H, m), 4.10 ( 3H, s), 6.69 (1H, q), 7.32 (2H, m), 7.75 (1H, m), 8.54 (1H, s), 8.75 (1H, s), 8.80 (1H, d), 13.14 (1 H, s). LRMS: m / z 553 (M + 1) +. [?] D = + 82.02 ° (c = 0.040, dichloromethane). ? (CDCb): 1.04 (3H, t), 1.40 (3H, m), 1.80 (3H, d), 2.41 (2H, q), 2.55 (4H, m), 3.00-3.18 (6H, m), 4.10 ( 3H, s), 6.69 (1 H, q), 7.34 (2H, m), 7.75 (1 H, m), 8.52 (1H, s), 8.76 (1H, s), 8.80 (1H, d), 13.16 (1H, s). LRMS: m / z 553 (M + 1) +.

EXAMPLE 118 (+) - 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy- (R) -methyl-ethoxy) -pyridin-3-yl ] -2-methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Example 78 (2.0 g, 4.2 mmol) and potassium bis (trimethylsilyl) amide (4.2 g, 21.0 mmol) in the title compound of Preparation 165 (16 mL) was heated to 110 ° C. for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient elution of diethylamine: methanol: ethyl acetate (2.5: 0: 97.5 to 0:10:90). The product was further purified by column chromatography on silica gel using ethyl methanoacetate (2.5: 97.5) as eluent to yield the title compound (640 mg, 29%) as a solid. Found: C, 53.16; H, 6.54; N, 18.37. C23H33N705S; 0.2 CH3C02C2H5 requires C, 53.21; H, 6.49; N, 18.25%. [?] D = + 16.6 ° (c = 0.10 methanol)? (CDCb): 1.04 (3H, t), 1.40 (3H, t), 1.52 (3H, d), 2.42 (2H, q), 2.57 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.56 (3H, s), 3.66 (1H,), 3.77 (1H, m), 4.09 (3H, s), 5.61 (1H, m), 8.62 (1H, s), 8.93 (1H, s) ), 10.82 (1H, s). LRMS: m / z 520 (M + 1) +.

EXAMPLE 119 5- [2-Ethoxy-5- (4-n-propyl-piperazin-1-ylsulfonyl) -pyridin-3-y -3-etl-2-methyl-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin] -7-ona 1-n-propylpiperazine (308 mg, 1.01 mmol) and triethylamine (440 ml, 3.2 mmol) were added to a solution of the title compound of preparation 164 (211 mg, 0.53 mmol) in dichloromethane (6 ml) and the mixture of reaction was stirred at room temperature for 2 hours. The mixture was purified directly by silica gel column chromatography, using dichloromethane: methanol (95: 5) as eluent to yield the title compound (210 mg, 85%) as a white foam,? (CDCb): 0.86 (3H, t), 1.42 (5H, m), 1.58 (3H, t), 2.29 (2H, t), 2.56 (4H, m), 3.03 (2H, q), 3.14 (4H, m), 4.10 (3H, s), 4.76 (2H, q), 8.62 (1 H, s), 9.04 (1 H, s), 10.67 (1H, s). LRMS: m / z 490 (M + 1f.

EXAMPLE 120 5- 2-Ethoxy-5-f4- (prop-2-yl) p¡perazin-1-ylsulfonylpyridin-3-yl} -3-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (71%), from the title compound of preparation 164 and 1- (prop-2-yl) -piperazine, following the procedure described in Example 119.? (CDCb): 0.99 (6H, d), 1.40 (3H, t), 1.57 (3H, t), 2.62 (4H, m), 2.70 (1H, m), 3.02 (2H, q), 3.13 (4H , m), 4.08 (3H, s), 4.74 (2H, q), 8.62 (1H, s), 9.03 (1H, s), 10.64 (1H, s). LRMS: m / z 490 (M + 1) +.

EXAMPLE 121 5- 2-Ethoxy-5- [4- (pyridin-2-yl) piperazin-1-ylsulfonylpyridin-3-yl) -3-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin] -7-ona Obtained in the form of a white solid (58%), from the compound of preparation 164 and 1- (pyridin-2-yl) piperazine, following the procedure described in example 119.? (CDCb): 1.41 (3H, t), 1.59 (3H, t), 3.05 (2H, q), 3.22 (4H, m), 3.70 (4H, m), 4.10 (3H, s), 4.75 (2H, q), 6.62 (2H, m), 7.47 (1H, m), 8.16 (1H, d), 8.64 (1H, s), 9.07 (1H, s), 10.65 (1H, s). LRMS: m / z 525 (M + 1) +.

EXAMPLE 122 3-Ethyl-5-. { 2- (2-rnetoxy-1-rnetyletoxy) -5- [4- (pyridin-2-yl) piperazin-1-ylsulfonylpyridin-3-yl} -2-methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Potassium bis (tr.methylsilyl) amide (76 mg, 0.38 mmol) was added to a solution of the title compound of Example 121 (50 mg, 0.095 mmol) in 1-methoxy-2-propanol (5 ml) and the reaction was heated to reflux for 18 hours. The cooled mixture was purified directly by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent to yield the title compound (32 mg, 59%) as a yellow oil,? (CDCI3): 1.40 (3H, t), 1.50 (3H, d), 3.04 (2H, q), 3.22 (4H, m), 3.54 (3H, s), 3.69 (6H, m), 4.09 (3H, s), 5.60 (1H, m), 6.63 (2H, m), 7.47 (1H, m), 8.16 (1H, d), 8.63 (1H, s), 8.94 (1H, s), 10.81 (1H, s). LRMS: m / z 569 (M + 1) +.

EXAMPLE 123 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-3-ethyl-1-methyl-1,6-dihydro-7H-pyrazolo [4,3-dlpyrimidin-7-] ona A mixture of the title compound of preparation 158 (596 mg, 1.21 mmol) and potassium bis (trimethylsilyl) amide (723 mg, 3.62 mmol) in ethanol (20 ml) was heated at 120 ° C for 18 hours in a sealed container. The cooled mixture was evaporated under reduced pressure and the residue was purified twice by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent. The product was triturated with ether to yield the title compound (358 mg, 62%) as an off-white solid. Found: C, 52.71; H, 6.00; N, 20.48. C2? H29N70 S requires C, 53.04; H, 6.15; N, 20.62%. ? (CDCb): 1.04 (3H, t), 1.40 (3H, t), 1.60 (3H, t), 2.42 (2H, q), 2.58 (4H, m), 2.99 (2H, q), 3.16 (4H, m), 4.28 (3H, s), 4.78 (2H, q), 8.64 (1H, s), 9.08 (1 H, s), 10.80 (1 H, s). LRMS: m / z 476 (M + 1) +.

EXAMPLE 124 5- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ill-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-] ona Obtained (42% from the compound the title of preparation 159, following a procedure similar to that described in Example 123. Found: C, 53.68; H, 6.34; N, 19.97. C22H3? N704S requires C, 53.97; H, 6.38; N, 20.03%.? (CDCb): 1.02 (6H, m), 1.60 (3H, t), 1.85 (2H, m), 2.42 (2H, q), 2.58 (4H, m), 2.95 (2H , t), 3.16 (4H,), 4.29 (3H, s), 4.78 (2H, q), 8.63 (1 H, s), 9.08 (1H, s), 10.78 (1 H, s). / z 491 (M + 1 f.

EXAMPLE 125 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-? 2-methoxy-1- (R) -methyletoxy) pyridin-3-yl] -1-methyl-1,6-dihydro -7H-p¡razolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Example 123 (70 mg, 0.15 mmol) and potassium bis (trimethylsilyl) amide (150 mg, 0.74 mmol) in the title compound of Preparation 165 (1 mL) was stirred at 110 °. C for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between water (5 ml) and dichloromethane (5 ml), and the mixture was neutralized by the addition of solid carbon dioxide. The layers were separated, the aqueous phase was extracted with dichloromethane (2 x 5 ml), the combined organic solutions were dried (Na 2 SO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate: diethylamine (97: 3) as eluent to yield the title compound (62 mg, 80%). ? (CDCl 3): 1.04 (3H, t), 1.39 (3H, t), 1.50 (3H, d), 2.42 (2H, q), 2.58 (4H, m), 2.98 (2H, q), 3.15 (4H, m), 3.58 (3H, s), ----,. --I- 3. 70 (2H, m), 4.28 (3H, s), 5.58 (1H, m), 8.62 (1H, s), 8.90 (1H, s) 11.07 (1H, s). LRMS: m / z 520 (M + 1) +.

EXAMPLE 126 5- [5- (4-ethylpip? Razin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [ 4.3-d] pyrimidin-7-one A mixture of the title compound of Example 124 (111 mg, 0. 23 mmol) and potassium bis (trimethylsilyl) amide (226 mg, 1.13 mmol) in 2-methoxyethanol (5 ml) was stirred under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: ethanol (96: 4) as eluent, and triturated with ether to yield the title compound (75 mg, 64%). %) in the form of a crystalline white solid. Found; C, 52.87; H, 6.35; N, 18.68. C23H33N7? 5S requires C, 53.16; H, 6.40; N, 18.87%. ? (CDCb): 1.02 (6H, m), 1.85 (2H, m), 2.42 (2H, q), 2.57 (4H, m), 2.94 (2H, t), 3.16 (4H, m), 3. 60 (3H, s), 3.86 (2H, t), 4.27 (3H, s), 4.78 (2H, t), 8.62 (1 H, s), 9.00 (1 H, s), 10.51 (1 H, s ). LRMS: m / z 521 (M + 1) +.

EXAMPLE 127 5-. { 5- (Ethylpiperazin-1-ylsulfonyl) -2 - [(pyridin-2-yl) methoxylpyridin-3-ylth-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo- [4.3 -d] pyrimidin-7-one A mixture of the title compound of Example 124 (100 mg, 0. 20 mmol) and potassium bis (trimethylsilyl) amide (204 mg, 1.02 mmol) in pyridine-2-ethanol (2 ml), was stirred at 100 ° C for 18 hours and then cooled. The solvent was removed by Kugelrohr distillation and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent. This product was triturated with ether to yield the title compound (8 mg, 7%) as a solid,? (CDCb): 1.03 (6H, m), 1.87 (2H, m), 2.42 (2H, q), 2.56 (4H, m), 2.95 (2H, t), 3.16 (4H, m), 4.30 (3H, s), 5.94 (2H, s), 7.36 (2H, m), 7.68 (1H, m), 8.60 (1H, s), 8.86 (2H, d), 13.34 (1H, s). LRMS: m / z 554 (M + 1) +.

EXAMPLE 128 (+) - 5- [5- (4-etll-piperazin-1-ylsulfonyl) -2- (2-methoxy-1-methoxy) pyridin-3-1,11-methyl -3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one and EXAMPLE 129 (•) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2 -n? ethoxy-1-methyloxy!) pyridin-3-yl] -1- methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one (isomer 1 e isomer 2) The title compounds of Examples 128 and 129 were prepared from Example 124 (17%, 99.5% ee) and (15%, 98.6% ee), respectively, following a procedure similar to that described in Examples 106 and 107, with the exception that hexane: isopropanol: diethylamine: trifluoroacetic acid (85: 15: 0.2: 0.3) was used as the HPLC eluent. [o] D = + 31.21 ° (c = 0.067 dichloromethane) Found: C, 53.77; H, 6.71; N, 17.89. C24H35N705S; 0.5 H20 requires C, 53.12; H, 6.69; N, 18.07%. ? (CDCb): 1.02 (6H, m), 1.50 (3H, d), 1.84 (2H, m), 2.42 (2H, q), 2.58 (4H, m), 2.94 (2H, t), 3.17 (4H, m), 3.58 (3H, s), 3.72 (2H, m), 4.28 (3H, s), 5.58 (1H, m), 8.62 (1H, s), 8.90 (1 H, s), 11.08 (1 H, s); and [?] D = -34.10 ° (c = 0.072 dichloromethane) Found: C, 53.75; H, 6.67; N, 18.04. C24H35N7? 5S requires C, 54.02; H, 6.61; N, 18.37%. ? (CDCb): 1.02 (6H, m), 1.50 (3H, d), 1.84 (2H, m), 2.42 (2H, q), 2.58 (4H, m), 2.94 (2H, t), 3.15 (4H, m), 3.59 (3H, s), 3.70 (2H, m), 4.28 (3H, s), 5.59 (1H, m), 8.62 (7H, s), 8.92 (1H, s), 11.17 (1H, s) ), respectively.

EXAMPLE 130 5- [5- (4-Ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl-2-methyl-3-n-propyl-2,6-dihydro-7H- pyrazolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Example 93 (130 mg, 0. 25 mmole) and 3-chloroperbenzoic acid (95 mg, 0.275 mmole) in dichloromethane (6 ml) was stirred at room temperature for 2.5 hours. The reaction mixture was washed with aqueous sodium bicarbonate solution (5 ml), dried (MgSO) and evaporated under reduced pressure. The residual foam was purified by column chromatography on silica gel, using a gradient elution of dichloromethane: methanol: ammonia 0.88 (93: 7.0 to 93: 7: 1) to yield the title compound (110 mg, 82%) in the form of a white solid. Found: C, 50.71; H, 6.27; N, 17.82. C23H33N706S requires C, 50.72; H, 6.30; N, 18.00%. ? (CDCb): 1.00 (3H, t), 1.40 (3H, t), 1.81 (2H, m), 2.98 (2H, t), 3.19 (2H, m), 3.33 (4H, m), 3.54 (5H, m), 3.70 (2H, m), 3.86 (2H, t), 4.06 (3H, s), 4.78 (2H, t), 8.63 (1 H, s), 8.97 (1 H, s), 10.87 (1 H, s). LRMS: m / z 536 (M + 1) + EXAMPLE 131 5- [2-Ethoxy-n- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) pyridin-3-yl-1-methyl-3-n-propyl-2,6-dihydro-7H-pyrazolo [4, 3-dlpyrimidin-7-one Obtained in the form of a white foam (81%), from the title compound of Example 80, following the procedure described in example 130.? (CDCb): 1.00 (3H, t), 1.40 (2H, t), 1.38 (3H, t), 1.81 (2H, m), 2.97 (2H, t), 3.16 (2H, m), 3.30 (4H, m), 3.50 (2H, m), 3.70 (2H, m), 4.08 (3H, s), 4.74 (2H, q), 8.64 (1H, s), 9.00 (1H, s), 10.75 (1H, s) ). LRMS: m / z 506 (M + 1) + EXAMPLE 132 3-Ethyl-5- [5- (4-etl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxy-1- (R) -methyletoxy) pyridin-3-ill-2 -methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-] 3-Chloroperbenzoic acid (95 mg, 0.28 mmol) was added to a solution of the title compound of Example 118 (130 mg, 0.25 mmol) in dichloromethane (2 mL) and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol: ammonia 0.88 (95: 5: 0 to 90: 10: 1) to produce the title compound (130 mg, 87%). ? (CDCb): 1.40 (6H, m), 1.52 (3H, d), 3.01 (2H, q), 3.22 (2H, m), 3.34 (4H, m), 3.54 (5H, m), 3.73 (4H, m), 4.08 (3H, s), 5.62 (1H, m), 8.64 (1 H, s), 8.94 (1 H, s). LRMS: m / z 536 (M + 1) + EXAMPLE 133 5- [5- (4-Ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-1-methyl-3-n-propyl-1,6-dihydro-7H- pyrazolo [4.3-dlpyrimidin-7-one] Obtained as a white solid (51%) from the title compound of example 126, using a procedure similar to that described in example 130.? (CDCl 3): 1.02 (3H, t), 1.41 (3H, t), 1.84 (2H, q), 2.92 (2H, t), 3.32 (2H, d), 3.36 (4H, m), 3.46-3.60 ( 5H, m), 3.74 (2H, m), 3.86 (2H, t), 4.29 (3H, s) 4.78 (2H, t), 8.64 (1H, s), 9.01 (1H, s), 11.05 (1H, s). LRMS: m / z 535 (M + 1 f EXAMPLE 134 2.3-Diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl1-2.6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] A mixture of the title compound of example 81 (200 mg, 0.41 mmol) and potassium bis (trimethylsilyl) amide (407 mg, 2.04 mmol) in n-propanol (5 ml) was stirred at 110 ° C for 18 hours and the The cooled reaction was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient elution of ethyl acetate: diethylamine (100: 0 to 95: 5) and triturated with ether to yield the title compound (160 mg, 68% ) in the form of a solid,? (CDCl 3): 1.02 (3H, t), 1.10 (3H, t), 1.42 (3H, t), 1.59 (3H, t), 2.00 (4H, m), 2.42 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.14 (4H, m), 4.38 (2H, q), 4.63 (2H, t), 8.63 (1H, s), 9.04 (1H, s). LRMS: m / z 504 (M + 1f EXAMPLE 135 5- [2-i-Butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -2.3-diethyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one Obtained as a solid (65%) from the title compound of Example 81 and α-butanol, using the procedure described in Example 134.? (CDCl 3): 1.02 (3H, t), 1.15 (6H, d), 1.42 (3H, t), 1.58 (3H, t), 2. 30 (1 H, m), 2.42 (2H, q), 2.57 (4H,), 3.06 (2H, q), 3.16 (4H, m), 4.38 (2H, q), 4.45 (2H, d), 8.62 (1H, s), 9.03 (1 H, s). LRMS: m / z 518 (M + 1) + EXAMPLE 136 2.3-Diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2.6- dihydro-7H-pyrrazolo [4.3-dlpyrim] Din-7-one Obtained as a solid (33%) from the title compound of example 81 and 2-methoxyethanol, using the procedure described in example 134. Found: C, 53.29; H, 6.20; N, 18.19. C23H33N705S requires C, 53.16; H, 6.40; N, 18.87%. ? (CDCb): 1.02 (3H, t), 1.42 (3H, t), 1.59 (3H, t), 2.44 (2H, q), 2.57 (4H, m), 3.05 (2H, q), 3.16 (4H, m), 3.58 (3H, s), 3.86 (2H, t), 4.28 (2H, q), 4.79 (2H, t), 8.62 (1H, s), 8.99 (1H, s). LRMS: m / z 520 (M + 1) + EXAMPLE 137 2.3-Diethyl-5- [5- (4-ethylpiperazin-1-ylsufoni-2- (3-hydroxy-n-propoxy) pyridin-3-yl-2,6-dihydro-7H-pyrazolo [4.3-dlpir Midin-7-one A mixture of the title compound of Example 81 (200 mg, 0.41 mmol) and potassium bis (trimethylsilyl) amide (407 mg, 2.04 mmol) in 1,3-propanediol (3 mL) was stirred at 110 ° C for 18 h. hours and then cooled and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using a gradient elution of ethyl acetate: diethylamine (100: 0 to 95: 5). The product was partitioned between water (5 ml) and dichloromethane (10 ml) and the phases were separated. The organic layer was washed with water (2 x 5 ml), dried (MgSO 4), evaporated under reduced pressure and triturated with ether, to yield the title compound (90 mg, 42%) as a solid, ? (CDCl 3): 1.02 (3H, t), 1.40 (3H, t), 1.57 (3H, t), 2.16 (2H, m), 2.42 (2H, q), 2.55 (4H, m), 3.02 (2H, q), 3.15 (4H, m), 4.00 (2H, t), 4.37 (2H, q), 4.80 (2H, t), 8.62 (1 H, s), 8.96 (1 H, s). LRMS: m / z 520 (M + 1) + EXAMPLE 138 2.3-Diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methyl-n-propoxy) pyridin-3-yl] -2,6-dihydro-7H-pyrazolo [4.3 -d1-pyrimidin-7-one (isomer 1) and EXAMPLE 139 2,3-diethyl-5- [5- (4-ethylpiperazin-1-ylsufonyl) -2- (1-methyl-n-propoxy) pyridin-3-yl ] - 2,6-Hydro-7H-pyrazolo [4.3-d1-pyridin-7-one (isomer 2) A mixture of the title compound of Example 81 (500 mg, 1.02 mmol) and potassium bis (trimethylsilyl) amide (1.01 g, 5.11 mmol) in 1-methyl-n-propanol (5 mL) was stirred at 110 ° C. for 18 hours and then cooled and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: diethylamine (100: 0 to 95: 5) and triturated with ether to give a solid. This racemate was further purified by chiral HPLC using an AD250 column and using hexane: isopropanol: diethylamine (90: 10: 1) as eluent, to yield the title compound of Example 138 (40 mg, 8%, 95% ee) as a solid. Found: C, 54.41; H, 6.71; N, 18.17; C24H35N704S; 0.2 CH2Cl2 requires C, 54.37; H, 6.67; N, 18.34%. ? (CDCb): 1.04 (6H, m), 1.41 (3H, t), 1.50 (3H, d), 1.58 (3H, t), 1.86 (1H, m), 1.98 (1H, m), 2.41 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.15 (4H, m), 4.38 (2H, q), 5.55 (1H, m), 8.61 (1H, s), 9.02 (1H, s) ), 10.66 (1H, s); and the title compound of Example 139 (70 mg, 13%, 86% ee) as a solid. Found: C, 55.91; H, 7.11; N, 18.55. C 24 H 35 H 7? 4 S requires C, 55.69; H, 6.82; N, 18.95%. ? (CDCb): 1.05 (6H, m), 1.40 (3H, t), 1.50 (3H, d), 1.57 (3H, t), 1.84 (1H, m), 1.98 (1H, m), 2.42 ( 2H, q), 2.58 (4H, m), 3.04 (2H, q), 3.15 (4H, m), 4.38 (2H, q), 5.54 (1 H, m), 8.61 (1 H, s), 9.03 (1 H, s), 10.67 (1 H, s).

EXAMPLE 140 2.3-Diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl] -2,6-dihydro-7H-pyrazolo [4.3 -d] pyrimidin-7-one (isomer 1) and EXAMPLE 141 2.3-diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl) ] -2.6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one (isomer 2) Obtained in the form of solids (10%, 99.5% ee) and (10%, 99.1% ee), respectively, from the title compound of example 81 and 1-methoxy-2-propanol (5 ml), following a procedure similar to that described above, with the exception that hexane: isopropanol: diethylamine (70: 30: 1) was used as the HPLC eluent. ? (CDCb): 1.03 (3H, t), 1.40 (3H, t), 1.50 (3H, d), 1.58 (3H, t), 2.42 (2H, q), 2.58 (4H, m), 3.03 (2H, q), 3.15 (4H, m), 3.55 (3H, s), 3.64 (1H, m), 3.76 (1H, m), 4.37 (2H, q), 5.60 (1H, m), 8.60 (1H, s ), 8.90 (1H, s). LRMS: m / z 535 (M + 1) + Found: C, 54.09; H, 6.91; N, 17. 03. C24H35N705S requires C, 54.02; H, 6.61; N, 18.38%. ? (CDCb): 1.04 (3H, t), 1.40 (3H, t), 1.50 (3H, d), 1.58 (3H, t), 2.42 (2H, q), 2.58 (4H, m), 3.02 (2H, q), 3.12 (4H, m), 3.56 (1H, m), 3.65 (1H, m), 3.74 (1H, m), 4.37 (2H, q), 5.60 (1H, m), 8.60 (1 H, s), 8.90 (1 H, s). LRMS: m / z 535 (M + 1) +, respectively.

EXAMPLE 142 3-? Tyl-5-f5- (4-ethylpiperazyl? -1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- (6-methyl-pyridin-2-yl) methyl- 2.6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Example 82 (100 mg, 0.176 mmol) and potassium bis (trimethylsilyl) amide (175 mg, 0.88 mmol) in 2-methoxyethanol (1 mL), was heated to reflux for 18 hours and then cooled The solution was concentrated under reduced pressure and the residue was partitioned between water (5 ml) and dichloromethane (10 ml) and the mixture was neutralized using hydrochloric acid (2 N). The phases were separated, the aqueous layer was extracted with dichloromethane (10 ml) and the combined organic solutions were dried (MgS? 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: ammonia 0.88 (96: 4: 0.4) as eluent, and triturated with pentane to yield the title compound (27 mg, 26%) in form of a whitish solid. Found: C, 56.14; H, 6.09; N, 18.53. C28H36N805S requires C, 56.36; H, 6.08; N, 18.78%. ? (CDCb): 1.02 (3H, t), 1.30 (3H, t), 2.42 (2H, q), 2.57 (7H, m), 3.04 (2H, q), 3.16 (4H,), 3.58 (3H, s) ), 3.86 (2H, t), 4.79 (2H, t), 5.63 (2H, s), 6.78 (1H, d), 7.08 (1H, d), 7.48 (1H, m), 8.61 (1H, s) , 8.98 (1 H, s), 10.82 (1 H, s).

EXAMPLE 143 3-Ethyl-5- [5- (4-etl-piperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2- (6-methylpyridin-2-yl) methoxy-2,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7- one Obtained as a white solid (12%) from the title compounds of Examples 82 and 165, using a procedure similar to that described in example 142, with the exception that the product was further purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol: ammonia 0.88 (100: 0: 0 to 90: 10: 1) and then triturated with pentane. ? (CDCb): 1.03 (3H, t), 1.30 (3H, t), 1.50 (3H, d), 2.42 (2H, q), 2.55 (6H, m), 3.02 (2H, q), 3.15 (4H, ), 3.56 (4H, m), 3.66 (1H, m), 3.76 (1H, m), 5.62 (3H, m), 6.78 (1H, d), 7.06 (1H, d), 7.49 (1H , m), 8.61 (1 H, s), 8.90 (1 H, s), 10.84 (1H, s). LRMS: m / z 611 (M + 1) + EXAMPLE 144 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- [1- (pyridin-2-yl) ethyl-2.6- dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one (isomer 1) and EXAMPLE 145 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ill-2- [1- (pyridin-2-yl) etyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidn-7-one (isomer 2) A mixture of the title compound of Example 84 (200 mg, 0.35 mmol) and potassium bis (trimethylsilyl) amide (350 mg, 1.76 mmol) in 2-methoxyethanol (5 mL) was stirred at 120 ° C for 18 h. hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml). The phases were separated, the aqueous layer was extracted with ethyl acetate (2 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give a foam. This racemate was further purified by HPLC using an AD250 column and hexane: isopropanol: diethylamine (50: 50: 1) as eluent to yield the title compound of Example 144 (24 mg, 11%, 100.0% ee). ? (CDCb): 1.02 (3H, t), 1.25 (3H, t), 2.10 (3H, d), 2.40 (2H, q), 2.56 (4H, m), 3.00 (2H, q), 3.13 (4H, m), 3.58 (3H, s), 3.86 (2H, t), 4.77 (2H, t), 5.83 (1H, q), 7.18 (2H, m), 7.60 (1H, m), 8.55 (1H, d) ), 8.60 (1H, s), 8.96 (1 H, s), 10.82 (1 H, s). LRMS: m / z 598 (M + 1f the title compound of example 145 (28 mg, 13%, 99.8% ee).? (CDCb): 1.00 (3H, t), 1.24 (3H, t), 2.10 ( 3H, d), 2.40 (2H, q), 2.55 (4H, m), 3.00 (2H, q), 3.14 (4H, m), 3.57 (3H, s), 3.84 (2H, t), 4.78 (2H , t), 5.82 (1 H, q), 7.18 (2 H, m), 7.60 (1 H, m), 8.54 (1 H, d), 8.60 (1 H, s), 8.94 (1 H, s) , 10.82 (1 H, s) LRMS: m / z 598 (M + 1) + EXAMPLE 146 5-f2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridyl-3-yl-2-yl-2- (pyridazin-3-yl) ) methyl-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one a suspension of the title compound of preparation 142 (1.12 g, 4.55 mmol) and triethylamine (1.5 g, 13.7 mmol) was added to an ice-cooled suspension of the title compound of Preparation 28 (2.0 g, 5.0 mmol) in dichloromethane (25 ml) and the reaction was stirred at room temperature environment for 2 hours. The reaction mixture was washed with brine (15 ml), saturated aqueous sodium bicarbonate solution (2 x 10 ml), plus brine (15 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: ammonia 0.88 (99: 0: 1 a 96: 3: 1) to give a solid (1.73 g). A mixture of this intermediate (829 mg, 1.45 mmol) and potassium bis (trimethylsilyl) amide (347 mg, 1.74 mmol) in 3-methyl-3-pentanol (3 ml) was heated to reflux for 6 hours and then it was stirred at temperature environment for 72 hours. Additional potassium bis (trimethylsilyl) amide (87 mg, 0.43 mmol) was added and the reaction was heated to reflux for 5 hours, then cooled, 2 M hydrochloric acid (2 ml) was added and the mixture was concentrated under reduced pressure. . The residue was partitioned between dichloromethane (20 ml) and water (10 ml), the layers were separated, the organic phase was washed consecutively with water (10 ml), saturated sodium bicarbonate solution (10 ml) and brine (10 ml). ), dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 10: 98: 2) to yield the title compound (1.24 g, 49%) as a foam. light brown,? (CDCb): 1.02 (3H, t), 1.36 (3H, t), 1.59 (3H, t), 2.40 (2H, q), 2.55 (4H, m), 3.14 (6H, m), 4.76 (2H, q), 5.90 (2H, s), 7.46 (1H, m), 7.56 (1H, m), 8.63 (1H, s); 9.01 (1 H, s), 9.18 (1 H, d), 10.70 (1 H, s). LRMS: m / z 554 (M + 1) + EXAMPLE 147 5- [2-n-Butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl-3-tyl-2- (pyridazin-3-yl) methyl-2,6-dihydro-7H- pyrazolo [4.3-d] pyrimidin-7-one Potassium bis (trimethylsilyl) amide (35 mg, 0.176 mmol) was added to a solution of the title compound of Example 146 (80 mg, 0.145 mmol) in n-butanol (2 mL), and the reaction was stirred at 110 °. C for 6.5 hours. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20 ml) and sodium bicarbonate solution (10 ml). The phases were separated, the organic layer was washed with more sodium bicarbonate solution (10 ml) and brine (10 ml), dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0 to 99.6: 0.4: 0.5) to yield the title compound (50 mg, 59% ) in the form of a white foam,? (CDCb): 1.04 (6H, m), 1.35 (3H, t), 1.58 (2H, m), 1.95 (2H, m), 2.41 (2H, q), 2.57 (4H, m), 3.10 (6H, m), 4.66 (2H, t), 5.90 (2H, s), 7.46 (1H, m), 7.56 (1H, m), 8.62 (1H, s), 9.01 (1H, s), 9.17 (1H, d), 10.79 ( 1H, s). LRMS: M / z 582 (M + 1) +.

EXAMPLE 148 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethylamino) pyridin-3-yl-2-methyl-2,6-dihydro-7H-pyrazole) d] pyrimidin-7-one a mixture of the title compound of Example 78 (200 mg, 0.42 mmol) and copper (II) sulfate pentahydrate (150 mg, 0.60 mmol) in 2-methoxyethylamine (2 mL) was heated to reflux for 2 hours and then cooled . The reaction was partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (5 ml) and the layers were separated. The organic phase was dried (Na 2 SO) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to yield the title compound (150 mg, 69%). ? (CDCb): 1.04 (3H, t), 1.40 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 2.92 (3H, s), 3.01 (2H, q); 3. 13 (4H, m), 3.50 (4H, m), 3.48 (3H, s), 3.68 (2H, t), 3.88 (2H, t), 4.07 (3H, s), 8.34 (1H, s), 8.58 (1 H, s). LRSM: m / z 519 (M + 1) + EXAMPLES 149 TO 153 The compounds of the general formula: were prepared from the appropriate pyrazolo [4,3-d] pyrimidin-7-ones and amines, using procedures similar to those described in the example EXAMPLE 154 5- [2- (N-Cyclopropylmethyl-N-methylamino) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridyl] -3-ill-3-ethyl-2-methyl-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one a mixture of the title compound of example 78 (200 mg, 0.42 mmol) and N-cyclopropylmethyl-N-methylamine (600 mg, 7.05 mmol, obtained from the title compound of preparation 168) and bis (trimethylsilyl) amyl of potassium (250 mg, 1.26 mmol) in NN-dimethylformamide (2 ml), was stirred at 100 ° C for 18 hours. The cooled mixture was partitioned between ethyl acetate (20 ml) and aqueous sodium bicarbonate solution (10 ml) and the phases were separated. The organic layer was dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to yield the title compound (100 mg, 46%) as a solid,? (CDCb): 0.54 (2H, m), 0.71 (2H, m), 1.02 (3H, t), 1.37 (4H, m), 2.40 (2H, q), 2.56 (4H, m), 2.78-3.13 (11H, m); 4.08 (3H, s), 8.32 (1 H, s), 8.60 (1 H, s). LRMS: m / z 515 (M + 1) + EXAMPLES 155 TO 156 The compounds of the general formula: were prepared from the title compound of Example 78 and the appropriate amines, using procedures similar to those described in Example 154.

EXAMPLE 157 3-Ethyl-5- [5- (4-ethyl-piperazin-1-ylsulfonyl) -2-n-propylaminopyridin-3-yl-2- (pyrimidin-2-ylmethyl-2.6) -dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one a mixture of the title compound of Preparation 160 (226 mg, 0.39 mmol) and potassium f-butoxide (112 mg, 1.0 mmol) in n-propanol (20 mL) was stirred under reflux for 5 days and then cooled. Solution was added saturated ammonium chloride (5 ml), this solution was poured into ethyl acetate (50 ml) and the layers were separated. The organic phase was washed with sodium bicarbonate solution (20 ml) and then with brine (20 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 94: 6) to give an oil. This was crystallized from ether to yield the title compound (9 mg, 4%) as a white solid,? (CDCb): 1.00 (3H, t), 1.18 (3H, t), 1.28 (3H, t), 1.70 (2H, m), 2.38 (2H, q), 2.50 (4H,), 3.00 (2H, q ), 3.07 (4H, m), 3.57 (2H, q), 5.62 (2H, s), 7.19 (1H, m); 7.63 (1 H, m), 8.02 (1 H, s), 8.55 (2H, m); 9.60 (1 H, s), 9.80 (1 H, s). LRMS: m / z 566 (M + 1) + PREPARATION 1 2-Ethoxypyridine-3-carboxylic acid A solution of potassium f-butoxide (44.9 g, 0.40 mol) in absolute ethanol (300 ml) was slowly added to a solution of 2-chloronicotinic acid (30 g, 0.19 mol) in absolute ethanol (100 ml) and the mixture of The reaction was heated in a sealed vessel at 170 ° C for 20 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue was dissolved in water (200 ml) and the solution acidified to pH 3 with hydrochloric acid and extracted with dichloromethane (4 x 200 ml). The combined extracts were dried (Na 2 SO 4) and evaporated under pressure reduced to give the title compound (27.4 g, 41%) as a white solid,? (CDCb): 1.53 (3H, t), 4.69 (2H, q), 7.13 (1H, m), 8.37 (1H, d), 8.48 (1H, d).

PREPARATION 2 2- (2-Methoxyethoxy) pyridine-3-carboxylic acid Obtained as a brown solid (92%) from 2-chloronicotinic acid and 2-methoxyethanol, using the procedure of preparation 1. Found: C, 54.89; H, 5.61; N, 7.03. C9HnN04 requires C, 54.82; H, 5.62; N, 7.10%. ? (CDCb): 3.45 (3H, s), 3.79 (2H, t), 4.74 (2H, t), 7.14 (1H, m), 8.36 (1 H, d), 8.46 (1H; d); LRMS: m / z 198 (M + 1) + PREPARATION 3 Ethyl esters of 3-? Toxipyridine-3-carboxylic acid A suspension of the title compound of preparation 1 (16.4 g, 98 mmol) and cesium carbonate (32 g, 98 mmol) in dimethylformamide (240 ml) was stirred at room temperature for 2 hours. Ethyl iodide (7.85 ml, 98 mmol) was added, the reaction mixture was stirred for 24 hours and then evaporated under reduced pressure. The residue was partitioned between aqueous sodium carbonate solution (100 ml) and ethyl acetate (100 ml), the phases were separated and the aqueous phase was extracted with acetate of ethyl (2 x 100 ml). The combined organic solutions were washed with brine, dried (Na 2 S 4) and evaporated under reduced pressure to yield the title compound (18.0 g, 94%) as a light yellow oil,? (CDCb): 1.41 (6H, m); 4.36 (2H, q), 4.48 (2H, q), 6.90 (1H, m), 5 8.12 (1H, d), 8.28 (1H, d).

PREPARATION 4 Ethyl 2- (2-methoxyethoxy) pyridine-3-carboxylic acid ethyl ester Obtained as a brown oil (98%) from the title compound of preparation 2, using the procedure of preparation 3. Found: C, 58.36; H, 6.74; N, 6.04. CnH? 5N? 4 requires C, 58.66; H, 6.71; N, 6.23%. ? (CDCb): 1.37 (3H, t), 3.44 (3H, s), 3.78 (2H, t), 4.34 (2H, q), 4.56 (2H, t), 6.92 (1H, m), 8.13 (1H, d), 8.26 (1 H, d). LRMS: m / z 226 (M + 1) + PREPARATION 5 2-Ethoxy-5-nitropyridine-3-carboxylic acid ethyl ester Ammonium nitrate (5.36 g, 66 mmol) was added portionwise to a stirred and ice-cooled solution of the title compound of Preparation 3 (4.66 g, 22.3 mmol) in trifluoroacetic anhydride (50 mL), the reaction mixture was added. stirred for 18 hours at room temperature and it was then poured carefully into chilled water with stirred ice (200 g). The resulting suspension was stirred for 1 hour, then the precipitate was collected, washed with water and dried by suction to give the title compound (3.29 g, 61%). ? (CDCb): 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 6 2- (2-Methoxyethoxy) -5-nitropyridine-3-carboxylic acid ethyl ester Ammonium nitrate (10.57 g, 131 mmol) was added portionwise to a stirred and ice-cooled solution of the title compound of preparation 4 (14.80 g, 65.7 mmol) in trifluoroacetic anhydride (150 mL), the reaction mixture was stirred for 3 hours at room temperature and then poured carefully into stirred ice (120 g). The resulting solution was extracted with dichloromethane (3 x 150 ml), then the combined extracts were dried (MgSO 4) and evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) to yield the title compound (11.49 g, 65%) as a solid white. Found: C, 48.78; H, 5.13; N, 10.29. CnH? 4N 0e requires C, 48.89; H, 5.22; N, 10.37%? (CDCb): 1.42 (3H, t), 3.46 (3H, s), 3.83 (2H, t), 4.41 (2H, q), 4.70 (2H, t), 8.92 (1 H, s), 9.16 (1 H, s). LRMS: m / z 271 (M + 1) +.

PREPARATION 7 5-amino-2-ethoxypyridine-3-carboxylic acid ethyl ester A stirred mixture of the title compound of preparation 5 (5.3 g, 22 mmol), Raney nickel (2.50 g) and ethanol (150 ml) was hydrogenated at 345 kPa (50 psi) and at 50 ° C for 18 hours, then let cool and filtered. The filtrate was combined with an ethanol wash (150 ml) of the filter layer and then evaporated under reduced pressure. The residue was triturated with dichloromethane and the resulting solid was collected and dried to yield the title compound (4.56 g, 98%) as a tan solid. Found: C, 57.12; H, 6.79; N, 12.98. C? 0H14N2O3 requires C, 57.13; H, 6.71; N, 13.33%. ? (CDCb): 1.39 (6H, 2xd), 3.41 (2H, s), 4.35 (4H, m), 7.55 (1H, s), 7.78 (1H, s). LRSM: m / z 211 (M + 1f.

PREPARATION 8 2-Ethoxy-5-nitropyridine-3-carboxylic acid M aqueous sodium hydroxide solution (4 ml, 20 mmol) was added to a stirred solution of the title compound of preparation 5 (5.1 g, 20 mmol) in ethanol (100 ml), the reaction mixture was stirred at room temperature. environment for 18 hours and then evaporated under reduced pressure. The residue was suspended in water (50 ml) and the stirred suspension was acidified to pH 3 with hydrochloric acid. The resulting aqueous solution is extracted with ethyl acetate (3 x 100 ml), the combined extracts were washed with brine (100 ml), dried (Na 2 S 4) and evaporated under reduced pressure to yield a beige solid. The crude product was crystallized from hexane-ethyl acetate to give the title compound (3.32 g, 78%) as beige crystals. ? (CDCb): 1.55 (3H, t), 4.78 (2H, q), 9.17 (1H, s), 9.23 (1H, s).

PREPARATION 9 2- (2-Methoxyethoxy) -5-nitropyridine-3-carboxylic acid A 1M aqueous solution of sodium hydroxide (40 ml, 40 mmol) was added to a stirred and ice-cooled solution of the title compound of preparation 6 (4.0 g, 14.8 mmol) in 1,4-dioxane (40 ml). and the reaction mixture was stirred for 1.5 hours, then concentrated under reduced pressure to half its volume and acidified with hydrochloric acid to pH 3. The resulting suspension was extracted with dichloromethane (3 x 50 ml), then the extracts The combined contents were dried (MgSO 4) and evaporated under reduced pressure to yield the title compound (2.61 g, 73%) as a buff solid. Found: C, 44.11; H, 4.04; N, 11.46. CgH-io ^ Oe requires C, 44.63; H, 4.16; N, 11.57%. ? (CDCb): 3.47 (3H, s), 3.83 (2H, t), 4.82 (2H, t), 9.15 (1 H, s), 9.21 (1H, s). LRMS: m / z 243 (M + 1) +.

PREPARATION 10 2-aminopyridine-5-sulfonic acid 2-aminopyridine (80 g, 0.85 mmol) was added portionwise over 30 minutes to stirred furant sulfuric acid (320 g), the resulting solution was heated at 140 ° C for 4 hours and allowed to cool. The reaction mixture was poured into stirred ice (200 g) and this mixture was stirred at the temperature of an ice-cooled salt bath for a further 2 hours. The resulting suspension was filtered, then the collected solid was washed successively with ice-cold water (200 ml) and cold industrial methylated spirit (IMS) (200 ml) and finally dried under suction to provide the title compound (111.3). g, 75%) in the form of a solid. LRMS: m / z 175 (M + 1) +.

PREPARATION 11 2-amino-3-bromopyridine-5-sulfonic acid Bromine (99 g, 0.62 mol) was added dropwise over 1 hour to a stirred distillation solution of the title compound of preparation 10 (108 g, 0.62 mol) in water (600 ml), at a rate such as to maintain a steady reflux. When the addition was complete, the reaction mixture was allowed to cool and then filtered. The resulting solid was washed with water and dried under suction to yield the title compound (53.4 g, 34%). ? (DMSOde): 8.08 (1 H, s), 8.14 (1H, s). LRMS: m / z 253 (M) +.

PREPARATION 12 3-Bromo-2-chloropyridine-5-sulfonyl chloride A solution of sodium nitrite (7.6 g, 110 mmol) in water (30 ml) was added dropwise to an ice-cooled and stirred solution of the title compound of preparation 11 (25.3 g, 100 mmol) in hydrochloric acid at room temperature. 20% (115 ml), at a rate such as to keep the temperature below 6 ° C. The reaction mixture was stirred for 30 minutes at 0 ° C for a further 1 hour at room temperature and then evaporated under reduced pressure. The residue was dried under vacuum at 70 ° C for 72 hours, then a mixture of the resulting solid, phosphorus pentachloride (30 g, 144 mmol) and phosphorus oxychloride (1 ml) was heated at 125 ° C for 3 hours and then it was allowed to cool. The reaction mixture was poured into stirred ice (100 g) and the resulting solid was collected and washed with water. The crude product was dissolved in dichloromethane, and then the solution was dried (MgSO 4) and evaporated under reduced pressure to yield the title compound (26.58 g, 91%) as a yellow solid,? (CDCb): 8.46 (1H, s), 8.92 (1 H, s).

* - ^ - ^ - ' PREPARATION 13 3-Bromo-2-chloro-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine A solution of 1-ethylpiperazine (11.3 ml, 89 mmol) and triethylamine (12.5 ml, 89 mmol) in dichloromethane (150 ml) was added dropwise to a stirred and ice-cooled solution of the title compound of preparation 12 ( 23 g, 79 mmol) in dichloromethane (150 ml), the reaction mixture was stirred at 0 ° C for 1 hour, and then evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound (14.5 g, 50%) as a solid orange,? (CDCb): 1.05 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 3.12 (4H, m), 8.24 (1H, s), 8.67 (1H, s).

PREPARATION 14 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-toxy) pyridine A 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene (8.1 ml, 4.07 mmol) was added to a stirred and ice-cooled solution of 2-methoxyethanol (416 μL, 5.4 mmol) in anhydrous tetrahydrofuran. (30 ml) and the resulting solution was stirred at 0 ° C for 1 hour. Then, the title compound of Preparation 13 (1.0 g, 2.71 mmol) was added portionwise, the reaction mixture was stirred at room temperature for 2 hours and it was then diluted with ethyl acetate (40 ml). The resulting mixture was washed with water (10 ml), dried (MgSO 4) and evaporated under reduced pressure to yield a yellow oil which was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent , to provide the title compound (1.02 g, 92%) as a colorless oil. Found: C, 40.83; H, 5.32; N, 9.99. C? H22BrN304S requires C, 41.18; H, 5.43; N, 10.29%. ? (CDCb): 1.04 (3H, t), 2.42 (2H, q), 2.53 (4H, m), 3.07 (4H, m), 3.46 (3H, s), 3.78 (2H, t), 4.60 (2H, t), 8.10 (1H, s), 8.44 (1 H, s). LRMS: m / z 408 (M + 1) +.

PREPARATION 15 3-Bromo-2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine Sodium metal (93 mg, 4 mmol) was added to a stirred solution of 2-ethoxyethanol (537 μL, 5.5 mmol) in anhydrous tetrahydrofuran (5 mL). When the sodium had dissolved, the title compound of Preparation 13 (1.0 g, 2.7 mmol) was added portionwise, the reaction mixture was stirred for 18 hours at room temperature and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10 ml) and brine (10 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic solutions were washed with brine, dried (MgSO 4) and evaporated under reduced pressure, then the residue was purified by gel column chromatography. silica, using an elution gradient of hexane: dichloromethane: methanol (50: 50: 0 to 0: 98: 2) to provide the title compound (985 g, 86%) as a yellow oil,? (CDCb): 1.03 (3H, t), 1.22 (3H, t), 2.40 (2H, q), 2.54 (4H,), 3.07 (4H, m), 3.61 (2H, q), 3.82 (2H, t ), 4.59 (2H, t), 8.10 (1 H, s), 8.43 (1 H, s). LRMS: m / z 423 (M + 1) +.

PREPARATION 16 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxyprop-1-oxhpyridine) Obtained in the form of an oil (95%) from the title compound of preparation 13 and 3-methoxypropan-1-ol, using the procedure of preparation 15.? (CDCl 3): 1.04 (3H, t), 2.09 (2H, m), 2.42 (2H, q), 2.52 (4H, m), 3.08 (4H, m), 3.37 (3H, s), 3.57 (2H, t), 4.54 (2H, t), 8.09 (1H, s), 8.45 (1H, s) ,. LRMS: m / z 423 (M + 1) +.

PREPARATION 17 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) - ilox-pyridine A mixture of a 2M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (1.83 ml, 3.66 mmol), (S) - (+) - 3-hydroxytetrahydrofuran (272 [mu] l, 6 mmol) and tetrahydrofuran (40 ml) was stirred for 30 minutes at room temperature. Then, the title compound of the ^^^ Preparation 13 (750 mg, 2 mmol), the reaction mixture was stirred for 18 hours and then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of hexane: ethyl acetate (25:75 to 0: 100) to yield the title compound (430 mg, 51%) as a oil,? (CDCb): 1.06 (3H, t), 2.20 (1H, m), 2.30 (1H, m), 2.42 (2H, q), 2.56 (4H, m), 3.08 (4H, m), 3.94 ( 2H, m), 4.02 (1H, m), 4.11 (1H, m), 5.62 (1H, m), 8.12 (1H, s), 8.44 (1H, s). LRMS: m / z 420 (M) +.

PREPARATION 18 Ethyl 2-ethoxy-5-? 4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester Sodium nitrite (2.22 mg, 32.1 mmol) was added to a stirred solution of the title compound of preparation 7 (4.5 g, 21.4 mmol) in a mixture of concentrated hydrochloric acid (90 ml) and glacial acetic acid (90 ml) at -20 ° C and the resulting mixture was stirred for 2 hours, while allowing the temperature to rise to 0 ° C. The mixture was again cooled to -20 ° C, liquid sulfur dioxide (50 ml) and copper (II) chloride solution (8.4 g, 62.5 mmol) in a mixture of water (9 ml) and acid were added. acetic acid (80 ml), the reaction mixture was stirred for 30 minutes at 0 ° C, followed by a further 2 hours at room temperature. The resulting mixture was poured into stirred ice (80 g) and the aqueous solution was extracted with dichloromethane (3 x 50 ml). The combined extracts were dried (MgSO) and evaporated under reduced pressure to give the crude sulphonyl chloride in the form of a brown oil. 1-Ethylpiperazine (10.9 ml, 85.6 mmol) was added to a stirred solution of the sulfonyl chloride in ethanol (60 ml), the reaction mixture was stirred for 18 hours at room temperature and then evaporated under reduced pressure. The residue was partitioned between water (20 ml) and dichloromethane (30 ml), the separated aqueous phase was extracted with dichloromethane (2x 30 ml), and then the combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 98: 2) to yield the title compound (5.0 g, 63%) as a light brown oil. Found: C, 51.40; H, 6.77; N, 11.15. C? EH25N305S requires C, 51.74; H, 6.78; N, 11.31%. ? (CDCb): 1.02 (3H, t), 1.39 (3H, t), 1.45 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 3.08 (4H, m), 4.38 (2H, q), 4.55 (2H, q), 8.37 (1 H, s), 8.62 (1 H, s). LRMS: m / z 372 (M + 1) +.

PREPARATION 19 5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylic acid ethyl ester Triethylamine (3 ml, 32.19 mmole) and tetrakis (triphenylphosphine) palladium (0) (260 mg, 0.22 mmole) were added to a solution of the Composition of the title of preparation 14 (1.30 g, 3 mmol) in ethanol (15 ml), the mixture was heated under carbon monoxide at 100 ° C and 1034 kPa (150 psi) in a sealed container for 18 hours and then let cool. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to yield a yellow solid. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) to yield the title compound (1.10 g, 92%) as an oil yellow, ? (CDCb): 1.02 (3H, t), 1.02 (3H, t), 1.38 (3H, t), 2.40 (2H, q), 2.53 (4H, m), 3.08 (4H, m), 3.43 (3H, s), 3.80 (2H, t), 4.38 (2H, q), 4.63 (2H, t), 8.40 (1H, s), 8.61 (1H, s). LRMS: m / z 402 (M + 1) +.

PREPARATION 20 Ethyl 2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester Obtained as a gum (96%) from the title compound of preparation 15, using the procedure of preparation 19.? (CDCb): 1.03 (3H, t), 1.22 (3H, t), 1.38 (3H, t), 2.40 (2H, q), 2.52 (4H, m), 3.08 (4H, m), 3.60 (2H, q), 3.83 (2H, t), 4.38 (2H, q), 4.62 (2H, t), 8.40 (1H, s), 8.62 (1H, s). LRMS: m / z 416 (M + 1) +.

PREPARATION 21 5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (3-methoxyprop-1-oxy) -pyridine-3-carboxylic acid ethyl ester A mixture of triethylamine (5 ml, 35.9 mmol), tetrakis (triphenylphosphine) palladium (0) (200 mg, 0.17 mmol), the title compound of preparation 16 (1.08 g 2.54 mmol) and ethanol (25 ml) was heated under carbon monoxide at 100 ° C and 1034 kPa (150 psi) in a sealed container for 18 hours and then allowed to cool. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40 ml) and the solution was washed sequentially with saturated aqueous sodium bicarbonate solution (20 ml), brine (20 ml) and 2 M hydrochloric acid (5 x 10 ml). The combined acid extracts were basified using solid sodium bicarbonate and the solution was extracted with ethyl acetate (2 x 25 ml). The combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure to yield the title compound (640 mg, 68%) as an oil,? (CDCI 3): 1.05 (3H, t), 1.39 (3H, t), 2.09 (2H, m), 2.41 (2H, q), 2.54 (4H, m), 3.08 (4H, m), 3.36 (3H , s), 3.58 (2H, t), 4.39 (2H, q), 4.57 (2H, t), 8.40 (1H, s), 8.64 (1H, s). LRMS: m / z 416 (M + 1) +.

PREPARATION 22 5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3- (S) -yloxy) -pyridine-3-carboxylic acid ethyl ester Obtained as a yellow oil (78%) from the title compound of preparation 17, using the procedure of preparation 19.? (CDCb): 1.05 (3H, t), 1.39 (3H, t), 2.20 (1H, m), 2.30 (1H, m), 2.42 (2H, q), 2.55 (4H, m), 3.09 (4H , m), 3.97 (3H, m), 4.14 (1 H, m), 4.38 (2H, q), 5.70 (1H, m), 8.41 (1H, s), 8.62 (1 H, s). LRMS: m / z 414 (M + 1) +.PREPARATION 23 2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid A mixture of the title compound of Preparation 18 (4.96 g, 13.35 mmol), 2 M aqueous sodium hydroxide solution (25 mL, 50 mmol) and ethanol (25 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to half the volume, washed with ether and acidified to pH 5 using 4M hydrochloric acid. This aqueous solution was extracted with dichloromethane (3 x 30 ml), and then the combined extracts were dried. dried (MgSO), and evaporated under reduced pressure to give the title compound (4.02, 88%) as a tan solid,? (DMSOde): 1.18 (3H, t), 1.37 (3H, t), 3.08 (2H, q), 3.17-3.35 (8H, m), 4.52 (2H, q), 8.30 (1H, s), 8.70 ( 1H, s).

PREPARATION 24 Sodium salt of 2-ethoxy-5- (4-ethylpiperazin-1-ylsulphonyl) pyridine-3-carboxylic acid A 1 M aqueous solution of sodium hydroxide (85 ml, 85 mmol) was added slowly to a stirred and ice-cooled solution of the title compound of preparation 18 (30.2 g, 85 mmol) in ethanol (300 ml) and the mixture of reaction was stirred at room temperature for 18 hours. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (225 ml) and ethyl acetate (250 ml). The phases were separated, then the aqueous phase was washed with ethyl acetate (2 x 200 ml) and evaporated under reduced pressure to yield the title compound (29.6 ml, 81%) as a white solid,? (DMSOde): 0.90 (3H, t), 1.25 (3H, t), 2.24 (2H, q), 2.40 (4H, m), 2.82 (4H, m), 4.39 (2H, q), 7.76 (1H , s), 8.28 (1 H, s).

PREPARATION 25 4- (4-Ethylpiperazin-1-ylsulphonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylic acid hydrochloride A solution of the title compound of Example 19 (1.18 g, 2. 94 mmol) in a mixture of ethanol (10 ml) and 1 M aqueous sodium hydroxide solution (10 ml, 10 mmol) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure to the half of its volume and the residual aqueous solution was washed with ethyl acetate (10 ml) and then acidified to pH 3 with dilute hydrochloric acid. The acid solution was extracted with dichloromethane: methanol (95: 5) (6 x 20 ml), then the combined extracts were dried (MgSO) and evaporated under reduced pressure to give the title compound (995 mg, 82%) in shape of a white foam,? (DMSOde): 1.06 (3H, t), 2.28 (2H, q), 2.75-3.20 (8H, m), 3.28 (3H, s), 3.69 (2H, t), 4.56 (2H, t), 8.29 ( 1H, s), 8.68 (1 H, s). LRMS: m / z 374 (M + 1) +.

PREPARATION 26 2- (2-Ethoxyethoxy) -5-4- (ethylpperazin-1-ylsulfonihpyridine-3-carboxylic acid hydrochloride A mixture of the title compound of Preparation 20 (859 mg, 2.07 mmol), 1 M aqueous sodium hydroxide solution (4.6 mL, 4.6 mmol) and 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. hours. The 1,4-dioxane was removed by evaporation under reduced pressure and the pH of the remaining aqueous solution was adjusted to 3 with hydrochloric acid. The resulting solution was evaporated under reduced pressure, the residue was triturated with hot ethanol and the mixture was filtered. The filtrate was then evaporated under reduced pressure to yield the title compound (760 mg, 87%) as a tan solid,? (DMSOde): 1.08 (3H, t), 1.18 (3H, t), 2.98 (2H, m), 3.07 (4H, m), 3.37 (2H, m), 3.48 (2H, q), 3.72 (4H, m), 4.55 (2H, t), 8.30 (1H, s), 8.72 (1 H, s). LRMS: m / z 387 / M + 1) +.

PREPARATION 27 5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (3-methoxyprop-1-oxy) pyridine-3-carboxylic acid hydrochloride Obtained as a solid (87%) from the title compound of preparation 21, using the procedure of preparation 26.? (DMSOde): 1.17 (3H, t), 1.96 (2H, m), 3.08 (2H, q), 3.22 (3H, s), 3.33 (8H, m), 3.48 (2H, t), 4.48 (2H, t), 8.30 (1 H, s), 8.73 (1 H, s). LRMS: m / z 388 (M + 1) +.

PREPARATION 28 2-Ethoxy-5- (4-ethylpiperazin-1-ylsulphonhpyridine-3-carboxylic acid chloride hydrochloride Oxalyl chloride (0.77 ml, 8.85 mmol) was added dropwise to a stirred and ice-cooled solution of the title compound of preparation 23 (1.52 g, 4.42 mmol) and dimethylformamide (2 drops) in dichloromethane (30 ml). , the reaction mixture was stirred for 18 hours at room temperature and then evaporated under reduced pressure. The residue was triturated with ethyl acetate and the resulting solid was collected, washed with ether and dried under suction to yield the title compound (1.68 g, 95%). Found: C, 41.51; H, 5.27; N, 10.32. C? 4H2? CI2N304S; 0.10 CH2Cl2 requires C, 41.73; H, 5.02; N, 10.36%. ? (CDCb): 1.46 (6H, m), 2.95 (2H, q), 3.11 (2H, m), 3.48 (2H, m), 3.55 (2H, m), 3.92 (2H, m), 4.60 (2H, q), 8.58 (1H, s), 8.66 (1 H, s), 13.16 (1 H, s).

PREPARATION 29 5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylic acid chloride hydrochloride Oxalyl chloride (270 [mu] L, 3.13 mmol) was added dropwise to a stirred and ice-cooled solution of the title compound of Preparation 25 (390 mg, 1.04 mmol), dimethylformamide (100 [mu] L) and dry dichloromethane ( 20 ml), and then the reaction mixture was stirred for 3 hours at room temperature. The resulting mixture was evaporated under reduced pressure and the residue made azeotropic with toluene (2 x 20 ml) to yield the title compound (390 mg, 95%) as a white solid,? (DMSOde): 1.20 (3H, t), 2.92 (2H, q), 3.08 (4H, m), 3.30 (3H, s), 3.49 (2H, m), 3.70 (2H, t), 3.76 (2H, m), 4.58 (2H, t), 8.32 (1 H, s), 8.72 (1 H, s), 14.20 (1 H, s).

PREPARATION 30 Ethyl 3-ethyl-1H-pyrazole-5-carboxylate A solution of ethanolic sodium ethoxide (21% w / w, 143 ml, 0.39 mole) was added dropwise to a stirred and ice-cooled solution of diethyl oxalate (59.8 ml, 0.44 mole) in absolute ethanol (200 ml) under nitrogen and the resulting solution was stirred for 15 minutes. After butan-2-one (39 ml, 0.44 mol) was added dropwise, the cooling bath was removed, the reaction mixture was stirred for 18 hours at room temperature. environment and then for 6 hours at 40 ° C and then the cooling bath was re-introduced. Then, glacial acetic acid (25 ml, 0.44 mmol) was added dropwise, the resulting solution was stirred for 30 minutes at 0 ° C, hydrazine hydrate (20 ml, 0.44 moles) was added dropwise, then the mixture was added dropwise. The reaction medium was allowed to warm to room temperature and was maintained at that temperature for a period of 18 hours, before evaporating under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (100 ml), then the organic phase was separated, washed with water (2 x 100 ml), dried (Na 2 SO 4) and concentrated under reduced pressure to give the compound of the title (66.0 g). ? (CDCb): 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 31 3-Ethyl-1 H-pyrazole-5-carboxylic acid Aqueous sodium hydroxide solution (10 M, 100 ml, 1.0 mol) was added dropwise to a stirred suspension of the title compound of preparation 30 (66.0 g, 0.39 mol) in methanol (400 ml) and the resulting solution was dried. heated to reflux for 4 hours. The cooled reaction mixture was concentrated under reduced pressure to approximately 200 ml, diluted with water (200 ml) and this mixture was washed with toluene (3 x 100 ml). The resulting aqueous phase was acidified with concentrated hydrochloric acid until pH 4 and the white precipitate was collected and dried by suction to provide the composed of the title (34.1 g). ? (DMSOde): 1.13 (3H, t), 2.56 (2H, q), 6.42 (1H, s).

PREPARATION 32 4-Nitro-3-n-propyl-1 H-pyrazole-5-carboxylic acid Fuming sulfuric acid (17.8 ml;) was added dropwise to ice-cold, stirred fuming nitric acid (16.0 ml), the resulting solution was heated to 50 ° C, then 3-n acid was added discontinuously for 30 minutes. -propyl-1 H-pyrazole-5-carboxylic acid (Chem. Pharm. Bull. 1984, 32, 1568; 16.4 g, 0.106 moles) while maintaining the reaction temperature below 60 ° C. The resulting solution was heated for 18 hours at 60 ° C, allowed to cool and then poured into ice. The white precipitate was collected, washed with water and dried by suction to yield the title compound (15.4 g), m.p. 170-172 ° C. Found: C, 42.35; H, 4.56; N, 21.07. C7H9N304 requires C, 42.21; H, 4.55; N, 21.10%. ? (DMSOde): 0.90 (3H, t), 1.64 (2H,), 2.83 (2H, m), 14.00 (1H, s).

PREPARATION 33 3-Ethyl-4-nitro-1 H-pyrazole-5-carboxylic acid Obtained from the title compound of preparation 31, by analogy with preparation 32, in the form of a brown solid (64%). ? (DMSOde): 1.18 (3H, t), 2.84 (2H, m), 13.72 (1H, s).

PREPARATION 34 4-Nitro-3-n-propyl-1 H-pyrazole-5-carboxamide A solution of the title compound of Preparation 32 (15.4 g, 0.077 mol) in thionyl chloride (75 mL) was heated to reflux for 3 hours and then the cooled reaction mixture was evaporated under reduced pressure. The residue was made azeotropic with tetrahydrofuran (2 x 50 ml) and subsequently suspended in tetrahydrofuran (50 ml), then the stirred suspension was cooled with ice and treated with gaseous ammonia for 1 hour. Water (50 ml) was added and the resulting mixture was evaporated under reduced pressure to give a solid which, after trituration with water and drying by suction, yielded the title compound (14.3 g). p.f. 197-199 ° C. Found; C, 42.35; H, 5.07; N, 28.38. C7H? 0N4O3 requires C, 42.42; H, 5.09; N, 28.27%. ? (DMSOd6): 0.90 (3H, t), 1.68 (2H, m), 2.86 (2H, t), 7.68 (1H, s), 8.00 (1H, s).

PREPARATION 35 3-Ethyl-4-nitro-1H-pyrazole-5-carboxamide Obtained from the title compound of preparation 33, by analogy with preparation 34, in the form of a white solid (90%). ? (DMSOde): 1.17 (3H, t), 2.87 (2H,), 7.40 (1H, s), 7.60 (1H, s), 7.90 (1H, s). LRMS: m / z 185 (M + 1 f.

PREPARATION 36 4-Amino-3-n-propyl-1H-pyrazole-5-carboxamide A stirred mixture of the title compound of preparation 34 (10.0 g, 0.050 mol), 10% palladium on carbon (1.5 g) and ethanol (400 ml) was hydrogenated for 18 hours at 345 kPa (50 psi) and 50 ° C. C and then filtered. The filtrate was combined with an ethanol wash (200 ml) of the filter layer and then evaporated under reduced pressure to give an orange solid which, after crystallization from ethyl acetate-methanol, yielded the title compound (6.8 g). ) in the form of a white solid, mp 196-201 ° C. Found: C, 48.96; H, 6.98; N, 32.08. C7H12N40; 0.25 H20 requires C, 48.68; H, 7.30; N, 32.44%. ? (DMSOde): 0.88 (3H, t), 1.55 (2H, m), 2.46 (2H, t), 4.40 (2H, s), 7.00 (1H, s), 7.12 (1H, s), 12.20 (1 H, s).

PREPARATION 37 4-Amino-3-ethyl-1 H-pyrazole-5-carboxamide Obtained from the title compound of preparation 35, by analogy with preparation 36, in the form of a brown solid (80%). ? (DMSOde): 1.08 (3H, t), 2.45 (2H, q), 4.50 (1H, s), 6.88 (1 H, s), 7.10 (1H, s), 7.26 (2H, s). LRMS: m / z 155 (M + 1) +.

PREPARATION 38a 3-Ethyl-4-nitro-1- (pyridin-2-yl) methylpyrazole-5-carboxamide and PREPARATION 38b 3-Ethyl-4-nitro-2- (pyridin-2-yl) methylpyrazole-5- carboxamide A mixture of the title compound of the preparation (20.0 g, 109 mmol), 2- (chloromethyl) pyridine hydrochloride (17.9 g, 109 mmol), cesium carbonate (74.7 g, 222 mmol) and dimethylformamide (120 mL), it was stirred for 18 hours at room temperature and then evaporated under reduced pressure. The residue was partitioned between water (100 ml) and dichloromethane (100 ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (3 x 100 ml) and the combined extracts were dried (MgSO) and evaporated under reduced pressure. The residue was crystallized from dichloromethane-methanol to yield the first title compound (Isomer 1; 6.5 g, 21%). ? (CDCb): 1.24 (3H, t), 2.90 (2H, q), 5.54 (2H, s), 6.03 (1H, s), 7.27 (1H, m), 7.36 (1H, d), 7.76 ( 1 H, m), 8.52 (1 H, d), 8.58 (1H, s). The mother liquor was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to provide the second title compound (isomer 2). 17.36 g, 58%) in the form of a white solid,? (CDCb): 1.16 (3H, t), 3.06 (2H, q), 5.48 (2H, s), 5.88 (1H, s), 7.19 (1H, d), 7.27 (1H, m), 7.70 (1H ,), 8.57 (1H, d).

PREPARATION 39a 4-Nitro-3-n-propyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide and PREPARATION 39b 4-Nitro-3-n-propyl-2- (pyr) d-n-2-yl) methylprazole-5-carboxamide 2- (Chloromethyl) -pyridine hydrochloride (24.6 g, 150 mmol) was added portionwise to a stirred solution of the title compound of preparation 34 (30.0 g, 150 mmol) and cesium carbonate (123.5 g, 380 mmol) in dimethylformamide (300 ml), the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure, the residue was suspended in water and the resulting solid was collected and dried under suction. The crude product was purified by two column chromatography operations on silica gel, using respectively dichloromethane: methanol (98: 2) and ethyl acetate: pentane (20:80) as eluents, to produce the first title compound (isomer 1; 424 mg, 1%) as a white solid. Found: C, 53.74; H, 5.20; N, 23.91. C 13 H 15 N 5 O 3 requires C, 53.97; H, 5.23; N, 24.21%. ? (CDCb): 0.94 (3H, t), 1.68 (2H, m), 2.86 (2H, t), 5.55 (2H, s), 6.07 (1H, s), 7.35 (1H, d), 7.75 ( 1H, m), 8.51 (1H, d), 8.56 (1H, s). LRMS: m / z 290 (M + 1) +. and the second title compound (isomer 2; 16.7 g, 38%) as a white solid,? (DMSOde): 0.84 (3H, t), 1.46 (2H, m), 2.95 (2H, t), 5.49 (2H, s), 7.31 (2H, m), 7.60 (1H, s), 7.79 (1H , m), 7.90 (1H, s), 8.49 (1 H, d).

PREPARATION 40 4-Amino-3-ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide A stirred mixture of the title compound of the compound of preparation 38b (16.36 g, 59 mmol), 10% palladium on carbon (4 g) and ethanol (150 ml) was hydrogenated at 345 kPa (50 psi) for 4 hours. hours and then it leaked. The filtrate was combined with a wash of ethyl acetate (150 ml) of the filter layer and then concentrated under reduced pressure to a volume of about 70 ml. The resulting precipitate was collected and dried under suction to yield the title compound (12.6 g, 87%) as a white solid,? (CDCb): 1.03 (3H, t), 2.53 (2H, q), 4.00 (2H, s), 5.22 (1H, s), 5.36 (2H, s), 6.60 (1H, s), 6.81 (1 H, d), 7.20 (1 H, m), 7.62 (1 H, m), 8.57 (1 H, d). LRMS: m / z 246 (M + 1) +.

PREPARATION 41 4-Amino-3-n-2-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide A stirred mixture of the title compound of preparation 39b (1.0 g, 3.46 mmol), Raney nickel (1 g) and ethanol (50 ml) was hydrogenated at 50 345 kPa (50 psi) and 50 ° C for 18 hours, then it was allowed to cool and filtered. The filtrate was combined with an ethanol wash (50 ml) of the filter layer and then evaporated under reduced pressure to give the title compound (830 mg, 93%) as a crystalline solid,? (DMSOd6): 0.79 (3H, t), 1.33 (2H, m), 3.28 (2H, t), 4.60 (2H, s), 5.30 (2H, s), 6.88 (1H, s), 6.98 (1 H, s), 7.13 (1H, s), 7.30 (1H, m), 7.74 (1H, m), 8.50 (1H, d). LRMS: m / z 274 (M + 1) +.

PREPARATION 42 4-Amino-3-ethyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide Obtained as a solid (94%) from the title compound of preparation 38a, using the procedure of preparation 40.? (CDCb): 1.20 (3H, t), 2.52 (2H, q), 3.72 (2H, s), 5.50 (2H, s), 7.21 (1H, m), 7.34 (1H, d), 7.68 (1 H, m), 8.49 (1 H, d), LRMS: m / z 246 (M + 1 f.

PREPARATION 43 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-ethyl-1 H -pyrazole-5-carboxamide hydrochloride A mixture of the title compound of preparation 28 (1.0 g, 2. 51 mmol), preparation 37 (387 mg, 2.51 mmol) and pyridine (15 ml) was stirred at room temperature for 18 hours. The resulting mixture was evaporated under reduced pressure and the result triturated with ether to yield the title compound (1.05 g, 87%) as a purple solid.

Found: C, 44.82; H, 5.72; N, 18.62. C20H29N 705S; HCl; H20 requires C, 44. 98; H, 6.04; N, 18.36%. ? (DMSOde): 1.17 (6H, m), 1.46 (3H, t), 2.77 (2H, q), 3.09 (2H, q), 3.49 (4H, m), 3.78 (4H, m), 4.68 (2H, q), 7.30 (1H, s), 7.49 (1 H, s), 8.52 (1 H, s), 8.76 (1 H, s), 10.54 (1 H, s), LRMS: m / z 480 (M + 1) +.

PREPARATION 44 5- [2-Ethoxy-5- (4-etll-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-1,6-dihydro-7H-pyrazolo [4.3-d1-pyrimidin-7] -one Potassium t-butoxide (943 mg, 8.41 mmol) was added to a stirred suspension of the title compound of Preparation 43 (1.10 g, 2.1 mmol) in absolute ethanol (50 mL), the reaction mixture was heated in a vessel sealed at 100 ° C for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was dissolved in water (15 ml). The aqueous solution was acidified to pH 6 using hydrochloric acid and the resulting solid was collected, washed with water and dried under suction. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (97: 3) as eluent, to give the title compound (445 mg, 46%) as a yellow solid. Found: C, 51.95; H, 5.89; N, 20.87. C20H27N 704S; requires C, 52.05; H, 5.90; N, 21.24%. ? (DMSOde): 0.92 (3H, t), 1.30 (6H, m), 2.30 (2H, q), 2.42 (4H, m), 2.86 (2H, q), 2.95 (4H, m), 4.49 (2H, q), 8.20 (1 H, s), 8.64 (1H, s), 12.19 (1H, s), 13.80 (1H, s). LRMS: m / z 462 (M + 1) +.

PREPARATION 45 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-carboxyl-idol-3-ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide Alternative A A mixture of the title compounds of preparation 28 (1.0 g, 2.5 mmol), preparation 40 (620 mg, 2.5 mmol) triethylamine (1.35 mL, 10 mmol) and dichloromethane (50 mL) was stirred at room temperature for 18 hours. The resulting mixture was poured into stirred water (50 ml), the phases were prepared and the aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic solutions were dried (MgSO 4) and evaporated under reduced pressure and then the residue was purified by column chromatography on silica gel, using an elution ingredient of dichloromethane: methanol (100: 0 to 95: 5) to produce the title compound (1.29 g, 90%) in the form of a foam,? (CDCb): 1.00 (6H, m), 1.55 (3H, t), 2.37 (2H, q), 2.50 (4H, m), 2.87 (2H, q), 3.08 (4H, m), 4.77 (2H, q), 5.28 (1H, s), 5.45 (2H, s), 6.68 (1 H, s), 6.90 (1H, d), 7.18 (1 H, m), 7.61 (1 H, m), 8.57 ( 1 H, d), 8.62 (1H, s), 8.80 (1 H, s), 10.57 (1H, s).

Alternative B: 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (17.6 g, 91.8 mmol) was added portionwise over 5 minutes to a stirred and ice-cooled suspension of 1-hydroxybenzotriazole hydrate (12 g, 88.9 mmoles) and the title compound of preparation 24 (24 g, 65.7 mmol) in tetrahydrofuran (300 ml) and then the mixture was stirred for 1 hour. N-Ethyldiisopropylamine (12.7 g, 98.3 mmol) and the title compound of preparation 40 (12.9 g, 52.6 mmol) were added, the reaction mixture was stirred at room temperature for 14 hours and then evaporated under reduced pressure. The residue was partitioned between water (100 ml) and ethyl acetate (200 ml), the phases were prepared, the organic phase was washed consecutively with water (50 ml), saturated aqueous sodium bicarbonate solution (50 ml) and brine ( 50 ml), and then dried (MgSO 4) and concentrated under reduced pressure to a low volume. The resulting suspension was cooled on ice for 1 hour, and then the precipitate was collected and dried under suction to yield the title compound (14.1 g, 47%) as a white crystalline solid, m.p. 180-187 ° C. Found: C, 54.59; H, 6.05; N, 19.32. C26H34N803S; requires C, 54.72; H, 6.00; N, 19.63%.

PREPARATION 46 2-n-propoxypyridine-3-carboxylic acid Obtained in the form of a light brown oil (50%) from 2-chloronicotico acid and n-propanol, using the procedure of preparation 1.? (CDCb): 1.08 (6H, m), 1.92 (2H, m), 4.56 (2H, t), 7.10 (1H, m), 8.35 (1H, d), 8.45 (1H, d).

PREPARATION 47 2-n-propoxypyridine-3-carboxylic acid methyl ester 46. Diethyl azodicarboxylate (2.2 ml, 14 mmol) was added dropwise to a stirred solution of the title compound of preparation 46. (2.30 g, 12.7 mmol), triphenylphosphine (3.67 g, 14 mmol) and methanol (0.60 mL, mmol) in tetrahydrofuran (20 ml), the reaction mixture was stirred for 18 hours at room temperature and then evaporated under reduced pressure. The residue was triturated with pentane: ether (80:20) and the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using pentane: ether (50:50) as eluent, to give the title compound (2.2 g, 89%) as a yellow oil,? (CDCb): 1.07 (3H, t), 1.86 (2H, m), 3.92 (3H, s), 4.38 (2H, t), 6. 93 (1H, m), 8.15 (1H, d), 8.30 (1H, d).

PREPARATION 48 5-Nitro-2-n-propoxypyridine-3-carboxylic acid methyl ester Obtained as light yellow needles (32%), after crystallization from methanol, from the title compound of preparation 47, using the procedure of preparation 5.? (CDCl 3): 1.04 (3H, t), 1.84 (2H, m), 3.92 (3H, s), 4.48 (2H, t), 8.88 (1H, s), 9.14 (1H, s).

PREPARATION 49 5-amino-2-n-propoxypyridine-3-carboxylic acid methyl ester A mixture of the title compound of preparation 48 (1.8 g, 7.46 mmol), Raney nickel (500 mg) and methanol (50 ml) was hydrogenated at 345 kPa (3.515 kg / cm2) and 50 ° C for 3 hours, then it was allowed to cool and filtered. The filtrate was combined with a methanol wash (100 ml) of the filter layer and then evaporated under reduced pressure to yield the title compound (1.5 g, 95%) as a brown oil,? (CDCb): 1.04 (3H, t), 1.80 (2H, m), 3.40 (2H, s), 3.89 (3H, s), 4.28 (2H, t), 7.57 (1 H, s), 7.80 (1 H, s). LRMS: m / z 211 (M + 1f.

PREPARATION 50 5- (4-Methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid methyl ester Obtained in the form of an oil (56%) from the title compound of preparation 49 and 1-methylpiperazine, using the procedure of preparation 18.

PREPARATION 51 5- (4-Methyl-piperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid Obtained as a white solid (82%) from the title compound of preparation 50, using the procedure of preparation 23.? (DMSOde): 0.97 (3H, t), 1.74 (2H, m), 2.15 (3H, s), 2.38 (4H, n), 2.93 (4H, m), 4.37 (2H, t), 8.15 (1H , s), 8.56 (1H, s).

PREPARATION 52 3-Ethyl-4- [5- (4-methyl-piperazin-1-ylsulfonyl) -2-n-propoxypyrdin-3-ylcarboxamido] -2- (pyridin-2-yl) methylpyrazole-5-carboxamide Oxalyl chloride (500 μL, 6.37 mmol) was added cautiously, followed by dimethylformamide (2 drops) to a stirred and ice-cooled suspension of the title compound of Preparation 51 (605 mg, 1.59 mmol), in dichloromethane (10 ml). ml), the reaction mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was azeotroped with toluene to produce a powder.

A solution of the crude acid chloride in dichloromethane (10 ml) was added dropwise to a stirred and ice-cooled suspension of the title compound of preparation 40 (430 mg, 1.76 mmol), triethylamine (558 μl, 4 mmol ) and dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 1.5 hours. The resulting mixture was washed successively with aqueous sodium bicarbonate solution and brine, then the organic phase was dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of hexane: ethyl acetate: methanol (70: 30: 0 to 0:90:10) to give the title compound (6.95 mg, 76%) in the form of a solid. Found: C, 53.96; H, 6.09; N, 19.00. C26H34N 805S; requires C, 54.22; H, 6.00; N, 19.64%. ? (CDCb): 1.07 (6H, m), 2.01 (2H, m), 2.26 (3H, s), 2.48 (4H, m), 2.88 (2H, q), 3.10 (4H, m), 4.67 (2H, t), 5.34 (1 H, s), 5.48 (2 H, s), 6.70 (1 H, s), 6.94 (1 H, m), 8.59 (1 H, m), 7.66 (1 H, m), (1H, d), 8.65 (1 H, s), 8.82 (1H, s), 10.48 (1 H, s). LRMS: m / z 572 (M + 2) +.

PREPARATION 53 4-f5- (4-Ethylpiperazin-1-ylsulfonih-2- (2-methoxyethoxy) pyridin-3-ylcarboxamidol-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide Obtained in the form of a white foam (70%) from the compounds of preparation 29 and of preparation 41, using the procedure of preparation 45A. ? (CDCb): 0.81 (3H, t), 1.02 (3H, t), 1.46 (2H, m), 2.39 (2H, q), 2.51 (4H, m), 2.82 (2H, t), 3.10 (4H, m), 3.39 (3H, s), 3.94 (2H, t), 4.85 (2H, t), 5.30 (1 H, s), 5.46 (2H, s), 6.69 (1 H, s), 6.90 (1 H, d), 7.21 (1H, m), 7.65 (1H, m), 8.60 (1H, d), 8.65 (1H, s), 8.82 (1H, s). 10.46 (1H, s). LRMS: m / z 615 (M + 1) +.

PREPARATION 54 4- [2- (2-Ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5 -carboxamide Obtained in the form of a white foam (69%) from the title compounds of Preparation 26 and of Preparation 41, using the procedure of Preparation 52. Found: C, 55.13; H, 6.45; N, 17.27. C29H4oN? 06S; requires C, 55.39; H, 6.41; N, 17.82%.? (CDCb): 0.80 (3H, t), 1.02 (3H, t), 1.10 (3H, m), 1.45 (2H, m), 2.40 (2H, q), 2.50 (4H, m), 2.81 (2H, t), 3.09 (4H, m), 3.54 (2H, q), 3.98 (2H, t), 4.80 (2H, t), 5.30 (1 H, s), 5.47 (2H, s), 6.70 (1 H , s), 6.89 (1 H, d), 7.22 (1 H, m), 7.63 (1 H, m), 8.59 (1 H, d), 8.65 (1 H, s). 8.82 (1 H, s), 10.45 (1 H, s). LRMS: m / z 629 (M + 1) +.

PREPARATION 55 4-f5- (4-Ethyl-piperazin-1-ylsulfonyl) -2- (3-methoxyprop-1-oxy) pyridin-3-ylcarboxamidol-3-n-propyl-2- (pyridin-2- il) methylpyrazole-5-carboxamide Obtained in the form of a foam (52%) from the title compounds of preparation 27 and of preparation 41, using the procedure of preparation 52.? (CDCb): 0.82 (3H, t), 1.02 (3H, t), 1.44 (2H, m), 2.25 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 2.84 (2H, t), 3.10 (4H, m), 3.29 (3H, s), 3.57 (2H, t), 4.79 (2H, t), 5.34 (1H, s), 5.47 (2H, s). 6.70 (1H, s), 6.92 (1H, d), 7.22 (1H, m), 7.66 (1H, m), 8.59 (1H, d), 8.65 (1H, s), 8.81 (1H, s) , 10.45 (1 H, s). LRMS: m / z 629 (M + 1) +.

PREPARATION 56 3-Ethyl-4-f5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) yloxy) pyridin-3-ylcarboxamido] -2- (pyridin-2-yl) methylpyrazole- 5-carboxamide A solution of the title compound of Preparation 22 (330 mg, 0.80 mmol) and 1 M aqueous sodium hydroxide solution (800 μL, 0.80 mmol) in ethanol (3 mL) was stirred for 3 hours at room temperature and then evaporated under reduced pressure. A mixture of the resulting solid, the title compound of preparation 40 (196 mg, 0.80 mmol), 1-hydroxybenzotriazole hydrate (135 mg, 0.88 mmol), N-ethyldiidopropylamine (307 μl, 1.76 mmol), hydrochloride of 1 - (3-Dimethylaminopropyl) -3-ethylcarbodiimide (169 mg, 0.88 mmol) and tetrahydrofuran (15 ml) was stirred for 72 hours at room temperature and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and water (15 ml), the phases were separated and the organic phase was dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (95: 5 to 90:10) to yield the title compound (382 mg, 78%) as a foam. . ? (CDCb): 1.05 (6H, m), 2.40 (3H, m), 2.54 (5H, m), 2.85 (2H, q), 3.11 (4H, m), 3.54 (1H, m), 4.15 ( 3H, m), 5.31, (1H, s), 5.48 (2H, s) 5.90 (1H, m), 6.69 (1H, s), 6.94 (1H, d), 7.24 (1H, m) , 7.67 (1H, m), 8.60 (1 H, m), 8.66 (1 H, s), 8.87 (1 H, s), 10.27 (1 H, s). LRMS: m / z 613 (M + 1) +.

PREPARATION 57 4- (2-Ethoxy-5-nitropyridin-3-ylcarboxamido) -3-n-propyl-2- (pyridin-2-yl) methypyrazole-5-carboxamide Oxalyl chloride (2.73 ml, 31 mol) was added dropwise to a stirred suspension of the title compound of preparation 8 (3.31 g, 15.7 mmol) in dichloromethane (50 ml), followed by dimethylformamide (2 drops) and the The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was evaporated under reduced pressure and the residue was azeotroped with hexane to give a white solid. A solution of crude acid chloride in dichloromethane (20 ml) was added dropwise to a stirred suspension of the title compound of preparation 41 (4.06 g, 15.7 mmol), triethylamine (4.37 ml, 31 mmol) and dichloromethane (80 ml). ml) and the reaction mixture was stirred at room temperature for 20 hours. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution (200 ml) and dichloromethane (300 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2 x 300 ml). The combined organic solutions were washed with brine, dried (Na 2 SO 4) and evaporated under reduced pressure to give a purple solid. The crude product was triturated with ether and the resulting solid was collected and dried under suction to yield the title compound (6.26 g, 88%) as an off-white solid. Found: C, 55.42; H, 5.05; N, 21.49. C2iH23N7? 5 requires C, 55.62; H, . eleven; N, 21.62%. (CDCl 3): 0.83 (3H, t), 1.46 (2H, m), 1.60 (3H, t), 2.89 (2H, t), 4.85 (2H, q), 5.32 (1 H, s), 5.48 ( 2H, s), 6.72, (1 H, s), 6.95 (1H, d) 7.24 (1H, m), 7.67 (1H, m), 8.60 (1 H, d), 9.16 (1H, s), 9.30 (1H, m), 10.59 (1H, s). LRMS: m / z 454 (M + 1) +.

PREPARATION 58 3-Ethyl-4- [2- (2-methoxyethoxy) -5-nitropyridin-3-ylcarboxamido] -2- (pyridin-2-yl) methylpyrazole-5-carboxamide Hydroxybenzotriazole hydrate (1.87 g, 12.2 mmol), N-ethyldiisopropylamine (2.13 ml, 12.2 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.34 g, 12.2 mmol) were added, and the titer of preparation 40 (3.0 g, 12.2 mmol), successively, to a stirred and ice-cooled suspension of the title compound of preparation 9 (2.96 g, 12.2 mmol) in dichloromethane (80 ml) and the reaction mixture was stirred for 18 hours at room temperature. The resulting mixture was washed consecutively with water (25 ml), 2 M hydrochloric acid (2 x 25 ml), saturated aqueous sodium bicarbonate solution (25 ml) and brine (25 ml), and then dried (gS04) and evaporated under reduced pressure. The residual solid was purified by column chromatography on silica gel, an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound (3.36, 58%) as a white solid. Found: C, 53.41; H, 4.90; N, 20.65. C21H23N706 requires C, 53.72; H, 4.94; N, 20.89%.

? (CDCb): 1.08 (3H, t) 2.88 (2H, q), 3.40 (3H, s), 3.98 (2H, t) 4.90 (2H, t), 5.28 (1H, s), 5.48 (2H, s), 6.70 (1 H, s), 6.92 (1 H, d), 7.23 (1 H, m), 7.66 (1 H, m), 8.60 (1 H, d), 9.15 (1 H, s), 9.31 (1H, s), 10.50 (1H, s). LRMS: m / z 470 (M-1) +.

PREPARATION 59 4- (5-Amino-2-ethoxypyridin-3-ylcarboxamido) -3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide A stirred mixture of the title compound of the preparation 57 (5 g, 11 mmol), Raney nickel (2.5 g) and ethanol (150 ml) was hydrogenated 345 kPa (3.515 kg / cm2) and 40 ° C for 3 hours, and then for 72 hours at room temperature. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to give a pale yellow solid. The crude product was purified by column chromatography on silica gel, using a gradient elution of dichloromethane: methanol (99: 1 to 95: 5) followed by trituration with ether, to yield the title compound (4.4 g, 94%) as a beige solid. Found: C, 59.42; H, 5.96; N, 22.98. C2? H25N705 requires C, 59.56; H, 5.95; N, 23.15%. ? (CDCI3): 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 (1 H, d), 7.22 (1 H, m), 7.65 (1 H, m), 7.78 (1 H, s), 7.94 (1 H, s), 8.58 (1 H, d), . 53 (1 H, s).

PREPARATION 60 5-f5-Amino-2- (2-methoxyethoxy) pyridin-3-ylcarboxamido] -3-ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide A stirred mixture of the title compound of the preparation 58 (3.3 g, 7.0 mmol) Raney nickel (2 g) and ethanol (120 ml) was hydrogenated at 345 kPa (3.515 kg / cm2) and 50 ° C for 18 hours. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to provide the title compound (3.01 g, 98%) as a light gray foam. Found: C, 56.47; H, 5.82; N, 21.40. C2? H25N704 0.40 H20 requires C, 56.47; H, 5.82; N, 21.95%. (CDCl 3): 1.06 (3H, t), 2.81 (2H, q), 3.38 (3H, s), 3.50 (2H, s), 3.92 (2H, t), 4.65 (2H, t), 5.33 (1H , s), 5.46, (2H, s), 6.70 (1H, s) 6.92 (1H, d), 7.22 (1H, m), 7.64 (1 H, m), 7.76 (1 H, s), 7.94 ( 1 H, s), 8.60 (1H, d), 10.47 (1 H, s). LRMS: m / z 440 (M + 1) +.

PREPARATION 61 5- [5-Amino-2- (2-ethoxypyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-p¡razolo [ 4.3-djpirimidin-7-one Potassium t-butoxide (2.32 g, 20 mmol) was carefully added to a stirred suspension of the title compound of the preparation 59 (2.11 g, 5 mmol) and molecular sieves of A in ethanol (50 ml) and the reaction mixture was heated to reflux for 18 hours, allowed to cool and filter. The filtrate was evaporated under reduced pressure and the residue was partitioned between 1 M hydrochloric acid (30 ml) and ethyl acetate (2 x 30 ml) and the combined organic solutions were washed with brine, dried (Na 2 S 4) and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4), to yield the title compound (1.22 g, 60%) as a a yellow solid. Found: C, 61.92; H, 5.69; N, 23.95. C21H23N702 requires C, 62.21; H, 5.72; N, 24.18%. ? (CDCb): 0.94 (3H, t), 1.51 (3H, t), 1.62 (2H, m), 2.95 (2H, t), 3.57 (2H, s), 4.50 (2H, q), 5.68 (2H , s), 7.06, (1H, d), 7.21 (1H, m) 7.60 (1H, m), 7.78 (1H, s), 8.16 (1H, d), 8.57 (1H, s), 11.07 (1H , s).

PREPARATION 62 5- [5-Amino-2- (2-methoxyethoxy) pyridin-3-yl-3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolof4. 3-d1-pyrimidin-7-one Potassium bis (trimethylsilli) amide (6.58 g, 33.0 mmol) was added to a suspension of the title compound of preparation 60 (2.90 g, 6.60 mmol) in 2-methoxyethanol (70 ml) and the reaction mixture was stirred at reflux for 18 hours. The resulting mixture was allowed to cool and then evaporated under reduced pressure to give a beige solid. The crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5), to yield the compound of the title (2.21 g, 79%) in the form of a white solid. Found: C, 59.10; H, 5.44; N, 22.86. C 21 H 23 N 703 requires C, 59.85; H, 5.50; N, 23.26%. (CDCI3): 1.28 (3H, t), 3.01 (2H, q), 3.53 (3H, s), 3.58 (2H, s), 3.82 (2H, t), 4.62 (2H, t), 5.66 (2H , s), 7.08, (1H, d), 7.20 (1H, m) 7.61 (1H, m), 7.75 (1H, s), 8.09 (1H, s), 8.57 (1H, d), 11.14 (1 H, s). LRMS: m / z 422 (M + 1) +.

PREPARATION 63 5- [5-Chlorosulfonyl-2-ethoxypyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) meth yl-2,6-dihydro-7 H -pyrazolo [4.3-d] pyrimidin-7-one Sodium nitrite (295 mg, 4.4 mmol) was added portionwise to a stirred and ice-cooled solution of the title compound of preparation 61 (900 mg, 2.2 mmol) in a mixture of glacial acetic acid (20 ml) and hydrochloric acid. concentrate (20 ml) at a rate such as to keep the temperature below -20 ° C. When the addition was complete, the mixture was allowed to slowly warm to 0 ° C for 2 hours and then re-cooled to -15 ° C. Then liquid sulfur dioxide (22 ml) and a solution of copper (II) chloride (860 mg, 6.6 mmol) in a mixture of water (2 ml) and glacial acetic acid (14 ml) and the reaction mixture were added. it was stirred at 0 ° C for 30 minutes, followed by a further 2 hours at room temperature. The resulting mixture was carefully poured into ice cold water and stirred (300 ml) and the suspension thus obtained was extracted with dichloromethane (3 x 100 ml). The combined extracts were washed with brine, dried (MgSO 4) and evaporated under reduced pressure, and then the residual oil was triturated with ether to yield the title compound (7.20 mg, 67%) as an off-white liquid solid. ? (CDCb): 0.97 (3H, t), 1.60 (3H, t), 1.73 (2H, m), 3.01 (2H, t), 4.82 (2H, q), 5.70 (2H, s), 7.10 (1 H, d), 7.22, (1 H, m), 7.64 (1 H,) 8.58 (1 H, d), 8.90 (1 H, s), 9.29 (1 H, s), 10.55 (1 H, s) .

PREPARATION 64 5- [5-Chlorosulfonyl-2- (2-ethoxymethoxy) pyridin-3-yl) -3-ethyl-2- (pyridin-2-yl) methyl-2,6-dihydro-7H -pyrazolo [4.3-d] pyrimidin-7-one Obtained as a cream colored solid (84%) from the title compound of preparation 62, using the procedure of preparation 63. (CDCl 3): 1.32 (3H, t), 3.08 (2H, q) , 3.58 (3H, s), 3.89 (2H, t), 4.85 (2H, t), 5.69 (2H, s), 7.12 (1H, d), 7.22, (1H, m), 7.64 (1H, m) 8.57 (1H, d), 8.89 (1H, s), 9.26 (1H, s), 10.57 (1H, s). LRMS: m / z 505 (M + 1) +.

PREPARATION 65 3-Ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl-2- (2-methoxyethoxy) pyridin-3-ylcarboxamido) -1 - (pyridin-2-yl) methylpyrazolo-5-carboxamide Obtained as a crystalline white solid (44%) from the title compound of preparation 19 and of preparation 42, using the procedure of preparation 56. (CDCb): 1.02 (3H, t), 1.20 ( 3H, t), 2. 40 (2H, q), 2.52 (4H, m), 2.66 (2H, q), 3.10 (4H, m), 3.39 (3H, s), 3.90, (2H, t), 4.81 (2H, t) 5.62 (2H, s), 5.70 (1 H, s), 7.26 (2H, m), 7.71 (1 H, m), 8.53 (1 H, d), 8.66 (1 H, s) 8.82 (1 H, s ), 9.04 (1 H, s). LRMS: m / z 601 (M + 1) +.

PREPARATION 66 3-Bronno-2- (1,3-dimethoxyprop-2-oxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine A dispersion of 60% sodium hydride in mineral oil (133 mg, 3.3 mmol) was added to a stirred and ice-cooled solution of 1,3-dimethoxypropan-2-ol (J. Amer. Chem. Soc, 1939, 61 433, 400 mg, 3.33 mmol) in tetrahydrofuran (30 ml) and the mixture was stirred for 30 minutes. The title compound of Preparation 13 (500 mg, 1.35 mmol) was added, the reaction mixture was stirred at reflux for 1 hour and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between water (30 ml) and ethyl acetate (30 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate (2 x 30 ml) and then the combined extracts were washed with brine (30 ml), dried (MgSO 4) and evaporated under reduced pressure to give the title compound. title (566 mg, 93%) as a yellow solid. (CDCl 3): 1.06 (3H, t), 2.43 (2H, q), 2.55 (4H, m), 3.08 (4H, m), 3.40 (6H, 2x), 3.70 (4H, 2xd), 5.60 (1H , m), 8.10, (1H, s), 8.44 (1 H, s). LRMS: m / z 452.

PREPARATION 67 2- (1,3-Dimethoxyprop-2-oxy) -5- (4-ethylpiperazin-1-ylsulphonopyridine-3-carboxylic acid ethyl ester Obtained as a yellow solid (84%) from the title compound of preparation 66, using the procedure of preparation 19. (CDCl 3): 1.05 (3H, t), 1.40 (3H, t), 2.42. (2H, q), 2.55 (4H, m), 3.09 (4H, m), 3.40 (6H, 2x), 3.70 (4H, 2xd), 4.37 (2H, q), 5.70 (1 H, m), 8.40 (1H, s), 8.62 (1 H, s). LRMS: m / z 446 (M + 1) +.

PREPARATION 68 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridine Obtained in the form of a clear oil (70%) from the title compound of preparation 13 and 4-hydroxytetrahydropyran, following the procedure of preparation 14, after purification by column chromatography on silica gel, using ethyl acetate. ethyl as eluent. ? (CDCl 3): 1.05 (3H, t), 1.88 (2H, m), 2.08 (2H, m), 2.42 (2H, q), 2.54 (4H, m), 3.08 (4H, m), 3.66 (2H, m), 3.99 (2H, m), 5.40 (1H, m), 8.10 (1H, s), 8.42 (1H, s). LRMS: m / z 434 (M) +.

PREPARATION 69 5- (4-Ethyl Pyrrazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy-pyridine-3-carboxylic acid) ethyl ester Obtained in the form of an oil (92%) from the title compound of preparation 68, using the procedure of preparation 19.? (CDCb): 1 -04 (3H, t), 1.40 (3H, t), 1.88 (2H, m), 2.08 (2H, m), 2.43 (2H, q), 2.55 (4H, m), 3.09 ( 4H, m), 3.66 (2H, m), 4.00 (2H, m), 4.40 (2H, q), 5.50 (1H, m), 8.40 (1H, s), 8.60 (1H, s). LRMS: m / z 427 (M) +.

PREPARATION 70 Sodium salt of 5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridine-3-carboxylic acid A mixture of the title compound of preparation 69 (611 mg, 1.4 mmol), 1 M aqueous solution of sodium hydroxide (1.6 ml, 1.6 mmol) and ethanol (6 ml) was stirred at room temperature for 6 hours and then evaporated under reduced pressure. The residue was dissolved in water (16 ml), and then the solution was washed with ethyl acetate (2 x 10 ml) and evaporated under reduced pressure to give the title compound (520 mg, 93%) as a solid chestnut color,? (DMSOde): 1.19 (3H, t), 1.70 (2H, m), 2.00 (2H, m), 2.80-3.88 (14H, m), 8.32 (1H, s), 8.73 (1 H, s), 10.93 (1H, s). LRMS: m / z 400 (M + 1) +.

PREPARATION 71 2- (1,3-Dimethoxyprop-2-oxy) -5- (4-ethyl-piperazin-1-ylsulfonyl) -pyridine-3-carboxylic acid sodium salt Obtained as a solid (92%) from the title compound of preparation 67, using the procedure of preparation 70. LRMS: m / z 418 (M + 1) +.

PREPARATION 72 4-f2- (1,3-Dimethoxyprop-2-oxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-ylcarboxamido] -3-n-propyl-2- (pyridine -2-il) methylpyrazole-5-carboxamide A mixture of the title compounds of preparation 71 (418 mg, 0.95 mmol) and of preparation 41 (250 mg, 1.0 mmol), 1-hydroxybenzotriazole hydrate (270 mg, 2.0 mmol), 1- (3-hydrochloride dimethylaminopropyl) -3-ethylcarbodiimide (380 mg, 2.0 mmol), triethylamine (280 μL, 2.0 mmol) and tetrahydrofuran (10 mL) was stirred at room temperature for 36 hours and then evaporated under reduced pressure. The residue was partitioned between dichloromethane (10 ml) and brine (10 ml), the phases were separated, the aqueous phase was extracted with dichloromethane (2 x 10 ml) and the combined organic solutions were dried (MgSO 4) and evaporated under pressure reduced. The residual yellow oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (98: 2 a). 96: 4) to produce the title compound (350 mg, 56%) as an off-white solid,? (CDCb): 0.81 (3H, t), 1.03 (3H, t), 1.44 (2H, m), 2.40 (2H, q), 2.52 (4H, m), 2.80 (2H, t), 3.10 (4H, m), 3.38 (6H, s), 3.78 (2H, dd), 3.92 (2H, dd), 5.31 (1 H, s), 5.47 (2H, s), 5.93 (1 H, m), 6.70 (1H , s), 6.92 (1 H, d), 7.23 (1 H, m), 7.65 (1 H, m), 8.58 (1 H, d), 8.65 (1 H, s), 8.80 (1 H, s) , 10.26 (1 H, s). LRMS: m / z 660 (M + 2) +.

PREPARATION 73 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridine Obtained in the form of an oil (89%) from the title compound of preparation 13 and (R) - (-) - 3-hydroxytetrahydrofuran, using the procedure of preparation 17.? (CDCb): 1.05 (3H, t), 2.20 (1H, m), 2.30 (1H, m), 2.42 (2H, q), 2.54 (4H, m), 3.07 (4H, m), 3.94 (2H , m), 4.02 (1 H, m), 4. 10 (1H, m), 5.63 (1H, m), 8.11 (1H, s), 8.43 (1H, s). LRMS: m / z 421 (M + 1) +.

PREPARATION 74 Ethyl ester of the acid 5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridine-3-carboxylic acid Obtained in the form of an oil (84%) from the title compound of preparation 73, using the procedure of preparation 19.? (CDCb): 1.03 (3H, t), 1.40 (3H, t), 2.26 (2H, m), 2.42 (2H, q), 2.55 (4H, m), 3.10 (4H, m), 3.98 (3H, m), 4.12 (1H, m), 4.38 (2H, q), 5.70 (1H, m), 8.42 (1 H, s), 8.62 (1 H, s). LRMS: m / z 414 (M + 1) +.

PREPARATION 75 3-Ethyl-4-r5- (4-ethy1-piperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridin-3-ylcarboxamido1-2- (pyridin-2-yl Methylprazole-5-carboxamide Obtained as a foam (78%) from the title compounds of preparation 74 and preparation 40, using the procedure of preparation 56.? (CDCb): 1.04 (6H, m), 2.40 (3H, m), 2.52 (5H, m), 2.84 (2H, q), 3.10 (4H, m), 3.94 (1H, m), 4.15 (3H , m), 5.28 (1 H, s), 5.48 (2 H, s), 5.90 (1 H, m), 6.68 (1 H, s), 6.92 (1 H, d), 7.22 (1 H, m) , 7.67 (1H, m), 8.60 (1 H, d), 8.64 (1 H, s), 8.86 (1 H, s), 10.28 (1 H, s). LRMS: m / z 613 (M + 1) +.

PREPARATION 76 4- [5- (4-Ethylpiperazin-1-ylsulphonyl) -2- (tetrahydro-pyridin-4-yloxy) pyridin-3-lcarboxamido-3-n-propyl-2- (pyridine -2-il) methylpyrazole-5-carboxamide A mixture of the title compounds of preparation 70 (520 mg, 1.3 mmol) and of preparation 41 (285 mg, 1.1 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250 mg, 1.3 mmoles), 1-hydroxybenzotriazole hydrate (199 mg, 1.3 mmol), N-ethyldiisopropylamine (226 μl, 1.3 mmol) and tetrahydrofuran (20 ml) was stirred for 1 week at room temperature. Then ethyl acetate (150 ml) was added and the resulting mixture was washed with brine (2 x 50 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: dichloromethane: methanol (32: 64: 4 to 0: 95: 5), to yield the title compound (603 mg, 86%) in the form of a white foam,? (DMSOde): 0.74 (3H, t), 0.91 (3H, t), 1.39 (2H, m), 1.90 (2H, m), 2.05 (2H, m), 2.30 (2H, q), 2.42 (4H, m), 2.74 (2H, t), 2.95 (4H, m), 3.50 (2H, m), 3.85 (2H, m), 5.48 (2H, s), 5.52 (1H, m), 7.09 (1H , d), 7.35 (3H, m), 7.48 (1 H, m), 8.39 (1H, s), 8.54 (1H, d), 8.65 (1 H, s), 10.18 (1 H, s). LRMS: m / z 641 (M + 1) +.

PREPARATION 77 4- [2-Ethoxy-5- (4-ethyl-piperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-n-propyl-2- (pyridin-2-ylmethylpyrazole-5-carboxamide A stirred mixture of the title compounds of Preparation 28 (3.07 g, 7.71 mmol) and of Preparation 41 (2.0 g, 7.71 mmol) in pyridine (50 mL), was heated at 50 ° C for 48 hours, and then it was allowed to cool and evaporated under reduced pressure. The residue was partitioned between dichloromethane (100 ml) and water (20 ml), then the organic phase was separated, dried (MgSO 4) and evaporated under reduced pressure. The residual brown foam • -Htti-Müill- * was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol (100: 0 to 90:10), to yield the title compound (3.19 g, 71%) as a foam white Found: C, 54.66; H, 6.17; N, 18.38. C27H36N805S; 0.40 H20 requires C, 54.79; H, 6.27; N, 18.93%. ? (CDCb): 0.82 (3H, t), 1.03 (3H, t), 1.45 (2H, m), 1.58 (3H, t), 2.40 (2H, q), 2.52 (4H, m), 2.86 (2H, t), 3.10 (4H, m), 4.79 (2H, q), 5.29 (1 H, s), 5.46 (2H, s), 6.70 (1 H, s), 6.93 (1 H, d), 7.21 ( 1 H, m), 7.64 (1 H, m), 8.59 (1 H, d), 8.64 (1 H, s), 8.81 (1 H, s), 10.56 (1 H, s). LRMS: m / z 585 (M + 1) +.

PREPARATION 78 5- (4-Ethylpiperazin-1-ylsulfonyl) -2-propoxypyridine-3-carboxylic acid methyl ester Obtained in the form of an oil (53%) from the title compound of preparation 49 and 1-ethylpiperazine, using the procedure of preparation 18.? (CDCl 3): 1.05 (6H, m), 1.86 (2H, m), 2.41 (2H, q), 2.54 (4H, m), 3.08 (4H, m), 3.92 (3H, s), 4.46 (2H, t), 8.40 (1 H, s), 8.62 (1 H, s). LRMS: m / z 372 (M + 1) +.

PREPARATION 79 5- (4-Ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid A mixture of the title compound of Preparation 78 (370 mg, 1.0 mmol), 2 M aqueous sodium hydroxide solution (1 mL, 2 mmol) and methanol (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was treated with solid carbon dioxide in order to adjust the pH to 7 and then evaporated under reduced pressure. The residue was triturated with dichloromethane (3 x 50 ml) and the combined organic solutions were evaporated under reduced pressure to yield the title compound (340 mg, 95%) as a white solid. LRMS: m / z 357 (M) +.

PREPARATION 80 4- [5-? 4-Ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-ylcarboxamidol-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide Oxalyl chloride (122 μL, 5.6 mmol) was added dropwise to a stirred solution of the title compound of preparation 79 (478 mg, 1.4 mmol) and dimethylformamide (3 drops) in dichloromethane (10 mL), the mixture The reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was made azeotropic with dichloromethane (3 x 10 ml), then added to a stirred and ice-cooled solution of the title compound of preparation 41 (360 mg, 1.4 mmoles) in pyridine (10 ml), the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (50 ml) and dichloromethane (50 ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2 x 50 ml). The combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure, and then the crude product was purified by column chromatography on silica gel, using ethyl acetate: methanol (80:20) as eluent, to give the compound of the title (500 mg, 37%) in the form of a colorless glass,? (CDCb): 0.81 (3H, t), 1.04 (3H, t), 1.27 (3H, t), 1.46 (2H, m), 2.00 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 2.86 (2H, t), 3.09 (4H, m), 4.66 (2H, t), 5.27 (1H, s), 5.47 (2H, s), 6.68 (1H, s), 6.93 (1H , d), 7.21 (1 H, m), 7.66 (1 H, m), 8.59 (1 H, d), 8.64 (1 H, s), 8.80 (1 H, s), 10.47 (1 H, s). LRMS: m / z 599 (M + 1) +.

PREPARATION 81 2- (2-Benzyloxyethoxy) -3-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine A mixture of a 2M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (4.1 ml, 8.2 mmol), 2-benzyloxyethanol (1.16 ml, 8.2 mmol) and tetrahydrofuran (5 ml) was stirred at about 0 ° C for 1 hour. The title compound of Preparation 13 (2.0 g, 5.43 mmol) was added, the reaction mixture was stirred at room temperature for 5 hours and then evaporated under reduced pressure. The residue was suspended in ethyl acetate (10 ml) and the suspension was extracted with 2 M hydrochloric acid (3 x 10 ml). The combined extracts were basified with aqueous sodium bicarbonate solution and extracted with ethyl acetate (3 x 15 ml). These combined extracts were dried (MgSO) and evaporated under reduced pressure, and then the crude product was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5), to produce the title compound (1.95 g, 74%) in the form of an oil,? (CDCb): 1.02 (3H, t), 2.40 (2H, q), 2.52 (4H, m), 3.07 (4H,), 3.88 (2H, t), 4.62 (4H, m), 7.26 (1H, m), 7.34 (4H, m), 8.09 (1H, s), 8.42 (1 H, s). LRMS: m / z 486 (M + 2f.

PREPARATION 82 2- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester Obtained in the form of an oil (42%) from the title compound of preparation 81, using the procedure of preparation 21.? (CDCb): 1.04 (3H, t), 1.38 (3H, t), 2.42 (2H, q), 2.54 (4H, m), 3.08 (4H,), 3.90 (2H, t), 4.38 (2H, q ), 4.67 (4H, m), 7.28 (1H, m), 7.35 (4H, m), 8.41 (1H, s), 8.62 (1H, s). LRMS: m / z 478 (M + 1) +.

PREPARATION 83 2- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid hydrochloride Obtained as a light yellow solid (88%) from the title compound of preparation 82, using the procedure of preparation 26.? (CDCb): 1.45 (3H, t), 2.82 (2H, m), 3.09 (2H, q), 3.26 (2H, m), 3.64 (2H, m), 3.90 (4H, m), 4.64 (2H, s), 4.78 (2H, t), 7.33 (1H, m), 7.37 (4H, m), 8.58 (1 H, s), 8.64 (1H, s), 12.17 (1 H, s). LRMS: m / z 450 (M + 1) +.

PREPARATION 84 4-f2- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidoj-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide Obtained as an orange solid (80%) from the title compounds of preparation 83 and of preparation 41, using the procedure of preparation 52.? (CDCb): 0.80 (3H, t), 1.02 (3H, t), 1.42 (2H, m), 2.40 (2H, q), 2.54 (4H, m), 2.81 (2H, t), 3.10 (4H, m), 4.06 (2H, t), 4.57 (2H, s), 4.86 (2H, t), 5.26 (1H, s), 5.45 (2H, s), 6.68 (1H, s), 6.90 (1H, d), 7.17-7.27 (5H, m), 7.34 (1H, m), 7.63 (1H, m), 8.59 (1H, s), 8.62 (1H, s), 8.82 (1 H, s), 10.50 ( 1H, s). LRMS: m / z 692 (M + 2) +.

PREPARATION 85 2-Benzyl-3-ethyl-4-nitropyrazole-5-carboxamide Cesium carbonate (2.9 g, 9.0 mmol) was added to a stirred and ice-cooled solution of the title compound of Preparation 35 (1.7 g, 8.8 mmol) in dimethylformamide (20 mL) and the suspension was stirred for 30 minutes. Benzyl bromide (10.6 ml, 9.0 mmol) was added, the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (125 ml) and brine (100 ml), the phases were separated and the organic phase was dried (MgSO) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using ethyl acetate as eluent to yield the title compound (1.13 g, 47%) as a white solid,? (DMSOde): 0.97 (3H, t), 2.96 (2H, q), 5.44 (2H, s), 7.24 (2H, m), 7.33 (3H,), 7.68 (1H, s), 7.95 (1H, s). LRMS: m / z 274 (M + 1) +.

PREPARATION 86 4-Amino-2-benzyl-3-ethylpyrazole-5-carboxamide Obtained as a light pink solid (90%) from the title compound of preparation 85, using the procedure of preparation 40.? (DMSOde): 0.87 (3H, t), 2.49 (2H, q), 4.46 (2H, s), 5.22 (2H, s), 6.85 (1 H, s), 7.09 (3H, m), 7.25 (1 H, m), 7.31 (2H, m). LRMS: m / z 245 (M + 1) +.

PREPARATION 87 2-Benzyl-4- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-ethylpyrazole-5-carboxamide Obtained as a white crystalline foam (46%) from the title compounds of preparation 18 and from preparation 86, using the procedure of preparation 56.? (DMSOd?): 0.92 (6H, m), 1.44 (3H, t), 2.30 (2H, q), 2.41 (4H, m), 2.74 (2H, q), 2.95 (4H, m), 4.62 (2H , q), 5.40 (2H, s), 7.17 (2H, m), 7.31 (4H, m), 7.50 (1 H, s), 8.39 (1 H, s), 8.65 (1 H, 10 s), 10.38 (1 H, s). LRMS: m / z 571 (M + 2) +.

PREPARATION 88a 3-Elyl-1- (1-methylimidazol-2-yl) methyl-4-nitropyrazole-5-carboxamide and PREPARATION 88b 3-Ethyl-2- (1-methylimidazole) -2-il) methyl-4-nitropyrazol-5-carboxamide A mixture of the title compound of preparation 35 (2.2 g, 11.95 mmol), 2-chloromethyl-1-methyl-midazole hydrochloride (J. Chem. Soc, 20 1957, 3305, 2.0 g, 11.95 mmol) cesium carbonate (8.5 g, 26.3 mmol) and dimethylformamide (100 ml) was stirred at room temperature for 6 hours and then evaporated under reduced pressure. The residue was partitioned between water (150 ml) and dichloromethane (150 ml), the phases were separated and the aqueous phase was separated. extracted with dichloromethane (2 x 150 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure, then the residue was triturated with dichloromethane: methanol (90:10) and the resulting solid was collected and dried under suction to give the first title compound (isomer 1 305 mg, 9%) in the form of a cream-colored solid,? (CDCb): 1.16 (3H, t), 2.82 (2H, q), 3.69 (3H, s), 5.40 (2H, s), 6.81 (1 H, s), 7.13 (1 H, s), 7.13 ( 1 H, s), 8.20 (1 H, s), 8.50 (1 H, s). LRMS: m / z 279 (M + 1) +. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 aqueous ammonia (90: 10: 1) as eluent, to produce the second title compound (isomer 2; 480 mg, 14%) in the form of a solid,? (CDCb): 1.16 (3H, t), 3.20 (2H, q), 3.77 (3H, s), 5.48 (2H, s), 6.22 (1H, s), 6.68 (1 H, s), 7.00 (1H , s), 7.25 (1H, s). LRMS: m / z 279 (M + 1) +.

PREPARATION 89 4-Amino-3-ethyl-2- (1-methylimidazol-2-ylmethylpyrazol-5-carboxamide Obtained as a pink solid (92%) from the title compound of preparation 88b, using the procedure of preparation 40.? (CDCb): 1.00 (3H, t), 2.68 (2H, q), 3.60 (3H, s), 5.34 (2H, s), 5.40 (1 H, s), 6.55 (1 H, s), 6.82 ( 1 H, s), 6.98 (1H, s). LRMS: m / z 249 (M + 1) +.

PREPARATION 90 3-Ethyl-4-f5-? 4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamidol-2- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide Obtained as a solid (48%) from the title compounds of preparation 29 and of preparation 89, using the procedure of preparation 45A. ? (CDCb): 1.01 (3H, t), 1.10 (3H, t), 2.40 (2H, q), 2.52 (4H, m), 2.98 (2H, q), 3.08 (4H, m), 3.36 (3H, s), 3.66 (3H, s), 3.92 (2H, t), 4.82 (2H, t), 5.35 (1H, s), 5.42 (2H, s), 6.61 (1H, s), 6.86 (1H, s), 7.00 (1H, s), 8.64 (1H, s), 8.81 (1 H, s), 10.33 (1 H, s). LRMS: m / z 604 (M + 1) +.

PREPARATION 91a 1- (1-Methylimidazol-2-yl) methyl-4-nitro-3-n-propylpyrazole-5-carboxamide and PREPARATION 91b 2- (1-Methylimidazol-2-yl) methyl-4-nitro -3-n-propylpyrazole-5-carboxamide A stirred mixture of the title compound of preparation 34 (5.0 g, 25.3 mmol), 2-chloromethyl-1-methy1midazole hydrochloride (J. Chem. Soc, 1957, 3305; 4.6 g, 27.7 mmol), cesium carbonate (18.1 g, 55.6 mmol) and acetonitrile (100 ml) was heated at 50 ° C for 5 hours and then allowed to cool. Ethyl acetate (300 ml) was added and the mixture was washed with water (2 x 400 ml), dried (MgSO 4) and concentrated under reduced pressure. up to a volume of approximately 200 ml. The resulting precipitate was collected and combined with the material produced by crystallization from ethyl acetate of the residue obtained by evaporation under reduced pressure of the filtrate, to produce, after drying, the first title compound (isomer 1; 1.0 g, 13% ) in the form of white crystals,? (DMSOd6): 0.89 (3H, t), 1.60 (2H, m), 2.76 (2H, t), 3.66 (3H, s), 5.39 (2H, s), 6.80 (1H, s), 7.12 (1H , s), 8.20 (1H, s), 8.48 (1H, s). LRMS: m / z 293 (M + 1) +. The mother liquors of the crystallization were evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to yield the second title compound (isomer 2, 700 mg, 9%) as a solid. ? (DMSOde): 0.92 (3H, t), 1.52 (2H, m), 3.04 (2H, t), 3.68 (3H, s), 5.49 (2H, s), 6. 82 (1 H, s), 7.14 (1 H, s), 7.66 (1 H, s), 7.93 (1 H, s). LRMS: m / z 293 (M + 1) +.

PREPARATION 92 4-Amino-2- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazol-5-carboxamide A stirred mixture of the title compound of preparation 91b (500 mg, 1.71 mmol), 10% palladium on carbon (150 mg) and ethanol (20 ml) was hydrogenated for 4 hours at 345 kPa (50 psi) and then filter. The filtrate was combined with a dichloromethane: methanol (80:20) wash (50 ml) of the filter layer, evaporated under reduced pressure and the residue was crystallized from ethyl acetate to yield the title compound (320 mg, 71%) in the form of a pink solid,? (CDCb): 0.90 (3H, t), 1.40 (2H, m), 2.60 (2H, t), 3.58 (3H, s), 3.94 (2H, s), 5.32 (3H, m), 6.54 (1H , s), 6.82 (1 H, s), 6.98 (1H, s).

PREPARATION 93 3- (2-Phenylethenyl) pyridazine Zinc chloride (820 mg, 6 mmol) was added to a stirred mixture of benzaldehyde (6.11 ml, 60 mmol) and 3-methylpyrrolidine (2.83 g, 30 mmol) and the resulting mixture was heated for 20 hours at 150 ° C. The cooled reaction mixture was partitioned between dichloromethane (40 ml) and 2 M aqueous sodium hydroxide solution (20 ml), then the organic phase was separated, combined with a dichloromethane extract (80 ml) of the aqueous phase, dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (99: 1) as eluent, to give the title compound (59%) as a solid,? (CDCb): 7.12 (1 H, d), 7.34 (3 H, m), 7.56 (2 H, d), 7.72 (1 H, d), 8.37 (1H, s), 8.50 (1H, s), 8.60 (1 H, s). LRMS: m / z 183 (M + 1) +.

PREPARATION 94 3-Hydroxymethylpyridazine Ozone was bubbled through a stirred solution of the title compound of preparation 93 (3.60 g, 0.02 mole) in methanol (150 ml) at -10 ° C. After 30 minutes, the mixture was purged with nitrogen, sodium borohydride (750 mg, 0.02 mole) was added portionwise and the resulting solution was stirred for 2 hours at room temperature. The mixture of The reaction was acidified with 2M hydrochloric acid, then basified with 0.880 aqueous ammonia solution and evaporated under reduced pressure. Purification of the residue by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (98: 2 to 96: 4), afforded the title compound (76%) as a solid,? (CDCl 3): 3.66 (1H, s), 4.92 (2H, s), 7.48 (2H, m), 9.06 (1H, d).

PREPARATION 95 3-Chloromethylpyridazine Hydrochloride Thionyl chloride (3.05 ml, 42 mmol) was added to an ice-cooled flask containing the title compound of preparation 94 (920 mg, 8 mmol), the reaction mixture was stirred for 45 minutes at room temperature and then evaporated under reduced pressure. The residue was made azeotropic with toluene (40 ml) to yield the crude title compound (1.4 g) as a brown solid,? (DMSOde): 4.98 (2H, s), 7.80 (1 H, m), 7.90 (1 H, d), 8.19 (1 H, s), 9.22 (1 H, d).

PREPARATION 96 4-Nitro-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide A mixture of the title compounds of preparation 95 (700 mg, 4.24 mmol) and of preparation 34 (840 mg, 4.24 mmol), Cesium carbonate (3.45 g, 10.6 mmol) and acetonitrile (30 ml) was stirred at 80 ° C for 2 hours and then allowed to cool. Brine (30 ml) was added. The mixture was extracted with dichloromethane (2 x 80 ml) and the combined extracts were dried (Na 2 SO 4) and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 90:10) to yield the title compound (480 mg, 39%) as a solid yellow,? (CDCl 3): 1.02 (3H, t), 1.60 (2H, m), 3.06 (2H, t), 5.72 (2H, s), 5.87 (1H, s), 7.25 (1H, s), 7.54 ( 2H, m), 9.20 (1 H, s).

PREPARATION 97 4-Amino-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide Obtained in the form of a pink gum (97%) from the title compound of preparation 96, using the procedure of preparation 40.? (CDCb): 0.90 (3H, t), 1.47 (2H, m), 2.51 (2H, t), 5.25 (1H, s), . 58 (2H, s), 6.58 (1 H, s), 7.09 (1 H, d), 7.43 (1 H, m), 9.14 (1 H, d). LRMS: m / z 261 (M + 1 f.

PREPARATION 98 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide Obtained in the form of an orange gum (42%) from the title compounds of preparation 28 and of preparation 97, using the procedure of preparation 45A. ? (CDCb): 0.81 (3H, t), 1.01 (3H, t), 1.47 (2H, m), 1.55 (3H, t), 2.39 (2H, q), 2.50 (4H, m), 2.87 (2H, t), 3.07 (4H, m), 4.77 (2H, q), 5.58 (1 H, s), 5.69 (2H, s), 6.71 (1 H, s), 7.18 (1H, d), 7.45 (1H , m), 8.63 (1 H, s), 8.79 (1 H, s), 9.15 (1 H, s), 10.52 (1 H, s). LRMS: m / z 586 (M + 1) +.

PREPARATION 99 1-2-methylpyrimidine oxide A freshly prepared solution of metallic sodium (11.5 g, 0.50 mol) in ethanol (170 ml) was added dropwise over 1 hour to a stirred suspension of hydroxylamine hydrochloride (34.75 g, 0.50 mol) and phenolphthalein (50 mg). in ethanol (200 ml), so as to maintain a colorless solution, and the mixture was stirred at room temperature for 3 hours. Acetonitrile (26 ml, 0.50 mol) was added and this mixture was stirred for a further 2 hours at room temperature and then at 45 ° C for 48 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to a volume of about 100 ml and then cooled up to 0 ° C. The resulting precipitate was collected and dried by suction to give the intermediate acetamidoxime (9.9 g, 27%) as white crystals. Boron trifluoride diethyl ether complex (9.5 ml, 75 mmol) was added, followed by 1,1, 3,3-tetramethoxypropane (11.5 ml, 70 mmol) to a stirred mixture of dimethylformamide (100 ml) and toluene (100 ml). ml). Then acetamidoxime (5.0 g, 67.5 mmol) was added, the reaction mixture was heated to reflux for 45 minutes and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual brown oil was partitioned between dichloromethane: methanol (80:20) (100 ml) and aqueous sodium carbonate solution (100 ml). The phases were separated, the aqueous phase was extracted with dichloromethane: methanol (80:20) (100 x 50 ml) and the combined organic solutions were dried (MgSO) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (98: 2) as eluent, to yield the title compound (2.5 g, 34%) as an orange solid,? (CDCb): 2.74 (3H, s), 7.19 (1H, m), 8.16 (1H, d), 8.39 (1H, d).

PREPARATION 100 2-Chloromethylpyrimidine A stirred mixture of the title compound of preparation 99 (2.5 g, 22.7 mmol) and phosphorus oxychloride (18 mL, 193 mmol) was heated to reflux for 2 hours and then allowed to cool. The resulting mixture is poured into stirred ice and neutralized using solid sodium carbonate for 3 hours. The aqueous solution thus obtained was extracted with dichloromethane (3 x 100 ml) and then the combined extracts were dried (MgSO 4) and evaporated under reduced pressure. The residual brown oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) to give the title compound (510 mg, 17%). ? (CDCb): 4.72 (2H, s), 7.22 (1 H, m), 8.75 (2H, d). LRMS: m / z 129 (M + 1) +.

PREPARATION 101a 4-Amino-3-n-propyl-1 - (pyrimidin-2-yl) methylpyrazole-5-carboxamide Y PREPARATION 101b 4-Amino-3-n-propyl-2- (pyrimidin-2-yhmethylpyrazol-5 - carboxamide Potassium hydroxide (393 mg, 7 mmol) was added to a stirred and ice-cooled solution of the title compound of Preparation 36 (1.2 g, 6 mmol) in dimethylformamide (10 mL) and the mixture was stirred for 1 hour at room temperature. room temperature. Then the title compound of preparation 100 (900 mg, 7 mmol) was added, the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (10 ml) and dichloromethane (15 ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2 x 15 ml). The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent, to produce a mixture of the title (not separated) (1.06 g, 67%) in the form of a pink solid. The analysis of the 1H nmr spectrum indicated a N1: N2 ratio (ie, isomer 1, isomer 2) of 22.78. ? (DMSOde): 0.81 (3H, t), 0.88 (3H, t), 1.38 (2H, m), 1.52 (2H, m), 2.48 (2H, t), 4.10 (2H, s), 4.44 (2H, s), 5.41 (2H, s), 5.73 (2H, s), 6.90 (1 H, s), 7.06 (1 H, s), 7.35 (1 H, m), 7.42 (1 H, m), 7.50 (2H, s), 8.68 (2H, d), 8.77 (2H, d). LRMS: m / z 261 (M + 1f.

PREPARATION 102a 4- [5- (4-Ethylpip? Razin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamido] -3-n-propyl-1- (pyrimidin-2-yl) methylpyrazole- 5-carboxamide Y PREPARATION 102b 4-f5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamido] -3-n-propyl-2- (pyrimidin-2-yl) methylpyrazole -5-carboxamide Triethylamine (1.12 ml, 8.0 mmol) was added to a stirred and ice-cooled suspension of the title compounds of preparation 29 (680 mg, 1.6 mmol) and from preparations 101 a / 101b (417 mg, 1.6 mmol) in dichloromethane (20 ml), then the reaction mixture was stirred at room temperature for 18 hours, washed with water (10 ml. ), dried (MgSO4) and evaporated under reduced pressure. The residual brown foam was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to yield the first title compound (isomer 1; 56 mg, 6%) in the form of an orange rubber,? (CDCb): 0.96 (3H, t), 1.04 (3H, t), 1.76 (2H, m), 2.42 (2H, q), 2.54 (4H, m), 3. 38 (3H, s), 3.86 (2H, t), 4.76 (2H, t), 6.13 (2H, s), 7.11 (1H, m), 8.44 (1H, s), 8.62 (2H, d), 8.78 (1H, s), 10.17 (1H, s). LRMS: m / z 616 (M + 1) +; followed by the second title compound (isomer 2; 460 mg, 47%) in the form of an orange foam,? (CDCb): 0.84 (3H, t), 1.03 (3H, t), 1.50 (2H, m), 2.40 (2H, q), 2.53 (4H, m), 2.88 (2H, t), 3.11 (4H, m), 3.39 (3H, s), 3.96 (2H, t), 4.85 (2H, q), 5.23 (1 H, s), 5.58 (2H, s), 6.70 (1H, s), 7.25 (1 H, m), 8.63 (1 H, s) , 8.74 (2H, d), 8.84 (1H, s), 10.52 (1H, s). LRMS: m / z 616 (M + 1) +.

PREPARATION 103a 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-n-propyl-1- (pyrimidin-2-yl) methylpyrazole-5-carboxamide Y PREPARATION 103b 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido] -3-n-propyl-2- (pyrimidin-2-yl) methylpyrazole-5-carboxamide Obtained as a mixture of isomers (88%) from the title compounds of preparation 28 and preparations 101a / 101b, using the procedure of preparation 45A. LRMS: m / z 586 (M + 1) +.

PREPARATION 104 4-Amino-3-n-propyl-1-. { pyridin-2-yl) methylpyrazole-5-carboxarnide Obtained as a solid (92%) from the title compound of preparation 39a, using the procedure of preparation 41.? (DMSOde): 0.88 (3H, t), 1.55 (2H, m), 2.43 (2H, t), 4.18 (2H, s), 5.59 (2H, s), 6. 73 (1 H, d), 7.22 (1H, m), 7.57 (2H, s), 7.69 (1H, m), 8.47 (1H, d). LRMS: m / z 260 (M + 1) +.

PREPARATION 105 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido] -3-n-propyl-1- (pyridin-2-ylmethylpyrazole-5-carboxamide Obtained in the form of a brown foam (74%) from the title compounds of preparation 28 and of preparation 104, using the procedure of preparation 45A. ? (CDCb): 0.94 (3H, t), 1.02 (3H, t), 1.62 (5H, m), 2.40 (2H, q), 2.52 (4H, m), 2.64 (2H, t), 3.09 (4H, m), 4.77 (2H, q), 5.58 (2H, s), 5.71 (1 H, s), 7.26 (1 H,), 7.40 (1 H, d), 7.74 (1 H, m), 8.52 ( 1 H, d), 8.67 (1 H, s), 8.82 (1 H, s), 9.60 (1 H, s), 9.96 (1 H, s). LRMS: m / z 585 (M + 1) +.

PREPARATION 106 4-Amido-3-ethyl-1- (1-methylimidazol-2-yl) methylprazole-5-carboxamide Obtained as a pink foam (95%) from the title compound of preparation 88a, using the procedure of preparation 40.? (DMSOde): 1.09 (3H, t), 2.43 (2H, q), 3.72 (3H, s), 4.37 (2H, s), 5.44 (2H, s), 6.79 (1H, s), 7.08 (1H , s). LRMS: m / z 249 (M + 1) +.

PREPARATION 107 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide] -3-etl-1- (1-methylimidazol-2-yl) methylp razol-5 -carboxamide Obtained as a solid (78%) from the title compounds of preparation 28 and preparation 106, using the procedure of preparation 45A. ? (CDCb): 1.01 (3H, t), 1.21 (3H, t), 1.60 (3H, t), 2.40 (2H, q), 2.53 (4H,), 2.72 (2H, q), 3.08 (4H, m ), 3.94 (3H, s), 4.76 (2H, q), 5.54 (2H, s), 5.93 (1H, s), 6.83 (1H, s), 6.92 (1 H, s), 8.65 (1 H, s), 8.82 (1H, s), 9.95 (1H, s), 10.27 (1H, s). LRMS: m / z 575 (M + 2) +.

PREPARATION 108 4-Amino-1- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazole-5-carboxamide Obtained as a cream colored solid (78%) from the title compound of preparation 91a, using the procedure of preparation 40.? (DMSOde): 0.87 (3H, t), 1.52 (2H, m), 2.38 (2H, t), 3.70 (3H, s), 4.35 (2H, s), 5.44 (2H, s), 6.78 (1H, s), 7.08 (1H, s). LRMS: m / z 263 (M + 1) +.

PREPARATION 109 4- [5-4-Ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamidol-1- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazole-5- carboxamide Obtained (67%) from the title compounds of preparation 25 and preparation 108, using the procedure of preparation 52.? (CDCl 3): 0.95 (3H, t), 1.02 (3H, t), 1.66 (2H, m), 2.40 (2H, q), 2.51 (4H, m), 2.63 (2H, t), 3.09 (4H, m), 3.39 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 4.80 (2H, t), 5.56 (2H, s), 5.81 (1H, s), 6.83 (1H, s) ), 6.92 (1H, s), 8.65 (1H, s), 8.82 (1H, s), 9.60 (1H, s), 10.08 (1H, s).

PREPARATION 110 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpyridin-4-yloxy) pyridine A mixture of 4-hydroxy-1-methylpyridine (560 mg, 4.89 mmol), a 60% dispersion in mineral oil of sodium hydride (100 mg, 4.89 mmol) and tetrahydrofuran (30 ml) was stirred at approximately 0 ° C for 30 minutes. The title compound of Preparation 13 (600 mg, 1.63 mmol) was added and the reaction mixture was heated to reflux for 90 minutes and then cooled. The resulting mixture was evaporated under reduced pressure, the residue was suspended in ethyl acetate (50 ml) and the suspension was washed consecutively with 2 M aqueous sodium hydroxide solution (2 x 20 ml), water (20 ml) and brine ( 20 ml). The resulting solution was dried (MgSO4) and evaporated under reduced pressure to give the title compound (660 mg, 70%) as a yellow oil,? (CDCb): 1.05 (3H, t), 1.92 (2H, m), 2.04 (2H, m), 2.33 (3H, s), 2.42 (4H, m), 2.55 (4H, m), 2.66 (2H, m), 3.08 (4H, m), 5.24 (1 H, m), 8.09 (1 H, s), 8.42 (1 H, s). LRMS: m / z 447 (M) +.

PREPARATION 111 5- (4-Ethyl-piperazin-1-ylsulphonyl) -2- (1-methylpiperidin-4-yloxy) pyridine-3-carboxylic acid ethyl ester Triethylamine (2 ml, 1.43 mmol) and tetrakis (triphenylphosphine) palladium (0) (200 mg, 0.173 mmol) were added to a stirred solution of the title compound of preparation 110 (640 mg, 1.43 mmol) in ethanol ( 20 ml) and the reaction mixture was heated under carbon monoxide at 100 ° C and 1034 kPa (150 psi) in a sealed container for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol (96.5: 3.5) as eluent, to yield the title compound (550 mg, 87%) as an eluent. an orange solid,? (CDCb): 1.02 (3H, t), 1.40 (3H, t), 2.16 (2H, m), 2.41 (2H, q), 2.56 (6H, m), 2.72 (3H, s), 3.08 (4H, m), 3.19 (4H, m), 4.38 (2H, q), 5.60 (1 H, m), 8.42 (1 H, s), 8.62 (1H, s). LRMS: m / z 441 (M + 1) +.

PREPARATION 112 Sodium salt of 5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridine-3-carboxylic acid A mixture of the title compound of preparation 111 (550 mg, 1.25 mmol), 1 M aqueous solution of sodium hydroxide (2.4 ml, 2.40 mmol) and ethanol (5 ml) was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (15 ml) and ethyl acetate (15 ml), the phases were separated and the aqueous phase was evaporated under reduced pressure to give the title compound (510 mg, 94%) as a solid White, ? (DMSOde): 0.93 (3H, t), 1.94 (2H, m), 2.10 (2H, m), 2.16 (3H, s), 2.29 (2H, q), 2.40 (4H, m), 2.68 (4H, m), 2.88 (4H, m), 5.08 (1H, m), 7.75 (1 H, s), 8.28 (1 H, s).

PREPARATION 113a 4-Amino-1- (2-morpholin-4-yl) etl-3-n-propylpyrazole-5-carboxamide Y PREPARATION 113b 4-Amino-2- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide 4- (2-Chloroethyl) morpholine (obtained by basification of the hydrochloride salt (2.67 g, 14.35 mmol) was added to a stirred solution of the title compound of preparation 36 (2.1 g, 11.96 mmol) and potassium hydroxide (800 mg, 14.35 mmol) in dimethylformamide (20 ml), the reaction mixture was heated to reflux for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using dichloromethane: methanol: glacial acetic acid (95: 5: 1) as eluent, to produce the second title compound (isomer 2). 480 mg, 14%). ? (CDCb): 0.98 (3H, t), 1.60 (2H, m), 2.48 (4H, m), 2.55 (2H, t), 2.76 (2H, t), 3.69 (4H, m), 3.94 (2H, s), 4.08 (2H, t), 5.19 (1 H, s), 6.55 (1 H, s). LRMS: m / z 282 (M + 1) +. followed by the first title compound (isomer 1, 350 mg, 10%). ? (CDCb): 0.97 (3H, t), 1.64 (2H, m), 2.50 (6H, m), 2.81 (2H, t), 3.48 (2H, s), 3.64 (4H, m), 4.50 (2H, t).

PREPARATION 114 3-t-Butyl-1 H-pyrazole-5-carboxylic acid hydrochloride Hydrazine hydrate (1.7 ml, 35 mmol) was added dropwise to a stirred solution of 5,5-dimethyl-2,4-dioxohexanoic acid ethyl ester (J. Org. Chem., 1997, 62, 5908; 6.1 g, 30.5 mmol) in ethanol (20 ml), the reaction mixture was stirred at room temperature for 4 hours and then evaporated under reduced pressure. The residue was partitioned between dichloromethane (20 ml) and water (20 ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2 x 20 ml). The combined organic solutions were dried (MgSO) and evaporated under reduced pressure to give the ester gross in the form of a yellow solid. A mixture of this product, 1,4-dioxane (100 ml) and 2 M aqueous sodium hydroxide solution (25.5 ml, 51 mmol) was stirred at room temperature for 72 hours, then the pH of the reaction mixture was adjusted to 2 with hydrochloric acid. The resulting mixture was evaporated under reduced pressure and the residue was triturated with hot ethanol. The mixture was filtered and the filtrate was evaporated under reduced pressure to yield the title compound (5.06 g, 81%) as an orange solid,? (DMSOde): 1.26 (9H, s), 6.46 (1H.s).

PREPARATION 115 3-t-Butyl-4-nitro-1H-pyrazole-5-carboxylic acid The title compound of Preparation 114 (1.5 g, 7.3 mmol) was added portionwise to stirred, concentrated, ice-cooled sulfuric acid (7.5 mL), the mixture was heated to 40 ° C and then nitric acid was added dropwise. smoked (1.13 ml) so that the internal temperature was maintained below 50 ° C. The reaction mixture was stirred at 50 ° C for 7 hours, allowed to cool and carefully poured into ice / water (100 g). The resulting suspension was stirred for 2 hours and filtered, then the collected solid was washed with water and dried under suction to give the title compound (975 mg, 63%) as a white solid,? (DMSOde): 1.33 (9H, s). LRMS: m / z 231 (M + 18) +.

PREPARATION 116 3-t-Butyl-4-nitro-1H-pyrazole-5-carboxamide Oxalyl chloride (1.59 mL, 18.2 mmol) was added dropwise to a stirred and ice-cooled solution of the title compound of Preparation 115 (970 mg, 4.55 mmol) and dimethylformamide (1 drop) in dichloromethane (20 mL). and the reaction mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was made azeotropic first with dichloromethane and then with 0.88 aqueous ammonia solution. The resulting material was triturated with hot ethanol and then with acetonitrile, the mixture was filtered and the filtrate was evaporated under reduced pressure to yield the title compound (955 mg, 99%) as a white solid,? (DMSOde): 1.36 (9H, s), 7.60 (1H, s), 7.88 (1H, s). LRMS: m / z 230 (M + 18) +.

PREPARATION 117 3-t-Butyl-4-nitro-1- (pyridin-2-yl) methylpyrazole-5-carboxamide A solution of the title compound of preparation 116 (960 mg, 4.55 mmol), cesium carbonate (3.7 g, 11.36 mmol) and hydrochloride 2- (Chloromethyl) pyridine (821 mg, 5.0 mmol) in acetonitrile (20 ml) was stirred 70 ° C for 20 hours, then allowed to cool and filtered. The filtrate was evaporated under reduced pressure and then the residue was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol (100: 0 to 95: 5) to give the title compound (300 mg, 22%) as a yellow solid,? (DMSOde): 1.35 (9H, s), 5.40 (2H, s), 7.18 (1H, d), 7.32 (1 H, m), 7.80 (1 H, m), 8.10 (1 H, s), 8.46 (1 H, s), 8.51 (1 H, d). LRMS: m / z 304 (M + 1) +.

PREPARATION 118 4-Amino-3-t-butyl-1- (pyridin-2-yl) methy1pyrazole-5-carboxamide A stirred mixture of the title compound of the preparation 117 (290 mg, 0.96 mmol) and 10% palladium on carbon (29 mg) in ethanol (20 ml) was hydrogenated at 345 kPa (50 psi) and at room temperature for 7 hours and then filtered. The filter layer was washed with ethanol and the combined washings and filtrate were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of ethyl acetate: methanol (100: 0 to 95: 5) to yield the title compound (220 mg, 84%) as a solid orange,? (CDCb): 1.36 (9H, s), 4.00 (2H, s), 5.50 (2H, s), 7.23 (1H, m), 7.38 (1H, d), 7.71 (1H, m), 8.50 (1H , d). LRMS: m / z 274 (M + 1) +.

PREPARATION 119 4- [5- (4-Ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridin-3-ylcarboxamido] -3-n-propyl-2- (pyridin-2- il) methylpyrazole-5-carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (350 mg, 1.8 mmol) was added to a stirred solution of 1-hydroxybenzotriazole hydrate (250 mg, 1.8 mmol), triethylamine (350 μm, 2.5 mmol) and the title compounds of preparation 112 (510 mg, 1.18 mmol) and of preparation 41 (330 mg, 1.25 mmol) in tetrahydrofuran (20 ml), the reaction mixture was stirred at room temperature for 72 hours and then evaporated under reduced pressure. The residue was triturated several times with ethyl acetate to yield the title compound (175 mg, 21%) as a white solid,? (CDCl 3): 0.81 (3H, t), 1.04 (3H, t), 1.47 (2H, m), 2.17 (4H, m), 2.32 (5H, m), 2.40 (2H, q), 2.53 (4H, m), 2.76 (2H, m), 2.84 (2H, t), 3.10 (4H,), 5.49 (3H, m), 5.64 (1H, s), 6.90 (2H, m), 7.22 (1H,), 7.68 (1H, m), 8.60 (1H, d), 8.64 (1H, s), 8.82 (1H, s), 10.35 (1H, s). LRMS: m / z 654 (M + 1) +.

PREPARATION 120 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-2- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (280 mg, 1.5 mmol) was added to a stirred solution of hydrate 1- hydroxybenzotriazole (200 mg, 1.5 mmol), triethylamine (278 μl, 2.0 mmol) and the title compounds of preparation 23 (371 mg, 1.0 mmol) and of preparation 113b (250 mg, 0.9 mmol) in dichloromethane (20 mg). ml) and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was washed with water (10 ml), dried (MgSO 4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (97: 3 to 95: 5), to give the title compound (430 mg, 60%) as a white solid,? (CDCb): 0.93 (3H, t), 1.02 (3H, t), 1.58 (5H,), 2.40 (2H, q), 2.52 (8H, m), 2.82 (2H, t), 2.90 (2H, t ), 3.12 (4H, m), 3.72 (4H, m), 4.20 (2H, t), 4.79 (2H, q), 5.28 (1H, s), 6.63 (1H, s), 8.64 (1H, s) , 8.82 (1H, s), 10.50 (1H, PREPARATION 121 3-t-Butyl-4-f2-ethoxy-5-? 4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido-1- (pyridin-2-yl) methylpyrazole-5-carboxamide The title compound of Preparation 28 (384 mg, 0.967 mmol) was added dropwise to an ice-cooled and stirred solution of the title compound of preparation 118 (220 mg, 0.805 mmol) and triethylamine (330 μl, 2.42 mmol) in dichloromethane (10 ml) and the reaction mixture was stirred at room temperature for 14 hours. The resulting mixture was washed with aqueous sodium bicarbonate solution (5 ml) and brine (5 ml), dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by two column chromatography operations on silica gel using an elution gradient of ethyl acetate: methanol (100: 0 to 90:10) and then dichloromethane: methanol (100: 0 to 95: 5) to produce the title compound (156 mg, 32%) as a white solid,? (CDCb): 1.02 (3H, t), 1.36 (9H, s), 1.55 (3H, t), 2.42 (2H, q), 2.55 (4H, m), 3.10 (4H, m), 4.77 (2H, q), 5.68 (3H, m), 7.02 (1H, d), 7.19 (1H, m), 7.65 (1H, m), 7.98 (1H, s), 8.56 (1H, d), 8.70 (1 H, s), 8.87 (1 H, s), 9.35 (1 H, s). LRMS: m / z 599 (M + 1) +.

PREPARATION 122 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido] -1- (2-morpholin-4-yl) ethyl-3-n-propyl-pyrazole- 5-carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.34 g, 7.0 mmol) was added to a stirred solution of 1-hydroxybenzotriazole hydrate (945 mg, 7.0 mmol), N-ethyldiisopropylamine (1.22 mL, 7.0 mmol). and the title compounds of preparation 113a (1.82 g, 6.5 mmol) and of preparation 23 (428 mg, 1.25 mmol) in tetrahydrofuran (120 ml) and the reaction mixture was stirred at room temperature for 72 hours. The resulting mixture was evaporated under reduced pressure and the residue was partitioned between aqueous sodium carbonate solution (50 ml) and dichloromethane (100 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 100 ml) and the combined organic solutions were washed with brine (3 x 50 ml), dried (Na 2 SO) and evaporated under reduced pressure. The residue was triturated with ether, then crystallized from ethyl acetate-methanol, to give the title compound (310 mg, 42%) as a white solid,? (CDCl 3): 0.92 (3H, t), 1.01 (3H, t), 1.54 (3H, t), 1.62 (2H, m), 2.36-2.60 (12H, m), 2.80 (2H, t), 3.08 ( 4H, m), 2.64 (4H, m), 4.49 (2H, t), 4.72 (2H, q), 5.78 (1H, s), 8.30 (1H, s), 8.66 (1H, s), 8.80 (1 H, s), 9.49 (1 H, s). LRMS: m / z 607 (M + 1) +.

PREPARATION 123 3-Ethyl-1-methyl-4-nitropyrazole-5-carboxamide PREPARATION 124 3-Ethyl-2-methyl-4-nitropyrazol-5-carboxamide A mixture of the title compound of preparation 35 (100 g, 0. 54 mmole) and cesium carbonate (194 mg, 0.60 mol) in N, N-dimethylformamide (1000 ml) was stirred at room temperature for 45 minutes and then cooled in an ice bath. It was added drop by drop Methyl iodide (37.2 ml, 0.60 mole) and once the addition was complete, the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (500 ml) and water (300 ml). The layers were separated, the aqueous phase was extracted with ethyl acetate (4 x 500 ml) and the combined organic solutions were dried (MgSO) and evaporated under reduced pressure. The crude product was recrystallized from dichloromethane / ethyl acetate to give some of the N1 isomer (17.0 g, 16%). The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using ethyl acetate: pentane (80:20) as eluent to yield the title compound of preparation 123 (25.0 g, 23% ) in the form of a white solid,? (CDCb): 1.27 (3H, t), 2.94 (2H, q), 4.06 (3H, s), 6.00 (1H, s a), 7.56 (1H, s a). LRMS: m / z 216 (M + 18) + and the title compound of preparation 124 (28.4 mg, 27%) as a white solid,? (CDCl 3): 1.29 (3H, t), 3.00 (2H, q), 3.92 (3H, s), 5.98 (1 H, s), 7.32 (1 H, s).

PREPARATION 125 2-Methyl-3-n-propyl-pyrazole-5-carboxylic acid methyl ester A solution of diethyloxalate (27.2 ml, 0.2 mol) in 2-pentanone (21.2 ml, 0.2 mol) was added dropwise to a solution of sodium (4.83 g, 0.21 mol) in ethanol (200 ml), the reaction was stirred at 60 ° C for 5 hours and then cooled in an ice bath. The solution was neutralized using acetic acid (11.5 ml, 0.2 mole) and N-methyl hydrazine (10.6 ml, 0.2 mole) was added dropwise. The mixture was stirred for a further 4 hours at room temperature and concentrated under reduced pressure. The residue was partitioned between dichloromethane (300 ml) and water (200 ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (3 x 100 ml)The combined organic solutions were dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate: hexane (25:75) as eluent to give ethyl 1-methyl-3-n-propyl-pyrazole-5-carboxylate (6.1 g) and the title compound (22.1 g, 56%). ? (CDCb): 1.00 (3H, t), 1.40 (3H, t), 1.70 (2H, m), 2.60 (2H, t), 3.87 (3H, s), 4.40 (2H, q), 6.60 (1H, s).

PREPARATION 126 2-Methyl-3-n-propylpyrazole-5-carboxylic acid A mixture of the title compound of preparation 125 (21.5 g, 0.11 mol) in aqueous sodium hydroxide solution (50 ml, 6 N, 0.3 mol) was heated to reflux for 3 hours. The cooled mixture was diluted with water (50 ml) and acidified using concentrated hydrochloric acid (25 ml) and the resulting precipitate was filtered and dried to give the title compound (17.3 g, 94%) as a yellow solid Clear. A portion (1 g) of this solid was recrystallized from water / ethanol m.p. 120-122 ° C. ? (DMSOde): 0.95 (3H, t), 1.59 (2H, m), 2.60 (2H, t), 3.78 (3H, s), 6.48 (1H, s), 12.45 (1H, s).

PREPARATION 127 2-Methyl-4-nitro-3-n-propylprazole-5-carboxylic acid Obtained as a solid (89%) from the title compound of preparation 126, using a procedure similar to that described in preparation 32.? (DMSOde): 0.95 (3H, t), 1.60 (2H, m), 2.96 (2H, t), 3.88 (3H, s), 13.75 (1H, s).

PREPARATION 128 2-Methyl-4-nitro-3-n-propylpyrazole-5-carboxamide A mixture of the title compound of preparation 127 (18.6 g, 87.3 moles) in thionyl chloride (75 ml) was heated to reflux for 2 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue was poured into a mixture of amide / ammonium hydroxide. This was extracted with dichloromethane (4 x 100 ml) and the combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol: 0.88 ammonia (95: 5: 1) as eluent to produce the title compound (6.8 g, 37%) as a solid, ? (CDCb): 1.07 (3H, t), 1.72 (2H, m), 3.00 (2H, t), 3.97 (3H, s), 6.14 (1H, s), 7.40 (1H, s).

PREPARATION 129 2.3-Diethyl-4-nitro-pyrazole-5-carboxamide Ethyl iodide (7.2 ml, 90.0 mmol) was added to a suspension of the title compound of preparation 35 (15.0 g, 81.0 mmol) and cesium carbonate (29.3 g, 90.0 mmol) in NN-dimethylformamide (100 ml) and The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was triturated with water (100 ml) and the resulting solid was filtered and dried. A suspension of this solid in ether (250 ml) was heated at 35 ° C for one hour and the precipitate was filtered and dried. This was recrystallized from ethyl acetate to give the title compound as a crystalline solid (5.8 g, 34%). ? (CDCb): 1.30 (3H, t), 1.54 (3H, t), 3.00 (2H, q), 4.20 (2H, q), 5.92 (1 H, s), 7.27 (1 H, s). LRMS: m / z 212 (M + 1) +.

PREPARATION 130 3-Ethyl-4-nitro-2- (pyridazin-3-yl) -pyrazol-5-carboxamide A mixture of the title compounds of preparation (2.66 g, 14.5 mmol) and 95 (2.65 g, 16.1 mmol) and cesium carbonate (13.1 g, 40.2 mmol) in acetonltryl (100 mL) was stirred under reflux for 18 h. hours.

The cooled reaction was concentrated under reduced pressure, the residue was suspended in water and extracted with dichloromethane (5 x 100 ml). The extracts The combined organics were dried (Na2SO4), adsorbed on silica gel and the product was isolated by column chromatography on silica gel, using an elution gradient of methanol: dichloromethane (5:95 to 10:90) to give 3- etll-4-nitro-1- (pyridazin-3-yl) methyl-pyrazole-5-carboxamide (1.31 g) and the title compound (1.81 g, 45%) as a light yellow solid,? (CDCb): 1.20 (3H, t), 3.11 (2H, q), 5.72 (2H, s), 5.89 (1H, s), 7.29 (1H, s), 7.55 (2H, m), 9.20 (1H, d). LRMS: m / z 277 (M + 1) +.

PREPARATION 131 3-Ethyl-4-nitro-2- [1 - (pyridin-2-yl) ethyl] -pyrazole-5-carboxamide A mixture of 2-ethylpyridine (20.0 g, 187 mmol), N-bromosuccinlmide (38.0 g, 213 mmol) and benzoyl peroxide (1.0 g, 75% in water) in 1,1,1-trichloroethane (200 ml), it was heated to reflux for 3 hours. The cooled mixture was filtered and the filtrate was washed with water (2 x 100 ml), aqueous sodium thiosulfate solution (100 ml) and brine (100 ml). The solution was dried (MgSO), filtered through carbon and then hydrobromic acid (25 ml, 62%) was added. This solution was concentrated under reduced pressure and made azeotropic with toluene to give 2- (1-bromoethyl) pyridine hydrochloride as a dark oil (66.0 g).

A mixture of the title compound of preparation 35 (8.0 g, 43.4 mmol), cesium carbonate (35.0 g, 107.4 mmol) and crude 2- (1-bromoethyl) pyridine hydrochloride (13.6 g, 52.0 mmol) in NN-dimethylformamide (80 ml) was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 ml) and water (50 ml). The layers were separated and the organic phase was washed with more water (3 x 50 ml) and with brine (50 ml), then dried (MgSO 4) and evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel, using an elution gradient of pentane: ethyl acetate: methanol (90: 10: 0 to 0: 100: 0 to 0:90:10) to produce the isomer N1 (4.3 g) and the title compound (5.7 g, 45%). ? (CDCb): 1.14 (3H, t), 2.01 (3H, d), 3.00 (2H, q), 5.66 (2H, q), 5.88 (1 H, s), 6.98 (1 H, s), 7.18 ( 1 H, d), 7.25 (1 H, m), 7.68 (1 H, m), 8.56 (1 H, d). LRMS: m / z 290 (M + 1) +.

PREPARATION 132 3-Ethyl-2- (6-methylpyridin-2-yl) methyl-4-nitropyrazole-5-carboxamide A mixture of the title compound of preparation 35 (4.32 g, 23.5 mmol) and 6-methyl-2-plcolyl chloride hydrochloride (5.0 g, 23.4 g) mmoles) in N. N-dimethylformamide (50 ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (50 ml) and dichloromethane (50 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (3 x 50 ml), the combined organic solutions were washed with brine (50 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel twice, using dichloromethane: methanol (95: 5) as eluent and repeated using an elution gradient of pentane: ethyl acetate (50:50 to 0: 100) to produce the N1 isomer (1.0 g) and the title compound (2.47 g, 36%) as a white solid,? (CDCb): 1.18 (3H, t), 2.53 (3H, s), 3.06 (2H, q), 5.42 (2H, s), 5.97 (1H, s), 6.90 (1H, d), 7.12 (1 H, d), 7.22 (1 H, s), 7.58 (1 H, m). LRMS: m / z 312 (M + 23) +.

PREPARATION 133 2-Methoxy-6-methylpyridine Trimethyloxonium tetrafluoroborate (10.0 g, 67.6 mmol) was added portionwise to a suspension of 6-methy1pyridin-2-one (7.3 g, 67.0 mmol) in dichloromethane (100 mL) and once the addition was complete, the reaction was stirred at room temperature for 24 hours. They were added dichloromethane (50 ml) and aqueous sodium hydroxide solution (50 ml, 2 N) and the layers were separated. The aqueous phase was extracted with dichloromethane (2 x 50 ml), the combined organic solutions were washed with brine (50 ml), dried (MgSO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using an elution gradient of pentane: dichloromethane (66:34 to 0: 100) to yield the title compound (2.25 g, 27%) as an oil colorless,? (CDCb): 2.49 (3H, s), 3.90 (3H, s), 6.38-6.73 (2H, m), 7.23-7.40 (1H, d a).

PREPARATION 134 6-bromomethyl-2-methoxypyridine A mixture of the title compound of preparation 133 (2.5 g, 20.3 mmol), N-bromosuccinimide (3.7 g, 20.8 mmol) and benzoyl peroxide (100 mg, 0.41 mmol) in 1,1,1-trichloroethane (50 ml) ) was stirred at reflux for 3 hours and for an additional 16 hours at room temperature. The reaction was washed with water (2 x 25 ml), aqueous sodium thiosulfate solution (25 ml), brine (25 ml) and dried (MgSO 4) and evaporated under reduced pressure. The residue was stirred well with hydrobromic acid (62%, 2.4 ml), the suspension was concentrated under reduced pressure and azeotroped twice with toluene, to give the title compound as a yellow solid,? (CDCb): 3.95 (3H, s), 4.46 (2H, s), 6.63 (1H, d), 6.98 (1H, d), 7.53 (1H, m). LRMS: m / z 202/204 (M + 1) +.

PREPARATION 135 3-Ethyl-2- (6-methoxypyridin-2-yl) methyl-4-nitro-pyrazole-5-carboxamide A mixture of the title compound of preparation 134 (5.2 g, 18.4 mmol), cesium carbonate (6.58 g, 32.5 mmol) and the title compound of preparation 35 (3.4 g, 18.4 mmol) in N.N-dimethylformamide (30 mL) was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure, the residue was partitioned between ether (100 ml) and water (50 ml) and the phases were separated. The organic layer was washed with brine (20 ml), dried (MgSO 4) and evaporated under reduced pressure. The residual gum was triturated with ether to give the title compound (640 mg, 11%) as a white solid. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using pentane: ethyl acetate (66:34) as eluent to give an additional amount (280 mg, 5%) of the title compound, ? (DMSOde): 1.18 (3H, t), 2.84 (2H, q), 3.68 (3H, s), 5.34 (2H, s), 6.73 (2H, m), 7.66 (1H, m), 8.17 (1H , s), 8.39 (1H, s). LRMS: m / z 306 (M + 1) +.

PREPARATION 136 4-Amino-2-methyl-3-n-propylpyrazol-5-carboxamide A mixture of the title compound of preparation 128 (6.17 g, 29.0 mmol) and tin (II) chloride dihydrate (32.8 g, 145 mmol) in industrial methylated spirits (IMS) (100 mL) was refluxed for 2 hours . The cooled mixture was concentrated under reduced pressure to about half its volume, basified to pH 9 using a 2 N aqueous solution of sodium hydroxide and extracted with dichloromethane (3 x 300 ml). The combined organic extracts were dried (MgSO 4) and evaporated under reduced pressure and the crude product was recrystallized from ethyl acetate / methanol to yield the title compound (4.86 g, 92%). p.f. 170-174 ° C. ? (DMSOde): 0.90 (3H, t), 1.47 (2H, m), 2.50 (2H, t), 3.68 (3H, s), 4.43 (2H, s), 6.92 (1 H, s), 7.04 (1 H, s).

PREPARATION 137 4-Amino-2,3-diethyl-pyrazole-5-carboxamide ? ^ j ^ A mixture of the title compound of Preparation 129 (5.7 g, 26.9 mmol) and tin (II) chloride dihydrate (29.0 g, 128 mmol) in ethanol (200 mL) was heated at reflux for 45 minutes. The cooled reaction mixture was evaporated under reduced pressure and re-dissolved in ethyl acetate (200 ml). This solution was poured into 10% aqueous sodium carbonate solution (400 ml) and the mixture was stirred vigorously for one hour. The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 100 ml). The combined organic solutions were dried (Na2SO4) and concentrated under reduced pressure to a volume of 50 ml and the resulting crystals were filtered off and dried to yield the title compound (3.3 g, 67%). ? (CDCb): 1.19 (3H, t), 1.40 (3H, t), 2.59 (2H, q), 3.94 (2H, s), 4.02 (2H, q), 5.20 (1H, s), 6.57 (1H , s). LRMS: m / z 183 (M + 1) +.

PREPARATION 138 4-Amino-3-tyl-2-methylpyrazole-5-carboxamide A mixture of the title compound of preparation 124 (5.8 g, 29.3 mmol) and 10% palladium on carbon (650 mg) in ethanol (100 ml) was hydrogenated at 4,218 kg / cm 2 (414 kPa) and at room temperature twenty hours. The reaction was filtered through Arbocel® and the filter layer was washed well with hot ethanol (200 ml). The combined filtrate was evaporated under reduced pressure to yield the title compound as a solid (4.7 g, 95%). ? (CDCb): 1.20 (3H, t), 2.59 (2H, q), 3.77 (3H, s), 3.95 (2H, s), 5.21 (1 H, s), 6.54 (1H, s).

PREPARATIONS 139 TO 142 The compounds of the following preparations indicated in the table, of the general formula: were prepared from the corresponding nitropyrazoles, using a procedure similar to that described in preparation 138. 1 = purified by column chromatography using ethyl acetate as eluent.

PREPARATION 143 4-Amino-3-ethyl-1-methyl-pyrazole-5-carboxamide A mixture of the title compound of preparation 123 (940 mg, 4.75 mmol) and 10% palladium on carbon (200 mg) in ethanol (100 ml) was hydrogenated at 50 ° C and 3.515 kg / cm2 (345 kPa) for 18 hours. The cooled mixture was filtered through Arbocel® and the filtrate was evaporated under pressure reduced to produce the title compound (786 mg, 98%) as a clear oil,? (CDCb): 1.23 (3H, t), 2.59 (2H, q), 2.82 (2H, s), 4.12 (3H, s). LRMS: m / z 169 (M + 1) +.

PREPARATION 144 3-Bromo-2-chloro-5- (4-methylpiperazin-1-ylsulfonyl) pyridine N-Methylpiperazine (7.65 mL, 69.0 mmol) was added dropwise to a solution of the title compound of Preparation 12 (10.0 g, 34.5 mmol) in ethanol (200 mL) and the reaction was stirred at room temperature for 3 hours . The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (200 ml) and water (100 ml) and the layers were separated. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to yield the title compound (10.53 g, 87%) as a yellow solid,? (CDCb): 2.28 (3H, s), 2.51 (4H, m), 3.14 (4H, m), 8.24 (1 H, s), 8.67 (1 H, s).

PREPARATION 145 3-Bromo-2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridine A mixture of the title compound of preparation 144 (10.0 g, 39.1 mmol), potassium bism (tritymethylsilyl) amide (5.92 g, 29.7 mmol) and ethanol (3.5 mL) in tetrahydrofuran (150 mL) was added. stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150 ml) and brine (50 ml). The layers were separated and the organic phase was dried (Na2SO4), filtered and evaporated under reduced pressure, to yield the title compound (9.1 g, 88%). ? (CDCb): 1.44 (3H, t), 2.29 (3H, s), 2.51 (4H, m), 3.08 (4H, m), 4.54 (2H, q), 8.10 (1H, s), 8.44 (1H, s). LRMS: m / z 365 (M + 1) +.

PREPARATION 146 3-Bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridine A mixture of the title compound of Preparation 13 (1.11 g, 3.0 mmol) and n-propylamine (590 mg, 10.0 mmol) in toluene (20 mL) was stirred at reflux for 90 minutes. The cooled mixture was partitioned between ethyl acetate (50 ml) and water (20 ml), and the layers were separated. The organic phase was washed with brine (20 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to yield the title compound (1.15 g, 98%) as a crystalline solid yellow, ? (CDCl 3): 1.02 (6H, m), 1.68 (2H, m), 2.41 (2H, q), 2.54 (4H, m), 3.06 (4H, m), 3.47 (2H, q), 5.57 (1H, m), 7.86 (1H, s), 8.40 (1H, s). LRMS: m / z 393 (M + 2) +.

PREPARATION 147 2-Ethoxy-5- (4-methyl-piperazin-1-ylsulfonyl) -pyridine-3-carboxylic acid ethyl ester Obtained (85%) as an orange solid, from the title compound of preparation 145 using a procedure similar to that described in preparation 21.? (CDCb): 1.40 (3H, t), 1.46 (3H, t), 2.28 (3H, s), 2.50 (4H, m), 3.09 (4H, m), 4.40 (2H, q), 4.57 (2H, q), 8.40 (1 H, s), 8.63 (1 H, s). LRMS: m / z 358 (M + 1) +.

PREPARATION 148 5- (4-Ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridine-3-carboxylic acid ethyl ester A mixture of the title compound of Preparation 146 (1.10 g, 2.81 mmol), triethylamine (5 mL) and tetrakis (triphenylphosphine) palladium (0) (250 mg, 0.216 mmol) in ethanol (25 mL) was stirred under a carbon monoxide atmosphere at 100 ° C and 7.03kg / cm2 (689 kPa) for 16 hours. The cooled solution was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to yield the title compound (1.07 g, 99%) in the form of a yellow oil,? (CDCb): 1.02 (6H, t), 1.40 (3H, t), 1.69 (2H, m), 2.40 (2H, q), 2.55 (4H, m), 3.05 (4H, m), 3.54 (2H, q), 4.37 (2H, q), 8.37 (1 H, s), 8.57 (2H, m). LRMS: m / z 385 (M + 1) +.

PREPARATION 149 2-Ethoxy-5- (4-methyl-piperazin-1-ylsulfonyl) -pyridine-3-carboxylic acid hydrochloride A solution of sodium hydroxide (21 ml, 2M, 42.0 mmol) was added to a solution of the title compound of preparation 147 (7.57 g, 21.0 mmol) in dioxane (150 ml) and the reaction was stirred at room temperature for 20 minutes. hours. The mixture was neutralized using hydrochloric acid, the dioxane was removed under reduced pressure and the remainder of the aqueous solution was acidified to pH 2 using hydrochloric acid. The solution was evaporated under reduced pressure, the residue was resuspended in hot ethanol, filtered and the filtrate re-evaporated to yield the title compound (5.46 g, 71%). ? (DMSOd?): 1.37 (3H, t), 2.50 (4H, m), 2.72 (3H, s), 3.13-3.39 (4H, m), 4.53 (2H, q), 8.30 (1H, s), 8.75 (1 H, s).

PREPARATION 150 Sodium salt of 5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridine-3-carboxylic acid A mixture of the title compound of Preparation 148 (1.06 g, 2.76 mmol) in sodium hydroxide solution (1.5 mL, 2 N, 3.0 mmol) and ethanol (10 mL) was stirred at room temperature for 4 hours. The reaction was evaporated under reduced pressure, the solid was triturated with ether and the suspension was filtered and dried to yield the title compound (950 mg). ? (DMSOde): 0.87 (6H, t), 1.50 (2H, m), 2.43 (2H, q), 2.56 (4H, m), 2.78 (4H, m), 3.34 (2H, t), 8.08 (1H, s), 8.16 (1H, s).

PREPARATION 151 4- [2-ethoxy-5- (4-methyl-piperazin-1-ylsulfonyl) -pyridin-3-ylcarboxamidol-2-methyl-3-n-propylpyrazol-5-carboxamide The title compound of preparation 136 (525 mg, 2.88 mmol) was added to a mixture of the title compound of preparation 149 (1.04 g, 3.2 mmol), 1-hydroxybenzotriazole hydrate (670 mg, 3.5 mmol), hydrochloride of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (670 mg, 3.5 mmol) and N-ethyldiisopropylamine (2.4 mL, 14.0 mmol) in tetrahydrofuran (50 mL), and the reaction was stirred at room temperature for 36 hours. The reaction mixture was concentrated under reduced pressure and the residue was suspended in sodium carbonate solution (20 ml) and extracted with dichloromethane (3 x 20 ml). The combined organic extracts were washed with brine (3 x 20 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The crude product was triturated with ether to give a yellow solid which was then purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound (720 mg, 51%) as a white solid. A sample (50 mg) of this product was recrystallized from ethyl acetate to give colorless crystals (32 mg) of the title compound, m.p. 242-244 ° C? (CDCb): 0.95 (3H, t), 1.59 (5H, m), 2.27 (3H, s), 2.48 (4H, m), 2.89 (2H, t), 3.10 (4H, m), 3.86 (3H, s), 4.79 (2H, q). 5.27 (1 H, s), 6.63 (1 H, s), 8.65 (1 H, s), 8.84 (1 H, s), 10.53 (1 H, s). LRMS: m / z 494 (M + 1) " PREPARATION 152 4- [2-Ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-ethyl-2-methylpyrazole-5-carboxamide Obtained as a solid (65%) from the title compounds of preparations 23 and 138, following the procedure described in preparation 151.? (CDCb): 1.02 (3H, t), 1.21 (3H, t), 1.58 (3H, t), 2.39 (2H, q), 2.54 (4H, m), 2.90 (2H, q), 3.10 (4H, m), 3.84 (3H, s). 4.78 (2H, q), . 30 (1 H, s), 6.63 (1 H, s), 8.64 (1 H, s), 8.83 (1 H, s), 10.54 (1 H, s). LRMS: m / z 494 (M + 1) " PREPARATION 153 4-f2-? -toxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido] -2-methyl-3-n-propylpyrazole-5-carboxamide Obtained as a solid (64%) from the title compounds of preparations 23 and 136, following a procedure similar to that described in preparation 151, with the exception that an elution gradient of methanol: acetate was used of ethyl (7:93 to 10:90) as the chromatographic eluent. ? (CDCb): 0.94 (3H, t), 1.02 (3H, t), 1.60 (5H, m), 2.40 (2H, q), 2.54 (4H, m), 2.89 (2H, t), 3.10 (4H, m), 3.84 (3H, s), 4.78 (2H, q), 5.25 (1H, s), 6.63 (1H, s), 8.65 (1H, s), 8.83 (1H, s), 10.52 (1H , s). LRMS: m / z 508 (M + 1) " PREPARATION 154 4- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxyl amido -2.3- The title compound of preparation 137 (3.3 g, 16.8 mmol) and triethylamine (7.5 mL, 54.0 mmol) were added to an ice-cold solution of the title compound of Preparation 28 (6.51 g, 18.0 mmol) in dichloromethane ( 100 ml) and the reaction was stirred at room temperature for 18 hours. The mixture was washed consecutively with brine (50 ml), aqueous sodium bicarbonate solution (2 x 50 ml) and then dried (Na 2 SO 3) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 90:10) to yield the title compound as a solid,? (CDCb): 1.04 (3H, t), 1.22 (3H, t), 1.50 (3H, t), 1.59 (3H, t), 2.40 (2H, q), 2.54 (4,), 2.91 (2H, q ), 3.10 (4H, m), 4.16 (2H, q), 4.78 (2H, q), 5.30 (1 H, s), 6.68 (1H, s), 8.65 (1 H, s), 8.84 (1H, s), 10.55 (1 H, s). LRMS: m / z 508 (M + 1) + PREPARATIONS 155 TO 157 The compounds of the following preparations presented in the table, of the general formula: were prepared from the title compound of preparation 28 and the appropriate amines, following procedures similar to those described in Preparation 154. 1 = the title compound was isolated by trituration with ether. 2 = ethyl acetate: methanol (94: 6) was used as the chromatographic eluent.

PREPARATION 158 4- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido-3-ethyl-1-methylpyrazole-5-carboxamide Obtained (51%) as a white solid from the title compounds of preparations 23 and 143, following a procedure similar to that described in preparation 151.? (CDCb): 1.03 (3H, t), 1.25 (3H, t), 1.57 (3H, t), 2.42 (2H, q), 2.58 (6H, m), 3.10 (4H, m), 4.06 (3H, s), 4.76 (2H, q), 5.57 (1 H, sa), 7.55 (1 H, s), 8.70 (1H, s), 8.83 (1 H, s), 9.24 (1H, s). LRMS: m / z 494 (M + 1) ".

PREPARATION 159 4- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido] -1-methyl-3-n-propylpyrazol-5-carboxamide A mixture of the title compounds of preparation 24 (2.0 g, 5.48 mmol), the hydrochloride salt of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide, EP-0463756; (1.08 g, 4.94 mmol), 1-hydroxybenzotriazole hydrate (920 mg, 6.87 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15 g, 6.0 mmol) and N-ethyldiisopropylamine (2.86 mL) , 16.5 mmol) in tetrahydrofuran (20 ml), was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The layers were separated and the organic phase was dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using dichloromethane: methanol (95: 5) as eluent to produce the title compound (940 mg, 38%) as a white solid,? (CDCb): 0.95 (3H, t), 1.02 (3H, t), 1.52 (3H, t), 1.63 (2H,), 2.40 (2H, q), 2.54 (6H, m), 3.09 (4H, m ), 4.05 (3H, s), 4.75 (2H, q), 5.81 (1 H, s), 7.58 (1H, s), 8.67 (1 H, s), 8.80 (1 H, s), 9.25 (1 H, s). LRMS: m / z 509 (M + 2) +.

PREPARATION 160 3-ethyl-4-f5- (4-tylpiperazin-1-ylsulphonyl) -2-n-propylaminopyridin-3-lcarboxamido] -2- (pyridyl) -2-yl) methylpyrazole -5 -carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250 mg, 1.3 mmol) was added to a solution of the title compounds of preparations 40 (245 mg, 1.0 mmol) and 150 (456 mg, 1.2 mmol) , N-ethyldiisopropylamine (194 mg, 1.5 mmol) and 1-hydroxybenzotriazole hydrate (203 mg, 1.5 mmol) in dichloromethane (10 ml) and the The reaction was stirred at room temperature for 16 hours. The reaction was poured into ethyl acetate (30 ml), washed with water (10 ml) and brine (10 ml), dried (MgSO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 94: 6) and triturated with ether, to yield the title compound (242 mg, 41%) in shape of a white solid,? (CDCb): 0.95 (3H, t), 1.01 (6H, m), 1.62 (2H, m), 2.39 (2H, q), 2.52 (4H, m), 2.86 (2H, q), 3.09 (4H, m), 3.46 (2H, q), 5.39 (1H, s), 5.43 (2H, s), 6.64 (1H, s), 6.87 (1H, d), 7.20 (1H, m), 7.63 (1 H, m), 8.17 (1 H, s), 8.53 (1 H, s), 8.58 (1 H, d), 8.64 (1 H, m), 9.58 (1 H, s). LRMS: m / z 584 (M + 1) +.

PREPARATION 161 4- (2-ethoxy-5-nitropyridin-3-ylcarboxamido) -3-ethyl-2-methy1pyrazole-5-carboxamide Oxalyl chloride (2.6 ml, 30.2 mmol) was added dropwise to an ice-cooled solution of the title compound of preparation 8 (1.6 g, 7.55 mmol) and NN-dimethylformamide (1 drop) in dichloromethane (40 ml) and the reaction was stirred at room temperature for 3 hours. Mix it was concentrated under reduced pressure and made azeotropic with dichloromethane several times. The intermediate acid chloride was added to an ice-cold solution of the title compound of Preparation 138 (960 mg, 5.74 mmol) and triethylamine (2.6 mL, 18.7 mmol) in dichloromethane (40 mL), and the reaction was stirred at room temperature for 2 hours. The mixture was washed with water (20 ml) and with brine (20 ml), dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 90:10) to yield the title compound (2.06 g, 99%)? (CDCb): 1.24 (3H, t), 1.61 (3H, t), 2.92 (2H, q), 3.88 (3H, s), 4.84 (2H, q), 5.27 (1 H, s), 6.66 (1H , s), 9.17 (1 H, s), 9.33 (1H, s), 10.57 (1 H, s). LRMS: m / z 363 (M + 1) +.

PREPARATION 162 4- (5-amino-2-ethoxypyridin-3-ylcarboxamido) -3-? Tyl-2-methylpyrazole-5- A mixture of the title compound of preparation 161 (2.06 g, 5.7 mmol) and 10% palladium on carbon (200 mg) in ethanol (70 ml) was hydrogenated at room temperature and 50 psi (345 kPa), for 6 hours. The reaction mixture was filtered through Arbocel®, the filter layer was washed with more ethanol and the combined filtrates were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to yield the title compound (760 mg, 40%) as a solid, ? (CDCb): 1.23 (3H, t), 1.54 (3H, t), 2.87 (2H, q), 3.50 (2H, s), 3.87 (3H, s), 4.60 (2H, q), 5.24 (1H, s), 6.62 (1 H, s), 7.78 (1 H, s), 7.96 (1 H, s), 10.54 (1H, s). LRMS: m / z 333 (M + 1.

PREPARATION 163 5- (5-amino-2-ethoxypyridin-3-yl) -3-ethyl-2-methylpyrazole-2,6-dihydro-7H-pyrazolo [4.3-d] pyrimidin-7-one A mixture of the title compound of Preparation 162 (760 mg, 2.29 mmol) and potassium bis (trimethylsilyl) (685 mg, 3.43 mmol) in ethanol (50 mL) was heated at 100 ° C in a sealed container for 20 hours . The cooled mixture was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to yield the title compound (550 mg, 75) as a solid,? (CDCl 3): 1.41 (3H, t), 1.53 (3H, t), 3.03 (2H, q), 3.58 (2H, s), 4.09 (3H, s), 4.58 (2H, q), 4.78 (1H, s), 8.20 (1 H, s), 11.17 (1 H, s). LRMS: m / z 315 (M + 1) +.

PREPARATION 164 5- (5-Chlorosulfonyl-2-ethoxypyridin-3-yl) -3-ethyl-2-methylpyrazole-2,6-dihydro-7H-pyrazolo [4.3-dlpyrimidin-7-one] Obtained (72%) from the title compound of preparation 163 following a procedure similar to that described in preparation 63.? (CDCb): 1.42 (3H, t), 1.60 (3H, t), 3.07 (2H, q), 4.14 (3H, s), 4.82 (2H, q), 8.92 (1H, s), 9.36 (1H, s), 10.58 (1H, s).

PREPARATION 165 (R) -1-m? Toxi-2-propanol .0 ^, ^ OH Sodium methoxide (54 g, 1 mole) was added per portion to ice-cooled methanol (1000 ml) and the resulting solution was stirred for 20 minutes in an ice bath. (R) -propylene oxide (58 g, 1 mole) was added dropwise over 30 minutes and upon completion of the addition, the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and acidified, with cooling on ice, using ethereal hydrochloric acid (1M) and the resulting mixture was stirred for one hour and then filtered. The filtrate was dried (K2CO3), filtered and evaporated under reduced pressure. The residue was heated to 70 ° C on dry calcium oxide for 30 minutes and then distilled at atmospheric pressure to yield the title compound (25.4 g, 28%) as an oil, m.p. 118-120 ° C. ? (CDCb): 1.16 (3H, d), 2.28 (1H, d), 3.20 (1H, m), 3.36 (1H, m), 3.40 (3H, s), 3.97 (1H, m). [?] D-20.83 ° (C = 1.02, dichloromethane) PREPARATION 166 4-methoxy-2-butanol Lithium aluminum hydride (220 ml, 1.0 M solution in tetrahydrofuran, 220 mmol) was added dropwise over 15 minutes to an ice-cooled solution of 4-methoxybut-3-en-2-one (20.0 g, 200 mmol) in tetrahydrofuran (200 ml) and the reaction was stirred at room temperature for 16 hours. The solution was re-cooled in an ice bath, water (8 ml) was added dropwise, followed by 15% aqueous sodium hydroxide solution (8 ml) and after 10 more minutes, by more water (24 ml). The mixture was stirred for 20 minutes, filtered and the filtrate was concentrated under reduced pressure to a volume of 100 ml. 10% Palladium on carbon (500 mg) was added and the mixture was hydrogenated at 60 psi (314 kPa) for 16 hours. The reaction was filtered through Arbocel® and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: ether (99: 1 to 50:50) to yield the title compound (4.0 g, 19%). ? (CDCb): 1.20 (3H, d), 1.67-1.78 (2H, m), 2.80 (1H, s), 3.38 (3H, s), 3.55-3.65 (2H, m), 4.00 (1H, m).

PREPARATION 167 N-methylcyclopropylcarboxamide O Cyclopropane carboxylic acid (15.83 ml, 200 mmol) was added dropwise to a warm solution (40 ° C) of thionyl chloride (16.71 ml, 213 mmol) in toluene (80 ml) and once the addition was complete, the The reaction was stirred at 80 ° C for 2 hours. The mixture was cooled in an ice bath, a solution of methylamine in tetrahydrofuran (300 ml, 2 M, 600 mmol) was added, the mixture was allowed to warm to room temperature and concentrated under reduced pressure. The residue was suspended in dichloromethane (200 ml), washed with saturated aqueous sodium bicarbonate solution (200 ml) and with brine (200 ml), dried (MgSO 4) and evaporated under reduced pressure. The residual white solid was recrystallized from hexane / ether to give the title compound (11.3 g, 57%) as a white crystalline solid. Found: C, 58.73; H, 9.30; N, 13.70. C5H9NO; 0.2 H20 requires C, 58.46; H, 9.22; N, 13.63%. ? (CDCb): 0.70 (2H, m), 0.95 (2H, m), 1.32 (1 H, m), 2.81 (3H, d), 5.73 (1 H, s). LRMS: m / z 199 (M + 1) +.

PREPARATION 168 N-Cyclopropylmethyl-N-methylamine hydrochloride A solution of the title compound of Preparation 167 (7.90 g, 79.7 mmol) in ether (75 mL) was added dropwise, over 5 minutes, to a suspension of lithium aluminum hydride (3.03 g, 96.0 mmol) in ether (100 ml), and the reaction was stirred at reflux for 4 hours. The cooled mixture is quenched by the consecutive addition of water (3 ml), 10% aqueous sodium hydroxide solution (9 ml) and water (3 ml). The resulting suspension was stirred for 5 minutes, filtered and the solids were washed well with ether (100 ml). The combined filtrate was dried (MgSO4), cooled in an ice bath and saturated with hydrochloric acid. This solution was evaporated under reduced pressure to yield the title compound (8.7 g, 90%) as a gum,? (CDCb): 0.45 (2H, m), 0.72 (2H, m), 1.24 (1H, m), 2.70 (3H, t), 2.88 (3H, t), 2.88 (2H, m), 9.48 (2H, sa).

PREPARATION 169 4- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamidol-3-ethyl-2- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2 g, 6.25 mmol) was added to a solution of preparations 23 (1.6 g, 4.66 mmol) and 89 (1.2 g, 4.84 mmol), hydroxybenzotriazole hydrate ( 960 mg, 6.2 mmol) and N-ethyldiisopropylamine (2.5 ml, 14.5 mmol) in tetrahydrofuran (15 ml) and NN-dimethylformamide (3 ml) and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with water (100 ml) and extracted with dichloromethane (3 x 150 ml). The combined organic extracts were dried (Na 2 SO 4) and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give the title compound (1.42 g, 2.55 mmol). ? (CDCb): 0.98-1.16 (6H, m), 1.52-1.70 (6H, m), 2. 40 (2H, q), 2.55 (4H, m), 2.99-3.16 (6H, m), 3.72 (3H, s), 4.78 (2H, q), 5.30 (1H, sa), 5.44 (2H, s) , 6.60 (1 H, sa), 6.86 (1 H, s), 7.00 (1 H, s), 8.65 (1 H, s), 8.82 (1 H, s), 10.48 (1 H, s). LRMS: m / z 574 (M + 18) + PREPARATION 170 5-r 2 -ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-β-3-etl-2- (1-methylimidazole-2-H) methyl- 2.6-dihydro-7H-pyrazole [4,3-dlpyrimidin-7-one] Obtained in the form of a cream-colored foam (62%) from the title compound of preparation 169 following a procedure similar to that described in example 78.? (CDCb): 1.00 (3H, t), 1.30 (3H, t), 1.57 (3H, t), 2.40 (2H, q), 2.54 (4H, m), 3.06-3.20 (6H, m), 3.78 ( 3H, s), 4.75 (2H, q), 5.64 (2H, s), 6.84 (1H, s), 6.99 (1H, s), 8.61 (1 H, s), 8.99 (1 H, s), 10.66 (1 H, s). LRMS: m / z 556 (M + 1).

Biological activity The following table illustrates the in vitro activities for a series of the compounds of the invention as inhibitors of cGMP PDE5.

PICTURE Safety profile Various compounds of the invention have been tested at doses up to 3 mg / kg i.v. in mice and at 0.5 mg / kg p.o. in dogs, without observing undesired effects.

Claims (22)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula (IA) or (IB): or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, wherein R1 is C1 to C3 alkyl optionally substituted with phenyl, Het or N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted with one or more substituents selected from Ci to C4 alkoxy; halo; CN; CF 3, OCF 3 or C 1 to C 4 alkyl, wherein said C 1 to C 4 alkyl group is optionally substituted with Ci to C 4 haloalkyl or Ci to C 4 haloalkoxy, either being substituted with one or more halo atoms; R2 is Ci to C6 alkyl; R13 is OR3 or NR5R ?; R3 is Ci to Ce alkyl optionally substituted with one or two substituents selected from C3 to C5 cycloalkyl, OH, C to C4 alkoxy, benzyloxy, NR5R6, ".-__. , -.-_ »-. phenyl, furanyl and pyridinyl; C3 cycloalkyl to Ce; 1 - (C 1 to C 4 alkyl) piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; and wherein said C 1 to C 1 alkyl groups or C 1 to C 4 alkoxy groups are optionally terminated by haloalkyl; R4 is SON2NR7R8; each of R5 and R6 is independently selected from H and C1 to C4 alkyl optionally substituted by C3 to C5 cycloalkyl or Ci to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl group or morpholinyl; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally substituted with one or two C1 to C4 alkyl groups and optionally in the form of its 4-N-oxide; R10 is H; C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with C-i to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 to C3 alkenyl, pyridinyl or pyrimidinyl; and Het is a 6-membered heterocyclic group attached to C containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a 5-membered heterocyclic group attached to C containing two or three nitrogen atoms , wherein any of said heterocyclic groups is optionally substituted with Ci to C4 alkyl, C1 to C4 alkoxy or NHR15, wherein R15 is H, C1 to C4 alkyl or C1 to C4 alkanoyl, and halo is Br, Cl, F or I

2. The compound according to claim 1, further characterized in that R1 is C1 to C2 alkyl optionally substituted with Het; 2- (morpholin-4-yl) ethyl or benzyl; R2 is C2 to C4 alkyl; R13 is OR3 or NR5R6; R3 is C1 to C4 alkyl optionally substituted with one or two substituents selected from cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR5R6, phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl; cyclobutyl; 1-methylpperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; each of R 5 and R 6 is independently selected from H and C 1 to C 2 alkyl optionally substituted with cyclopropyl or methoxy, or together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl or morpholinyl group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally substituted with one or two methyl groups and optionally in the form of its 4-N-oxide; R10 is H, Ci to C3 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with methoxy, benzodioxol-5-yl and benzodioxan-2-yl; allyl; pyridin-2-yl; pyrldin-4-yl or pyrimidin-2-yl; and Het is selected from pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxyprop-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylmidazol-2-yl.

3. The compound according to claim 2, further characterized in that R1 is C1 to C2 alkyl optionally substituted with Het; 2- (morpholin-4-yl) ethyl or benzyl; R2 is C2 to C alkyl; R13 is OR3; R3 is C4 to C4 alkyl optionally monosubstituted with cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl; cyclobutyl; tetrahydrofuran-3-yl or tetrahldropyran-4-yl; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally in the form of their 4-N-oxide, R10 is Ci to C3 alkyl optionally monosubstituted with OH; and Het select between pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypyridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl.

4. The compound according to any of claims 1 to 3, further characterized in that it is selected from: 3-etl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) ) pyridin-3-yl) -2- (pyridin-2-yl) methyl-2,6-dihydro-7 H -pyrazolo [4,3-d] pyrimidin-7-one; 3-Ethyl-5- [5- (4-etl-piperazin-1-ylsulphonyl) -2- (2-methoxy-ethoxy) pyridin-3-yl] -2- (pyridin-2-yl) methyl- 2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-Ethyl-5- [5- (4-ethyl-4-oxydodoperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -2- (pyridn-2-yl) L) methyl-2,6-dlhydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [2- (2-methoxyethoxy) -5- (4-methyl-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-n-propyl-2- (pyridin-2) -yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl] -3-n-propyl-2- (pyridin-2-yl) methyl -2,6-d and H-d-7H-pyrazolo [4,3-d) pyrimidin-7-one; (+) - 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2 -methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methyletoxy) pyridin-3-yl] -2- (6-methy1pyridin-2) -yl) methyl-2,6-dihydro-7H-pyrazolo [4,3-d] pyrimidn-7-one; 5- [2-ethoxy-5- (4-ethyl-piperazin-1-ylsulfonyl) pyridin-3-yl] -3-ethyl-2- (6-methoxypyridin-2-yl) methyl-2, 6-dihydro-7H-plrazolo [4,3-d] pyrimidin-7-one; 5- [2-i-Butoxy-5- (4-ethyl-piperazin-1-ylsulfonyl) -pyridin-3-yl] -2,3-diethyl-2,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one, and 5- [2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl] -3-etl-2- [ 1- (pyridin-2-ethyl] -2,6-d, h -dro-7H-pyrazolo [4,3-d] pyrimid-7-one.

5. A pharmaceutical composition comprising a compound of formula (IA) or (IB) according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, together with a pharmaceutically acceptable diluent or carrier.

6. A veterinary formulation comprising a compound of formula (IA) or (IB) according to claim 1, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of any entity, together with a diluent or veterinarily vehicle acceptable.

7. A compound of formula (IA) or (IB) according to claim 1, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate of any entity, or a pharmaceutical composition containing any of the foregoing, for use as medically human.

8. A compound of formula (IA) or (IB) according to claim 1, a veterinarily acceptable salt thereof, a veterinarily acceptable solvate of any entity, or a veterinary formulation containing any of the foregoing, for its use as an animal medicine.

9. The use of a compound of formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which an inhibitor of cGMP PDE5 is indicated.

10. The use of a compound of formula (IA) or (IB) as claimed in claim 1, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of any entity, for the manufacture of a medicament animal for the curative or prophylactic treatment of a medical condition for which an inhibitor of cGMP PDE5 is indicated.

11. The use of a compound of formula (IA) or (IB) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate containing any entity, for the manufacture of a human medicine for the curative or prophylactic treatment of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outflow tracts, incontinence, stable angina, unstable and variable (Prinzmetal), hypertension, pulmonary hypertension, heart failure congestive, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, blood vessel patency reduction conditions, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by bowel motility disorders.

12. - The use of a compound of formula (IA) or (IB) as claimed in claim 1, or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate containing any entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH), obstruction of bladder outlet routes, incontinence, stable angina , unstable and variable (Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, diseases of reduced blood vessel patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by bowel motility disorders.

13. The use of a compound of the formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, or a pharmaceutical composition or veterinary formulation containing any of the above for the manufacture of a human medicament for the treatment or prevention of a medical condition for which it is indicating a cGMP PDE5 inhibitor, in a mammal (including a human).

14. The use of a compound of the formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, or a pharmaceutical composition or veterinary formulation containing any of the above for the manufacture of a medicament for the treatment or prevention of erectile dysfunction in males (MED), sexual dysfunction in females (FSD), premature birth, dysmenorrhea, benign prostatic hyperplasia (BPH) ), obstruction of the exit routes of the bladder, incontinence, stable, unstable and variable angina (Prinzmetal), hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, cerebrovascular accidents, peripheral vascular disease, conditions of reduction of permeability of blood vessels, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterized by bowel motility disorders in a mammal (including a human being).

15. A compound of formula (NA) or (IIB): wherein Y is halo, and R1, R2 and R13 are as defined in claim 1.

16. The compound according to claim 15, further characterized in that Y is chloro.

17. - A compound of the formula (IVA) or (IVB): (IVA) (IVB) wherein R1, R2 and R13 are as defined in claim 1. 18.- A compound of the formula (VA) or (VB): (VA) (VB) wherein R1, R2 and R13 are as previously defined in claim 1. 19. A compound of the formula (IXA) or (IXB): (IXA) (IXB) wherein R1, R2, R4 and R13 are as previously defined in claim 1. 20. A process for the preparation of a compound of the formula (IA) or (IB): wherein R1 is alkyl d to C3 optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted with one or more substituents selected from C 1 to C alkoxy, halo, CN; CF 3, OCF 3 or C 1 to C 4 alkyl, wherein said C 1 to C alkyl group is optionally substituted with haloalkyl or C 1 to C 4 haloalkoxy, either of which is substituted with one or more halo atoms; R2 is C1 alkyl to Ce; R13 is OR3 or NR5R6; R3 is C1 to Ce alkyl optionally substituted with one or two substituents selected from C3 to C5 cycloalkyl, OH, C to C4 alkoxy, benzyloxy, NR5R ?, phenyl, furanyl and pyridinyl; C3 cycloalkyl to Ce; 1 - (C1 to C4 alkyl) piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; and wherein said C1 to C6 alkyl groups or said C1 to C4 alkoxy groups are optionally terminated by haloalkyl; R4 is SON2N7R8; each of R5 and R? is independently selected from H and alkyl Ci to d optionally substituted with C3 to C5 cycloalkyl or C1 to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, plrrolidinyl, piperidinyl or morpholinyl group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R1c-piperazinyl group optionally substituted with one or two C1 to C4 alkyl groups and optionally in the form of its 4-N-oxide; R10 is H; C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with C-i to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 alkenyl to Ce, pyridinyl or pyrimidinyl; and Het is a 6-membered heterocyclic group attached to C containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a 5-membered heterocyclic group attached to C containing two or three nitrogen atoms , wherein any of said heterocyclic groups is optionally substituted with Ci to C4 alkyl, C1 to C4 alkoxy or NHR15, wherein R15 is H, CT to C4 alkyl or Ci to C4 alkanoyl, and halo is Br, Cl, F or I; process comprising reacting a compound of the formula (HA) or (IIB), respectively: HD-l-áll-l wherein Y is halo, and R1, R2 and R13 are as previously defined in this claim, with a compound of formula (III): R7R8NH (III) wherein R7 and R8 are as previously defined in this claim , optionally followed by the formation of a pharmaceutically or veterinarily acceptable salt of the required product or a pharmaceutically or veterinarily acceptable solvate of any entity. 21. A process for the preparation of a compound of formula (IA) or (IB) according to claim 20, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, comprising the cyclization of a compound of formula (VA) or (VB), respectively: (VA) (VB) wherein R1, R2 and R13 are as previously defined for formulas (IA) and (IB) in claim 20, to form a compound of formula (IVA) or (IVB): (VAT) (IVB) which can be converted into a compound of formula (HA) or (IIB), by reaction with a compound of formula (III) R7R8NH, wherein R7 and R8 are as defined in claim 20, and said compound of formula ( HA) or (IIB) can be converted in turn by the process according to claim 20, to form a compound of formula (IA) or (IB), which optionally is followed by the formation of a pharmaceutically or veterinarily acceptable salt of the required product or a pharmaceutically or veterinarily acceptable solvate of any entity. 22. A process for the preparation of a compound of formula (IA) or (IB) according to claim 20, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity, comprising the cyclization of a compound of formula (IXA) or (IXB), respectively: (LXA) (LXB) wherein R1, R2, R4 and R13 are as defined in claim 20.