HK1037365A

HK1037365A - Pyrazolopyrimidinone cgmp pde5 inhibitors for the tratment of sexual dysfunction

Info

Publication number: HK1037365A
Application number: HK01107948.7A
Authority: HK
Inventors: M‧E‧邦纳格; J‧P‧马蒂尔斯; S‧D‧A‧斯特雷特; A‧伍德
Original assignee: 美国辉瑞有限公司
Priority date: 1998-04-20
Filing date: 1999-03-25
Publication date: 2002-02-08

Description

Pyrazolopyrimidinone cGMP PDE5 inhibitors for the treatment of sexual dysfunction

The present invention relates to a series of pyrazolo [4,3-d ] pyrimidin-7-ones which inhibit 3 ', 5' -cyclic guanosine phosphodiesterase (cGMP PDEs). It is further noted that the compounds of the present invention are potent and selective inhibitors of type 53 ', 5' -cyclic guanosine phosphodiesterase (cGMP PDEs) and thus have utility in a number of therapeutic areas.

The compounds are particularly valuable in the treatment of Male Erectile Dysfunction (MED) and Female Sexual Dysfunction (FSD), but are also significantly effective for the treatment of other diseases for which treatment with potent and selective cGMP PDE5 inhibitors is effective. Such conditions include premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (pregnanmer's) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, conditions that reduce vascular patency such as post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma, and conditions characterized by intestinal motility disorders such as Irritable Bowel Syndrome (IBS).

Other conditions that may be mentioned include pre-convulsive symptoms, cutaneous mucosal lymph node syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, cutaneous necrosis, cancer metastasis, hair loss, shrivelled mouth, anal fissure and hypoxic vasoconstriction.

Particularly mentioned diseases include MED and FSD.

The invention therefore provides compounds of formulae (IA) and (IB) or their pharmaceutically or veterinarily acceptable salts, or pharmaceutically or veterinarily acceptable solvates of either entity,wherein R is¹Is C optionally substituted by phenyl, Het or N-linked heterocyclyl selected from piperidinyl and morpholinyl₁To C₃An alkyl group; wherein said phenyl group is substituted by one or more groups selected from C₁To C₄Alkoxy, halo, CN, CF₃、OCF₃Or C₁To C₄The substituent of the alkyl group is optionally substituted, wherein C is₁To C₄Alkyl radicals derived from C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy, any of which is substituted with one or more halogen atoms;

R²is C₁To C₆An alkyl group;

R¹³is OR³Or NR⁵R⁶；

R³Is formed by one or two selected from C₃To C₅Cycloalkyl, OH, C₁To C₄Alkoxy, benzyloxy, NR⁵R⁶Phenyl, furyl and pyridyl optionally substituted C₁To C₆Alkyl radical, C₃To C₆Cycloalkyl, 1- (C)₁To C₄Alkyl) piperidinyl, tetrahydrofuranyl or tetrahydropyranyl; and wherein C₁To C₆Alkyl and C₁To C₄Alkoxy groups may be substituted with haloalkyl groups such as CF₃Optionally end-capping;

R⁴is SO₂NR⁷R⁸；

R⁵And R⁶Each independently selected from H and C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-optionally substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;

R⁷and R⁸Together with the nitrogen atom to which they are attached form a group consisting of one or two C₁To C₄Alkyl optionally substituted 4-R¹⁰-piperazinyl and optionally in the form of its 4-N-oxide;

R¹⁰is H; by one or two selected from OH, NR⁵R⁶、CONR⁵R⁶From C₁To C₄C optionally substituted by substituents of alkoxy, benzodioxolyl and benzodioxolyl optionally substituted phenyl₁To C₄An alkyl group; c₃To C₆An alkenyl group; pyridyl or pyrimidinyl;and

het is a C-linked 6-membered heterocycle containing one or two nitrogen atoms optionally present in the form of its mono-N-oxide or a C-linked 5-membered heterocycle containing two or three nitrogen atoms, wherein any of the heterocycles are substituted by C₁To C₄Alkyl radical, C₁To C₄Alkoxy or NHR¹⁵Is optionally substituted, wherein R¹⁵Is H, C₁To C₄Alkyl or C₁To C₄An alkanoyl group.

In the above definitions, unless otherwise specified, alkyl, alkoxy and alkenyl groups having three or more carbon atoms and alkanoyl groups having four or more carbon atoms may be straight or branched. The term halogen atom includes Cl, Br, F and I. Haloalkyl and haloalkoxy are each preferably CF₃And OCF₃。

The compounds of the formulae (IA) and (IB) may contain one or more chiral centers and can therefore occur as stereoisomers, i.e. as enantiomers or diastereomers, and mixtures thereof. The invention includes both individual stereoisomers of the compounds of formula (IA) and (IB) and any mixtures thereof. Separation of the diastereomers is obtained by conventional techniques, for example by fractional crystallization or chromatography (including HPLC) of a mixture of diastereomers of the compounds of formulae (ia) and (ib), or a suitable salt or derivative thereof. The respective enantiomers of the compounds of formula (ia) or (ib) can be prepared from the corresponding optically pure intermediates, either by resolution or by HPLC of the racemate using a suitable chiral carrier, or, where appropriate, by fractional crystallization of the diastereomeric salts formed by reaction of the racemate with a suitable optically active acid or base.

The compounds of formulae (IA) and (IB) may also exist in tautomeric forms, the invention including mixtures thereof and the respective tautomers thereof.

The invention also includes radiolabeled derivatives of compounds of formula (IA) and (IB) which are suitable for biological studies.

Pharmaceutically or veterinarily acceptable salts of the compounds of formulae (ia) and (ib) containing a basic centre are, for example, non-toxic acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid, with carboxylic acids or with organic sulphonic acids. The compounds of formulae (IA) and (IB) also provide pharmaceutically or veterinarily acceptable metal salts with bases, especially non-toxic alkali metal salts. Examples include sodium and potassium salts.

A preferred group of compounds of formula (IA) and (IB) is that wherein R is¹Is C optionally substituted by Het₁To C₂Alkyl, 2- (morpholin-4-yl) ethyl or benzyl; r²Is C₂To C₄An alkyl group; r¹³Is OR³Or NR⁵R⁶；R³Is prepared from one or two of cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR⁵R⁶C optionally substituted with substituents of phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl₁To C₄Alkyl, cyclobutyl, 1-methylpiperidin-4-yl, tetrahydrofuran-3-yl or tetrahydropyran-4-yl; r⁵And R⁶Each independently selected from H and C optionally substituted by cyclopropyl or methoxy₁To C₂Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl or morpholinyl; r⁷And R⁸Together with the nitrogen atom to which they are attached form 4-R optionally substituted by one or two methyl groups¹⁰-piperazinyl and optionally in the form of its 4-N-oxide; r¹⁰Is H, one or two selected from OH, NR⁵R⁶、CONR⁵R⁶C optionally substituted by the substituents of phenyl optionally substituted by methoxy, benzodioxol-5-yl and benzodioxan-2-yl₁To C₃Alkyl, allyl, pyridin-2-yl, pyridin-4-yl, or pyrimidin-2-yl; 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 more preferred group of compounds of formula (IA) and (IB) is that wherein R is¹Is C optionally substituted by Het₁To C₂Alkyl, 2- (morpholin-4-yl) ethyl or benzyl; r²Is C₂To C₄An alkyl group; r¹³Is OR³；R³Is C optionally monosubstituted by cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl₁To C₄Alkyl, cyclobutyl, tetrahydrofuran-3-yl or tetrahydropyran-4-yl; r⁷And R⁸Together with the nitrogen atom to which they are attached form 4-R optionally in its 4-N-oxide form¹⁰-a piperazinyl group; r¹⁰Is C optionally monosubstituted by OH₁To C₃An alkyl group; 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.

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-7H-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-piperazinol-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-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-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one; (+) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) 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) -methylethoxy) pyridin-3-yl ] -2- (6-methylpyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [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-isobutoxy-5- (4-ethylpiperazin-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-ethyl-2- [1- (pyridin-2-yl) ethyl ] -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one.

According to a further aspect of the invention there is provided compounds of formulae (IA) and (IB) as hereinbefore defined, but wherein R is¹Not being unsubstituted C₁An alkyl group; at R¹C of (A)₁The optional substituents on the alkyl are not substituted phenyl or N-linked heterocycle; at R¹C of (A)₂Or C₃Optional substituents on alkyl are not phenyl or Het; or wherein R is¹³Is not NR⁵R⁶(ii) a Or wherein R is³Alkyl of not C₅To C₆(ii) a Or wherein at R³The above optional substituents being other than C₃To C₅A cycloalkyl group; or wherein at R³The alkyl or optional alkoxy substituents on (a) are not capped with haloalkyl groups; or wherein R is⁵And R⁶C of (A)₁To C₄Alkyl radicals other than C₃To C₅Cycloalkyl or C₁To C₄Alkoxy substitution; or wherein R is⁵And R⁶C of (A)₁To C₁Alkyl groups do not form, together with the nitrogen group to which they are attached, an azetidinyl group; or wherein Het is not C₁To C₄Alkoxy or HNR¹⁵A group.

In another aspect, the invention provides processes for the preparation of compounds of formula (ia) and (ib), their pharmaceutically and veterinarily acceptable salts and pharmaceutically and veterinarily acceptable solvates of any of the entities, as set forth below.

It will be readily understood by those skilled in the art that in certain of the methods described, the order of the synthetic steps used may be varied and will depend, inter alia, on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the strategy (if any) of protecting groups to be employed. It is clear that such factors will also influence the choice of reagents used in the synthetic steps.

An exemplary protecting group strategy is the route to 21- (2-hydroxyethoxy) analogues (example 33), the precursors of which (example 32) contain a benzyl group as the protecting group for the alcohol.

It will also be appreciated that interconversion and conversion of various standard substituents or functional groups in some compounds of formula (IA) and (IB) will provide other compounds of formula (IA) and (IB). Examples include alkoxide exchange at the 2-position of the 5- (pyridin-3-yl) substituent (see example 1 for example 4B, 9, 11, 13, 23, 24, 32 and 64, example 2 for example 14, example 20 for example 21, example 26 for example 29, 65, 66, 67 and 68, example 35 for example 36, example 38 for examples 39 and 40 and example 45 for example 46), amine exchange at the 2-position on the 5- (pyridin-3-yl) substituent (see example 78 for example 148 and 154) and piperazine and/or pyridine N-oxidation (see example 1 for example 70, example 28 for example 71, and example 4 for 72 and 73).

The following methods are illustrative of the general synthetic methods that may be employed to obtain the compounds of the present invention.

1. By reacting a compound of formula (IIA) or (IIB)Wherein Y is halo, preferably chloro and R¹、R²And R¹³As previously defined for formulae (IA) and (IB), with a compound of formula (III):

R⁷R⁸NH (III) wherein R⁷And R⁸Preparation of formula (IA) or (IB) as previously defined for formula (IA) and (IB)B) A compound is provided.

The reaction is generally carried out at about 0 ℃ to about room temperature, preferably in a suitable solvent such as C₁To C₃Excess of (iii) or other suitable base such as triethylamine is used in the presence of an alkanol or dichloromethane to scavenge the acid by-product (HY).

The reaction is conveniently suitable for "high speed analogue synthesis" (HSAS) in which a particular compound of formula (IIB) is coupled to a series of readily available amines of formula (III), as described in examples 203 to 212.

Conversion of amino groups to SO by applying known methods₂Y, from a compound of formula (IVA) or (IVB) a compound of formula (IIA) or (IIB), respectively, can be prepared:wherein R is¹、R²And R¹³As previously defined for formulae (IIA) and (IIB), wherein Y is also as previously defined for formulae (IIA) and (IIB). For example, when Y is chloro, it is treated with an excess of liquid sulfur dioxide and an approximately three-fold excess of cupric chloride solution in aqueous acetic acid at about-15 ℃ to about room temperature by the action of an approximately two-fold excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid at about-25 ℃ to about 0 ℃. When R is¹³When containing primary or secondary amino groups, it will generally be advantageous to protect the amino groups with acid stabilizing groups such as acetyl or benzyl.

Compounds of formula (IVA) or (IVB) may be prepared by ring closure of a compound of formula (VA) or (VB), respectively:wherein R is¹、R²And R¹³As previously defined for formulae (IVA) and (IVB). The cyclization is preferably base-mediated using alkali metal salts of sterically hindered alcohols or amines. For example, about 1.5 to 5, preferably 3 to 5, are used in a suitable solvent at the reflux temperature of the reaction mixture, or, optionally, in a closed vessel at about 100 ℃, optionally in the presence of molecular sievesA5-fold excess of potassium tert-butoxide or potassium bis (trimethylsilyl) amide can effect the desired cyclization. When R is¹³Is OR³And selecting an alcohol as solvent, the appropriate formula R should be used³OH alcohols to eliminate potential problems associated with alkoxide exchange at the 2 position of the pyridine ring.

The compounds of formula (VA) or (VB) may be prepared by reduction of a compound of formula (VIA) or (VIB), respectively, by conventional catalytic or catalytic transfer hydrogenation processes:wherein R is¹、R²And R¹³As previously defined for formulae (VA) and (VB). The hydrogenation is generally obtained using a Raney nickel catalyst or a palladium catalyst such as 10% Pd on charcoal in a suitable solvent such as ethanol under a hydrogen pressure of about 345kPa (50psi) to about 414kPa (60psi) at about room temperature to about 60 deg.C, preferably about 40 deg.C to about 50 deg.C.

By reacting a compound of formula (I) wherein R is¹And R²The compounds of formula (VIIA) or (VIIB) are prepared by reacting a compound of formula (VIIA) or (VIIB), respectively, with a compound of formula (VIII), as previously defined for formulae (VIA) and (VIB).Wherein R is¹³As also previously defined for formulae (via) and (vib). Further, with respect to (IVA) and (IVB), when R is¹³Where primary or secondary amino groups are included, conventional amino protecting group strategies are preferably employed for (VIII).

The coupling reaction may be obtained by the acid chloride derivative of (viii) using conventional amide bond formation techniques, for example at about 0 ℃ to about room temperature in a suitable solvent such as dichloromethane, optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in the presence of up to about five times an excess of a tertiary amine such as triethylamine or pyridine as a scavenger for the by-product of the acid (HY). Pyridine may also be conveniently used as a solvent.

In particular, amino acid coupled variants of either host (host) may be used. For example, the acid of formula (VIII) or a suitable salt thereof (e.g. the sodium salt) may be activated, optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as 4-dimethylaminopyridine, either by using a halogenated triaminophosphonium such as bromo (trispyrrolidinyl) phosphonium hexafluorophosphate or by using a suitable pyridinium salt such as 2-chloro-1-methylpyridinium iodide, using a carbodiimide such as 1, 3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminoprop-1-yl) carbodiimide. Any type of coupling is carried out in a suitable solvent such as dichloromethane or tetrahydrofuran at about 0 ℃ to about room temperature, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (e.g., whether the compound of formula (VIIA) or (VIIB) or the activating reagent is in the form of an acid addition salt). It is presently preferred to use from 1 to 2 molar equivalents of the activating reagent and from 1 to 3 molar equivalents of any tertiary amine.

In another variation, the carboxylic acid function of (VIII) is first activated using up to about 5% excess reagent such as N, N-carbonyldiimidazole at about room temperature to about 80 deg.C in a suitable solvent such as ethyl acetate or butan-2-one, followed by reaction of the intermediate imidazolidine (imidazolide) with (VIIA) or (VIIB) at about 20 deg.C to about 90 deg.C.

2. Another generally applicable synthetic route for the compounds of formulae (IA) and (IB) involves the introduction of R at an earlier stage of the synthesis⁴And (4) a substituent.

Thus by a process analogous to the ring closure of the compounds of formulae (VA) and (VB) described previously, from which R may be derived¹、R²、R¹³And R⁴The compounds of formula (IA) and (IB) are prepared by ring closure of a compound of formula (IX A) or (IX B) as hereinbefore defined for the compounds of formula (IA) and (IB), respectively.Another reaction condition is to carry out the reaction with about 1.2 to 4 molar equivalents of the sterically hindered base in a closed vessel at about 100 ℃ to about 120 ℃ or, alternatively, to use a sterically hindered alcohol such as 3-methylpent-3-ol instead of formula R³OH alcohol as solvent withAbout 1.5 to 4.5 molar equivalents of a sterically hindered base such as potassium tert-butoxide or KHMDS and optionally at about 120 ℃ to about 150 ℃ in a closed vessel.

By reacting the already described nicotinic acid derivatives of the formula (VIII) analogously to (VIIA) and (VIIB), by reacting the compounds in which R is¹And R²A compound of formula (VIIA) or (VIIB) as hereinbefore defined for formula (IX A) and (IX B) and wherein R¹³And R⁴Preparing a compound of formula (IX A) or (IX B), respectively, also by reaction of a compound of formula (X) as previously defined for formula (IX A) or (IX B):

as detailed previously herein, by reduction and subsequent conversion to R⁴The compounds of formula (X) can be prepared directly from the compounds of formula (VIII).

3. As mentioned earlier, certain compounds of formula (IA) and (IB) may be interconverted by introducing an alkoxide exchange or substitution at the 2-position of the 5- (pyridin-3-yl) substituent. When R is¹³Is OR³Where this is achieved by treating the appropriate alcohol with an alkali metal salt of a sterically hindered alcohol or amine to form the desired alkoxide anion, which is then reacted with the substrate. Generally, in a two-step process, a mixture of about 5 to about 8 molar equivalents of potassium bis (trimethylsilyl) amide and the desired alcohol as solvent is heated at about 80 ℃ to about 100 ℃ for about 0.5 to 1 hour, followed by addition of the compound of formula (IA) or (IB) and heating of the reaction mixture at about 100 ℃ to about 120 ℃. Alternatively, in a one-step process, the substrate may be treated directly with from about 1.2 to about 6, preferably from about 4 to about 6, molar equivalents of, for example, potassium bis (trimethylsilyl) amide or potassium tert-butoxide, in the desired alcohol as solvent at from about 80 ℃ to about 130 ℃. Another variant uses the desired alcohol saturated with ammonia as solvent in a closed vessel at about 100 ℃. (ii) when R is¹³Is NR⁵R⁶In an appropriate solvent, in excessWith an excess of R in the presence of a sterically hindered amine of (2)⁵R⁶NH or a suitable acid addition salt thereof. Generally, R is in Dimethylformamide (DMF) as a solvent at about 100 deg.C⁵R⁶NH acts as a free base with an approximately 3-fold excess (over the substrate) of potassium bis (trimethylsilyl) amide (KHMDS). Or, an excess of R⁵R⁶NH may be used as solvent and the reaction is carried out in the presence of about 50% excess copper (II) sulfate at a reflux temperature up to the reaction medium. When the desired amino substituent on the compound of formula (IA) or (IB) is-NR⁵R⁶And R is⁵Or R⁶When either is H, the exchange reaction can then be carried out in DMF by refluxing with the appropriate amine, copper (II) sulfate penta-or hexa-hydrate or KHDMS. Typically, NHR is a cross-coupled type⁵R⁶Of other amines, e.g. wherein R⁵Or R⁶OR of compounds selected from aliphatic OR cyclic amines optionally containing oxygen³The reaction is preferably carried out for about 18 hours at 100 c by treatment with the appropriate amine and about 3 equivalents of potassium bis (trimethylsilyl) amide in DMF.

4. It is apparent that by using the cyclization and alkoxide exchange methodologies described herein, for certain of those wherein R¹³Is OR³It may be particularly advantageous to produce compounds of formula (IA) or (IB) respectively directly from compounds of formula (IX A) or (IX B) in a "one-pot reaction", in which the 2-alkoxy group of the 5- (pyridin-3-yl) substituent in the former is different from that in the latter.

When the new 2-alkoxy alcohol provided as reaction solvent is too deficient or too expensive, then it will be convenient to use a suitable alternative such as 1, 4-dioxane.

5. Another generally applicable synthetic route for the compounds of formulae (IA) and (IB) involves the introduction of R in the final step of the synthesis¹And (4) a substituent.

Thus, one or more of a number of well known methods are employedVarious processes by reacting R therein¹Is hydrogen and R²、R¹³And R⁴Compounds of formula (IA) or (IB) may be prepared by alkylation of compounds of formula (IA) or (IB) as hereinbefore defined for formula (IA) and (IB). For example: reacting a compound of formula R at a temperature of from about-70 ℃ to about 100 ℃ in the presence of a suitable base, optionally sodium iodide or potassium iodide¹Compound of X, wherein R¹As previously defined for formulae (IA) and (IB) and X is a suitable leaving group such as halo (preferably chloro, bromo or iodo), C₁To C₄An alkylsulfonyloxy group, a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group (e.g., a benzenesulfonyloxy group or a p-toluenesulfonyloxy group). The alkylation is preferably carried out at about room temperature to about 80 ℃. Suitable base-solvent compositions may be selected from:

(a) sodium, potassium or cesium carbonate, sodium or potassium bicarbonate, or tertiary amines such as triethylamine or pyridine with C₁To C₄Alkanol, 1, 2-dimethoxyethane, tetrahydrofuran, 1, 4-dioxane, acetonitrile, pyridine, dimethylformamide or N, N-dimethylacetamide;

(a) hydroxides of sodium or potassium or C of sodium or potassium₁To C₄Alkoxide with C₁To C₄Alkanol, water or mixtures thereof;

(b) lithium, sodium or potassium hydride, lithium, sodium or potassium bis (trimethylsilyl) amide, lithium diisopropylamide or butyllithium together with toluene, diethyl ether, 1, 2-dimethoxyethane, tetrahydrofuran or 1, 4-dioxane; or

(d) Under the condition of phase transfer catalysis, the tetraalkyl ammonium halide or the tetraalkyl ammonium hydroxide and the mixture of the aqueous solution of sodium hydroxide or potassium hydroxide and dichloromethane, 1, 2-dichloroethane or chloroform are mixed together; using the classical Mitsunobu methodology, and wherein R¹Formula R as previously defined for formulae (IA) and (IB)¹And (3) reacting OH compounds. Typical reaction conditions include about-5 ℃ to about room temperature in a suitable solventSuch as tetrahydrofuran or 1, 4-dioxane, between a triarylphosphine and a di (C)₁To C₄) Treating the substrate with an alkanol in the presence of an alkyl azodicarboxylate.

Typically, an about 10% excess of sodium hydride is added to a solution of the substrate in a suitable solvent, such as anhydrous tetrahydrofuran, and the desired R is added in an about 10% excess¹And treating the generated anion with X.

When R is¹From which R, when other than hydrogen, may be removed by subsequent acidification of the reaction mixture to a pH of about 6 under the same conditions as those used for converting a compound of formula (IX A) or (IX B) into a compound of formula (IA) or (IB), respectively¹Is hydrogen and R²、R¹³And R⁴The compounds of formulae (IX A) and (IX B) as previously defined for formulae (IX A) and (IX B) respectively are obtained wherein R¹Is hydrogen and R²、R¹³And R⁴Compounds of formula (IA) or (IB) as previously defined for formulae (IA) and (IB).

When neither commercially available nor subsequently described, amines of formula (III), 4-aminopyrazole-5-carboxamides of formulae (VIIA) and (VIIB), carboxylic acids of formulae (VIII) and (X), nitriles of formula (VIII) and esters of formula (XVI) can be obtained from readily available starting materials by analogous procedures to those described in the preparative section or by conventional synthetic procedures in accordance with standard organic chemistry textbooks or previous literature using appropriate reagents and reaction conditions.

Furthermore, the person skilled in the art will be aware of the variations and modifications to those processes described below in his examples and preparation section which enable the compounds defined by the formulae (IA) and (IB) obtained.

Pharmaceutically acceptable acid addition salts of the compounds of formulae (IA) and (IB) which contain a basic center may also be prepared in a conventional manner. For example, a solution of the free base is treated with a suitable acid, either neat or in a suitable solvent, and the resulting salt is isolated by evaporation of the reaction solvent under vacuum or by filtration.

Pharmaceutically acceptable base addition salts can be obtained in a similar manner by treating a solution of a compound of formula (IA) or (IB) with a suitable base. Both types of salts can be formed or interconverted using ion exchange resin techniques.

The biological activity of the compounds of the invention was determined by the following test methods. Phosphodiesterase (PDE) inhibition activity

By measuring their IC₅₀Values (concentration of compound requiring 50% enzyme inhibitory activity) to determine PDE inhibitory activity in vitro against 3 ', 5' -cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) phosphodiesterase.

The required PDE enzymes were isolated from a variety of sources including human cavernous bodies, human and rabbit platelets, human ventricles, human skeletal muscle and bovine retina, essentially according to the methods of w.j.thompson and m.m.appleman (biochem.,1971,10, 311). In particular cGMP-specific PDE (PDE5) and said cGMP-inhibiting cAMP PDE (PDE3) obtained from human sponge body tissue, human platelets or rabbit platelets; cGMP-stimulating PDE (PDE2) obtained from human sponge; obtaining a calcium/calmodulin (Ca/CAM) -dependent PDE (PDE1) from the human ventricle; obtaining cAMP-specific PDE (PDE4) from human skeletal muscle; and photoreceptor PDE (PDE6) is obtained from bovine retina.

The assay was performed using a modified "batch" method of W.J. Thompson et al (Biochem,1979,18, 5228). The results from these experiments show that the compounds of the present invention are potent and selective cGMP-specific PDE5 inhibitors. Functional Activity

This activity was postulated by determining in vitro the ability of the compounds of the invention to enhance sodium nitroprusside-induced relaxation of pre-contracted rabbit penile cavernous tissue strips as described by s.a.balard et al (brit.j.pharmacol.,1996,118 (supplement), abstract 153P). In vivo Activity

Following i.v. administration, compounds were screened on anesthetized dogs to determine that they potentiate the increase in pressure in the corpora cavernosa induced by intracapsular injection of sodium nitroprusside, using a method described based on Trigo-Rocha et al (neuroourol and urodyn, 1994,13, 71).

In human therapy, the compounds of formula (ia) and (ib), their pharmaceutically acceptable salts and solvates of either entity may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected for the intended route of administration and standard pharmaceutical practice. They are preferably administered orally in the form of tablets containing such excipients as starch or lactose, or in the form of capsules or ovules, alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other substances, for example, enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. The compounds may 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 formulae (ia) and (ib) and their pharmaceutically acceptable salts and solvates may be from 10 to 500mg (in single or divided doses). Thus, for example, tablets or capsules may contain from 5 to 250mg of the active compound for single administration or, if appropriate, for administration in two or more doses over a period of time. The physician will in any event determine the actual dosage which will be most suitable for an individual patient and the dosage will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the general case, and there will of course be higher or lower dosage ranges given for individual conditions and such dosage ranges are within the scope of the invention. The skilled artisan will also appreciate that the compounds of the invention may be administered on an "as needed" basis (i.e., as needed or desired) as a single dose in the treatment of certain disorders, including MED and FSD.

In humans, in general, oral administration of the compounds of the invention is the preferred route, which is the most convenient and avoids the well-known adverse conditions associated with intracavernosal (i.c.) administration, for example in MED. A preferred oral dosage regimen for a typical human in MED is 25 to 250mg of the compound, when required. The drug may be administered parenterally, sublingually or buccally in the event that the recipient suffers from a swallowing disorder following oral administration or suffers from impaired absorption of the drug.

For veterinary use, the compounds of formula (ia) or (ib), or their veterinarily acceptable salts, or any of the physical, veterinarily acceptable solvates, are administered as a readily acceptable formulation according to normal veterinary practice and the veterinarian will determine the dosage regimen and route of administration which is most appropriate for the particular animal.

Accordingly, the present invention provides a pharmaceutical composition comprising a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent or carrier.

The invention further provides a veterinary formulation comprising a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, together with a veterinarily acceptable diluent or carrier.

The invention also provides a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of the entities thereof, or a pharmaceutical composition comprising any of the foregoing, for use as a human medicament.

In addition, the present invention provides a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or a tangible, veterinarily acceptable solvate of any of the foregoing, or a veterinary formulation containing any of the foregoing, as a veterinary medicament.

In a further aspect, the present invention provides the use of a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of the entities thereof, for the manufacture of a human medicament for the therapeutic or prophylactic treatment of a disease for which an inhibitor of cGMPPDE5 is indicated.

The invention further provides 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 disease in which inhibition of cGMP PDE5 is desirable.

The invention also provides the use of a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, for the manufacture of a veterinary medicament for the therapeutic or prophylactic treatment of a disease for which an inhibitor of cGMP PDE5 is indicated.

In addition, the present invention provides the use of a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a human medicament for the therapeutic or prophylactic treatment of a disease or disorder selected from: male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (pregnanmer's) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, diseases that reduce vascular patency (e.g., post-percutaneous transluminal angioplasty (post-PTCA)), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or diseases characterized by intestinal dyskinesias (e.g., Irritable Bowel Syndrome (IBS)). Other conditions that may be mentioned include pre-convulsive symptoms, cutaneous mucosal lymph node syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, cutaneous necrosis, cancer metastasis, hair loss, shrivelled mouth, anal fissure and hypoxic vasoconstriction. Particularly mentioned diseases include MED and FSD.

The invention also provides the use of a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate comprising either entity, for the manufacture of a veterinary medicament for the therapeutic or prophylactic treatment of diseases comprising: male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (prinzmetal's) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, a condition that reduces vascular patency (e.g., after PTCA), stroke, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or a condition characterized by intestinal motility disorders (e.g., IBS). Other conditions that may be mentioned include pre-convulsive symptoms, cutaneous mucosal lymph node syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer's disease, acute respiratory failure, psoriasis, cutaneous necrosis, cancer metastasis, hair loss, shrivelled mouth, anal fissure and hypoxic vasoconstriction. Particularly mentioned diseases include MED and FSD.

In addition, the present invention provides a method of treating or preventing diseases for which an inhibitor of cGMPPDE5 is indicated in a mammal, including a human, which comprises administering to said mammal a therapeutically effective amount of a compound of formula (ia) or (ib), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.

The invention still further provides a method of treating or preventing Male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (prinzmetal's) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, conditions which reduce vascular patency (e.g., following PTCA), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or conditions characterised by intestinal dyskinesia in a mammal, including a human being, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula (ia) or (ib), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, Or a pharmaceutical composition or veterinary formulation comprising any of the above.

The invention also includes any novel intermediates described herein, such as those of formula (IIA), (IIB), (IVA), (IVB), (IX A), (IX B), (VA) and (VB).

The synthesis of the compounds of the present invention and the intermediates used therein is illustrated by the following examples and preparations.

1H nuclear magnetic resonance spectra (NMR) were recorded using a Varian Unity 300 or Varian Inova 400 spectrometer and were in all cases consistent with the intended structure. The characteristic chemical shifts (δ) are given in parts per million low field from tetramethylsilane, using conventional abbreviations for identifying major peaks, e.g., s, singlet; d, double peak; t, triplet; q, quartet; m, multiplet; br, broad peak.

Mass spectra (m/z) were recorded using a Fisons Instruments Trio mass spectrometer in thermal spray ionization mode.

Room temperature means 20 to 25 ℃. EXAMPLE 15- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one selection A

60% sodium hydride (14.3g,0.36mmol) suspended in mineral oil was added to a stirred suspension of the title compound of preparation 44 (150mg,0.325mmol) in anhydrous tetrahydrofuran (5ml) under nitrogen. After 1h, a solution of 2- (chloromethyl) pyridine (45.5mg,0.36mmol) in tetrahydrofuran (1ml) was added and the reaction mixture was heated at 40 ℃ for 16 h, then allowed to standIt is cooled. The resulting mixture was evaporated under reduced pressure and the residue partitioned between dichloromethane (15ml) and water (5 ml). The organic phase was separated, combined with dichloromethane extract (20ml) of the aqueous phase and dried (MgSO)₄) And evaporated under reduced pressure. The remaining yellow foam was purified by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent followed by HPLC using a5 μm spherical adsorption (Spherisorb) silica gel column with water: acetonitrile: diethylamine (50: 0.1) as eluent at a flow rate of 1ml/min to give the title compound as a white foam (30mg, 17%). Delta (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(1H,s),10.65(1H,s)。LRMS:m/z 553(M+1)⁺. Selection B

A mixture of the title compound of preparation 45B (17.4g,30.5mmol) and potassium bis (trimethylsilyl) amide (7.28g,36.5mmol) in ethanol (155ml) was heated in a closed vessel at 120 ℃ for 10 h, allowed to cool and evaporated under reduced pressure. The residue was suspended in water (200ml), the suspension was extracted with dichloromethane (2X 300ml) and dried (MgSO₄) The combined extracts were 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 pale yellow foam (11.2g, 66%) which was crystallized from diisopropyl ether-methanol to give the title compound as a crystalline solid. Measured value: c, 55.58; h, 5.90; n, 19.58. C₂₆H₃₂N₈O₄S；0.50 H₂Calculated value of O: c, 55.60; h, 5.92; and N,19.95 percent. Example 25- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

1-Methylpiperazine (0.2ml,1.8mmol) was added dropwise to a stirred suspension of the title compound of preparation 63 (450mg,0.92mmol) in ethanol (40ml) and the reaction mixture was stirred at room temperature for 18 h and then evaporated under reduced pressure. The residue was taken up in saturated aqueous sodium bicarbonate (30ml) and ethyl acetate (90ml)Partitioned between, the organic phase was then separated, washed with brine (2X 20ml) and dried (Na)₂SO₄) 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 96: 4) followed by crystallization from hexane-ethyl acetate to provide the title compound as a white solid (340mg, 67%). Measured value: c, 55.90; h, 5.85; and N, 20.04. C₂₆H₃₂N₈O₄S；0.50H₂Calculated value of O: c, 55.60; h, 5.92; and N,19.95 percent. Delta (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 522(M)⁺. Example 33-Ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Triethylamine (83. mu.l, 0.59mmol) and 1-methylpiperazine (36mg,0.356mmol) were added to a stirred ice-cooled suspension of the title compound of preparation 64 (150mg,0.30mmol) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was washed with water (5ml) and dried (MgSO)₄) And evaporated under reduced pressure to give a beige solid which was purified by silica gel column chromatography using an elution gradient of dichloromethane methanol (98: 2 to 95: 5) followed by trituration with ether to give the title compound as a white solid (145mg, 85%). Measured value: c, 54.53; h, 5.69; n, 19.38. C₂₆H₃₂N₈O₅S calculated value: c, 54.92; h, 5.67; n,19.71 percent. Delta (CDCl)₃):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 43-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]Selection of pyrimidine-7-one A

Potassium tert-butoxide (56 m)g,0.50mmol) was added to a stirred solution of the title compound of preparation 45A (200mg,0.35mmol) in 2-methoxyethanol (10ml) and the reaction mixture was stirred under reflux for 2 hours and then allowed to cool. Saturated aqueous ammonium chloride (1ml) was added followed by water (5ml) and the mixture was extracted with ethyl acetate (2X 10 ml). Drying (MgSO)₄) The combined extracts were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound (11mg, 5%) as a solid. Delta (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/z583(M+1)⁺. Selection B

A mixture of potassium bis (trimethylsilyl) amide (16.58g,83mol) and 2-methoxyethanol (250ml) was stirred at 90 ℃ for 30 minutes and then allowed to cool. The title compound of example 1 (9.21g,16.7mmol) was then added and the reaction mixture was stirred at 110 ℃ for 6 hours. When cooled, the resulting mixture was evaporated under reduced pressure, the residue was dissolved in water (300ml) and the solution was neutralized to pH7 with 2M hydrochloric acid and then extracted with ethyl acetate (3X 200 ml). The combined extracts were washed with brine (3X 200ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The remaining yellow solid was purified by silica gel column chromatography using dichloromethane: methanol (98: 2) as eluent followed by trituration with ether, crystallization from ethyl acetate and recrystallization from acetone to give the solvate of the title compound (with acetone) (7.7g, 79%) as colorless crystals, m.p.171.5-173 ℃. Measured value: c, 55.59; h, 5.94; n, 18.78. C₂₇H₃₄N₈O₅S；0.125 C₃H₆Calculated value of O: c, 55.72; h, 5.94; n,19.00 percent.

The product was suspended in water (200ml), dissolved by addition of sufficient 2M hydrochloric acid and the solution was then washed with diethyl ether (3X 50ml) and neutralised with saturated aqueous sodium bicarbonate. The precipitate formed is collected, washed with water and at 80 ℃Drying gave the hemihydrate of the title compound as a white solid (5.99g, 61.6%), m.p.139-140 ℃. Measured value: c, 54.74; h, 5.92; n, 18.86. C₂₇H₃₄N₈O₅S；0.50H₂Calculated value of O: c, 54.81; h, 5.96; n,18.94 percent. Example 53-Ethyl-5- {2- (2-methoxyethoxy) -5- [4- (prop-1-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the procedure of example 3, from the title compound of preparation 64 and 1- (prop-1-yl) piperazine dihydrobromide, the title compound was obtained as a yellow foam (88%). Measured value: c, 56.12; h, 6.06; n, 18.62. C₂₈H₃₆N₈O₅S calculated value: c, 56.36; h, 6.08; n, 18.78%. Delta (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(1H,d),8.62(1H,s),8.97(1H,s),10.81(1H,s)。LRMS:m/z 597(M+1)⁺. Example 63-Ethyl-5- {2- (2-methoxyethoxy) -5- [4- (prop-2-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a white powder (78%) from the title compound of preparation 64 and 1- (prop-2-yl) piperazine using the method of example 3. Measured value: c, 55.95; h, 6.06; n, 18.46. C₂₈H₃₆N₈O₅S calculated value: c, 56.36; h, 6.08; n, 18.78%. Delta (CDCl)₃)1.00(6H,2×d),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(1H,d),7.22(1H,m),7.62(1H,m),8.58(1H,d),8.62(1H,s),8.97(1H,s),10.71(1H,s)。LRMS:m/z 597(M+1)⁺. Example 75- {5- [4- (2-aminoethyl) piperazin-1-ylsulfonyl 1-2- (2-methoxyethoxy) pyridin-3-yl } -3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound of preparation 64 (100mg,0.198mmol) in dichloromethane was added over 1 hour(10ml) the solution was added dropwise to a stirred solution of 1- (2-aminoethyl) piperazine (102mg,0.79mmol) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for a further 1 hour. The resulting mixture was washed with water (10ml) and dried (MgSO)₄) And evaporated under reduced pressure to give a beige solid. It was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 0 to 90: 10: 1) to give the title compound as a white foam (104mg, 88%). Delta (CDCl)₃):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 85- [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-ones

Potassium tert-butoxide (104mg,0.97mmol) was added to a stirred suspension of the title compound of preparation 53 (380mg,0.618mmol) in 3-methylpentan-3-ol (30ml) and the reaction mixture was heated at reflux for 1h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the remaining yellow gum was partitioned between dichloromethane (20ml) and saturated aqueous sodium bicarbonate (10 ml). The phases were separated, the aqueous phase extracted with dichloromethane (2X 10ml) and dried (MgSO)₄) The combined extracts were evaporated under reduced pressure. The crude product was purified by chromatography on silica gel using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to give the title compound as a white foam (75mg, 13%). Delta (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 95- [2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Stirring the bis (trimethylsilyl) solution at 90 deg.C) A mixture of potassium amide (434mg,2.2mmol) and 2-ethoxyethanol (2ml) was heated for 30 minutes and then allowed to cool. A solution of the title compound of example 1 (153mg,0.27mmol) in 2-ethoxyethanol (2ml) was added and the reaction mixture was stirred at 110 ℃ for 18 h 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 give the title compound as a yellow foam (110mg, 68%). Delta (CDCl)₃):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(1H,s),8.99(1H,s),10.78(1H,s)。LRMS:m/z 597(M+1)⁺. Example 105- [2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of potassium tert-butoxide (110mg,0.98mmol), the title compound of preparation 54 (400mg,0.63mmol) and 3-methylpentan-3-ol (5ml) was stirred at 150 ℃ for 3h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (5ml) and ethyl acetate (5 ml). The phases were separated, the aqueous phase extracted with ethyl acetate (2X 10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: 0.88 ammonia (99: 1: 0.5 to 98: 2: 0.5) to give the title compound as a white foam (74mg, 12%). Measured value: c, 56.92; h, 6.33; and N, 17.80. C₂₉H₃₆N₈O₅S calculated value: c, 57.21; h, 5.96; n,18.41 percent. Delta (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(1H, m),8.57(1H, d),8.62(1H, s),8.98(1H, s),10.77(1H, s). Example 113-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-oxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 1 (200mg,0.36mmol), potassium bis (trimethylsilyl) amide (361mg,1.81mmol) and 3-methoxypropan-1-ol (1.5ml) was stirred at 90 ℃ for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (97: 3 to 95: 5) to give the title compound as a foam (81mg, 38%). Measured value: c, 55.36; h, 6.11; and N, 18.18. C₂₈H₃₆N₈O₅S；0.50H₂Calculated value of O: c, 55.52; h, 6.16; n,18.50 percent. Delta (CDCl)₃):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/z597(M+1)⁺. Example 125- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-yloxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a foam (26%) from the title compound of preparation 55 using the method of example 10. Measured value: c, 56.86; h, 6.47; n, 17.78. C₂₉H₃₈N₈O₅S calculated value: c, 57.04; h, 6.27; n,18.35 percent. Delta (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(1H,s),8.94(1H,s),10.83(1H,s)。LRMS:m/z 611(M+1)⁺. Example 133-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methoxypropan-2 (S) -oxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The procedure of example 9 was used, but diethyl ether: methanol: 0.88 ammonia (97: 3: 1) was used as the chromatography eluent. The title compound was obtained as a foam (33%) from the title compound of example 1 and 1-methoxypropan-2 (S) -ol (j. chemsoc., Perkin Trans 1,1996,1467). Measured value: c, 55.91; h, 6.17; n, 18.10. C₂₈H₃₆N₈0₅S；0.50 H₂Calculated value of O: c, 55.52; h, 6.16; n,18.50 percent. Delta (CDCl)₃):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(1H,dd),3.74(1H,dd),5.60(1H,m),5.68(2H,s),7.08(1H,d),7.21(1H,m),7.62(1H,m),8.57(1H,d),8.61(1H,s),8.89(1H,s),10.85(1H,s)。LRMS:m/z 597(M+1)⁺. Example 145- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of potassium bis (trimethylsilyl) amide (460mg,2.3mmol) and 2-methoxyethanol (40ml) was stirred at 90 ℃ for 30 minutes and then allowed to cool. The title compound of example 2 (270mg,0.46mmol) was added and the reaction mixture was stirred at 110 ℃ for 5h, allowed to cool and evaporated under reduced pressure. The residue was suspended in water (20ml), the pH was adjusted to 7 with hydrochloric acid and the resulting solution was extracted with ethyl acetate (3X 30 ml). The combined extracts were washed with brine (3X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residual oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) followed by crystallization from hexane-ethyl acetate to give the title compound as a white solid (200mg, 75%). Measured value: c, 54.83; h, 5.83; n, 18.90. C₂₇H₃₄N₈O₅S；0.50H₂Calculated value of O: c, 54.81; h, 5.96; n,18.94 percent. Delta (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 155- [2- (1, 3-Dimethoxypropan-2-yloxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]-pyrimidin-7-ones

A mixture of the title compound of preparation 72 (70mg,0.10mmol), potassium tert-butoxide (23mg,0.20mmol) and 3-methylpent-3-ol (3ml) was brought to refluxStirred for 4 hours, then allowed to cool 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 as an off-white solid (6 mg, 9%). Delta (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 163-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-1- (pyridin-2-yl) methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 65, using the method of example 10, the title compound was obtained as a white solid (50%). Measured value: c, 55.45; h, 5.91; n, 18.94. C₂₇H₃₄N₈O₅S calculated value: c, 55.66; h, 5.88; n,19.23 percent. Delta (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 173-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) -yloxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 56, using the method of example 10, the title compound was obtained as a solid (29%). Measured value: c, 55.85; h, 5.98; and N, 17.86. C₂₈H₃₄N₈O₅S；0.20 H₂O；0.10CH₂Cl₂Calculated values: c, 55.24; h, 5.73; n,18.41 percent. Delta (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(1H,d),8.63(1H,s),8.98(1H,s),10.42(1H,s)。LRMS:m/z 594(M)⁺。[α]²⁵ _D-13.8°(c=0.10,CH₃OH). Example 183-Ethyl-5- [5- (4-ethylpiperazine)-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 75, using the method of example 10, the title compound was obtained as a solid (24%). Measured value: c, 55.32; h, 5.82; and N, 17.70. C₂₈H₃₄N₈O₅S；H₂Calculated value of O: c, 54.88; h, 5.92; n,18.29 percent. Delta (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(1H,d),8.63(1H,s),8.98(1H,s),10.42(1H,s)。LRMS: m/z 595(M+1)⁺。[α]²⁵ _D+14.0°(c=0.14,CH₃OH). Example 195- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 76, using the procedure of example 10, the title compound was obtained as a white solid (30%). Delta (CDCl)₃):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(1H,m),7.63(1H,m),8.57(1H,d),8.61(1H,s),9.01(1H,s),10.55(1H,s)。LRMS:m/z 623(M+1)⁺. Example 203-Ethyl-5- [5- (4-methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (540mg,4.8mmol) was added to a stirred solution of the title compound of preparation 52 (683mg,1.2mmol) in n-propanol (10ml) and the reaction mixture was stirred at reflux for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a foam (290mg, 44%). Measured value: c, 56.32; h, 6.04; n,19.36.C₂₆H₃₂N₈O₄S calculated value: c, 56.50; h, 5.83; and N, 20.27%. Delta (CDCl)₃):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(1H,s),10.66(1H,s)。LRMS:m/z 553(M+1)⁺. Example 213-Ethyl-5- [5- (4-methylpiperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (290mg,2.60mmol) was added to a stirred solution of the title compound of example 20 (239mg,0.43mmol) in propan-2-ol (7ml) under nitrogen and the reaction mixture was heated at reflux for 48 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (20ml) and ethyl acetate (20 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a foam (84mg, 35%). Delta (CDCl)₃):1.28(3H,t),1.56(6H,2×d),2.28(3H,s),2.50(4H,m),3.04(2H,q),3.14(4H,m),5.68(3H,m),7.09(1H,d),7.22(1H,m),7.62(1H,m),8.57(1H,d),8.62(1H,s),9.02(1H,s),10.68(1H,s)。LRMS:m/z 553(M+1)⁺. Example 223-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 45A (200mg,0.35mmol), 60% sodium hydride (400mg,10mmol) suspended in mineral oil and propan-2-ol (20ml) was stirred at reflux for 18 h and then allowed to cool. Saturated aqueous ammonium chloride (20ml) was added and the resulting mixture was extracted with ethyl acetate (3X 50ml), and the combined extracts were washed with aqueous sodium bicarbonate (150ml) and 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 as a foam (11mg, 6%). Delta (CDC)l₃):1.04(3H,t),1.30(3H,t),1.56 (6H,2×d),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(1H,s),10.68(1H,s)。LRMS:m/z 567(M+1)⁺. Example 235- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d [ pyrimidin-7-one

A mixture of the title compound of example 1 (200mg,0.36mmol), potassium bis (trimethylsilyl) amide (360mg,1.81mmol) and n-butanol (5ml) was stirred at 100 ℃ for 18 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (5ml) and dichloromethane (5 ml). The phases were separated and the aqueous layer was extracted with dichloromethane (2X 10ml) and then dried (MgSO)₄) The combined organic solutions were 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 as a white solid (145mg, 69%). Measured value: c, 57.43; h, 6.29; n,18.82.C₂₈H₃₆N₈O₄S；0.20 H₂Calculated value of O: c, 57.56; h, 6.28; n,19.18 percent. Delta (CDCl)₃):1.03(6H,2×t),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(1H,d),8.62(1H,s),9.01(1H,s),10.64(1H,s)。LRMS:m/z 581(M+1)⁺. Example 245- [ 2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a white solid (67%) from the title compound of example 1 and isobutanol using the method of example 23. Measured value: c, 57.25; h, 6.24; n, 18.84. C₂₈H₃₆N₈O₄S；0.20 H₂Calculated value of O: c, 57.56; h, 6.28; n,19.18 percent. Delta) (CDCl₃):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(1H,d),8.62(1H,s),9.02(1H,s),10.63(1H,s)。LRMS:m/z 581(M+1)⁺. Example 255- [ 2-Cyclobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of the title compound of preparation 45A (200mg,0.35mmol), cyclobutanol (144mg,2mmol), potassium tert-butoxide (80mg,0.70mmol) and 1, 4-dioxane (5ml) was heated at reflux for 24 h and then allowed to cool. The resulting mixture was poured into a stirred aqueous sodium bicarbonate solution (20ml) and the mixture was extracted with ethyl acetate (3 × 20 ml). Drying (MgSO)₄) The combined extracts were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a solid (9mg, 4%). Delta (CDCl)₃):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,m),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(1H,s),9.01(1H,s),10.67(1H,s)。LRMS:m/z579(M+1)⁺. Example 265- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (2.38g,21.2mmol) was added to a solution of the title compound of preparation 77 (3.1g,5.3mmol) in absolute ethanol (95ml) and the reaction mixture was heated in a closed vessel at 100 ℃ for 40 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue was dissolved in water (20ml) and the aqueous solution was acidified to pH5 with 2M hydrochloric acid. The aqueous suspension thus obtained was extracted with dichloromethane (3X 30ml) and dried (MgSO₄) The combined extracts were 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 as a foam (1.39g, 46%). Delta (CDCl)₃):0.93(3H,t),1.02(3H,t),1.58(3H,t),1.74(2H,m),2.40(2H,q),2.54(4H,m),2.98(2H,t),3.13(4H,m),4.75(2H,q),5.68(2H,s),7.09(1H,d),7.23(1H,m),763(1H, m),8.58(1H, d),8.63(1H, s),9.02(1H, s),10.64(1H, s). Example 275- {5- [4- (3-dimethylaminoprop-1-yl) piperazin-1-ylsulfonyl]-2-ethoxypyridin-3-yl } -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one trihydrochloride

A solution of freshly distilled 1- (3-dimethylaminoprop-1-yl) piperazine (J.chem.Soc. (C),1971,132; 160mg,0.93mmol) in ethanol (2ml) was added to a stirred solution of the title compound of preparation 63 (230mg,0.467mmol) in ethanol (10ml) and the reaction mixture was stirred at room temperature for 18 h and then evaporated under reduced pressure. The residue was suspended in aqueous sodium bicarbonate (30ml), the suspension was extracted with ethyl acetate (3X 30ml) and the combined extracts were washed with brine (2X 30ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residual oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) and then the product was dissolved in a minimum amount of ethyl acetate. Saturated ethereal hydrogen chloride solution was added and the resulting white precipitate was collected, triturated with ether and dried under suction to give the title compound as a white solid (140mg, 37%). Measured value: c, 44.45; h, 6.34; n, 15.38. C₃₀H₄₁N₉O₄S；3HCl；4H₂Calculated value of O: c, 44.75; h, 6.51; n,15.66 percent. Delta (DMSOd)₆):0.86(3H,t),1.34(3H,t),1.64(2H,m),2.12(2H,m),2.72(6H,2xs),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 285- [5- (4-ethylpiperazin-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-ones

From the title compound of preparation 80, using the method of example 20, the title compound was obtained as a colorless solid (40%). Measured value: c, 57.16; h, 6.15; n, 18.85. C₂₈H₃₆N₈O₄S；0.50H₂Calculated value of O: c, 57.03; h, 6.32; n is a radical of,19.00％。δ(CDCl₃):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,m),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(1H,d),8.62(1H,s),9.02(1H,s),10.63(1H,s)。LRMS:m/z 582(M+2)⁺. Example 295- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (prop-2-oxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a solid (48%) from the title compound of example 26 and propan-2-ol using the method of example 21. Delta (CDCl)₃):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(1H,d),8.63(1H,s),9.02(1H,s),10.67(1H,s)。LRMS:m/z 581(M+1)⁺. Example 305- { 2-ethoxy-5- [4- (2-hydroxyethyl) piperazin-1-ylsulfonyl]Pyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 63 and 1- (2-hydroxyethyl) piperazine using the method of example 2, the title compound was obtained as a white solid (49%). Measured value: c, 55.48; h, 5.93; n, 18.85. C₂₇H₃₄N₈O₅S；0.10C₄H₈O₂Calculated values: c, 55.64; h, 5.93; n,18.94 percent. Delta (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(1H,m),8.58(1H,d),8.64(1H,s),9.04(1H,s),10.66(1H,s)。LRMS:m/z 583(M+1)⁺. Example 315- { 2-ethoxy-5- [4- (3-hydroxypropan-1-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the method of example 2, from the title compound of preparation 63 and 1- (3-hydroxypropan-1-yl) piperazine, the title compound was obtained as a white solid (52%). Measured value: c, 56.27; h, 6.13; n, 18.38. C₂₈H₃₆N₈O₅S calculated value: c, 56.36; h, 6.08; n, 18.78%. Delta (CDCl)₃):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(1H,s),4.77(2H,q),5.69(2H,s),7.08(1H,d),7.23(1H,m),7.63(1H,m),8.58(1H,d),8.61(1H,s),9.01(1H,s),10.67(1H,s)。LRMS:m/z 596(M)⁺. Example 325- [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-d]Pyrimidin-7-ones

The title compound was obtained as a yellow oil (57%) from the title compound of example 1 and 2-benzyloxyethanol using the method of example 11. Delta (CDCl)₃):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,m),8.60(2H,m),8.98(1H,s),10.80(1H,s)。LRMS:m/z 659(M+1)⁺. Example 333-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-hydroxyethoxy) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Ammonium formate (62mg,0.99mmol) was added to a mixture of the title compound of example 32 (130mg,0.197mmol), 10% palladium on charcoal (15mg) and acetone (9ml) and the reaction mixture was stirred at reflux for 14 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound (18mg, 16%) as a solid. Delta (CD)₃OD):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 345- [2- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound of preparation 84 (500mg,0.72mmol) and potassium bis (trimethylsilyl) amide (347 m) were stirredg,3.09mmol) and 3-methylpentan-3-ol (8ml) were heated at reflux for 36 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (10ml) and dichloromethane (10 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2X 10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The crude product was purified by two silica gel column chromatography operations, first using a gradient of dichloromethane: methanol: 0.88 ammonia (90: 10: 1) and then ethyl acetate: methanol (100: 0 to 80: 20) as eluent, to give the title compound as an oil. Delta (CDCl)₃):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 352-benzyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 87 using the procedure of example 10, the title compound was obtained as a white foam (27%). Delta (CDCl)₃):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 362-benzyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a cream foam (80%) from the title compound of example 35 and 2-methoxyethanol using the procedure of example 9. Measured value: c, 57.05; h, 6.19; and N, 16.15. C₂₈H₃₅N₇O₅S；0.10 CH₂Cl₂Calculated values: c, 57.19; h, 6.01; n, 16.61%. Delta (CDCl)₃) 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(1H, s). Example 373-Ethyl-5- [5- (4)-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- (1-methylimidazol-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 90, using the method of example 10, the title compound was obtained as a foam (33%). Delta (CDCl)₃):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(1H,s),7.00(1H,s),8.62(1H,s),8.94(1H,s),10.83(1H,s)。LRMS:m/z 586(M+1)⁺. Example 385- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2- (1-methylimidazol-2-yl) methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of preparation 28(232mg,0.58mmol) and preparation 92(152mg,0.58mmol) of the title compound, triethylamine (403. mu.l, 2.9mmol) and dichloromethane (8ml) was stirred at room temperature for 18 hours. Brine (20ml) was added and the resulting mixture was extracted with dichloromethane (2X 20ml) and dried (MgSO₄) The combined extracts were evaporated under reduced pressure.

A stirred solution of this intermediate and potassium bis (trimethylsilyl) amide (305mg,1.53mmol) in ethanol (10ml) was heated at 100 ℃ for 14 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound (163mg, 49%) as a yellow oil. Delta (CDCl)₃)；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(1H,s),8.63(1H,s),9.00(1H,s),10.65(1H,s)。LRMS:m/z 570(M+1)⁺. Example 395- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- (1-methylimidazol-2-yl) methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound (61%) was obtained as a solid using the method of example 9 from the title compound of example 38 and 2-methoxyethanol. Delta (CDCl)₃):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(1H,s),7.00(1H,s),8.62(1H,s),8.94(1H,s),10.82(1H,s)。LRMS:m/z 600(M+1)⁺. Example 405- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2- (1-methylimidazol-2-yl) methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the procedure of example 9, from the title compound of example 38 and n-butanol, the title compound was obtained as a cream colored foam (76%). Measured value: c, 54.83; h, 6.74; and N, 20.08. C₂₈H₃₉N₉O₄S；H₂Calculated value of O: c, 54.62; h, 6.71; and N,20.47 percent. Delta (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(1H,s),10.64(1H,s)。LRMS:m/z 599(M+2)⁺. Example 415- [5- (4-ethylpiperazin-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-ones

A mixture of the title compound of preparation 98 (230mg,0.38mmol), potassium tert-butoxide (258mg,2.3mmol) and propan-2-ol (10ml) was heated in a closed vessel at 100 ℃ for 24 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by two silica gel column chromatography operations, first using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) and then using an elution gradient of ethyl acetate: methanol (90: 10 to 80: 20), to give the title compound as an orange gum (42mg, 19%). Delta (CDCl)₃):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,d),10.70(1H,s)。LRMS:m/z 582(M+1)⁺. Example 425- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-3-n-propyl-2- (pyrimidin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 102b, using the method of example 10, the title compound was obtained as a yellow foam (14%). Delta (CDCl)₃):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(1H,s),10.72(1H,s)。LRMS:m/z 597(M)⁺. Example 43a5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-1- (pyrimidin-2-yl) methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one and example 43b5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyrimidin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of the title compounds of preparation 103a and preparation 103b (390mg,0.66mmol), potassium tert-butoxide (224mg,2.0mmol), 4A molecular sieve and ethanol (10ml) was heated in a closed vessel at 100 ℃ for 18 h, then allowed to cool and filtered. The filtrate was evaporated under reduced pressure and the residual brown oil was suspended in dichloromethane (25 ml). The mixture was washed with water (5ml) and dried (MgSO)₄) And evaporated under reduced pressure, then the residue was purified by silica gel column chromatography using a gradient eluting from dichloromethane to methanol (99: 1 to 95: 5) to give an orange foam. The product was further purified by HPLC using C₁₈Magellan column and using methanol: water: diethylamine (50: 0.1) at 20ml/min as eluent, the title compound (1-isomer; 20mg) was obtained as a first white solid. Delta (CDCl)₃):1.04(6H,m),1.58(3H,t),1.88(2H,m),2.42(2H,q),2.57(4H,m),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(1H,s),10.75(1H,s)。LRMS:m/z 568(M+1)⁺(ii) a The title compound (2-isomer; 20mg) was subsequently obtained as a second white solid. Delta (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(1H,s)。LRMS:m/z568(M+1)⁺. Example 445- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-1- (pyridin-2-yl) methyl1, 6-dihydro-7H-pyrazolo [4,3-d ] yl]Pyrimidin-7-ones

A stirred mixture of the title compound of preparation 105 (304mg,0.52mmol), potassium tert-butoxide (175mg,1.56mmol) and ethanol (10ml) was heated in a closed vessel at 100 ℃ for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residual brown oil was partitioned between dichloromethane (15ml) and water (5 ml). The phases were separated and then dried (MgSO)₄) The organic phase was evaporated under reduced pressure to give a brown foam which was purified by silica gel column chromatography using dichloromethane: methanol (97: 3) as eluent to give the title compound as a white foam (230mg, 78%). Measured value: c, 56.93; h, 6.03; n, 19.42. C₂₇H₃₄N₈O₄S calculated value: c, 57.22; h, 6.04; n,19.77 percent. Delta (CDCl)₃):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(1H,s),10.85(1H,s)。LRMS:m/z 567(M+1)⁺. Example 455- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-1- (1-methylimidazol-2-yl) methyl-1, 6-di-hydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 107 using the procedure of example 44, the title compound was obtained as a pale yellow solid (60%). Delta (CDCl)₃):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 463-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-1- (1-methylimidazol-2-yl) methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of the title compound of example 45 (150mg,0.27mmol), potassium tert-butoxide (126mg,1.1mmol) and 2-methoxyethanol (6ml) was heated at reflux for 48 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethaneMethanol: 0.88 ammonia (90: 10: 1) as eluent, triturated the product with diisopropyl ether, filtered the mixture and the filtrate evaporated under reduced pressure to give the title compound as a foam (43mg, 27%). Delta (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,t),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)⁺. Example 475- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-1- (1-methylimidazol-2-yl) methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 109, using the method of example 10, the title compound was obtained as a solid (11%). Measured value: c, 52.43; h, 6.11; and N, 20.12. C₂₇H₃₇N₉O₅S；H₂Calculated value of O: c, 52.50; h, 6.36; n,20.41 percent. Delta (CDCl)₃):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 485- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-3-n-propyl-1- (pyrimidin-2-yl) methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the method of example 10, from the title compound of preparation 102a, the title compound was obtained as a yellow foam (5%). Delta (CDCl)₃):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,m),8.65(3H,m),9.03(1H,s),11.00(1H,s)。LRMS:m/z 598(M+1)⁺. Example 495- { 2-ethoxy-5- [4- (pyrrolidin-1-ylcarbonylmethyl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 63 (350mg,0.715mmol), 1- (pyrrolidin-1-ylcarbonylmethyl) piperazine (150mg,0.715mmol) and ethanol (40ml) at room temperatureStirred for 18 hours and then evaporated under reduced pressure. The residue was suspended in aqueous sodium bicarbonate (30ml) and the suspension was extracted with ethyl acetate (3X 30 ml). The combined extracts were washed with brine (3X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give an oil which was triturated with ether to give the title compound as a colorless foam (240mg, 52%). Measured value: c, 56.79; h, 6.30; n, 18.49. C₃₁H₃₉N₉O₅S；0.50H₂O；0.25C₄H₁₀Calculated value of O: c, 56.75; h, 6.32; n, 18.61%. Delta (CDCl)₃):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(1H,m),8.58(1H,d),8.63(1H,s),9.00(1H,s),10.66(1H,s)。LRMS:m/z 650(M+1)⁺. Example 505- [ 2-ethoxy-5- (4-allyl-2 (S),5(R) -dimethylpiperazin-1-ylsulfonyl ] -]Pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A solution of (-) -1-allyl-2 (R),5(S) -dimethylpiperazine (WO 93/15062; 502mg,3.2mmol) in ethanol (4ml) was added dropwise to a stirred suspension of the title compound of preparation 63 (800mg,1.6mmol) in ethanol and the reaction mixture was stirred at room temperature for 18 h and then evaporated under reduced pressure. The residue was partitioned between aqueous sodium carbonate (20ml) and ethyl acetate (20ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2X 20 ml). The combined organic solutions were washed with brine (20ml) and dried (Na)₂SO₄) 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 give the title compound as a colourless foam (550mg, 57%). Measured value: c, 59.07; h, 6.37; and N, 18.18. C₃₀H₃₈N₈O₄S; calculated values: c, 59.39; h, 6.31; n,18.47 percent. Delta (CDCl)₃):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(1H,m),3.00(4H,m),3.20(1H,dd),3.48(1H,dd),3.85(1H,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(1H,s),9.08(1H,s),10.69(1H,s)。LRMS:m/z 607(M+1)⁺. Example 50a 3-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl]-2- (1-methylimidazol-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Following a similar procedure to that described in example 11, from the title compounds of preparations 165 and 170, the title compound was obtained as a white foam (82%). Measured value: c, 52.14; h, 6.15; n, 19.73. C₂₇H₃₇N₉O₅S；1.5H₂Calculated value of O: c, 51.74; h, 6.43; and N, 20.11%. Delta (CDCl)₃):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(1H,s),8.60(1H,s),8.84(1H,s),10.87(1H,s)。LRMS:m/z 600(M+1)⁺. Examples 51 to 60

By high speed analog synthesis techniques (HSAS) as described below, to obtain compounds wherein R is¹⁰The substituents are varied based on the same set of analogs as the above structural formula.

A0.4M solution of triethylamine in dichloromethane (100. mu.l, 40. mu. mol) was added to each well of a 96-well plate containing 1-substituted piperazine in the desired range (10. mu. mol). A0.1M solution of the title compound of preparation 63 in dichloromethane (100. mu.l, 10. mu. mol) was added to each well, then the plate was covered and shaken at room temperature for 18 hours. The reaction mixture was filtered through a 96-well filter plug, washed with dichloromethane (1ml) and the filtrate was evaporated under reduced pressure. The residue was dissolved in dimethyl sulfoxide (1ml) and purified by HPLC using a5 μ Hypersil C18 column (10X 0.46cm) with a flow rate of 4ml/min and an elution gradient of 0.1% trifluoroacetic acid in water to acetonitrile.

The following compounds are thus obtained:^*=R¹⁰attachment point of example 613-ethyl-5- [2- (2-methoxyethoxy) -5- (3,4, 5-trimethylpiperazin-1-ylsulfonyl) -pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the procedure of example 50, from the title compound of preparation 64 and 1,2, 6-trimethylpiperazine (j.med.chem.,1968,11,592), the title compound was obtained as a white solid (170mg, 47%). Measured value: c, 55.78; h, 6.02; n, 18.42. C₂₈H₃₆N₈O₅S；0.50H₂Calculated value of O: c, 55.22; h, 6.16; n,18.58 percent. Delta (CDCl)₃):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(1H,s)。LRMS:m/z 597(M+1)⁺. Example 623-Ethyl-5- [2- (2-methoxyethoxy) -5-piperazin-1-ylsulfonyl) pyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A solution of preparation 64 of the title compound (200mg,0.40mmol) in dichloromethane (10ml) was added dropwise to a stirred solution of piperazine (136mg,1.58mmol) and triethylamine (110. mu.1, 0.79mmol) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for 1 hour, then washed with water (10ml), dried (MgSO 2)₄) And evaporated under reduced pressure. The residual yellow solid was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (98: 2 to 92: 8) followed by trituration with dichloromethane to give the title compound as a white foam (189mg, 86%). Measured value: c, 52.75; h, 5.43; n, 19.18. C₂₅H₃₀N₈O₅S；0.75H₂Calculated value of O: c, 52.85; h, 5.59; n,19.72 percent. Delta (CDCl)₃):1.30(3H,t),2.94-3.13(10H,m),3.58(3H,s),3.88(2H,t),4.79(2H,t),5.68(2H,s),7.10(1H,d),7.22(1H,m),7.62(1H,m),8.58(1H,d),8.62(1H,s),8.98(1H,s),10.82(1H,s)。LRMS:m/z 555(M+1)⁺. Example 633-Ethyl radical-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-methoxypyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of the title compound of example 1 (350mg,0.63mmol), potassium bis (trimethylsilyl) amide (630mg,3.15mmol) and n-propanethiol (5ml) was heated in a closed vessel at 110 ℃ for 48 hours, then allowed to cool and evaporated under reduced pressure. The residue was azeotroped with dichloromethane: methanol (95: 5) and then partitioned between water (10ml) and dichloromethane (15 ml). The phases were separated, the aqueous phase extracted with dichloromethane (2X 15ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (97: 3) as eluent to give the title compound (170mg, 50%) as a yellow solid. Measured value: c, 54.50; h, 5.64; n, 19.93. C₂₅H₃₀N₈O₄S；0.75H₂Calculated value of O: c, 54.38; h, 5.75; and N,20.29 percent. Delta (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(1H,d),7.22(1H,m),7.64(1H,m),8.58(1H,d),8.66(1H,s),9.05(1H,s),10.59(1H,s)。LRMS:m/z 540(M+2)⁺. Example 645- [ 2-benzyloxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium bis (trimethylsilyl) amide (360mg,1.81mmol) was added to a stirred solution of the title compound of example 1 (200mg,0.36mmol) in benzyl alcohol (5ml) at 100 ℃ and the reaction mixture was stirred for 14 h and then allowed to cool. The resulting mixture was partitioned between dichloromethane (10ml) and brine (10ml), the phases were separated, the aqueous phase was extracted with dichloromethane (2X 10ml) and dried (Na)₂SO₄) The combined organic solutions were evaporated under reduced pressure. Residual benzyl alcohol was removed by Kugelif distillation, and the crude product was purified by silica gel column chromatography using dichloromethane: methanol (97.5: 2.5) as eluent to give the title compound as a white solid (86mg, 39%). Measured value: c, 59.92; h, 5.64;N,17.60。C₃₁H₃₄N₈O₄S；0.40 H₂calculated value of O: c, 59.87; h, 5.64; n,18.02 percent. Delta (CDCl)₃):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(1H,d),8.65(1H,s),9.02(1H,s),10.58(1H,s)。LRMS:m/z 615(M+1)⁺. Example 655- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (furan-3-ylmethoxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium bis (trimethylsilyl) amide (176mg,0.88mmol) was added to a stirred suspension of the title compound of example 26 (100mg,0.17mmol) in 3-hydroxymethylfuran (4ml) and the reaction mixture was heated at reflux for 24 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound as a pale yellow foam (33mg, 31%). Delta (CDCl)₃):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(1H,d),8.68(1H,s),9.02(1H,s),10.53(1H,s)。LRMS:m/z 619(M+1)⁺. Example 665- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (pyridin-2-ylmethoxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of potassium bis (trimethylsilyl) amide (260mg,1.32mmol) and 2-hydroxymethylpyridine (5ml) was heated at 100 ℃ for 1 hour, then the title compound from example 26 (150mg,0.26mmol) was added and the reaction mixture was stirred at 100 ℃ for 14 hours. The resulting cold mixture was partitioned between dichloromethane (10ml) and brine (10ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 10 ml). Drying (MgSO)₄) The combined organic solutions were evaporated under reduced pressure and the remaining yellow oil was purified by silica gel column chromatography using dichloromethane: ethyl acetate: methanol (47.5: 47)5: 5) as eluent, to give the title compound as a white solid (35mg, 21%). Delta (CDCl)₃):0.94(3H,t),1.03(3H,t),1.73(2H,m),2.40(2H,q),2.55(4H,m),2.98(2H,t),3.14(4H,m),5.69(2H,s),5.92(2H,s),7.07(1H,d),7.21(1H,m),7.33(2H,m),7.62(1H,m),7.76(1H,m),8.58(2H,m),8.81(1H,s),8.85(1H,d),12.80(1H,s)。LRMS:m/z 630(M+1)⁺. Example 675- [2- (2-dimethylaminoethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 26 (200mg,0.35mmol), potassium bis (trimethylsilyl) amide (352mg,1.76mmol) and 2-dimethylaminoethanol (1.5ml) was stirred at 90 ℃ for 18 hours and then allowed to cool. Water (5ml) was added, the mixture was extracted with ethyl acetate (3X 5ml) and dried (MgSO₄) The combined extracts were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (95: 5 to 90: 10) to give the title compound as an off-white foam (147mg, 68%). Measured value: c, 56.35; h, 6.37; and N, 20.12. C₂₉H₃₉N₉O₄S；0.50 H₂Calculated value of O: c, 56.29; h, 6.52; n,20.37 percent. Delta (CDCl)₃):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 685- (5- (4-ethylpiperazin-1-ylsulfonyl) -2- [2- (morpholin-4-yl) ethoxy)]Pyridin-3-yl } -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of potassium bis (trimethylsilyl) amide (180mg,0.88mmol) and 4- (2-hydroxyethyl) morpholine (4ml) was stirred at 100 ℃ for 1h, then the title compound of example 26 (100mg,0.17mmol) was added and the reaction mixture was stirred at 110 ℃ for 18 h. The resulting cold mixture was partitioned between water (10ml) and dichloromethane (20ml), the phases separated and the organic phase washed with water (10ml), dried (MgSO)₄) And evaporated under reduced pressure. The residual yellow oil was purified by silica gel column chromatography using an elution gradient of ethyl acetate: methanol (90: 10 to 80: 20) to give the title compound as a white solid (33mg, 30%). Delta (CDCl)₃):0.95(3H,t),1.04(3H,t),1.74(2H,m),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(1H,m),8.58(1H,d),8.62(1H,s),8.92(1H,s),11.16(1H,s)。LRMS:m/z 652(M+1)⁺. Example 695- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridin-3-yl]-3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Cesium tert-Butanol (76mg,0.37mmol) was added to a stirred solution of the title compound of preparation 119 (160mg,0.24mmol) in 3-methylpentan-3-ol (5ml) and the reaction mixture was stirred at 120 ℃ for 3 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between dichloromethane (10ml) and water (10 ml). The phases were separated, the aqueous phase was washed with dichloromethane (2X 10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residual yellow oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (95: 5 to 92.5: 7.5) to give the title compound as a yellow foam. Delta (CDCl)₃):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(1H,m),8.57(1H,d),8.61(1H,s),9.00(1H,s),10.63(1H,s)。LRMS:m/z 636(M+1)⁺. Example 705- [ 2-ethoxy-5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound from example 1 (180mg,0.32mmol), 3-chlorobenzoic acid (13mg,0.08mmol) and dichloromethane (10ml) was stirred at room temperature for 20 minutes, 3-chloroperoxybenzoic acid (112mg,0.32mmol) was added and the reaction mixture stirred for an additional 18 hours and then partitioned between dichloromethane (20ml) and aqueous sodium bicarbonate (10 ml).The phases were separated, the aqueous phase extracted with dichloromethane (2X 20ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (80: 20) as eluent to give the title compound (82mg, 45%) as a white powder. Measured value: c, 52.73; h, 5.67; n, 17.69. C₂₆H₃₂N₈O₅S；0.50 CH₂Cl₂Calculated values: c, 52.08; h, 5.44; n,18.34 percent. Delta (CDCl)₃) 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 715- [5- (4-Ethyl-4-piperazinen-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-ones

3-Chloroperoxybenzoic acid (93mg,0.27mmol) was added to a stirred solution of the title compound of example 28 (155mg,0.27mmol) in dichloromethane (2ml) and the reaction mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) as eluent to give the title compound (40mg, 25%) as a solid. Delta (CDCl)₃):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(1H,m),8.58(1H,d),8.66(1H,s),9.06(1H,s),10.67(1H,s)。LRMS:m/z 598(M+1)⁺. Example 723-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]Pyrimidine-7-one known example 733-Ethyl-5- [5- (4-ethyl-4-piperazinol-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- (1-pyrid-2-oxide) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

3-Chlorobenzoic acid (15mg,0.096mmol) was added to a stirred solution of the title compound of example 4 (223mg,0.38mmol) in dichloromethane (3ml)To the solution and the mixture was stirred at room temperature for 30 minutes. 3-Chloroperoxybenzoic acid (132mg,0.38mmol) was then added and the reaction mixture was stirred at room temperature for 14 h, then partitioned between dichloromethane (5ml) and aqueous sodium bicarbonate (5 ml). The phases were separated, the aqueous phase extracted with dichloromethane (3X 10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (90: 10 to 80: 20) to give the first title compound as a solid (78mg, 34%). Measured value: c, 51.77; h, 5.82; n, 17.33. C₂₇H₃₄N₈O₆S；1.75 H₂Calculated value of O: c, 51.46; h, 6.00; n, 17.78%. Delta (CDCl)₃):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(1H,s)；

This then gave the second title compound as a solid (50mg, 22%). Measured value: c, 50.15; h, 5.81; n, 16.85. C₂₇H₃₄N₈O₆S；2.0 H₂Calculated value of O: c, 49.84; h, 5.89; n,17.22 percent. Delta (CDCl)₃) 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 745- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2- (2-morpholin-4-yl) ethyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (110mg,0.99mmol) was added to a stirred solution of the title compound of preparation 120 (400mg,0.66mmol) in 3-methylpentan-3-ol (20ml) and the reaction mixture was heated at reflux for 3h and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue was suspended in water (10ml) and the suspension was extracted with dichloromethane (3X 10 ml). Drying (MgSO)₄) The combined extracts were evaporated under reduced pressure and the remaining yellow oil was purified by silica gel column chromatography using dichloromethane: AAlcohol (97.5: 2.5) was used as eluent to give the title compound as a white foam (65mg, 17%). Measured value: c, 54.51; h, 6.95; and N, 18.18. C₂₇H₄₀N₈O₅S；0.15 CH₂Cl₂Calculated values: c, 54.51; h, 6.92; n,18.14 percent. Delta (CDCl)₃):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 755- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- (2-morpholin-4-yl) ethyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a white solid (24%) from the title compound of example 74 and 2-methoxyethanol using the procedure of example 66. Measured value: c, 53.81; h, 6.93; n, 16.89. C₂₈H₄₂N₈O₆S；0.30 C₄H₈O₂；0.20 H₂Calculated value of O: c, 54.06; h, 6.96; n, 17.27%. Delta (CDCl)₃):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(1H,s),10.78(1H,s)。LRMS:m/z 619(M+1)⁺. Example 763-tert-butyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-1- (pyridin-2-yl) methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A stirred mixture of the title compound of preparation 121 (150mg,0.25mmol), potassium tert-butoxide (71mg,0.625mmol) and ethanol (10ml) was heated in a sealed vessel at 100 ℃ for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (10ml) and ethyl acetate (15 ml). The phases were separated, the aqueous phase extracted with ethyl acetate (2X 15ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol (100: 0 to 95: 5) as eluent to give the title compound as a white solid (140mg, 97%). Measured value: c, 56.30; h, 6.39; n,18.43。C₂₈H₃₆N₆O₄S；H₂Calculated value of O: c, 56.17; h, 6.40; n,18.72 percent. Delta (CDCl)₃):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(1H,d),7.18(1H,m),7.60(1H,m),8.58(1H,d),8.64(1H,s),9.08(1H,s),10.82(1H,s)。LRMS:m/z 581(M+1)⁺. Example 775- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-1- (2-morpholin-4-yl) ethyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of preparation 122, using the procedure of example 74, the title compound was obtained as a white solid (68%). Measured value: c, 54.59; h, 6.91; and N, 18.08. C₂₇H₄₀N₈O₅S；0.15 CH₂Cl₂Calculated values: c, 54.59; h, 6.89; n,18.08 percent. Delta (CDCl)₃):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(1H,s),9.09(1H,s),10.81(1H,s)。LRMS:m/z 589(M+1)⁺. Example 785- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 152 (25.9g,52.5mmol) and potassium bis (trimethylsilyl) amide (22.0g,110.0mmol) in ethanol (1500ml) was heated in a closed vessel at 120 ℃ for 18 h. The cooled solution was concentrated under reduced pressure and pre-absorbed on silica gel. The crude product was purified by silica gel column chromatography using an elution gradient of ethyl acetate: diethylamine (97: 3 to 95: 5) and trituration with ether to give the title compound as a white solid (11.0g, 44%). Delta (CDCl)₃):1.03(3H,t),1.40(3H,t),1.59(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(1H,s),9.04(1H,s),10.64(1H,s)。LRMS:m/z 476(M+1)⁺. Example 795- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound of preparation 151 (500mg,1.0mmol) was added to a solution of potassium bis (trimethylsilyl) amide (610mg,3.06mmol) in ethanol (20ml) and the reaction was heated in a closed vessel at 110 ℃ for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was dissolved in water and neutralized with hydrochloric acid. The aqueous suspension was extracted with dichloromethane (3X 30ml), the combined organic extracts washed with brine (3X 30ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residual oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97.5: 2.5) and triturated with ether to give the title compound as an off-white solid (207mg, 44%). Delta (CDCl)₃):1.03(3H,t),1.59(3H,t),1.83(2H,m),2.29(3H,s),253(4H,m),3.00(2H,t),3.16(4H,m),4.10(3H,s),4.75(2H,q),8.63(1H,s),9.06(1H,s),10.65(1H,s)。LRMS:m/z 476(M+1)⁺. Examples 80 to 84

Following a similar procedure to that described in example 79, compounds of the general formula were prepared from the appropriate pyrazole-5-carboxamides, i.e. preparations 153, 154, 156, 157 and 155, respectively. In examples 80 to 84, R¹Is methyl and R¹³is-OR³。1= using 1.5 equivalents of potassium bis (trimethylsilyl) amide 2= using dichloromethane: methanol: 088 ammonia (96: 4: 0.4) as eluent for chromatography example 853-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-methoxypyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 78 (100mg,0.21mmol) and copper (II) sulfate heptahydrate (75mg,0.3mmol) in saturated methanolic ammonia (20ml) was heated in a closed vessel at 100 ℃ for 4hThen (c) is performed. The cooled mixture was evaporated under reduced pressure and the residue was suspended in aqueous sodium carbonate (20ml) and extracted with dichloromethane (3X 20 ml). The combined organic extracts were washed with brine (3X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure to give a green solid. The crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and recrystallized from hexane/ethyl acetate/methanol to give the title compound as a white solid (23mg, 24%). Measured value: c, 51.22; h, 5.81; n, 20.61. C₂₀H₂₇N₇O₄S；0.5 H₂Calculated value of O: c, 51.05; h, 6.00; n,20.84 percent. Delta (CDCl)₃):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(1H,s)。LRMS:m/z 462(M+1)⁺. Example 863-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-ones

The title compound of example 78 (400mg,0.84mmol) was added to a mixture of potassium bis (trimethylsilyl) amide (840mg,4.2mmol) in (R) -2-butanol (4ml) and the mixture was stirred at 110 ℃ for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was suspended in water (10ml) and neutralized with 2N hydrochloric acid. The aqueous suspension was extracted with ethyl acetate (3X 30ml), the combined organic extracts were washed with sodium hydroxide solution (20ml), brine (2X 30ml) and dried (Na)₂SO₄) 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 diethyl ether and evaporated under reduced pressure. The solid was recrystallized from hexane/ethyl acetate to give the title compound as a white solid (72mg, 17%). [ alpha ] to]_DMeasured value of = 20.88 ° (c =0.083, dichloromethane): c, 54.65; h, 6.63; and N, 19.25. C₂₃H₃₃N₇O₄S；0.5 H₂Calculated value of O: c, 53.89; h, 6.69; n,19.13 percent. Delta (CDCl)₃):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

Following a similar procedure to that described in example 86, starting from the appropriate alcohols and pyrazolo [4,3-d]Pyrimidine-7-ones, preparation of compounds of the general formula, in which R is¹Is methyl and R¹³is-OR³。1= dichloromethane: methanol: 0.88 ammonia (100: 0: 0.5 to 99.5: 1: 0.5) was used as the chromatographic eluent and the compound was isolated without crystallization. 2= dichloromethane: methanol: 088 ammonia (100: 0: 0.5 to 99.5: 1: 0.5) was used as chromatography eluent and the compound was triturated with ether. 3= separation without crystallization. Example 983-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2- (R) -methoxy-1- (R) -methylpropoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

(R, R) -2, 3-butanediol (7.78ml,85mmol) was added dropwise to an ice-cooled solution of sodium hydride (3.74g, 60% suspended in mineral oil, 93.5mmol) in diethyl ether (800ml) and the solution was stirred at room temperature for 30 minutes. Methyl iodide (5.6ml,89.3mmol) was added dropwise and the reaction stirred at reflux for 48 h. 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone (10.24ml,85mmol) was added and stirring continued under reflux for another 90 min. The cooled reaction was washed with aqueous ammonium chloride (500ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residual oil was purified by silica gel column chromatography using an elution gradient of diethyl ether: pentane (10: 90 to 50: 50) to give a pale yellow oil. At 110 deg.C, will be inThe title compound of example 78 (100mg,0.2mmol) and potassium bis (trimethylsilyl) amide (121mg,0.61mmol) in intermediate alcohol (1ml) were heated for 30 hours, then the reaction was cooled and concentrated under reduced pressure. The residual brown solid was purified by silica gel column chromatography using an elution gradient of diethylamine: ethyl acetate (10: 90 to 50: 50), diethylamine: ethyl acetate (5: 95) as eluent and methanol: ethyl acetate (5: 95) was repeated as eluent. The product was triturated with ether to give the title compound as a white solid (7mg, 6%). Delta (CDCl)₃):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(1H,m),4.09(3H,s),5.39(1H,m),8.60(1H,s),8.97(1H,s)。LRMS:m/z 534(M+1)⁺. Example 993-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (pyridin-2-yl) methoxypyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 78 (100mg,0.2mmol), potassium bis (trimethylsilyl) amide (210mg,1.1mmol) in pyridine-2-methanol (1ml) was heated to 110 ℃ for 18 hours. The cooled mixture was partitioned between ethyl acetate (10ml) and water (10ml) and the phases were separated. The aqueous layer was extracted with ethyl acetate (2X 5ml) and dichloromethane (10ml) and dried (Na)₂SO₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methanol: ethyl acetate (10: 90) as eluent and trituration with ether to give the title compound as a solid (49mg, 43%). Delta (CDCl)₃):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(1H,m),8.58(1H,s),8.82(2H,m),12.72(1H,s)。LRMS:m/z 539(M+1)⁺. Example 1005- [ 2-cyclobutylmethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound (69%) was obtained from the title compound of example 78 and cyclobutanemethanol according to a similar method to that described in example 99. Measured value: c, 55.71; h, 6.44; n, 18.83. C₂₄H₃₃N₇O₄S calculated value: c, 55.90; h, 6.45; n,19.01 percent. Delta (CDCl)₃):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(1H,s),9.04(1H,s),10.61(1H,s)。LRMS:m/z 516(M+1)⁺. Example 1015- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 90 (104mg,0.2mmol) and potassium bis (trimethylsilyl) amide (200mg,1.0mmol) in n-butanol (5ml) was stirred at reflux for 5 days. The cooled mixture was concentrated under reduced pressure, the residue was suspended in ethyl acetate (20ml) and the mixture was neutralized with 1M hydrochloric acid. The layers were separated and the organic phase was washed with brine (10ml) and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was triturated with ether and the resulting solid filtered and further purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0: 0.5 to 99: 1: 0.5) to give the title compound as a solid (86mg, 82%). Delta (CDCl)₃):1.02(9H,m),1.57(2H,m),1.82(2H,m),1.95(2H,m),2.42(2H,q),2.58(4H,m),2.99(2H,t),3.15(4H,m),4.08(3H,s),4.68(2H,t),8.62(1H,s),9.02(1H,s),10.62(1H,s)。LRMS:m/z 518(M+1)⁺. Example 1023-Ethyl-5- [2- (2-methoxy-1-methylethoxy) -5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and example 1033-ethyl-5- [2- (2-methoxy-1-methylethoxy) -5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)Bis (trimethylsilyl) amide potassium (325mg,1.63mmol) was addedTo a solution of the title compound of example 119 (200mg,0.41mmol) in 1-methoxy-2-propanol (6ml) was added and the reaction stirred at reflux for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give 193mg of a colorless oil. The product was further purified by HPLC using an AD250 column, using hexane: isopropanol: diethylamine (70: 30: 0.3) as eluent to give the title compound of example 102 (58mg, 26%, 99.5% ee). Delta (CDCl)₃):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(1H,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 (47mg, 21%, 98.7% ee). Delta (CDCl)₃):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- [2- (2-methoxy-1-methylethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and example 105(-) -5- [2- (2-methoxy-1-methylethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)

The title compound from example 79 (198mg,0.42mmol) was added to a solution of potassium bis (trimethylsilyl) amide (415mg,2.1mmol) in 1-methoxy-2-propanol (5ml) and the reaction was heated at 110 ℃ for 72 h. The cooled mixture was evaporated under reduced pressure, the residue was dissolved in water and neutralized with 2M hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3X 30ml), the combined organic extracts washed with brine (3X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. Purifying the residual yellow oil by silica gel column chromatography using a gradient of dichloromethane to methanol (100: 0 to 97: 3) and evaporation from diethyl ether to giveA white solid.

The racemic product was purified by manual HPLC using an AD250 column, and hexane: isopropanol: trifluoroacetic acid (80: 20: 0.5) was used as eluent. The first enantiomer was resolved in water, basified using aqueous sodium carbonate and the mixture extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed with brine (2X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The product was then further purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and evaporated from ether to give the title compound of example 104 as a colourless solid (39mg, 18%, 98.1% ee). [ alpha ] to]_DMeasured value of = 30.31 ° (c =0.067, dichloromethane): c, 53.32; h, 6.49; n, 18.48. C₂₃H₃₃N₇O₅S calculated value: c, 53.16; h, 6.40; n,18.87 percent. Delta (CDCl)₃):1.02(3H,t),1.50(3H,d),1.82(2H,m),2.28(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(1H,s),8.92(1H,s),10.82(1H,s)LRMS:m/z 520(M+1)⁺。

The title compound of example 105 (26mg, 12%, 94.0% ee) was isolated using the same method as for example 104. [ alpha ] to]_D= 30.31 ° (c =0.067, dichloromethane) δ (CDCl)₃):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(1H,m),3.77(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 520(M+1)⁺. Example 106(+) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one and example 107(-) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomers 1 and 2)

Potassium bis (trimethylsilyl) amide (1.47g,7.4mmol) was added to the reaction mixtureA solution of the title compound of example 80 (720mg,1.5mmol) in 1-methoxy-2-propanol (10ml) was added and the reaction stirred at reflux for 72 h. The cooled mixture was evaporated under reduced pressure and the residual brown gum was purified by silica gel column chromatography using ethyl acetate: diethylamine (97: 3) as eluent. The racemic mixture was purified by manual 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 (20ml) and aqueous sodium carbonate (10ml), the phases were separated and dried (Na)₂SO₄) The organic layer was evaporated under reduced pressure. The product was further purified by silica gel column chromatography using ethyl acetate: methanol (95: 5) as eluent to give the title compound of example 106 as a white foam (130mg, 16%, 99.76% ee). [ alpha ] to]_DMeasured value of = 15.65 ° (c =0.093, methanol): c, 53.47; h, 6.66; n, 17.92. C₂₄H₃₅N₇O₅S；0.3 H₂Calculated value of O: c, 53.48; h, 6.66; n,18.19 percent. Delta (CDCl)₃):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(1H,m),3.76(1H,m),4.08(3H,s),5.60(1H,s),8.61(1H,s),8.90(1H,s),10.81(1H,s)。LRMS:m/z 534(M+1)⁺。

The same procedure as used in example 106 was used to give the title compound of example 107 as a white foam (94mg, 12%, 97.2% ee). [ alpha ] to]_DMeasured value of = 14.52 ° (c =0.10, methanol): c, 53.66; h, 6.73; and N, 17.89. C₂₄H₃₅N₇O₅S；0.25 H₂Calculated value of O: c, 53.57; h, 6.65; n,18.22 percent. Delta (CDCl)₃):1.03(6H,m),1.50(3H,d),1.82(2H,m),2.42(2H,q),2.57(4H,m),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 1083-Ethyl-5- [5- (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) and example 1093-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-n-butyl)Propoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)

The title compound was prepared from the title compound of example 78 and 2-methoxy-1-propanol by a similar method to that described for 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. The product was repurified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) and trituration with ether to give the title compound of example 108 (8mg, 2%, 82% ee) as a white solid. Delta (CDCl)₃):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(1H,m),8.62(1H,s),8.97(1H,s),10.90(1H,s)。LRMS:m/z 520(M+1)⁺。

The title compound of example 109 (5mg, 1%, 93% ee) was isolated as a white solid using the same methods as described for example 108. Delta (CDCl)₃):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(1H,m),4.72(1H,m),8.61(1H,s),8.98(1H,s),10.89(1H,s)。LRMS:m/z 520(M+1)⁺. Example 1103-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxy-1-methyl-n-propoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one and example 1113-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxy-1-methyl-n-propoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomers 1 and 2)

A mixture of the title compound of example 78 (330mg,0.70mmol) and potassium bis (trimethylsilyl) amide (693mg,3.47mmol) in the title compound of preparation 166 (2.5ml) was heated at 110 ℃ for 16 h. Suspending the cooled reactantSuspended in ethyl acetate (25ml) and washed successively with saturated ammonium chloride solution (5ml), saturated sodium bicarbonate solution (10ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using methanol: dichloromethane (5: 95) as eluent and diethylamine: ethyl acetate (10: 90) as eluent to give a gum.

The racemate was purified by HPLC using an AD250 column and hexane: ethanol: diethylamine (85: 15: 1) as eluent to give the title compound of example 110 (25mg, 6.7%, 98.9% ee). Delta (CDCl)₃):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 (29mg, 7.8%, 99.7% ee). Delta (CDCl)₃):1.03(3H,t),1.40(3H,t),1.48(3H,d),2.04(1H,m),2.24(1H,m),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(1H,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-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and 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 (70%) was prepared according to the method described for examples 104 and 105, from the title compound of example 78 and 1-ethoxy-2-propanol.

The racemate was purified by manual HPLC using an AD250 column and hexane: isopropanol: diethylamine (70: 30: 0.3) as eluent to give enantiomer 1. The product was further purified by silica gel column chromatography using dichloromethane: methanol (97: 3) as eluent and evaporated from ether to yieldThe title compound of example 112 (52mg, 15%, 99.5% ee) was a foam. [ alpha ] to]_DMeasured value of = 18.60 ° (c =0.067, dichloromethane): c, 53.20; h, 6.70; n, 17.78. C₂₄H₃₅N₇O₅S；0.5H₂Calculated value of O: c, 53.12; h, 6.69; n,18.07 percent. Delta (CDCl)₃):1.04(3H,t),1.25(3H,t),1.40(3H,t),1.52(3H,d),2.42(2H,q),2.57(4H,m),3.02(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(1H,s)。LRMS:m/z 534(M+1)⁺。

The title compound of example 113 was isolated according to the same method as described for example 112 (11mg, 3%, 99.5% ee). [ alpha ] to]_DMeasured value of = 19.43 ° (c =0.070, dichloromethane): c, 53.34; h, 6.66; and N, 17.86. C₂₄H₃₅N₇O₅S；0.5 H₂Calculated value of O: c, 53.12; h, 6.69; n,18.07 percent. Delta (CDCl)₃):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(1H,s),8.92(1H,s),10.82(1H,s)。LRMS:m/z 534(M+1)⁺. Example 114(+) -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-d]Pyrimidin-7-one and 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-d]Pyrimidin-7-one (isomers 1 and 2)

From the title compound of example 78 and 1-methoxy-2-butanol, the title compounds of examples 114 and 115 were obtained (11%, 93% ee) and (6.7%, 97% ee), respectively, using the methods described in examples 108 and 109. [ alpha ] to]_D= 37.04 ° (c =0.097, dichloromethane). Measured value: c, 53.36; h, 6.73; n, 17.84. C₂₄H₃₅N₇O₅S；0.5 H₂Calculated value of O: c, 53.12; h, 6.69; n,18.07 percent. Delta (CDCl)₃):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(1H,m),8.60(1H,s),8.88(1H,s),10.84(1H,s)。LRMS:m/z 534(M+1)⁺(ii) a And [ alpha ]]_DMeasured value of = 40.08 ° (c =0.093, dichloromethane): c, 53.44; h, 6.75; n, 17.76. C₂₄H₃₅N₇O₅S；0.5 H₂Calculated value of O: c, 53.12; h, 6.69; n,18.07 percent. Delta (CDCl)₃) 1.03(6H, m),1.40(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),3.68(1H, m),3.78(1H, m),4.10(3H, s),5.57(1H, m),8.61(1H, m),8.89(1H, s),10.83(1H, s). Example 116(-) -3-Ethyl-5- {5- (4-ethylpiperazin-1-ylsulfonyl) -2- [1- (pyridin-2-yl) ethoxy]Pyridin-3-yl } -2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and example 117(+) -3-ethyl-5- {5- (4-ethylpiperazin-1-ylsulfonyl) -2- [1- (pyridin-2-yl) ethoxy]Pyridin-3-yl } -2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)

The title compounds of examples 116 and 117 (4%, 99.0% ee) and (2%, 99.0% ee) were obtained as solids from the title compound of example 78 and 1- (pyridin-2-yl) ethanol (helv. chim. acta.,1955,38,1114) in a similar manner to that described for examples 112 and 113, except that hexane: isopropanol: diethylamine (70: 30: 1) was used as the HPLC eluent. [ alpha ] to]_D= 90.11 ° (c =0.033, dichloromethane). Delta (CDCl)₃):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(1H,s)。LRMS:m/z553(M+1)⁺[α]_D= 82.02 ° (c =0.040, dichloromethane) δ (CDCl)₃):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(1H,q),7.34(2H,m),7.75(1H,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-1 (R) -methylethoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidines-7-ketones

A mixture of the title compound from example 78 (2.0g,4.2mmol) and potassium bis (trimethylsilyl) amide (4.2g,21.0mmol) in the title compound of preparation 165 (16ml) was heated at 110 ℃ for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of diethylamine: methanol: ethyl acetate (2.5: 0: 97.5 to 0: 10: 90). The product was further purified by silica gel column chromatography using methanol: ethyl acetate (2.5: 97.5) as eluent to give the title compound as a solid (640mg, 29%). Measured value: c, 53.16; h, 6.54; n, 18.37. C₂₃H₃₃N₇O₅S；0.2 CH₃CO₂C₂H₅Calculated values: c, 53.21; h, 6.49; n,18.25 percent. [ alpha ] to]_D= 16.6 ° (c =0.10, methanol). Delta (CDCl)₃):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,m),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 1195- [ 2-ethoxy-5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

1-n-propylpiperazine (308mg,1.01mmol) and triethylamine (440ml,3.2mmol) were added to a solution of the title compound of preparation 164 (211mg,0.53mmol) in dichloromethane (6ml) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was directly purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound as a white foam (210mg, 85%). Delta (CDCl)₃):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(1H,s),9.04(1H,s),10.67(1H,s)。LRMS:m/z 490(M+1)⁺. Example 1205- { 2-ethoxy-5- [4- (prop-2-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Following the method described in example 119, from the title compound of preparation 164 and 1- (prop-2-yl) -piperazine, the title compound was obtained as a white solid (71%). Delta (CDCl)₃):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 1215- { 2-ethoxy-5- [4- (pyridin-2-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Following the method described in example 119, from the title compound of preparation 164 and 1- (pyridin-2-yl) piperazine, the title compound was obtained as a white solid (58%). Delta (CDCl)₃):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 1223-Ethyl-5- {2- (2-methoxy-1-methylethoxy) -5- [4- (pyridin-2-yl) piperazin-1-ylsulfonyl]Pyridin-3-yl } -2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium bis (trimethylsilyl) amide (76mg,0.38mmol) was added to a solution of the title compound of example 121 (50mg,0.095mmol) in 1-methoxy-2-propanol (5ml) and the reaction was heated at reflux for 18 h. The cooled mixture was directly purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound as a yellow oil (32mg, 59%). Delta (CDCl)₃):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)⁺. Fruit of Chinese wolfberryExample 1235- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]3-ethyl-1-methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 158 (596mg,1.21mmol) and potassium bis (trimethylsilyl) amide (723mg,3.62mmol) in ethanol (20ml) was heated in a closed vessel at 120 ℃ for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified twice by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent. The product was triturated with ether to give the title compound as an off-white solid (358mg, 62%). Measured value: c, 52.71; h, 6.00; and N, 20.48. C₂₁H₂₉N₇O₄S calculated value: c, 53.04; h, 6.15; n,20.62 percent. Delta (CDCl)₃):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(1H,s),10.80(1H,s)。LRMS:m/z 476(M+1)⁺. Example 1245- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound (42%) was obtained from the title compound of preparation 159 according to a similar method to that described in example 123. Measured value: c, 53.68; h, 6.34; and N, 19.97. C₂₂H₃₁N₇O₄S calculated value: c, 53.97; h, 6.38; and N,20.03 percent. Delta (CDCl)₃):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,m),4.29(3H,s),4.78(2H,q),8.63(1H,s),9.08(1H,s),10.78(1H,s)。LRMS:m/z 491(M+1)⁺. Example 1253-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl]-1-methyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

At 110 deg.CNext, a mixture of the title compound of example 123 (70mg,0.15mmol) and potassium bis (trimethylsilyl) amide (150mg,0.74mmol) in the title compound of preparation 165 (1ml) was stirred for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between water (5ml) and dichloromethane (5ml) and the mixture was neutralized by addition of solid carbon dioxide. The layers were separated and the aqueous phase was extracted with dichloromethane (2X 5ml) and dried (Na)₂SO₄) The combined organic solutions were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate: diethylamine (97: 3) as eluent to give the title compound (62mg, 80%). Delta (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),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 1265- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound from example 124 (111mg,0.23mmol) and potassium bis (trimethylsilyl) amide (226mg,1.13mmol) in 2-methoxyethanol (5ml) was stirred at reflux for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol (96: 4) as eluent and trituration with ether to give the title compound as a white crystalline solid (75mg, 64%). Measured value: c, 52.87; h, 6.35; n, 18.68. C₂₃H₃₃N₇O₅S calculated value: c, 53.16; h, 6.40; n,18.87 percent. Delta (CDCl)₃):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(1H,s),9.00(1H,s),10.51(1H,s)。LRMS:m/z 521(M+2)⁺. Example 1275- (5- (4-ethylpiperazin-1-ylsulfonyl) -2- [ (pyridin-2-yl) methoxy]Pyridin-3-yl } -1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 124 (100mg,0.20mmol) and potassium bis (trimethylsilyl) amide (204mg,1.02mmol) in pyridine-2-methanol (2ml) was stirred at 110 ℃ for 18 h and then cooled. The solvent was removed by Kugelif distillation and the residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent. The product was triturated with ether to give the title compound as a solid (8mg, 7%). Delta (CDCl)₃):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-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl]-1-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-methoxy-1-methylethoxy) pyridin-3-yl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomers 1 and 2)

The title compounds of examples 128 and 129 (17%, 99.5% ee) and (15%, 98.6% ee) were prepared from example 124 in a similar manner to that described in examples 106 and 107, respectively, except that hexane: isopropanol: diethylamine: trifluoroacetic acid (85: 15: 0.2: 0.3) was used as the HPLC eluent. Respectively as follows: [ alpha ] to]_D= 31.21 ° (c =0.067, dichloromethane). Measured value: c, 53.77; h, 6.71; and N, 17.89. C₂₄H₃₅N₇O₅S；0.5 H₂Calculated value of O: c, 53.12; h, 6.69; n,18.07 percent. Delta (CDCl)₃) 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(1H, s),11.08(1H, s); and [ alpha ]]_DMeasured value of = 34.10 ° (c =0.072, dichloromethane): c, 53.75; h, 6.67; n, 18.04. C₂₄H₃₅N₇O₅S calculated value: c, 54.02; h, 6.61; n,18.37 percent. Delta (CDCl)₃):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(1H, s),8.92(1H, s),11.17(1H, s). Example 1305- [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-ones

A mixture of the title compound of example 93 (130mg,0.25mmol) and 3-chloroperbenzoic acid (95mg,0.275mmol) in dichloromethane (6ml) was stirred at room temperature for 21/2 hours. The reaction mixture was washed with aqueous sodium bicarbonate (5ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residual foam was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (93: 7: 0 to 93: 7: 1) to give the title compound as a white solid (110mg, 82%). Measured value: c, 50.71; h, 6.27; n, 17.82. C₂₃H₃₃N₇O₆S calculated value: c, 50.72; h, 6.30; n,18.00 percent. Delta (CDCl)₃):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(1H,s),8.97(1H,s),10.87(1H,s)。LRMS:m/z 536(M+1)⁺. Example 1315- [ 2-ethoxy-5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) pyridin-3-yl]-2-methyl-3-n-propyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Following the procedure described in example 130, from the title compound of example 80, the title compound was obtained as a white foam (81%). Delta (CDCl)₃):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 1323-Ethyl-5- [5- (4-ethyl-4-oxidopiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

3-Chloroperbenzoic acid (95mg,0.28mmol) was added to a solution of the title compound of example 118 (130mg,0.25mmol) in dichloromethane (2ml) and the reaction was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: 0.88 ammonia (95: 5: 0 to 90: 10: 1) to give the title compound (130mg, 87%). Delta (CDCl)₃):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(1H,s),8.94(1H,s)。LRMS:m/z 536(M+1)⁺. Example 1335- [5- (4-Ethyl-4-piperazinen-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-1-methyl-3-n-propyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

From the title compound of example 126, using a similar method to that described in example 130, the title compound was obtained as a white solid (51%). Delta (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)⁺. Example 1342, 3-diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 81 (200mg,0.41mmol) and potassium bis (trimethylsilyl) amide (407mg,2.04mmol) in n-propanol (5ml) was stirred at 110 ℃ for 18 h and the reaction was cooled and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of ethyl acetate: diethylamine (100: 0 to 95: 5) and triturated with ether to give the title compound as a solid (160mg, 68%). Delta (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+1)⁺. Example 1355- [ 2-isobutoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-2, 3-diethyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the method described in example 134, from the title compound of example 81 and isobutanol, the title compound was obtained as a solid (65%). Delta (CDCl)₃):1.02(3H,t),1.15(6H,d),1.42(3H,t),1.58(3H,t),2.30(1H,m),2.42(2H,q),2.57(4H,m),3.06(2H,q),3.16(4H,m),4.38(2H,q),4.45(2H,d),8.62(1H,s),9.03(1H,s)。LRMS:m/z 518(M+1)⁺. Example 1362, 3-diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound was obtained as a solid (33%) from the title compound of example 81 and 2-methoxyethanol using the method described in example 134. Measured value: c, 53.29; h, 6.20; n, 18.19. C₂₃H₃₃N₇O₅S calculated value: c, 53.16; h, 6.40; n,18.87 percent. Delta (CDCl)₃):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 1372, 3-diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-hydroxy-n-propoxy) pyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 81 (200mg,0.41mmol) and potassium bis (trimethylsilyl) amide (407mg,2.04mmol) in 1, 3-propanediol (3ml) was stirred at 110 ℃ for 18 h, then cooled and evaporated under reduced pressure. Purifying the residue by silica gel column chromatography using a second column chromatographyEthyl acetate diethylamine (100: 0 to 95: 5). The product was partitioned between water (5ml) and dichloromethane (10ml) and the phases were separated. The organic layer was washed with water (2X 5ml) and dried (MgSO)₄) Evaporation under reduced pressure and trituration with ether gave the title compound as a solid (90mg, 42%). Delta (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(1H,s),8.96(1H,s)。LRMS:m/z 520(M+1)⁺. Example 1382, 3-diethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methyl-n-propoxy) pyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and example 1392, 3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methyl-n-propoxy) pyridin-3-yl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)

A mixture of the title compound of example 81 (500mg,1.02mmol) and potassium bis (trimethylsilyl) amide (1.01g,5.11mmol) in 1-methyl-n-propanol (5ml) was stirred at 110 ℃ for 18 h, then cooled and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of ethyl acetate: diethylamine (100: 0 to 95: 5) and triturated with ether to give a solid. The racemate was further purified by manual HPLC using an AD250 column and hexane: isopropanol: diethylamine (90: 10: 1) as eluent to give the title compound of example 138 (40mg, 8%, 95% ee) as a solid. Measured value: c, 54.41; h, 6.71; and N, 18.17. C₂₄H₃₅N₇O₄S；0.2 CH₂Cl₂Calculated values: c, 54.37; h, 6.67; n,18.34 percent. Delta (CDCl)₃) 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 (70mg, 13%, 86% ee) as a solid. Measured value: c, 55.91; h, 7.11; n, 18.55. C₂₄H₃₅N₇O₄S calculated value: c, 55.69; h, 6.82; n,18.95 percent. Delta(CDCl₃) 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(1H, m),8.61(1H, s),9.03(1H, s),10.67(1H, s). Example 1402, 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 1412, 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)

In a similar manner to that described above, except that hexane: isopropanol: diethylamine (70: 30: 1) was used as the HPLC eluent, the title compound of example 81 (10%, 99.5% ee) and (10%, 99.1% ee) were obtained as solids from 1-methoxy-2-propanol (5ml), respectively. Respectively as follows: delta (CDCl)₃):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+2)⁺. Measured value: c, 54.09; h, 6.91; and N, 17.03. C₂₄H₃₅N₇O₅S calculated value: c, 54.02; h, 6.61; n,18.38 percent. Delta (CDCl)₃):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(4H,m),3.65(1H,m),3.74(1H,m),4.37(2H,q),5.60(1H,m),8.60(1H,s),8.90(1H,s)。LRMS:m/z 535(M+2)⁺. Example 1423-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- (6-methyl-pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of example 82 (100mg,0.176mmol) and potassium bis (trimethylsilyl) amide (175mg,0.88mmol) in 2-methoxyethanol (1ml) was heated at reflux for 18 h and then cooled. Concentrating the solution under reduced pressureThe solution was partitioned between water (5ml) and dichloromethane (10ml) and the mixture was neutralized with (2N) hydrochloric acid. The phases were separated and the aqueous layer was extracted with dichloromethane (10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (96: 4: 0.4) as eluent and triturated with pentane to give the title compound as an off-white solid (27mg, 26%). Measured value: c, 56.14; h, 6.09; n, 18.53. C₂₈H₃₆N₈O₅S calculated value: c, 56.36; H. 6.08 of; n, 18.78%. Delta (CDCl)₃) 1.02(3H, t),1.30(3H, t),2.42(2H, q),2.57(7H, m),3.04(2H, q),3.16(4H, m),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(1H, s),10.82(1H, s). Example 1433-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) pyridin-3-yl]-2- (6-methylpyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compounds were obtained as white solids (12%) from the title compounds of examples 82 and 165 using a similar method to that described in example 142, except that the product was additionally purified by silica gel column chromatography using an elution gradient of ethyl acetate: methanol: 0.88 ammonia (100: 0 to 90: 10: 1) and then triturated with pentane. Delta (CDCl)₃):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,m),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(1H,s),8.90(1H,s),10.84(1H,s)。LRMS: m/z 611(M+1)⁺. Example 1443-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- [1- (pyridin-2-yl) ethyl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 1) and example 1453-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl]-2- [1- (pyridin-2-yl) ethyl]-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-one (isomer 2)

A mixture of the title compound of example 84 (200mg,0.35mmol) and potassium bis (trimethylsilyl) amide (350mg,1.76mmol) in 2-methoxyethanol (5ml) was stirred at 120 ℃ for 18 h. The cooled mixture was concentrated under reduced pressure and the residue partitioned between saturated sodium bicarbonate water (20ml) and ethyl acetate (20 ml). The phases were separated and the aqueous layer was extracted with ethyl acetate (2X 10ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give a foam and the racemate was further purified by HPLC using an AD250 column and hexane: isopropanol: diethylamine (50: 1) as eluent to give the title compound of example 144 (24 mg, 11%, 100.0% ee). Delta (CDCl)₃):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(1H,s),10.82(1H,s)。LRMS:m/z 598(M+1)⁺(ii) a And the title compound of example 145 (28mg, 13%, 99.8% ee). Delta (CDCl)₃):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(1H,q),7.18(2H,m),7.60(1H,m),8.54(1H,d),8.60(1H,s),8.94(1H,s),10.82(1H,s)。LRMS:m/z 598(M+1)⁺. Example 1465- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridazin-3-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A suspension of the title compound of preparation 142 (1.12g,4.55mmol) and triethylamine (1.5g,13.7mmol) was added to an ice-cooled suspension of the title compound of preparation 28 (2.0g,5.0mmol) in dichloromethane (25ml) and the reaction stirred at room temperature for 2 h. The reaction mixture was washed with brine (15ml), saturated aqueous sodium bicarbonate (2X 10ml), then brine (15ml) and dried (MgSO₄) And evaporated under reduced pressure. Chromatography on silica gel columnThe residue was purified using an elution gradient of dichloromethane: methanol: 0.88 ammonia (99: 0: 1 to 96: 3: 1) to give a solid (1.73 g).

A mixture of this intermediate (829mg,1.45mmol) and potassium bis (trimethylsilyl) amide (347mg,1.74mmol) in 3-methyl-3-pentanol (3ml) was heated at reflux for 6 hours and then stirred at room temperature for 72 hours. Additional potassium bis (trimethylsilyl) amide (87mg,0.43mmol) was added, the reaction was heated at reflux for an additional 5 hours, then cooled, 2M hydrochloric acid (2ml) was added and the mixture was concentrated under reduced pressure. The residue was partitioned between dichloromethane (20ml) and water (10ml), the layers were separated, the organic phase was washed successively with water (10ml), saturated sodium bicarbonate solution (10ml), brine (10ml), dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 98: 2) to give the title compound as a light brown foam (1.24g, 49%). Delta (CDCl)₃):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(1H,s),9.18(1H,d),10.70(1H,S)。LRMS:m/z 554(M+1)⁺. Example 1475- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (pyridazin-3-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium bis (trimethylsilyl) amide (35mg,0.176mmol) was added to a solution of the title compound of example 146 (80mg,0.145mmol) in n-butanol (2ml) and the reaction was stirred for 61/2 h at 110 ℃. The cooled mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (20ml) and sodium bicarbonate solution (10 ml). The phases were separated and the organic layer was washed with additional sodium bicarbonate solution (10ml), brine (10ml) and dried (MgS 0)₄) And evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol: 0.88 ammonia (100: 0 to 99.6: 0.4: 0.5) to give the title compound as a white foam (50mg, 59%). Delta (CDCl)₃):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 1483-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethylamino) pyridin-3-yl]-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound from example 78 (200mg,0.42mmol) and copper (II) sulfate pentahydrate (150mg,0.60mmol) in 2-methoxyethylamine (2ml) was heated at reflux for 2h and then cooled. The reaction was partitioned between dichloromethane (20ml) and aqueous sodium carbonate (5ml) and the layers separated. Drying (Na)₂SO₄) The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to give the title compound (150mg, 69%). Delta (CDCl)₃):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(1H,s)。LRMS: m/z 519(M+1)⁺. Examples 149 to 153 Using a similar procedure to that described in example 148, from the appropriate pyrazolo [4,3-d]Pyrimidine-7-ones and amines, compounds of the general formula:example 1545- [2- (N-Cyclopropylmethyl-N-methylamino) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2-methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound of example 78 (200mg,0.42mmol) and N-cyclopropylmethyl-N-methylamine (600mg,7.05 mmol; from the title compound of preparation 168) and potassium bis (trimethylsilyl) amide (250mg,1.26mmol) were added to a solution of N, N-dimethylThe mixture in formamide (2ml) was stirred at 100 ℃ for 18 hours. The cooled mixture was partitioned between ethyl acetate (20ml) and aqueous sodium bicarbonate (10ml) and the phases were separated. Drying (MgSO)₄) The organic layer was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound (100mg, 46%) as a solid. Delta (CDCl)₃):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(1H,s),8.60(1H,s)。LRMS:m/z 515(M+1)⁺. Examples 155 to 156

Using a method similar to that described in example 154, from the title compound of example 78 and the appropriate amine, a compound of the general formula:example 1573-Ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridin-3-yl]-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 160 (226mg,0.39mmol) and potassium tert-butoxide (112mg,1.0mmol) in n-propanol (20ml) was stirred at reflux for 5 days and then cooled. Saturated ammonium chloride solution (5ml) was added, the solution was poured into ethyl acetate (50ml) and the layers were separated. The organic phase was washed with sodium bicarbonate solution (20ml) then brine (20ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 94: 6) to give an oil. It was crystallized from diethyl ether to give the title compound as a white solid (9mg, 4%). Delta (CDCl)₃):1.00(3H,t),1.18(3H,t),1.28(3H,t),1.70(2H,m),2.38(2H,q),2.50(4H,m),3.00(2H,q),3.07(4H,m),3.57(2H,q),5.62(2H,s),7.19(1H,m),7.63(1H,m),8.02(1H,s),8.55(2H,m),9.60(1H,s),9.80(1H,s)。LRMS:m/z 566(M+1)⁺. Preparation of 12-ethoxypyridinylmethanesAcid(s)

A solution of potassium tert-butoxide (44.9g,0.40mol) in absolute ethanol (300ml) was slowly added to a solution of 2-chloronicotinic acid (30g,0.19mol) in absolute ethanol (100ml) and the reaction mixture was heated in a closed vessel at 170 ℃ for 20 hours and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue was dissolved in water (200ml) and the solution was acidified to pH3 with hydrochloric acid and extracted with dichloromethane (4 × 200 ml). Drying (Na)₂SO₄) The combined extracts were evaporated under reduced pressure to give the title compound as a white solid (27.4g, 41%). Delta (CDCl)₃) 1.53(3H, t),4.69(2H, q),7.13(1H, m),8.37(1H, d),8.48(1H, d). Preparation of 22- (2-methoxyethoxy) pyridine-3-carboxylic acid

Using the procedure of preparation 1, from 2-chloronicotinic acid and 2-methoxyethanol, the title compound was obtained as a brown solid (92%). Measured value: c, 54.89; h, 5.61; and N, 7.03. C₉H₁₁NO₄Calculated values: c, 54.82; h, 5.62; and N, 7.10%. Delta (CDCl)₃):3.45(3H,s),3.79(2H,t),4.74(2H,t),7.14(1H,m),8.36(1H,d),8.46(1H,d)。LRMS:m/z 198(M+1)⁺. Preparation of 32-ethoxypyridine-3-carboxylic acid ethyl ester

A suspension of the title compound of preparation 1 (16.4g,98mmol) and cesium carbonate (32g,98mmol) in dimethylformamide (240ml) was stirred at room temperature for 2 hours. Iodothane (7.85ml,98mmol) was added and the reaction mixture was stirred for 24 hours and then evaporated under reduced pressure. The residue was partitioned between aqueous sodium carbonate (100ml) and ethyl acetate (100ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2X 100 ml). The combined organic solutions were washed with brine and dried (Na)₂SO₄) And evaporated under reduced pressure to give the title compound as a pale yellow oil (18.0g, 94%). Delta (CDCl)₃) 1.41(6H, m),4.36(2H, q),4.48(2H, q),6.90(1H, m),8.12(1H, d),8.28(1H, d). Preparation of 42- (2-methoxyethoxy) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 2, using the method of preparation 3, the title compound was obtained as a brown oil (98%). Measured value: c, 58.36; h, 6.74; and N, 6.04. C₁₁H₁₅NO₄Calculated values: c, 58.66; h, 6.71; n,6.23 percent. Delta (CDCl)₃):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(1H,d)。LRMS:m/z 226(M+1)⁺. Preparation of 52-ethoxy-5-nitropyridine-3-carboxylic acid ethyl ester

Ammonium nitrate (5.36g,66mmol) was added portionwise to a stirred ice-cooled solution of the title compound of preparation 3 (4.66g,22.3mmol) in trifluoroacetic anhydride (50ml) and the reaction mixture was stirred at room temperature for 18 hours and then carefully poured into stirred ice-water (200 g). The resulting suspension was stirred for 1 hour, then the precipitate was collected, washed with water and dried under suction to give the title compound (3.29g, 61%). Delta (CDCl)₃) 1.41(3H, t),1.48(3H, t),4.41(2H, q),4.62(2H, q),8.89(1H, s),9.16(1H, s). Preparation of 62- (2-methoxyethoxy) -5-nitropyridine-3-carboxylic acid ethyl ester

Ammonium nitrate (10.57g,131mmol) was added portionwise to a stirred ice-cooled solution of the title compound of preparation 4 (14.80g,65.7mmol) in trifluoroacetic anhydride (50ml) and the reaction mixture was stirred at room temperature for 3 hours and then carefully poured into stirred ice (120 g). The resulting solution was extracted with dichloromethane (3X 150ml) and then dried (MgSO)₄) The combined extracts were evaporated under reduced pressure. The residual orange oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) to give the title compound as a white solid (11.49g, 65%). Measured value: c, 48.78; h, 5.13; n, 10.29. C₁₁H₁₄N₂O₆Calculated values: c, 48.89; h, 5.22; n,10.37 percent. Delta (CDCl)₃):1.42(3H,t),3.46(3H,s),3.83(2H,t),4.41(2H,q),4.70(2H,t),8.92(1H,s),9.16(1H,s)。LRMS:m/z 271(M+1)⁺. Preparation of 75-amino-2-ethoxypyridine-3-carboxylic acid ethyl ester

A stirred mixture of the title compound of preparation 5 (5.3g,22mmol), Raney nickel (2.50g) and ethanol (150ml) was hydrogenated at 345Kpa (50psi) and 50 deg.C for 18 h, then allowed to cool and filtered. The filtrate was combined with the ethanol wash (150ml) of the filter padAnd then evaporated under reduced pressure. The residue was triturated with dichloromethane and the resulting solid collected and dried to give the title compound as a brown solid (4.56g, 98%). Measured value: c, 57.12; h, 6.79; n, 12.98. C₁₀H₁₄N₂O₃Calculated values: c, 57.13; h, 6.71; n, 13.33%. Delta (CDCl)₃):1.39(6H,2×d),3 41(2H,s),4.35(4H,m),7.55(1H,s),7.78(1H,s)。LRMS:m/z 211(M+1)⁺. Preparation of 82-ethoxy-5-nitropyridine-3-carboxylic acid

A5M aqueous solution of sodium hydroxide (4ml,20mmol) was added dropwise to a stirred solution of the title compound of preparation 5 (5.1g,20mmol) in ethanol (100ml) and the reaction mixture was stirred at room temperature for 18 h and then evaporated under reduced pressure. The residue was suspended in water (50ml) and the stirred suspension was acidified to pH3 with hydrochloric acid. The resulting aqueous solution was extracted with ethyl acetate (3X 100ml), and the combined extracts were washed with brine (100ml) and dried (Na)₂SO₄) And evaporated under reduced pressure to give a beige solid. The crude product was crystallized from hexane-ethyl acetate to give the title compound as beige crystals (3.32g, 78%). Delta (CDCl)₃) 1.55(3H, t),4.78(2H, q),9.17(1H, s),9.23(1H, s). Preparation of 92- (2-methoxyethoxy) -5-nitropyridine-3-carboxylic acid

A1M aqueous solution of sodium hydroxide (40ml,40mmol) was added to a stirred ice-cooled solution of the title compound of preparation 6 (4.0g,14.8mmol) in 1, 4-dioxane (40ml) and the reaction mixture was stirred for 1.5 h, then concentrated to half its volume under reduced pressure and acidified to pH3 with hydrochloric acid. The resulting suspension was extracted with dichloromethane (3X 50ml) and then dried (MgSO)₄) The combined extracts were evaporated under reduced pressure to give the title compound as a beige solid (2.61g, 73%). Measured value: c, 44.11; h, 4.04; n, 11.46. C₉H₁₀N₂O₆Calculated values: c, 44.63; h, 4.16; n, 11.57%. Delta (CDCl)₃):3.47(3H,s),3.83(2H,t),4.82(2H,t),9.1 5(1H,s),9.21(1H,s)。LRMS:m/z 243(M+1)⁺. Preparation of 102-aminopyridine-5-sulfonic acid

Within 30 minutes, 2 is addedAminopyridine (80g,0.85mol) was added portionwise to stirred oleum (320g) and the resulting solution was heated at 140 ℃ for 4 hours and then allowed to cool. The reaction mixture was poured into stirred ice (200g) and the mixture was stirred at the ice-salt bath temperature for an additional 2 hours. The resulting suspension was filtered, then the collected solid was washed successively with ice-water (200ml) and cold technical methanolic denatured alcohol (IMS) (200ml) and finally dried under suction to give the title compound as a solid (111.3g, 75%). LRMS M/z 175(M +1)⁺. Preparation of 112-amino-3-bromopyridine-5-sulfonic acid

Bromine (99g,0.62mol) was added dropwise to a stirred, hot solution of the title compound of preparation 10 (108g,0.62mol) in water (600ml) over 1 hour at such a rate as to maintain a stable 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 give the title compound (53.4g, 34%). Delta (DMSOd)₆):8.08(1H,s),8.14(1H,s)。LRMS:m/z 253(M)⁺. Preparation of 123-bromo-2-chloropyridine-5-sulfonyl chloride

A solution of sodium nitrite (7.6g,110mmol) in water (30ml) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 11 (25.3g,100mmol) in 20% hydrochloric acid (115ml) at such a rate as to maintain the temperature below 6 ℃ or below. The reaction mixture was stirred at 0 ℃ for 30 minutes and at room temperature for another 1 hour, then evaporated under reduced pressure. The residue was dried under vacuum at 70 ℃ for 72 hours, and then a mixture of the resulting solid, phosphorus pentachloride (30g,144mmol) and phosphorus oxychloride (1ml) was heated at 125 ℃ for 3 hours and then allowed to cool. The reaction mixture was poured onto stirred ice (100g) and the resulting solid was collected and washed with water. The crude product was dissolved in dichloromethane and then dried (MgSO₄) The solution was evaporated under reduced pressure to give the title compound as a yellow solid (26.58g, 91%). Delta (CDCl)₃) 8.46(1H, s) and 8.92(1H, s). Preparation of 133-bromo-2-chloro-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

1-ethylpiperazine (11.3ml,89mmol) and triethylamine (12.5 m)l,89mmol) in dichloromethane (150ml) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 12 (23g,79mmol) in dichloromethane (150ml) and the reaction mixture was stirred at 0 ℃ for 1h and then evaporated under reduced pressure. The residual brown oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound as an orange solid (14.5g, 50%). Delta (CDCl)₃) 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 143-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridine

A0.5M solution of potassium bis (trimethylsilyl) amide in toluene (8.1ml,4.07mmol) was added to a stirred, ice-cooled solution of 2-methoxyethanol (416. mu.l, 5.4mmol) in anhydrous tetrahydrofuran (30ml) and the resulting solution was stirred at 0 ℃ for 1 hour. Subsequently, the title compound of preparation 13 (1.0g,2.71mmol) was added portionwise and the reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate (40 ml). The resulting mixture was washed with water (10ml) and dried (MgSO)₄) And evaporated under reduced pressure to give a yellow oil which was purified by silica gel column chromatography using dichloromethane: methanol (97: 3) as eluent to give the title compound as a colourless oil (1.02g, 92%). Measured value: c, 40.83; h, 5.32; and N, 9.99. C₁₄H₂₂BrN₃O₄S calculated value: c, 41.18; h, 5.43; n,10.29 percent. Delta (CDCl)₃):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(1H,s)。LRMS:m/z 408(M)⁺. Preparation 153-bromo-2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

Metallic sodium (93mg,4mmol) was added to a stirred solution of 2-ethoxyethanol (537. mu.l, 5.5mmol) in anhydrous tetrahydrofuran (5 ml). When sodium was dissolved, the title compound of preparation 13 (1.0g,2.7mmol) was added portionwise and the reaction mixture was stirred at room temperature for 18 h, then concentrated under reduced pressure. The residue was partitioned between ethyl acetate (10ml) and brine (10ml), the phases were separated and washed with ethyl acetate (2X 1)0ml) of the aqueous phase. The combined organic solutions were washed with brine and dried (MgSO)₄) And evaporated under reduced pressure, then the residue was purified by silica gel column chromatography using an elution gradient of hexane: dichloromethane: methanol (50: 0 to 0: 98: 2) to give the title compound (985mg, 86%) as a yellow oil. Delta (CDCl)₃):1.03(3H,t),1.22(3H,t),2.40(2H,q),2.54(4H,m),3.07(4H,m),3.61(2H,q),3 82(2H,t),4.59(2H,t),8.10(1H,s),8.43(1H,s)。LRMS:m/z 423(M+1)⁺. Preparation of 163-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-oxy) pyridine

Using the procedure of preparation 15, from the title compound of preparation 13 and 3-methoxypropan-1-ol, the title compound was obtained as an oil (95%). Delta (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)⁺. Example 173-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) -yloxy) pyridine

A mixture of 2M solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran (1.83ml,3.66mmol), (S) - (+) -3-hydroxytetrahydrofuran (272. mu.l, 6mmol) and tetrahydrofuran (40ml) was stirred at room temperature for 30 minutes. Next, the title compound of preparation 13 (750mg,2mmol) was added and the reaction mixture was stirred for 18 hours and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of hexane: ethyl acetate (25: 75 to 0: 100) to give the title compound as an oil (430mg, 51%). Delta (CDCl)₃):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 of 182-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester

Sodium nitrite (2.22g,32.1mmol) was added to a stirred solution of the title compound of preparation 7 (4.5g,21.4mmol) in a mixture of concentrated hydrochloric acid (90ml) and glacial acetic acid (90ml) at-20 ℃ and the resulting mixture was stirred for 2 hours while the temperature was raised to 0 ℃. The mixture is again mixedCooled to-20 ℃ and a solution of liquid sulphur dioxide (50ml) and copper (II) chloride (8.4g,62.5mmol) in a mixture of water (9ml) and acetic acid (80ml) was added and the reaction mixture was stirred at 0 ℃ for 30 minutes and subsequently at room temperature for a further 2 hours. The resulting mixture was poured onto stirred ice (80g) and the aqueous solution thus obtained was extracted with dichloromethane (3X 50 ml). Drying (MgSO)₄) The combined extracts were evaporated under reduced pressure to give the crude sulfonyl chloride as a brown oil.

1-ethylpiperazine (10.9ml,85.6mmol) was added to a stirred solution of the sulfonyl chloride in ethanol (60ml) and the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (20ml) and dichloromethane (30ml), the separated aqueous phase was extracted with dichloromethane (2X 30ml) and then dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The residual brown oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 98: 2) to give the title compound as a light brown oil (5.0g, 63%). Measured value: c, 51.40; h, 6.77; n, 11.15. C₁₆H₂₅N₃O₅S calculated value: c, 51.74; h, 6.78; n,11.31 percent. Delta (CDCl)₃):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(1H,s),8.62(1H,s)。LRMS:m/z 372(M+1)⁺. Preparation of 195- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylic acid ethyl ester

Triethylamine (3ml,19mmol) and tetrakis (triphenylphosphine) palladium (0) (260mg,0.22mmol) were added to a solution of the title compound of preparation 14 (1.30g,3mmol) in ethanol (15ml) and the mixture was heated in a closed vessel under carbon monoxide at 100 ℃ and 1034kPa (150psi) for 18 h and then allowed to cool. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give a yellow solid. The crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 97: 3) to give the title compound as a yellow oil (1.10g, 92%). Delta (CDCl)₃):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 of 202- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 15, using the procedure of preparation 19, the title compound was obtained as a gum (96%). Delta (CDCl)₃):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 215- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-yloxy) -pyridine-3-carboxylic acid ethyl ester

A mixture of triethylamine (5ml,35.9mmol), tetrakis (triphenylphosphine) palladium (0) (200mg,0.17mmol), the title compound of preparation 16 (1.08g,2.54mmol), and ethanol (25ml) was heated in a closed vessel under carbon monoxide at 100 ℃ and 1034kPa (150psi) for 18 h and then allowed to cool. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (40ml) and the solution was washed successively with saturated aqueous sodium bicarbonate (20ml), brine (20ml) and 2M hydrochloric acid (5X 10 ml). The combined acidic extracts were basified using solid sodium bicarbonate and the solution was extracted with ethyl acetate (2X 25 ml). Drying (MgSO)₄) The combined organic extracts were evaporated under reduced pressure to give the title compound as an oil (640mg, 68%). Delta (CDCl)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 of 225- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) -yloxy) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 17 using the procedure of preparation 19, the title compound was obtained as a yellow oil (78%). Delta (CDCl)₃):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(1H,m),4.38(2H,q),5.70(1H,m),8.41(1H,s),8.62(1H,s)。LRMS:m/z 414(M+1)⁺. Preparation of 232-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid

A mixture of preparation 18 of the title compound (4.96g,13.35mmol), 2M aqueous sodium hydroxide (25ml,50mmol) and ethanol (25ml) was stirred at room temperature for 2 hours. The resulting mixture was concentrated to half its volume under reduced pressure, washed with diethyl ether and acidified to pH5 using 4M hydrochloric acid. The aqueous solution was extracted with dichloromethane (3X 30ml) and then dried (MgSO₄) The combined extracts were evaporated under reduced pressure to give the title compound as a brown solid (4.02g, 88%). Delta (DMSOd)₆) 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 of 242-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid sodium salt

A1M aqueous solution of sodium hydroxide (85ml,85mmol) was slowly added to a stirred, ice-cooled solution of the title compound of preparation 18 (30.2g,85mmol) in ethanol (300ml) and the reaction mixture was stirred at room temperature for 18 hours. The resulting mixture was evaporated under reduced pressure and the residue partitioned between water (225ml) and ethyl acetate (250 ml). The phases were separated and the aqueous phase was washed with ethyl acetate (2X 200ml) and evaporated under reduced pressure to give the title compound as a white solid (29.6g, 81%). Delta (DMSOd)₆) 0.90(3H, t),1.25(3H, t), 224 (2H, q),2.40(4H, m),2.82(4H, m),4.39(2H, q),7.76(1H, s),8.28(1H, s). Preparation of 254- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylate

A solution of the title compound of preparation 19 (1.18g,2.94mmol) in a mixture of ethanol (10ml) and 1M aqueous sodium hydroxide (10ml,10mmol) was stirred at room temperature for 1 hour. The resulting mixture was concentrated to half volume under reduced pressure and the aqueous solution of the residue was washed with ethyl acetate (10ml), followed by acidification to pH3 with dilute hydrochloric acid. The acidic solution was extracted with dichloromethane: methanol (95: 5) (6X 20ml) and dried (MgSO)₄) The combined extracts were evaporated under reduced pressure to give the title compound as a white foam (995mg, 82%). Delta (DMSOd)₆):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(1H,s)。LRMS:m/z 374(M+1)⁺. Preparation of 262- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid hydrochloride

A mixture of the title compound of preparation 20 (859mg,2.07mmol), 1M aqueous sodium hydroxide (4.6ml,4.6mmol) and 1, 4-dioxane (5ml) was stirred at room temperature for 2 hours. The 1, 4-dioxane was removed by evaporation under reduced pressure and the remaining aqueous solution was adjusted to pH3 with hydrochloric acid. The resulting solution was evaporated under reduced pressure, the residue triturated with hot ethanol and the mixture filtered. The filtrate was then evaporated under reduced pressure to give the title compound as a brown solid (760mg, 87%). Delta (DMSOd)₆):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(1H,s)。LRMS:m/z 387(M)⁺. Preparation of 274- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-yloxy) pyridine-3-carboxylic acid hydrochloride

From the title compound of preparation 21, using the procedure of preparation 26, the title compound was obtained as a solid (87%). Delta (DMSOd)₆):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(1H,s),8.73(1H,s)。LRMS:m/z 388(M+1)⁺. Preparation of 282-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid chloride hydrochloride

Oxalyl chloride (0.77ml,8.85mmol) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 23 (1.52g,4.42mmol) and dimethylformamide (2 drops) in dichloromethane (30ml) and the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was triturated with ethyl acetate and the resulting solid collected, washed with ether and dried under suction to give the title compound (1.68g, 95%). Measured value: c, 41.51; h, 5.27; n, 10.32. C₁₄H₂₁Cl₂N₃O₄S；0.10 CH₂Cl₂Calculated values: c, 41.73; h, 5.02; n,10.36 percent. Delta (CDCl)₃) 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(1H, s),13.16(1H, s). Preparation 295- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridine-3-carboxylic acid chloride hydrochloride

Oxalyl chloride (270. mu.l, 3.13mmol) was added dropwise to a stirred, ice-cooled suspension of the title compound of preparation 25 (390mg,1.04mmol), dimethylformamide (100. mu.l) and dry dichloromethane (20ml), and 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 toluene (2X 20ml) to give the title compound as a white solid (390mg, 95%). Delta (DMSOd)₆) 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(1H, s),8.72(1H, s),14.20(1H, s). Preparation of 303-ethyl-1H-pyrazole-5-carboxylic acid ethyl ester

A solution of sodium ethoxide (21% w/w; 143ml,0.39mol) in ethanol was added dropwise to a stirred, ice-cooled solution of diethyl oxalate (59.8ml,0.44mol) in anhydrous ethanol (200ml) under nitrogen and the resulting solution was stirred for 15 minutes. Butan-2-one (39ml,0.44mol) was then added dropwise, the cooling bath was removed, the reaction mixture was stirred at room temperature for 18 hours and then at 40 ℃ for 6 hours, and then introduced into the cooling bath again. Next, glacial acetic acid (25ml,0.44mol) was added dropwise and the resulting solution was stirred at 0 ℃ for 30 minutes. Hydrazine hydrate (20ml,0.44mol) was added dropwise and then the reaction mixture was allowed to warm to room temperature and maintained for 18 hours, after which it was evaporated under reduced pressure. The residue was partitioned between dichloromethane (300ml) and water (100ml) and the organic phases were separated, washed with water (2X 100ml) and dried (Na)₂SO₄) And concentrated under reduced pressure to give the title compound (66.0 g). Delta (CDCl)₃):1.04(3H,t),1.16(3H,t),2.70(2H,q),4.36(2H,q),6.60(1H,s)。LRMS:m/z 169(M+1)⁺. Preparation of 313-ethyl-1H-pyrazole-5-carboxylic acid

An aqueous solution of sodium hydroxide (10M; 100ml,1.0mol) was added dropwise to a stirred suspension of the title compound of preparation 30 (66.0g,0.39mol) in methanol (400ml) and the resulting solution was heated at reflux for 4 hours. The cooled reaction mixture was concentrated under reduced pressure to a calculated volume of 200ml, diluted with water (200ml) and the mixture washed with toluene (3X 100 ml). The resulting aqueous phase was acidified to pH4 with concentrated hydrochloric acid and the white precipitate was collected and dried under suction to give the titleCompound (34.1 g). Delta (DMSOd)₆) 1.13(3H, t),2.56(2H, q),6.42(1H, s). Preparation of 324-nitro-3-n-propyl-1H-pyrazole-5-carboxylic acid

Oleum (17.8ml) was added dropwise to stirred, ice-cooled fuming nitric acid (16.0ml), the resulting solution was heated to 50 ℃ and 3-n-propyl-1H-pyrazole-5-carboxylic acid (chem. pharm. Bull.,1984,32, 1568; 16.4g,0.106mol) was added portionwise over 30 minutes, while maintaining the reaction temperature below 60 ℃. The resulting solution was heated at 60 ℃ for 18 hours, allowed to cool, and then poured onto ice. The white precipitate was collected, washed with water and dried under suction to give the title compound (15.4g), m.p.170-172 ℃. Measured value: c, 42.35; h, 4.56; and N, 21.07. C₇H₉N₃O₄Calculated values: c, 42.21; h, 4.55; and N, 21.10%. Delta (DMSOd)₆) 0.90(3H, t),1.64(2H, m),2.83(2H, m),14.00(1H, s). Preparation of 333-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid

From the title compound of preparation 31 by a method similar to preparation 32, the title compound was obtained as a brown solid (64%). Delta (DMSOd)₆) 1.18(3H, t),2.84(2H, m),13.72(1H, s). Preparation of 344-nitro-3-n-propyl-1H-pyrazole-5-carboxamide

A solution of the title compound of preparation 32 (15.4g,0.077mol) in thionyl chloride (75ml) was heated at reflux for 3 hours and the cooled reaction mixture was then evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran (2 × 50ml) and then suspended in tetrahydrofuran (50ml), and then the stirred suspension was cooled with ice and treated with ammonia gas for 1 hour. Water (50ml) was added and the resulting mixture was evaporated under reduced pressure to give a solid which, after trituration with water and drying under suction, gave the title compound (14.3g) m.p.197-199 ℃. Measured value: c, 42.35; h, 5.07; n, 28.38. C₇H₁₀N₄O₃Calculated values: c, 42.42; h, 5.09; n, 28.27%. Delta (DMSOd)₆) 0.90(3H, t),1.68(2H, m),2.86(2H, t),7.68(1H, s),8.00(1H, s). Preparation of 353-ethyl-4-nitro-1H-pyrazole-5-carboxamide

Prepared by a method similar to that of preparation 34The title compound of example 33 was prepared as a white solid (90%). Delta (DMSOd)₆):1.17(3H,t),2.87(2H,m),7.40(1H,s),7.60(1H,s),7.90(1H,s)。LRMS:m/z 185(M+1)⁺. Preparation of 364-amino-3-n-propyl-1H-pyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 34 (10.0g,0.050mol), 10% palladium on charcoal (1.5g) and ethanol (400ml) was hydrogenated at 345Kpa (50psi) and 50 deg.C for 18 h, then filtered. The filtrate was combined with an ethanol wash of the filter pad (200ml) and then evaporated under reduced pressure to give an orange solid which crystallized from ethyl acetate-methanol to give the title compound as a white solid (6.8g), m.p.196-201 ℃. Measured value: c, 48.96; h, 6.98; n, 32.08. C₇H₁₂N₄O；0.25H₂Calculated value of O: c, 48.68; h, 7.30; n,32.44 percent. Delta (DMSOd)₆) 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(1H, s). Preparation of 374-amino-3-ethyl-1H-pyrazole-5-carboxamide

From the title compound of preparation 35 by a method similar to preparation 36, the title compound was obtained as a brown solid (80%). Delta (DMSOd)₆):1.08(3H,t),2.45(2H,q),4.50(1H,s),6.88(1H,s),7.10(1H,s),7.26(2H,s)。LRMS:m/z 155(M+1)⁺. Preparation of 38a 3-ethyl-4-nitro-1- (pyridin-2-yl) methylpyrazole-5-carboxamide and preparation of 38b 3-ethyl-4-nitro-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 35 (20.0g,109mmol), 2- (chloromethyl) pyridine hydrochloride (17.9g,109mmol), cesium carbonate (74.7g,222mmol) and dimethylformamide (120ml) was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (100ml) and dichloromethane (100ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (3X 100ml) and dried (MgSO₄) The combined extracts were evaporated under reduced pressure. The residue was crystallized from dichloromethane-methanol to give the first title compound (1-isomer; 6.5g, 21%). Delta (CDCl)₃):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(1H,m),8.52(1H,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 give the second title compound (2-isomer; 17.36g, 58%) as a white solid. Delta (CDCl)₃) 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, m),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- (pyridin-2-yl) methylpyrazole-5-carboxamide

2- (chloromethyl) pyridine hydrochloride (24.6g,150mmol) was added portionwise to a stirred solution of the title compound of preparation 34 (30.0g,150mmol) and cesium carbonate (123.5g,380mmol) in dimethylformamide (300ml) and the reaction mixture was stirred at room temperature for 18 h 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 silica gel column chromatography operations using dichloromethane: methanol (98: 2) and ethyl acetate: pentane (20: 80) as eluents to give the first title compound as a white solid (1-isomer; 424mg, 1%). Measured value: c, 53.74; h, 5.20; n, 23.91. C₁₃H₁₅N₅O₃Calculated values: c, 53.97; h, 5.23; n,24.21 percent. Delta (CDCl)₃):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 a second title compound as a white solid (2-isomer; 16.7g, 38%). Delta (DMSOd)₆) 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(1H, d). Preparation of 404-amino-3-ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 38b (16.36g,59mmol), 10% palladium on charcoal (4g) and ethanol (150ml) was hydrogenated at 345kPa (50psi) for 4h and then filtered. The filtrate was combined with the ethyl acetate wash of the filter pad (150ml) and then concentrated under reduced pressure to a volume of about 70 ml. Collecting the generated sedimentPrecipitation and drying under suction gave the title compound as a white solid (12.6g, 87%). Delta (CDCl)₃):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(1H,d),7.20(1H,m),7.62(1H,m),8.57(1H,d)。LRMS:m/z 246(M+1)⁺. Preparation of 414-amino-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 39b (1.0g,3.46mmol), Raney nickel (1g) and ethanol (50ml) was hydrogenated at 345kPa (50psi) and 50 ℃ for 18 h, then allowed to cool and filtered. The filtrate was combined with ethanol washings of the filter pad (50ml), then evaporated under reduced pressure to give the title compound as a crystalline solid (830mg, 93%). Delta (DMSOd)₆):0.79(3H,t),1.33(2H,m),3.28(2H,t),4.60(2H,s),5.30(2H,s),6.88(1H,d),6.98(1H,s),7.13(1H,s),7.30(1H,m),7.74(1H,m),8.50(1H,d)。LRMS:m/z 274(M)⁺. Preparation 424-amino-3-ethyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 40, from the title compound of preparation 38a, the title compound was obtained as a solid (94%). Delta (CDCl)₃):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(1H,m),8.49(1H,d)。LRMS:m/z 246(M+1)⁺. Preparation 434- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethyl-1H-pyrazole-5-carboxamide hydrochloride

A mixture of the title compound of preparation 28 (1.0g,2.51mmol), the title compound of preparation 37 (387mg,2.51mmol) and pyridine (15ml) was stirred at room temperature for 18 hours. The resulting mixture was evaporated under reduced pressure and the residue was triturated with ether to give the title compound as a purple-red solid (1.05g, 87%). Measured value: c, 44.82; h, 5.72; n, 18.62. C₂₀H₂₉N₇O₅S；HCl；H₂Calculated value of O: c, 44.98; h, 6.04; n,18.36 percent. Delta (DMSOd)₆):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(1H,s),8.52(1H,s),8.76(1H,s),10.54(1H,s)。LRMS:m/z 480(M+1)⁺. Preparation 445- [ 2-ethoxy-5- (4-ethyl) ethyl esterPiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-1, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (943g,8.41mmol) was added to a stirred suspension of the title compound of preparation 43 (1.10g,2.1mmol) in absolute ethanol (50ml) and the reaction mixture was heated in a closed vessel at 100 ℃ for 18 h 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 pH6 using hydrochloric acid and the resulting solid was collected, washed with water and dried under suction. The crude product was purified by silica gel column chromatography using dichloromethane: methanol (97: 3) as eluent to give the title compound as a yellow solid (445mg, 46%). Measured value: c, 51.95; h, 5.89; and N, 20.87. C₂₀H₂₇N₇O₄S calculated value: c, 52.05; h, 5.90; and N, 21.24%. Delta (DMSOd)₆):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(1H,s),8.64(1H,s),12.19(1H,s),13.80(1H,s)。LRMS:m/z 462(M+1)⁺. Preparation of 454- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-Ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide selection A

A mixture of the title compound of preparation 28 (1.0g,2.5mmol), the title compound of preparation 40 (620mg,2.5mmol), triethylamine (1.35ml,10mmol) and dichloromethane (50ml) was stirred at room temperature for 18 hours. The resulting mixture was poured into stirred water (50ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). Drying (MgSO)₄) The combined organic solutions were evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a foam (1.29g, 90%). Delta (CDCl)₃) 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(1H, s),6.90(1H, d),7.18(1H, m),7.61(1H, m),8.57(1H, s),8.62(1H, s),8.80(1H, s),10.57(1H, s). Selection B

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride(17.6g,91.8mmol) was added portionwise over 5 minutes to a stirred, ice-cooled suspension of 1-hydroxybenzotriazole hydrate (12g,88.9mmol) and preparation 24 of the title compound (24g,65.7mmol) in tetrahydrofuran (300ml), and the mixture was stirred for 1 hour. N-ethyldiisopropylamine (12.7g,98.3mmol) and the title compound of preparation 40 (12.9g,52.6mmol) were added and the reaction mixture was stirred at room temperature for 14 h and then evaporated under reduced pressure. The residue was partitioned between water (100ml) and ethyl acetate (200ml), the phases were separated and the organic phase was washed successively with water (50ml), saturated aqueous sodium bicarbonate (50ml) and brine (50ml) and then dried (MgSO)₄) And concentrated to low volume under reduced pressure. The resulting suspension was cooled in ice for 1 hour, then the precipitate was collected and dried under suction to give the title compound as a white crystalline solid (14.1g, 47%), m.p.185-187 ℃. Measured value: c, 5459; h, 6.05; n, 19.32. C₂₆H₃₄N₈O₃S calculated value: c, 54.72; h, 6.00; n,19.63 percent. Preparation of 462-n-propoxypyridine-3-carboxylic acid

Using the procedure of preparation 1, from 2-chloronicotinic acid and n-propanol, the title compound was obtained as a light brown oil (50%). Delta (CDCl)₃) 1.08(3H, t),1.92(2H, m),4.56(2H, t),7.10(1H, m),8.35(1H, d),8.45(1H, d). Preparation of 472-n-propoxypyridine-3-carboxylic acid methyl ester

Diethyl azidodicarboxylate (2.2ml,14mmol) was added dropwise to a stirred solution of the title compound of preparation 46 (2.30g,12.7mmol), triphenylphosphine (3.67g,14mmol) and methanol (0.60ml,15mmol) in tetrahydrofuran (20ml) and the reaction mixture was stirred at room temperature for 18 h 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 silica gel column chromatography using pentane: ether (50: 50) as eluent to give the title compound as a pale yellow oil (2.2g, 89%). Delta (CDCl)₃) 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 of 485-nitro-2-n-propoxypyridine-3-carboxylic acid methyl ester

Using the method of preparation 5From the title compound of preparation 47, after crystallization from methanol, the title compound was obtained as pale yellow needles (32%). Delta (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). Example 495-amino-2-n-propoxypyridine-3-carboxylic acid methyl ester

A mixture of the title compound of preparation 48 (1.8g,7.46mmol), Raney nickel (500mg) and methanol (50ml) was hydrogenated at 345kPa (50psi) and 50 ℃ for 3h, then allowed to cool and filtered. The filtrate was combined with methanol washings of the filter pad (100ml) and then evaporated under reduced pressure to give the title compound as a brown oil (1.5g, 95%). Delta (CDCl)₃):1.04(3H,t),1.80(2H,m),3.40(2H,s),3.89(3H,s),4.28(2H,t),7.57(1H,s),7.80(1H,s)。LRMS:m/z 211(M+1)⁺. Preparation 505- (4-Methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid methyl ester

Using the procedure of preparation 18, from the title compound of preparation 49 and 1-methylpiperazine, the title compound was obtained as an oil (56%). Preparation 515- (4-Methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid

Using the procedure of preparation 23, from the title compound of preparation 50, the title compound was obtained as a white solid (82%). Delta (DMSOd)₆) 0.97(3H, t),1.74(2H, m),2.15(3H, s),2.38(4H, m),2.93(4H, m),4.37(2H, t),8.15(1H, s),8.56(1H, s). Example 523-Ethyl-4- [5- (4-methylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-ylcarboxamide]-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Oxalyl chloride (550 μ l,6.37mmol), dimethylformamide (2 drops) were added carefully to a stirred, ice-cooled suspension of the title compound of preparation 51 (605mg,1.59mmol) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for 2 hours and then evaporated under reduced pressure. The residue was azeotroped with toluene to yield a powder.

A solution of the crude acid chloride in dichloromethane (10ml) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 40 (430mg,1.76mmol), triethylamine (558. mu.l, 4mmol) and dichloromethaneMethyl chloride (10ml) and the reaction mixture was stirred at room temperature for 1.5 hours. The resulting mixture was washed successively with saturated aqueous sodium bicarbonate solution and brine, and then dried (MgSO)₄) The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of hexane: ethyl acetate: methanol (70: 30: 0 to 0: 90: 10) to give the title compound (695mg, 76%) as a solid. Measured value: c, 53.96; h, 6.09; n, 19.00. C₂₆H₃₄N₈O₅S calculated value: c, 54.22; h, 6.00; n,19.64 percent. Delta (CDCl)₃):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(1H,s),5.48(2H,s),6 70(1H,s),6.94(1H,d),7.22(1H,m),7.66(1H,m),8.59(1H,d),8 65(1H,s),8.82(1H,s),10.48(1H,m)。LRMS:m/z 572(M+2)⁺. Preparation 534- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 45A, the title compound was obtained as a white foam from the title compounds of preparation 29 and preparation 41 (70%). Delta (CDCl)₃):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(1H,s),5.46(2H,s),6.69(1H,s),6.90(1H,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 of 544- [2- (2-ethoxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 52, from the title compounds of preparation 26 and preparation 41, the title compound was obtained as a foam (69%). Measured value: c, 55.13; h, 6.45; n, 17.27. C₂₉H₄₀N₈O₆S calculated value: c, 55.39; h, 6.41; n, 17.82%. Delta (CDCl)₃):0.80(3H,t),1.02(3H,t),1.10(3H,t),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(1H,s),5.47(2H,s),6.70(1H,s),6.89(1H,d),7.22(1H,m),7.63(1H,m),8.59(1H,d),8.65(1H,s),8.82(1H,s),10 45(1H,s)。LRMS:m/z 629(M+1)⁺. Preparation of 554- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (3-methoxypropan-1-yloxy) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 52, from the title compounds of preparation 27 and preparation 41, the title compound was obtained as a foam (52%). Delta (CDCl)₃):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(1H,s)。LRMS:m/z 629(M+1)⁺. Preparation 563-Ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (S) -yloxy) pyridin-3-ylcarboxamide]-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A solution of the title compound of preparation 22 (330mg,0.80mmol) and 1M sodium hydroxide solution (800. mu.l, 0.80mmol) in ethanol (3ml) was stirred at room temperature for 3 hours and then evaporated under reduced pressure.

A mixture of the resulting solid, the title compound of preparation 40 (196mg,0.80mmol), 1-hydroxybenzotriazole hydrate (135mg,0.88mmol), N-ethyldiisopropylamine (307. mu.l, 1.76mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (169mg,0.88mmol) and tetrahydrofuran (15ml) was stirred at room temperature for 72 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (50ml) and water (15ml), the phases were separated and dried (Na)₂SO₄) The organic phase was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (95: 5 to 90: 10) to give the title compound as a foam (382mg, 78%). Delta (CDCl)₃):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(1H,m),8.66(1H,s),8.87(1H,s),10.27(1H,s)。LRMS:m/z 613(M+1)⁺. Example 574- (2-ethoxy-5-nitropyridin-3-ylcarboxamide) -3-n-propyl-2- (pyridine)-2-yl) methylpyrazole-5-carboxamide

Oxalyl chloride (2.73ml,31mmol) was added dropwise to a stirred suspension of the title compound of preparation 8 (3.31g,15.7mmol) in dichloromethane (50ml), followed by dimethylformamide (2 drops) and the reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was evaporated under reduced pressure and the residue azeotroped with hexane to give a white solid.

A solution of the crude acid chloride in dichloromethane (20ml) was added dropwise to a stirred suspension of the title compound of preparation 41 (4.06mg,15.7mmol), triethylamine (4.37ml,31mmol) and dichloromethane (80ml) and the reaction mixture was stirred at room temperature for 20 h. The resulting mixture was evaporated under reduced pressure and the residue partitioned between saturated aqueous sodium bicarbonate (200ml) and dichloromethane (300 ml). The phases were separated and the aqueous phase was extracted with dichloromethane (2X 300 ml). The combined organic solutions were washed with brine and dried (Na)₂SO₄) And evaporated under reduced pressure to give a magenta solid. The crude product was triturated with ether and the resulting solid collected and dried under suction to give the title compound as an off-white solid (6.26g, 88%). Found C, 55.42; h, 5.05; n, 21.49. C₂₁H₂₃N₇O₅Calculated values: c, 55.62; h, 5.11; and N,21.62 percent. Delta (CDCl)₃):0.83(3H,t),1.46(2H,m),1.60(3H,t),2.89(2H,t),4.85(2H,q),5.32(1H,s),5.48(2H,s),6.72(1H,s),6.95(1H,d),7.24(1H,m),7.67(1H,m),8.60(1H,d),9.16(1H,s),9.30(1H,s),10.59(1H,s)。LRMS:m/z 454(M+1)⁺. Example 583-Ethyl-4- [2- (2-methoxyethoxy) -5-nitropyridin-3-ylcarboxamide]-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

1-hydroxybenzotriazole hydrate (1.87g,12.2mmol), N-ethyldiisopropylamine (2.13ml,12.2mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.34g,12.2mmol) and the title compound of preparation 40 (3.0g,12.2mmol) were added successively to a stirred, ice-cooled suspension of the title compound of preparation 9 (2.96g,12.2mmol) in dichloromethane (80ml) and the reaction mixture was stirred at room temperature for 18 hours. With water (25 m)l), 2M hydrochloric acid (2X 25ml), saturated aqueous sodium bicarbonate (25ml) and brine (25ml) the resulting mixture was washed successively and then dried (MgSO 2₄) And evaporated under reduced pressure. The residual solid was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound as a white solid (3.36g, 58%). Measured value: c, 53.41; h, 4.90; and N, 20.65. C₂₁H₂₃N₇O₆Calculated values: c, 53.72; h, 4.94; and N, 20.89%. Delta (CDCl)₃):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(1H,s),6.92(1H,d),7.23(1H,m),7.66(1H,m),8.60(1H,d),9.15(1H,s),9.31(1H,s),10.50(1H,s)。LRMS:m/z 470(M+1)⁺. Example 594- (5-amino-2-ethoxypyridin-3-ylcarboxamide) -3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 57 (5g,11mmol), Raney nickel (2.5g) and ethanol (150ml) was hydrogenated at 345kPa (50Psi) and 40 ℃ for 3h, then reacted further at room temperature for 72 h. 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 silica gel column chromatography using an elution gradient of dichloromethane: methanol (99: 1 to 95: 5) followed by trituration with ether to give the title compound as a beige solid (4.4g, 94%). Measured value: c, 59.42; h, 5.96; n, 22.98. C₂₁H₂₅N₇O₃Calculated values: c, 59.56; h, 5.95; and N,23.15 percent. Delta (CDCl)₃) 0.78(3H, t),1.43(2H, m),1.52(3H, t),2.82(2H, t),3.49(2H, s),4.59(2H, q),5.30(1H, s),5.46(2H, s),6.70(1H, s),6.93(1H, d),7.22(1H, m),7.65(1H, m),7.78(1H, s),7.94(1H, s),8.58(1H, d),10.53(1H, s). Example 604- [ 5-amino-2- (2-methoxyethoxy) pyridin-3-ylcarboxamide) -3-ethyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 58 (3.3g,7.0mmol), Raney nickel (2g) and ethanol (120ml) was hydrogenated at 345kPa (50Psi) and 50 ℃ for 18 h. The resulting mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as a light grey foam(3.01g, 98%). Measured value: c, 56.47; h, 582; and N, 21.40. C₂₁H₂₅N₇O₄；0.40H₂Calculated value of O: c, 56.47; h, 5.82; and N,21.95 percent. Delta (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(1H,m),7.76(1H,s),7.94(1H,s),8.60(1H,d),10.47(1H,s)。LRMS:m/z 440(M+1)⁺. Preparation 615- (5-amino-2-ethoxypyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium tert-butoxide (2.32g,20mmol) was carefully added to a stirred suspension of the title compound of preparation 59 (2.11g,5mmol) and 4A molecular sieve in ethanol (50ml) and the reaction mixture was heated at reflux for 18 h, allowed to cool and filtered. The filtrate was evaporated under reduced pressure and the residue partitioned between 1M hydrochloric acid (30ml) and ethyl acetate (30 ml). The phases were separated, the aqueous phase was extracted with ethyl acetate (2X 30ml) and the combined organic solutions were washed with brine and dried (Na)₂SO₄) And evaporated under reduced pressure. The residual brown oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a pale yellow solid (1.22g, 60%). Measured value: c, 61.92; h, 5.69; and N, 23.95. C₂₁H₂₃N₇O₂Calculated values: c, 62.21; h, 5.72; and N,24.18 percent. Delta (CDCl)₃) 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),8.15(1H, d),8.57(1H, s),11.07(1m, s). Preparation of 625- [ 5-amino-2- (2-methoxyethoxy) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Potassium bis (trimethylsilyl) amide (6.58g,33.0mmol) was added to a stirred suspension of the title compound of preparation 60 (2.90g,6.60mmol) in 2-methoxyethanol (70ml) and the reaction mixture was stirred at reflux for 18 h. The resulting mixture was allowed to cool and then evaporated under reduced pressure to give a beige solid. Purifying the crude product by silica gel column chromatographyUsing an elution gradient of dichloromethane: methanol (98: 2 to 95: 5), the title compound was obtained as a white solid (2.21g, 79%). Measured value: c, 59.10; h, 5.44; n, 22.86. C₂₁H₂₃N₇O₃Calculated values: c, 59.85; h, 5.50; and N, 23.26%. Delta (CDCl)₃):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(1H,s)。LRMS:m/z 422(M+1)⁺. Preparation 635- (5-chlorosulfonyl-2-ethoxypyridin-3-yl) -3-n-propyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3, d]Pyrimidin-7-ones

Sodium nitrite (295mg,4.4mmol) was added portionwise to a stirred, ice-cooled solution of the title compound of preparation 61 (900mg,2.2mmol) in a mixture of glacial acetic acid (20ml) and concentrated hydrochloric acid (20ml) at such a rate that the temperature was maintained below-20 ℃. When the addition was complete, the mixture was allowed to warm slowly to 0 ℃ over 2 hours and then cooled again to-15 ℃. Then a solution of liquid sulphur dioxide (22m1) and copper (II) chloride (860mg,6.6mmol) in a mixture of water (2ml) and glacial acetic acid (14ml) was added and the reaction mixture was stirred at 0 ℃ for 30 minutes, then at room temperature for a further 2 hours. The resulting mixture was carefully poured into ice-water (300ml) and the suspension thus obtained was extracted with dichloromethane (3 × 100 ml). The combined extracts were washed with brine and dried (MgSO)₄) And evaporated under reduced pressure then the residual oil was triturated with ether to give the title compound as an off-white solid (720mg, 67%). Delta (CDCl)₃) 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(1H, d),7.22(1H, m),7.64(1H, m),8.58(1H, d),8.90(1H, s),9.29(1H, s),10.55(1H, s). Preparation 645- [ 5-chlorosulfonyl-2- (2-methoxyethoxy) pyridin-3-yl]-3-ethyl-2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Using the procedure of preparation 63, the title compound was obtained as a cream solid from the title compound of preparation 62 (84%). Delta (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),10.75(1H,s)。LRMS:m/z 505(M+1)⁺. Preparation of 653-ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide]-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

The title compound was obtained as a white crystalline solid (44%) from the title compound of preparation 19 and preparation 42 using the method of preparation 56. Delta (CDCl)₃):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(1H,s),7.26(2H,m),7.71(1H,m),8.53(1H,d),8.66(1H,s),8.82(1H,s),9.04(1H,s)。LRMS:m/z601(M+1)⁺. Preparation 663-bromo-2- (1, 3-dimethoxyprop-2-yloxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

60% sodium hydride (133mg,3.33mmol) suspended in mineral oil was added to a stirred, ice-cooled solution of 1, 3-dimethoxypropan-2-ol (J.Amer.chem.Soc.,1939,61, 433; 400mg,3.33mmol) in tetrahydrofuran (30ml) and the mixture was stirred for 30 minutes. The title compound of preparation 13 (500mg,1.35mmol) was added and 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 partitioned between water (30ml) and ethyl acetate (30 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (2X 30ml) and the combined extracts were washed with brine (30ml) and dried (MgSO)₄) And evaporated under reduced pressure to give the title compound as a yellow solid (566mg, 93%). Delta (CDCl)₃) 1.06(3H, t),2.43(2H, q),2.55(4H, m),3.08(4H, m),3.40(6H,2 xs), 3.70(4H,2 xd), 5.60(1H, m),8.10(1H, s),8.44(1H, s). LRMS m/z 452. Preparation of 672- (1, 3-Dimethoxypropan-2-yloxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 66, using the procedure of preparation 19, the title compound was obtained as a yellow solid (84%). Delta (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,2×s),3.70(4H,2×d),4.37(2H,q),5.70(1H,m),8.40(1H,s),8.62(1H,s)。LRMS:m/z446(M+1)⁺. Preparation 683-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridine

After purification by silica gel column chromatography according to the method of preparation 14 from the title compound of preparation 13 and 4-hydroxytetrahydropyran using ethyl acetate as eluent, the title compound was obtained as a clear oil (70%). Delta (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 of 695- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 68, using the procedure of preparation 19, the title compound was obtained as an oil (92%). Delta (CDCl)₃):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 705- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridine-3-carboxylic acid sodium salt

A mixture of the title compound of preparation 69 (611mg,1.4mmol), 1M aqueous sodium hydroxide (1.6ml,1.6mmol) and ethanol (6ml) was stirred at room temperature for 6 hours and then evaporated under reduced pressure. The residue was dissolved in water (16ml), the solution was then washed with ethyl acetate (2 × 10ml) and evaporated under reduced pressure to give the title compound as a brown solid (520mg, 93%). Delta (DMSOd)₆):1.19(3H,t),1.70(2H,m),2.00(2H,m),2.80-3.88(14H,m),8.32(1H,s),8.73(1H,s),10.93(1H,s)。LRMS:m/z 400(M+1)⁺. Preparation 712- (1, 3-Dimethoxypropan-2-yloxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid sodium salt

From the title compound of preparation 67, using the method of preparation 70, the title compound was obtained as a solid (92%). LRMS M/z 418(M +1)⁺. Preparation 724- [2- (1, 3-Dimethoxyprop-2-yloxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 71 (418mg,0.95mmol) and the title compound of preparation 41 (250mg,1.0mmol), 1-hydroxybenzotriazole hydrate (270mg,2.0mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (380mg,2.0mmol), triethylamine (280. mu.l, 2.0mmol) and tetrahydrofuran (10ml) was stirred at room temperature for 36 hours, then evaporated under reduced pressure. The residue was partitioned between dichloromethane (10ml) and brine (10ml), the phases were separated, the aqueous phase was extracted with dichloromethane (2X 10ml) and dried (MgSO 2₄) The combined organic solutions were evaporated under reduced pressure. The residual yellow oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (98: 2 to 96: 4) to give the title compound as an off-white solid (350mg, 56%). Delta (CDCl)₃):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(1H,s),5.47(2H,s),5.93(1H,m),6.70(1H,s),6.92(1H,d),7.23(1H,m),7.65(1H,m),8.58(1H,d),8.65(1H,s),8.80(1H,s),10.26(1H,s)。LRMS:m/z 660(M+2)⁺. Preparation 733-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridine

Using the procedure of preparation 17, from the title compound of preparation 13 and (R) - (-) -3-hydroxytetrahydrofuran, the title compound was obtained as an oil (89%). Delta (CDCl)₃):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(1H,m),4.10(1H,m),5.63(1H,m),8.11(1H,s),8.43(1H,s)。LRMS:m/z 421(M+1)⁺. Preparation 745- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 73 using the procedure of preparation 19, the title compound was obtained as an oil (84%). Delta (CDCl)₃):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(1H,s),8.62(1H,s)。LRMS:m/z 414(M+1)⁺. Preparation 753-ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydrofuran-3 (R) -yloxy) pyridin-3-ylcarboxamide]-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

The title compound was obtained as a foam (78%) from the title compounds of preparation 74 and preparation 40 using the procedure of preparation 56. Delta (CDCl)₃):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(1H,s),5.48(2H,s),5.90(1H,m),6.68(1H,s),6.92(1H,d),7.22(1H,m),7.67(1H,m),8.60(1H,d),8.64(1H,s),8.86(1H,s),10.28(1H,s)。LRMS:m/z 613(M+1)⁺. Preparation 764- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydropyran-4-yloxy) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 70 (520mg,1.3mmol) and the title compound of preparation 41 (285mg,1.1mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250mg,1.3mmol), 1-hydroxybenzotriazole hydrate (199mg,1.3mmol), N-ethyldiisopropylamine (226. mu.l, 1.3mmol) and tetrahydrofuran (20ml) was stirred at room temperature for 1 week. Ethyl acetate (150ml) was then added and the resulting mixture was washed with brine (2X 50ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of ethyl acetate: dichloromethane: methanol (32: 64: 4 to 0: 95: 5) to give the title compound as a white foam (603mg, 86%). Delta (DMSOd)₆):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(1H,m),8.39(1H,s),8.54(1H,d),8.65(1H,s),10.18(1H,s)。LRMS:m/z 641(M+1)⁺. Preparation 774- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 28 (3.07g,7.71mmol) and the title compound of preparation 41 (2.0g,7.71mmol) in pyridine (50ml) was heated at 50 ℃ for 48 h, then allowed to cool and evaporated under reduced pressure. The residue was partitioned between dichloromethane (100ml) and water (20ml) and the organic phase was separated and dried (MgSO₄) And evaporated under reduced pressure. Chromatography on silica gel columnThe residual brown foam was purified using an elution gradient of ethyl acetate: methanol (100: 0 to 90: 10) to give the title compound as a white foam (3.19g, 71%). Measured value: c, 54.66; h, 6.17; n, 18.38. C₂₇H₃₆N₈O₅S；0.40H₂Calculated value of O: c, 54.79; h, 6.27; n,18.93 percent. Delta (CDCl)₃):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(1H,s),5.46(2H,s),6.70(1H,s),6.93(1H,d),7.21(1H,m),7.64(1H,m),8.59(1H,d),8.64(1H,s),8.81(1H,s),10.56(1H,s)。LRMS:m/z 585(M+1)⁺. Preparation 785- (4-ethylpiperazin-1-ylsulfonyl) -2-propoxypyridine-3-carboxylic acid methyl ester

Using the procedure of preparation 18, from the title compound of preparation 49 and 1-ethylpiperazine, the title compound was obtained as an oil (53%). Delta (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(1H,s),8.62(1H,s)。LRMS:m/z 372(M+1)⁺. Preparation 795- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridine-3-carboxylic acid

A mixture of the title compound of preparation 78 (370mg,1.0mmol), 2M aqueous sodium hydroxide (1ml,2mmol) and methanol (10ml) was stirred at room temperature for 2 hours. The resulting mixture was treated with solid carbon dioxide to adjust its pH to 7 and then evaporated under reduced pressure. The residue was triturated with dichloromethane (3X 50ml) and the combined organic solutions evaporated under reduced pressure to give the title compound as a white solid (340mg, 95%). LRMS M/z 357(M)⁺. Preparation 804- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Oxalyl chloride (122 μ l,5.6mmol) was added dropwise to a stirred solution of the title compound of preparation 79 (478mg,1.4mmol) and dimethylformamide (3 drops) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was azeotroped with dichloromethane (3X 10ml) and added to a stirred, ice-cooled title compound of preparation 41 (360 m)g,1.4mmol) in pyridine (10ml) and the reaction mixture was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (50ml) and dichloromethane (50ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 50 ml). Drying (Na)₂SO₄) The combined organic solutions were evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using ethyl acetate: methanol (80: 20) as eluent to give the title compound as a colorless glass (500mg, 37%). Delta (CDCl)₃):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(1H,m),7.66(1H,m),8.59(1H,d),8.64(1H,s),8.80(1H,s),10.47(1H,s)。LRMS:m/z 599(M+1)⁺. Preparation 812- (2-benzyloxyethoxy) -3-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

A mixture of 2M sodium bis (trimethylsilyl) amide in tetrahydrofuran (4.1ml,8.2mmol), 2-benzyloxyethanol (1.16ml,8.2mmol) and tetrahydrofuran (5ml) was stirred at about 0 ℃ for 1 hour. The title compound of preparation 13 (2.0g,5.43mmol) was added and the reaction mixture was stirred at room temperature for 5 hours and then evaporated under reduced pressure. The residue was suspended in ethyl acetate (10ml) and the suspension was extracted with 2M hydrochloric acid (3X 10 ml). The combined extracts were basified with aqueous sodium bicarbonate and extracted with ethyl acetate (3X 15 ml). Drying (MgSO)₄) These combined extracts were evaporated under reduced pressure and the crude product was purified by silica gel column chromatography using a gradient eluting from dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as an oil (1.95g, 74%). Delta (CDCl)₃):1.02(3H,t),2.40(2H,q),2.52(4H,m),3.07(4H,m),3.88(2H,t),4.62(4H,m),7.26(1H,m),7.34(4H,m),8.09(1H,s),8.42(1H,s)。LRMS:m/z 486(M+2)⁺. Preparation 822- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 81, using the method of preparation 21, the title compound was obtained as an oil (42%). Delta (CDCl)₃):1.04(3H,t),1.38(3H,t),2.42(2H,q),2.54(4H,m),3.08(4H,m),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 of 832- (2-Benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridine-3-carboxylate

Using the procedure of preparation 26, from the title compound of preparation 82, the title compound was obtained as a pale yellow solid (88%). Delta (CDCl)₃):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(1H,s),8.64(1H,s),12.17(1H,s)。LRMS:m/z 450(M+1)⁺. Preparation 844- [2- (2-benzyloxyethoxy) -5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 52, from the title compound of preparation 83 and preparation 41, the title compound was obtained as an orange solid (80%). Delta (CDCl)₃):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,d),8.62(1H,s),8.82(1H,s),10.50(1H,s)。LRMS:m/z 692(M+2)⁺. Preparation 852-benzyl-3-ethyl-4-nitropyrazole-5-carboxamide

Cesium carbonate (2.9g,9.0mmol) was added to a stirred, ice-cooled solution of the title compound of preparation 35 (1.7g,8.8mmol) in dimethylformamide (20ml) and the suspension was stirred for 30 minutes. Benzyl bromide (10.6ml,9.0mmol) was added and the reaction mixture was stirred at room temperature for 18 h, then evaporated under reduced pressure. The residue was partitioned between ethyl acetate (125ml) and brine (100ml), the phases were separated and dried (MgSO₄) The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate as eluent to give the title compound as a white solid (1.13g, 47%). Delta (DMSOd)₆):0.97(3H,t),2.96(2H,q),5.44(2H,s),7.24(2H,m),7.33(3H,m),7.68(1H,s),7.95(1H,s)。LRMS:m/z 274(M+1)⁺. Preparation of 864-amino-2-benzyl-3-ethylpyrazole-5-carboxamides

Using the procedure of preparation 40, from the title compound of preparation 85, the title compound was obtained as a pale pink solid (90%). Delta (DMSOd)₆):0.87(3H,t),2.49(2H,q),4.46(2H,s),5.22(2H,s),6.85(1H,s),7.09(3H,m),7.25(1H,m),7.31(2H,m)。LRMS:m/z 245(M+1)⁺. Preparation of 872-benzyl-4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethylpyrazole-5-carboxamide

From the title compounds of preparation 18 and preparation 86, using the method of preparation 56, the title compound was obtained as a white crystalline foam (46%). Delta (DMSOd)₆):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(1H,s),8.39(1H,s),8.65(1H,s),10.38(1H,s)。LRMS:m/z 571(M+2)⁺. Preparation of 88a 3-ethyl-1- (1-methylimidazol-2-yl) methyl-4-nitropyrazole-5-carboxamide and preparation of 88b 3-ethyl-2- (1-methylimidazol-2-yl) methyl-4-nitropyrazole-5-carboxamide

A mixture of the title compound of preparation 35 (2.2g,11.95mmol), 2-chloromethyl-1-methylimidazole hydrochloride (J.chem.Soc.,1957,3305; 2.0g,11.95mmol), cesium carbonate (8.5g,26.3mmol) and dimethylformamide (100ml) was stirred at room temperature for 6 hours and then evaporated under reduced pressure. The residue was partitioned between water (150ml) and dichloromethane (150ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 150 ml). Drying (MgSO)₄) The combined extracts were evaporated under reduced pressure, then the residue triturated with dichloromethane: methanol (90: 10) and the resulting solid collected and dried under suction to give the first title compound (1-isomer; 305mg, 9%). Delta (DMSOd)₆):1.16(3H,t),2.82(2H,q),3.69(3H,s),5.40(2H,s),6.81(1H,s),7.13(1H,s),8.20(1H,s),8.50(1H,s)。LRMS:m/z 279(M+1)⁺。

The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol: 0.88 aqueous ammonia (90: 10: 1) as eluent to give the second title compound (2-isomer; 480mg, 1) as a solid4％)。δ(CDCl₃):1.16(3H,t),3.20(2H,q),3.77(3H,s),5.48(2H,s),6.22(1H,s),6.68(1H,s),7.00(1H,s),7.25(1H,s)。LRMS:m/z 279(M+1)⁺. Preparation 894-amino-3-ethyl-2- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 40, from the title compound of preparation 88b, the title compound was obtained as a pink solid (92%). Delta (CDCl)₃) 1.00(3H, t),2.68(2H, q),3.60(3H, s),5.34(2H, s),5.40(1H, s),6.55(1H, s),6.82(1H, s),6.98(1H, s). Preparation of 903-ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide from LRMS M/z 249(M +1)]-2- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide

The title compound was obtained as a solid (48%) from the title compound of preparation 29 and preparation 89 using the procedure of preparation 45A. Delta (CDCl)₃):1.01(3H,t),1.10(3Ht),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(1H,s),10.33(1H,s)。LRMS:m/z 604(M+1)⁺. Preparation 91a1- (1-methylimidazol-2-yl) methyl-4-nitro-3-n-propylpyrazole-5-carboxamide and preparation 91b2- (1-methylimidazol-2-yl) methyl-4-nitro-3-n-propylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 34 (5.0g,25.3mmol), 2-chloromethyl-1-methylimidazole hydrochloride (J.chem.Soc.,1957,3305; 4.6g,27.7mmol), cesium carbonate (18.1g,55.6mmol) and acetonitrile (100ml) was heated at 50 ℃ for 5 hours and then allowed to cool. Ethyl acetate (300ml) was added and the mixture was washed with water (2X 400ml) and dried (MgSO₄) And concentrated under reduced pressure to a volume of about 200 ml. The resulting precipitate was collected and combined with a material produced by crystallizing the residue obtained by evaporating the filtrate under reduced pressure from ethyl acetate to obtain the first title compound (1-isomer; 1.0g, 13%) as white crystals after drying. Delta (DMSOd)₆):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 crystallization mother liquor was evaporated under reduced pressure and the residue was recrystallized from ethyl acetate to give the second title compound (2-isomer; 700mg, 9%) as a solid. Delta (DMSOd)₆):0.92(3H,t),1.52(2H,m),3.04(2H,t),3.68(3H,s),5.49(2H,s),6.82(1H,s),7.14(1H,s),7.66(1H,s),7.93(1H,s)。LRMS:m/z 293(M+1)⁺. Preparation 924-amino-2- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 91b (500mg,1.71mmol), 10% palladium on charcoal (150mg) and ethanol (20ml) was hydrogenated at 345kPa (50psi) for 4h and then filtered. The filtrate was combined with washings of the filter pad with dichloromethane: methanol (80: 20) (50ml), evaporated under reduced pressure and the residue crystallized from ethyl acetate to give the title compound as a pale pink solid (320mg, 71%). Delta (CDCl)₃) 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(1H, s),6.98(1H, s). Preparation 933- (2-phenylvinyl) pyridazine

Zinc chloride (820mg,6mmol) was added to a stirred mixture of benzaldehyde (6.11ml,60mmol) and 3-methylpyridazine (2.83g,30mmol) and the resulting mixture was heated at 150 ℃ for 20 h. The cold reaction mixture was partitioned between dichloromethane (40ml) and 2M aqueous sodium hydroxide (20ml), the organic phase was then separated, combined with the aqueous dichloromethane extract (80ml), dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (99: 1) as eluent to give the title compound (59%) as a solid. Delta (CDCL)₃):7.12(1H,d),7.34(3H,m),7.56(2H,d),7.72(1H,d),8.37(1H,s),8.50(1H,s),8.60(1H,s)。LRMS:m/z 183(M+1)⁺. Preparation 943-hydroxymethylpyridazine

Ozone was bubbled through a stirred solution of the title compound of preparation 93 (3.60g,0.02mol) in methanol (150ml) at-10 ℃. After 30 minutes, the mixture was purged with nitrogen, sodium borohydride (750mg,0.02mol) was added in portions and the resulting solution was stirred at room temperature 2And (4) hours. The reaction mixture was acidified with 2M hydrochloric acid, then basified with 0.880 aqueous ammonia solution and evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (98: 2 to 96: 4) to give the title compound as a solid (76%). Delta (CDCl)₃) 3.66(1H, s),4.92(2H, s),7.48(2H, m),9.06(1H, d). Preparation 953-Chloromethylpyridazine hydrochloride

Thionyl chloride (3.05ml,42mmol) was added to an ice-cooled flask containing the title compound of preparation 94 (920mg,8mmol) and the reaction mixture was stirred at room temperature for 45 minutes, then evaporated under reduced pressure. The residue was azeotroped with toluene (40ml) to give the title compound (1.4g) as a brown solid. Delta (DMSOd)₆) 4.98(2H, s),7.80(1H, m),7.90(1H, d),8.19(1H, s),9.22(1H, d). Preparation 964-Nitro-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 95 (700mg,4.24mmol) and the title compound of preparation 34 (840mg,4.24mmol), cesium carbonate (3.45g,10.6mmol) and acetonitrile (30ml) was stirred at 80 ℃ for 2 hours and then allowed to cool. Brine (30ml) was added and the mixture was extracted with dichloromethane (2X 80ml) and dried (Na)₂SO₄) The combined extracts were evaporated under reduced pressure. The residual brown oil was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound as a yellow solid (480mg, 39%). Delta (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(1H, s). Preparation 974-amino-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide

From the title compound of preparation 96 using the procedure of preparation 40, the title compound was obtained as a pink gum (97%). Delta (CDCl)₃):0.90(3H,t),1.47(2H,m),2.51(2H,t),5.25(1H,s),5.58(2H,s),6.58(1H,s),7.09(1H,d),7.43(1H,m),9.14(1H,d)。LRMS:m/z 261(M+1)⁺. Preparation of 984- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridazin-3-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 45A, from the title compounds of preparation 28 and preparation 97, the title compound was obtained as an orange gum (42%). Delta (CDCl)₃):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(1H,s),5.69(2H,s),6.71(1H,s),7.18(1H,d),7.45(1H,m),8.63(1H,s),8.79(1H,s),9.15(1H,s),10.52(1H,s)。LRMS:m/z 586(M+1)⁺. Preparation of 992-methylpyrimidine-1-oxide

A freshly prepared solution of sodium metal (11.5g,0.50mol) in ethanol (170ml) was added dropwise over 1 hour to a stirred suspension of hydroxylamine hydrochloride (34.75g,0.50mol) and phenolphthalein (50mg) in ethanol (200ml) to maintain a colourless solution and the mixture was stirred at room temperature for 3 hours. Acetonitrile (26ml,0.50mol) was added and the mixture was stirred at room temperature for a further 2 hours, then at 45 ℃ for 48 hours. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to a volume of ca.100ml, then cooled to 0 ℃. The resulting precipitate was collected and dried under suction to give the intermediate acetamidoxime as white crystals (9.9g, 27%).

Boron trifluoride etherate (9.5ml,75mol) and 1,1,3, 3-tetramethoxypropane (11.5ml,70mol) were added successively to a stirred mixture of dimethylformamide (100ml) and toluene (100 ml). Acetamidoxime (5.0g,67.5mmol) was then added and the reaction mixture was heated at 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) (100ml) and aqueous sodium carbonate (100 ml). The phases were separated, the aqueous phase extracted with dichloromethane methanol (80: 20) (10X 50ml) and dried (MgSO 4)₄) The combined organic solutions were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (98: 2) as eluent to give the title compound as an orange solid (2.5g, 34%). Delta (CDCl)₃) 2.74(3H, s),7.19(1H, m),8.16(1H, d),8.39(1H, d). Preparation of 1002-chloromethylpyrimidine

A stirred mixture of the title compound of preparation 99 (2.5g,22.7mmol) and phosphorus oxychloride (18ml,193mmol)The mixture was heated at reflux for 2 hours and then allowed to cool. Over 3 hours, the resulting mixture was poured onto stirred ice and neutralized with solid sodium carbonate. The aqueous solution thus obtained was extracted with dichloromethane (3X 100ml) and then dried (MgSO₄) The combined extracts were 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 (510mg, 17%). Delta (CDCl)₃):4.72(2H,s),7.22(1H,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 and preparation 101b 4-amino-3-n-propyl-2- (pyrimidin-2-yl) methylpyrazole-5-carboxamide

Potassium hydroxide (393mg,7mmol) was added to a stirred, ice-cooled solution of the title compound of preparation 36 (1.2g,6mmol) in dimethylformamide (10ml) and the mixture was stirred at room temperature for 1 hour. The title compound of preparation 100 (900mg,7mmol) was then added and the reaction mixture was stirred at room temperature for 18 h, then evaporated under reduced pressure. The residue was partitioned between water (10ml) and dichloromethane (15ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 15 ml). Drying (MgSO)₄) The combined organic solutions were evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give a mixture of the title compound as a pale pink solid (not isolated) (1.06g, 67%).¹Analysis of the H nmr spectrum indicated a ratio of N1 to N2 (i.e., 1-isomer: 2-isomer) of 22: 78. Delta (DMSOd)₆):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(1H,s),7.06(1H,s),7.35(1H,m),7.42(1H,m),7.50(2H,s),8.68(2H,d),8.77(2H,d)。LRMS:m/z 261(M+1)⁺. Preparation 102a4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide]-3-n-propyl-1- (pyrimidin-2-yl) methylpyrazole-5-carboxamide and preparation 102b4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyrimidin-2-yl) methylpyrazole-5-carboxamide

Triethylamine (1.12ml,8.0mmol) was added to a stirred, ice-cooled suspension of the title compound of preparation 29 (680mg,1.6mmol) and the title compound of preparation 101a/101b (417mg,1.6mmol) in dichloromethane (20ml), and the reaction mixture was stirred at room temperature for 18 hours, washed with water (10ml), dried (MgSO 2H)₄) And evaporated under reduced pressure. The residual brown foam was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (98: 2 to 95: 5) to give the first title compound as an orange gum (1-isomer; 56mg, 6%). Delta (CDCl)₃):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)⁺. This gave a second title compound (2-isomer; 460mg, 47%) as an orange foam. Delta (CDCl)₃):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(1H,s),5.58(2H,s),6.70(1H,s),7.25(1H,m),8.63(1H,s),8.74(2H,d),8.84(1H,s),10.52(1H,s)。LRMS:m/z 616(M+1)⁺. Preparation 103a4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-1- (pyrimidin-2-yl) methylpyrazole-5-carboxamide and preparation 103b4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyrimidin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 45A, the title compound was obtained as an isomeric mixture (88%) from preparation 28 and preparation 101a/101 b. LRMS M/z 586(M +1)⁺. Preparation 1044-amino-3-n-propyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 41, from the title compound of preparation 39a, the title compound was obtained as a solid (92%). Delta (DMSOd)₆):0.88(3H,t),1.55(2H,m),2.43(2H,t),4.18(2H,s),5.59(2H,s),6.73(1H,d),7.22(1H,m),7.57(2H,s),7.69(1H,m),8.47(1H,d)。LRMS:m/z 260(M+1)⁺. Preparation of 1054- [ 2-ethoxy-5- (4-ethylpiperazin-1-yl)Sulfonyl) pyridin-3-ylcarboxamide]-3-n-propyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 45A, from the title compounds of preparation 28 and preparation 104, the title compound was obtained as a brown foam (74%). Delta (CDCl)₃):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(1H,s),7.26(1H,m),7.40(1H,d),7.74(1H,m),8.52(1H,d),8.67(1H,s),8.82(1H,s),9.60(1H,s),9.96(1H,s)。LRMS:m/z 585(M+1)⁺. Preparation 1064-amino-3-ethyl-1- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 40, from the title compound of preparation 88a, the title compound was obtained as a pink foam (95%). Delta (DMSOd)₆):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/z249(M+1)⁺. Preparation 1074- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethyl-1- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide

Using the procedure of preparation 45A, the title compound was obtained as a solid (78%) from the title compounds of preparation 28 and preparation 106. Delta (CDCl)₃):1.01(3H,t),1.21(3H,t),1.60(3H,t),2.40(2H,q),2.53(4H,m),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(1H,s),8.65(1H,s),8.82(1H,s),9.95(1H,s),10.27(1H,s)。LRMS:m/z 575(M+2)⁺. Preparation 1084-amino-1- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazole-5-carboxamide

Using the procedure of preparation 40, the title compound was obtained as a cream solid from the title compound of preparation 91a (78%). Delta (DMSOd)₆):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 1094- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-ylcarboxamide]-1- (1-methylimidazol-2-yl) methyl-3-n-propylpyrazole-5-carboxamide

The title compound was obtained (67%) from the title compound of preparation 25 and preparation 108 using the method of preparation 52. Delta (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 of 1103-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridine

A mixture of 4-hydroxy-1-methylpiperidine (560mg,4.89mmol), 60% sodium hydride (200mg,4.89mmol) suspended in mineral oil and tetrahydrofuran (30ml) was stirred at about 0 ℃ for 30 minutes. The title compound of preparation 13 (600mg,1.63mmol) was added and the reaction mixture was heated at reflux for 90 min and then allowed to cool. The resulting mixture was evaporated under reduced pressure, the residue suspended in ethyl acetate (50ml) and the suspension washed successively with 2M aqueous sodium hydroxide (2X 20ml), water (20ml) and brine (20 ml). Drying (MgSO)₄) The resulting solution was evaporated under reduced pressure to give the title compound as a yellow oil (660mg, 70%). Delta (CDCl)₃):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(1H,m),8.09(1H,s),8.42(1H,s)。LRMS:m/z 447(M)⁺. Preparation 1115- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridine-3-carboxylic acid ethyl ester

Triethylamine (2ml,1.43mmol) and tetrakis (triphenylphosphine) palladium (0) (200mg,0.173mmol) were added to a stirred solution of the title compound of preparation 110 (640mg,1.43mmol) in ethanol (20ml) and the reaction mixture was heated under carbon monoxide at 100 ℃ and 1034kPa (150psi) in a closed vessel for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol (96.5: 3.5) as eluent to give the title compound as an orange solid (550mg, 87%). Delta (CDCl)₃):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(1H,m),8.42(1H,s),8.62(1H,s)。LRMS:m/z 441(M+1)⁺. Preparation 1125- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridine-3-carboxylic acid sodium salt

A mixture of the title compound of preparation 111 (550mg,1.25mmol), 1M aqueous sodium hydroxide (2.4ml,2.40mmol) and ethanol (5ml) was stirred at room temperature for 18 hours and then evaporated under reduced pressure. The residue was partitioned between water (15ml) and ethyl acetate (15ml), the phases were separated and the aqueous phase was evaporated under reduced pressure to give the title compound as a white solid (510mg, 94%). Delta (DMSOd)₆) 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(1H, s),8.28(1H, s). Preparation 113a 4-amino-1- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide preparation 113b 4-amino-2- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide

4- (2-chloroethyl) morpholine (obtained by basifying its hydrochloride (2.67g,14.35mmol)) was added to a stirred solution of the title compound of preparation 36 (2.0g,11.96mmol) and potassium hydroxide (800mg,14.35mmol) in dimethylformamide (20ml) and the reaction mixture was heated at reflux for 18 h and then allowed to cool. The resulting mixture was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane: methanol: glacial acetic acid (95: 5: 1) as eluent to give the second title compound (2-isomer; 480mg, 14%). Delta (CDCl)₃):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(1H,s),6.55(1H,s)。LRMS:m/z 282(M+1)⁺。

The first title compound (1-isomer; 350mg, 10%) was then obtained. Delta (CDCl)₃) 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 of 1143-tert-butyl-1H-pyrazole-5-carboxylic acid hydrochloride

Hydrazine hydrate (1.7ml,35mmol) is added dropwise to a stirred solution of ethyl 5, 5-dimethyl-2, 4-dioxohexanoate (j.org.chem.,1997,62, 5908; 6.1g,30.5mmol) in ethanol (20ml) and the reaction mixture is stirred at room temperature for 4 hours and then evaporated under reduced pressure. Mixing the residuePartitioned between dichloromethane (20ml) and water (20ml), the phases were separated and the aqueous phase was extracted with dichloromethane (2X 20 ml). Drying (MgSO)₄) The combined organic solutions were evaporated under reduced pressure to give the crude ester as a yellow solid.

A mixture of this product, 1, 4-dioxane (100ml) and 2M aqueous sodium hydroxide (25.5ml,51mmol) was stirred at room temperature for 72 hours, and 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 triturated with hot ethanol. The mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as an orange solid (5.06g, 81%). Delta (DMSOd)₆) 1.26(9H, s) and 6.46(1H, s). Preparation of 1153-tert-butyl-4-nitro-1H-pyrazole-5-carboxylic acid

The title compound of preparation 114 (1.5g,7.3mmol) was added portionwise to stirred, ice-cooled concentrated sulfuric acid (7.5ml), the mixture was warmed to 40 ℃ and fuming nitric acid (1.13ml) was then added dropwise to maintain the internal temperature below 50 ℃. The reaction mixture was stirred at 50 ℃ for 7 hours, allowed to cool and poured carefully onto 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 as a white solid (975mg, 63%). Delta (DMSOd)₆):1.33(9H,s)。LRMS:m/z 231(M+18)⁺. Preparation of 1163-tert-butyl-4-nitro-1H-pyrazole-5-carboxamide

Oxalyl chloride (1.59ml,18.2mmol) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 115 (970mg,4.55mmol) and dimethylformamide (1 drop) in dichloromethane (20ml) and the reaction mixture was stirred at room temperature for 3 hours and then evaporated under reduced pressure. The residue was first azeotroped with dichloromethane and then with 0.88 aqueous ammonia solution. The resulting material was triturated with hot ethanol then acetonitrile, the mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as a white solid (955mg, 99%). Delta (DMSOd)₆):1.36(9H,s),7.60(1H,s),7.88(1H,s)。LRMS:m/z 230(M+18)⁺. Preparation of 1173-tert-butyl-4-nitro-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 116 (960mg,4.55mmol), cesium carbonate (3.7g,11.36mmol) and 2- (chloromethyl) pyridine hydrochloride (821mg,5.00mmol) in acetonitrile (20ml) was stirred at 70 ℃ for 20 h, then allowed to cool and filtered. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using an elution gradient of ethyl acetate: methanol (100: 0 to 95: 5) to give the title compound (300mg, 22%) as a yellow solid. Delta (DMSOd)₆):1.35(9H,s),5.40(2H,s),7.18(1H,d),7.32(1H,m),7.80(1H,m),8.10(1H,s),8.46(1H,s),8.51(1H,d)。LRMS:m/z 304(M+1)⁺. Preparation 1184-amino-3-tert-butyl-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

A stirred mixture of the title compound of preparation 117 (290mg,0.96mmol) and 10% palladium on charcoal (29mg) in ethanol (20ml) was hydrogenated at 345kPa (50psi) at room temperature for 7h, then filtered. The filter pad was washed with ethanol and the combined washings and filtrate were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of ethyl acetate: methanol (100: 0 to 95: 5) to give the title compound as an orange solid (220mg, 84%). Delta (CDCl)₃):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 1194- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylpiperidin-4-yloxy) pyridin-3-ylcarboxamide]-3-n-propyl-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (350mg,1.8mmol) was added to a stirred solution of 1-hydroxybenzotriazole hydrate (250mg,1.8mmol), triethylamine (350. mu.l, 2.5mmol) and the title compound of preparation 112 (510mg,1.18mmol) and the title compound of preparation 41 (330mg,1.25mmol) in tetrahydrofuran (20ml) and the reaction mixture was stirred at room temperature for 72 h and then evaporated under reduced pressure. The residue was triturated several times with ethyl acetate to give the title compound as a white solid (175mg, 21%). Delta (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,m),5.49(3H,m),5.64(1H,s),6.90(2H,m),7.22(1H,m),7.68(1H,m),8.60(1H,d),8.64(1H,s),8.82(1H,s),10.35(1H,s)。LRMS:m/z654(M+1)⁺. Preparation 1204- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-2- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (280mg,1.5mmol) was added to a stirred solution of 1-hydroxybenzotriazole hydrate (200mg,1.5mmol), triethylamine (278. mu.l, 2.0mmol) and the title compound of preparation 23 (371mg,1.0mmol) and the title compound of preparation 113b (250mg,0.9mmol) in dichloromethane (20ml) and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was washed with water (10ml) and dried (MgSO)₄) And evaporated under reduced pressure, then the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (97: 3 to 95: 5) to give the title compound as a white solid (430mg, 68%). Delta (CDCl)₃) 0.93(3H, t),1.02(3H, t),1.58(5H, m),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, s). Preparation 1213-tert-butyl-4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-1- (pyridin-2-yl) methylpyrazole-5-carboxamide

The title compound of preparation 28 (384mg,0.967mmol) was added dropwise to a stirred, ice-cooled solution of the title compound of preparation 118 (220mg,0.805mmol) and triethylamine (330. mu.l, 2.42mmol) in dichloromethane (10ml) and the reaction mixture was stirred at room temperature for 14 h. The resulting mixture was washed with aqueous sodium bicarbonate (5ml) and brine (5ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was purified by two silica gel column chromatography operations using an elution gradient of ethyl acetate: methanol (100: 0 to 90: 10) and then dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a white solid (156mg, 32%). Delta (CDCl)₃):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(1H,s),8.87(1H,s),9.35(1H,s)。LRMS:m/z 599(M+1)⁺. Preparation 1224- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-1- (2-morpholin-4-yl) ethyl-3-n-propylpyrazole-5-carboxamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.34g,7.0mmol) was added to a stirred solution of 1-hydroxybenzotriazole hydrate (945mg,7.0mmol), N-ethyldiisopropylamine (1.22ml,7.0mol) and the title compound of preparation 113a (1.82g,6.5mmol) and the title compound of preparation 23 (428mg,1.25mmol) in tetrahydrofuran (120ml) and the reaction mixture was stirred at room temperature for 72 h. The resulting mixture was evaporated under reduced pressure and the residue partitioned between aqueous sodium carbonate (50ml) and dichloromethane (100 ml). The phases were separated, the aqueous phase extracted with dichloromethane (2X 100ml) and the combined organic solutions washed with brine (3X 50ml), dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was triturated with ether then crystallized from ethyl acetate-methanol to give the title compound as a white solid (310mg, 42%). Delta (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),3.64(4H,m),4.49(2H,t),4.72(2H,q),5.78(1H,s),8.30(1H,s),8.66(1H,s),8.80(1H,s),9.49(1H,s)。LRMS:m/z 607(M+1)⁺. Preparation of 1233-ethyl-1-methyl-4-nitropyrazole-5-carboxamide and preparation of 1243-ethyl-2-methyl-4-nitropyrazole-5-carboxamide

A mixture of the title compound of preparation 35 (100g,0.54mol) and cesium carbonate (194g,0.60mol) in N, N-dimethylformamide (1000ml) was stirred at room temperature for 45 minutes and then cooled on an ice bath. Methyl iodide (37.2ml,0.60mol) was added dropwise 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 (500ml) and water (300 ml). The layers were separated, the aqueous phase extracted with ethyl acetate (4X 500ml) and dried (MgS 0)₄) The combined organic solutions were evaporated under reduced pressure. The crude product is separated from dichloromethane/ethyl acetateRecrystallization of the ester gave some N1 isomer (17.0g, 16%).

The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using ethyl acetate: pentane (80: 20) as eluent to give the title compound of preparation 123 (25.0g, 23%) as a white solid. Delta (CDCl)₃):1.27(3H,t),2.94(2H,q),4.06(3H,s),6.00(1H,br s),7.56(1H,br s)。LRMS:m/z 216(M+18)⁺. And the title compound of preparation 124 as a white solid (28.4g, 27%). Delta (CDCl)₃) 1.29(3H, t),3.00(2H, q),3.92(3H, s),5.98(1H, s),7.32(1H, s). Preparation of 1252-methyl-3-n-propylpyrazole-5-carboxylic acid ethyl ester

A solution of diethyl oxalate (27.2ml,0.2mol) in 2-pentanone (21.2ml,0.2mol) was added dropwise to a solution of sodium (4.83g,0.21mmol) in ethanol (200ml) and the reaction stirred at 60 ℃ for 5 hours and then cooled on an ice bath. The solution was neutralized with acetic acid (11.5ml,0.2mol) and then N-methylhydrazine (10.6ml,0.2mol) was added dropwise. The mixture was stirred at room temperature for another 4 hours and concentrated under reduced pressure. The residue was partitioned between dichloromethane (300ml) and water (200ml) and the phases were separated. The aqueous layer was extracted with dichloromethane (3X 100ml) and dried (MgSO)₄) The combined organic solutions were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using ethyl acetate: hexane (25: 75) as eluent to give ethyl 1-methyl-3-n-propylpyrazole-5-carboxylate (6.1g) and the title compound (22.1g, 56%). Delta (CDCl)₃) 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 of 1262-methyl-3-n-propylpyrazole-5-carboxylic acid

A mixture of the title compound of preparation 125 (21.5g,0.11mol) in aqueous sodium hydroxide (50ml,6N,0.3mol) was heated at reflux for 3 hours. The cooled mixture was diluted with water (50ml) and acidified using concentrated hydrochloric acid (25ml) and the resulting precipitate filtered and dried to give the title compound as a pale yellow solid (17.3g, 94%).

A portion of this solid (1g) was recrystallized from water/ethanol. m.p.120-122 ℃. Delta (DMSOd)₆) 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 of 1272-methyl-4-nitro-3-n-propylpyrazole-5-carboxylic acid

From the title compound of preparation 126, using a method similar to that described in preparation 32, the title compound was obtained as a solid (89%). Delta (DMSOd)₆) 0.95(3H, t),1.60(2H, m),2.96(2H, t),3.88(3H, s),13.75(1H, s). Preparation of 1282-methyl-4-nitro-3-n-propylpyrazole-5-carboxamide

A mixture of the title compound of preparation 127 (18.6g,87.3mmol) in thionyl chloride (75ml) was heated at reflux for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was poured into an ice/ammonium hydroxide mixture. The mixture was extracted with dichloromethane (4X 100ml) and dried (MgSO)₄) The combined organic extracts were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using dichloromethane: methanol: 0.88 ammonia (95: 5: 1) as eluent to give the title compound as a solid (6.8g, 37%). Delta (CDCl)₃) 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 of 1292, 3-diethyl-4-nitropyrazole-5-carboxamide

Iodothane (7.2ml,90.0mmol) was added to a suspension of the title compound of preparation 35 (15.0g,81.0mmol) and cesium carbonate (29.3g,90.0mmol) in N, N-dimethylformamide (100ml) and the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue triturated with water (100ml) and the resulting solid filtered and dried. A suspension of the solid in diethyl ether (250ml) was heated at 35 ℃ for 1 hour and the precipitate was filtered and dried. The material was recrystallized from ethyl acetate to give the titled compound as a crystalline solidCompound (5.8g, 34%). Delta (CDCl)₃):1.30(3H,t),1.54(3H,t),3.00(2H,q),4.20(2H,q),5.92(1H,s),7.27(1H,s)。LRMS:m/z 212(M)⁺. Preparation 1303-ethyl-4-nitro-2- (pyridazin-3-yl) methyl-pyrazole-5-carboxamide

A mixture of the title compound of preparation 35 (2.66g,14.5mmol) and the title compound of preparation 95 (2.65g,16.1mmol) and cesium carbonate (13.1g,40.2mmol) in acetonitrile (100ml) was stirred at reflux for 18 h. The cooled reaction was concentrated under reduced pressure and the residue was suspended in water and extracted with dichloromethane (5X 100 ml). Drying (Na)₂SO₄) The combined organic extracts were adsorbed onto silica gel and the product isolated by silica gel column chromatography using an elution gradient of methanol: dichloromethane (5: 95 to 10: 90) to give 3-ethyl-4-nitro-1- (pyridazin-3-yl) methylpyrazole-5-carboxamide (1.31g) and the title compound as a pale yellow solid (1.81g, 45%). Delta (CDCl)₃):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 1313-ethyl-4-nitro-2- [1- (pyridin-2-yl) ethyl]-pyrazole-5-carboxamides

A mixture of 2-ethylpyridine (20.0g,187mmol), N-bromosuccinimide (38.0g,213mmol) and benzoyl peroxide (1.0g, 75% in water) in 1,1, 1-trichloroethane (200ml) was heated at reflux for 3 hours. The cooled mixture was filtered and the filtrate was washed with water (2X 100ml), aqueous sodium thiosulfate (100ml) and brine (100 ml). Drying (MgSO)₄) The solution was filtered through charcoal and then hydrobromic acid (25ml, 62%) was added. The solution was concentrated under reduced pressure and azeotroped with toluene to give 2- (1-bromoethyl) pyridine hydrochloride (66.0g) as a dark oil.

A mixture of preparation 35 (8.0g,43.4mmol), cesium carbonate (35.0g,107.4mmol) and crude 2- (1-bromoethyl) pyridine hydrochloride (13.6g,52.0mmol) in N, N-dimethylformamide (80ml) was stirred at room temperatureFor 20 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150ml) and water (50 ml). The layers were separated and the organic phase was washed with additional water (3X 50ml), brine (50ml) and then dried (MgSO)₄) And evaporated under reduced pressure. The residual oil was purified by silica gel column chromatography using an elution gradient of pentane: ethyl acetate: methanol (90: 10: 0 to 0: 100: 0 to 0: 90: 10) to give N1 isomer (4.3g) and the title compound (5.7g, 45%). Delta (CDCl)₃):1.14(3H,t),2.01(3H,d),3.00(2H,q),5.66(2H,q),5.88(1H,s),6.98(1H,s),7.18(1H,d),7.25(1H,m),7.68(1H,m),8.56(1H,d)。LRMS:m/z 290(M+1)⁺. Preparation 1323-ethyl-2- (6-methylpyridin-2-yl) methyl-4-nitropyrazole-5-carboxamide

A mixture of the title compound of preparation 35 (4.32g,23.5mmol) and 6-methyl-2-picolyl chloride hydrochloride (5.0g,23.4mmol) in N, N-dimethylformamide (50ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between water (50ml) and dichloromethane (50 ml). The layers were separated and the aqueous phase was extracted with dichloromethane (3X 50ml), the combined organic solutions were washed with brine (50ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent and a repeated elution gradient using pentane: ethyl acetate (50: 50 to 0: 100) to give the N1 isomer (1.0g) and the title compound as a white solid (2.47g, 36%). Delta (CDCl)₃):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(1H,d),7.22(1H,s),7.58(1H,m)。LRMS:m/z 312(M+23)⁺. Preparation of 1332-methoxy-6-methylpyridine

Trimethyloxonium tetrafluoroborate (10.0g,67.6mmol) was added portionwise to a suspension of 6-methylpyridin-2-one (7.3g,67.0mmol) in dichloromethane (100ml) and once the addition was complete the reaction was stirred at room temperature for 24 h. Dichloromethane (50ml) and hydrogen hydroxide were addedAqueous sodium solution (50ml,2N) and the layers were separated. The aqueous phase was extracted with dichloromethane (2X 50ml), the combined organic solutions were washed with brine (50ml), dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by silica gel column chromatography using an elution gradient of pentane: dichloromethane (66: 34 to 0: 100) to give the title compound as a colourless oil (2.25g, 27%). Delta (CDCl)₃) 2.49(3H, s),3.90(3H, s),6.38-6.73(2H, m),7.23-7.40(1H, br d). Preparation 1346-bromomethyl-2-methoxypyridine

A mixture of the title compound of preparation 133 (2.5g,20.3mmol), N-bromosuccinamide (3.7g,20.8mmol) and benzoyl peroxide (100mg,0.41mmol) in 1,1, 1-trichloroethane (50ml) was stirred at reflux for 3 hours and at room temperature for a further 16 hours. The reaction was washed with water (2X 25ml), aqueous sodium thiosulfate (25ml), brine (25ml) and dried (MgSO 4)₄) And evaporated under reduced pressure. The residue was shaken well with hydrobromic acid (62%, 2.4ml) and the suspension was concentrated under reduced pressure and azeotroped twice with toluene to give the title compound as a yellow solid. Delta (CDCl)₃):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 1353-ethyl-2- (6-methoxypyridin-2-yl) methyl-4-nitropyrazole-5-carboxamide

A mixture of the title compound of preparation 134 (5.2g,18.4mmol), cesium carbonate (6.58g,32.5mmol) and the title compound of preparation 35 (3.4g,18.4mmol) in N, N-dimethylformamide (30ml) was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure, the residue partitioned between ether (100ml) and water (50ml) and the phases separated. The organic layer was washed with brine (20ml) and dried (MgSO)₄) And evaporated under reduced pressure. The residual gum was triturated with ether to give the title compound as a white solid (640mg, 11%).

The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using pentane: ethyl acetate (66: 34)As an eluent, the title compound (280mg, 5%) was further obtained. Delta (DMSOd)₆):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 of 1364-amino-2-methyl-3-n-propylpyrazole-5-carboxamide

A mixture of preparation 128 of the title compound (6.17g,29.0mmol) and tin (II) chloride dihydrate (32.8g,145mmol) in technical methylated ethanol (IMS) (100ml) was heated at reflux for 2 h. The cooled mixture was concentrated under reduced pressure to about half its volume, basified to pH9 using 2N aqueous sodium hydroxide and extracted with dichloromethane (3 × 300 ml). Drying (MgSO)₄) The combined organic extracts were evaporated under reduced pressure and the crude product was recrystallized from ethyl acetate/methanol to give the title compound (4.86g, 92%). m.p.170-174 ℃. Delta (DMSOd)₆) 0.90(3H, t),1.47(2H, m),2.50(2H, t),3.68(3H, s),4.43(2H, s),6.92(1H, s),7.04(1H, s). Preparation 1374-amino-2, 3-diethylpyrazole-5-carboxamide

A mixture of preparation 129 of the title compound (5.7g,26.9mmol) and tin (II) chloride dihydrate (29.0g,128mmol) in ethanol (200ml) was heated at reflux for 45 min. The cooled reaction mixture was evaporated under reduced pressure and redissolved in ethyl acetate (200 ml). The solution was poured into 10% aqueous sodium carbonate solution (400ml) and the mixture was stirred vigorously for 1 hour. The layers were separated and the aqueous phase was extracted with ethyl acetate (2X 100 ml). Drying (Na)₂SO₄) The combined organic solutions were concentrated to a volume of 50ml under reduced pressure and the resulting crystals were filtered off and dried to give the title compound (3.3g, 67%). Delta (CDCl)₃):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 1384-amino-3-ethyl-2-methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 124 (5.8g,29.3mmol) and 10% palladium on charcoal (650mg) in ethanol (100ml) was hydrogenated at 60psi for 20 h at room temperature. The reaction was filtered through Arbocel  and the filter pad was washed well with hot ethanol (200 ml). The combined filtrates were evaporated under reduced pressure to give the title compound as a solid (4.7g, 95%). Delta (CDCl)₃) 1.20(3H, t),2.59(2H, q),3.77(3H, s),3.95(2H, s),5.21(1H, s),6.54(1H, s). Preparation 139 to 142

Using a method similar to that described in preparation 138, prepared compounds having the formula shown in the following list were prepared from the corresponding nitropyrazoles:

preparation of1= preparation of 1434-amino-3-ethyl-1-methylpyrazole-5-carboxamide by purification by column chromatography using ethyl acetate as eluent

A mixture of the title compound of preparation 123 (940mg,4.75mmol) and 10% palladium on carbon (200mg) in ethanol (100ml) was hydrogenated at 50 ℃ for 18 h at 50 Psi. The cooled mixture was filtered through Arbocel  and the filtrate was evaporated under reduced pressure to give the title compound as a clear oil (786mg, 98%). Delta (CDCl)₃):1.23(3H,t),2.59(2H,q),2.82(2H,s),4.12(3H,s)。LRMS:m/z 169(M+1)⁺. Preparation 1443-bromo-2-chloro-5- (4-methylpiperazin-1-ylsulfonyl) pyridine

N-methylpiperazine (7.65ml,69.0mmol) was added dropwise to a solution of the title compound of preparation 12 (10.0g,34.5mmol) in ethanol (200ml) and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (200ml) and water (100ml) and the layers separated. Drying (Na)₂SO₄) The organic phase was evaporated under reduced pressure,the title compound was obtained as a yellow solid (10.53g, 87%). Delta (CDCl)₃) 2.28(3H, s),2.51(4H, m),3.14(4H, m),8.24(1H, s),8.67(1H, s). Preparation of 1453-bromo-2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridine

A mixture of the title compound of preparation 144 (10.0g,39.1mmol), potassium bis (trimethylsilyl) amide (5.92g,29.7mmol) and ethanol (3.5ml) in tetrahydrofuran (150ml) was stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (150ml) and brine (50 ml). The layers were separated and dried (Na)₂SO₄) The organic phase was filtered and evaporated under reduced pressure to give the title compound (9.1g, 88%). Delta (CDCl)₃):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 of 1463-bromo-5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridineA mixture of the title compound of preparation 13 (1.11g,3.0mmol) and n-propylamine (590mg,10.0mmol) in toluene (20ml) was stirred at reflux for 90 minutes. The cooled mixture was partitioned between ethyl acetate (50ml) and water (20ml) and the layers were separated. The organic phase was washed with brine (20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a yellow crystalline solid (1.15g, 98%). Delta (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 of 1472-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridine-3-carboxylic acid ethyl ester

From the title compound of preparation 145 using a similar method to that described in preparation 21, the title compound was obtained as an orange solid (85%). Delta (CDCl)₃):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(1H,s),8.63(1H,s)。LRMS:m/z 358(M+1)⁺. Preparation 1485- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridine-3-carboxylic acid ethyl ester

A mixture of the title compound of preparation 146 (1.10g,2.81mmol), triethylamine (5ml) and tetrakis (triphenylphosphine) palladium (0) (250mg,0.216mmol) in ethanol (25ml) was stirred under carbon monoxide atmosphere at 100 ℃ and 100psi for 16 h. The cooled solution was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a yellow oil (1.07mg, 99%). Delta (CDCl)₃):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(1H,s),8.57(2H,m)。LRMS:m/z 385(M+1)⁺. Preparation of 1492-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridine-3-carboxylate

Sodium hydroxide solution (21ml,2M,42.0mmol) was added to a solution of the title compound of preparation 147 (7.57g,21.0mmol) in dioxane (1.50ml) and the reaction was stirred at room temperature for 18 h. The mixture was neutralized with hydrochloric acid, dioxane was removed under reduced pressure and the remaining aqueous solution was acidified to pH2 with hydrochloric acid. The solution was evaporated under reduced pressure, the residue was resuspended in hot ethanol, filtered and the filtrate re-evaporated to give the title compound (5.46g, 71%). Delta (DMSOd)₆):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(1H,s)。LRMS:m/z 330(M+1)⁺. Preparation 1505- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridine-3-carboxylic acid sodium salt

A mixture of the title compound of preparation 148 (1.06g,2.76mmol) in sodium hydroxide solution (1.5ml,2N,3.0mmol) and ethanol (10ml) was placed in a chamberStirred at room temperature for 4 hours. The reaction was evaporated under reduced pressure, the solid was triturated with ether and the suspension filtered and dried to give the title compound (950 mg). Delta (DMSOd)₆) 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 1514- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-2-methyl-3-n-propylpyrazole-5-carboxamide

The title compound of preparation 136 (525mg,2.88mmol) was added to a mixture of the title compound of preparation 149 (1.04g,3.2mmol), 1-hydroxybenzotriazole hydrate (470mg,3.5mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (670mg,3.5mmol) and N-ethyldiisopropylamine (2.4ml,14.0mmol) in tetrahydrofuran (50ml) and the reaction stirred at room temperature for 36 h. The reaction mixture was concentrated under reduced pressure and the residue was suspended in sodium carbonate solution (20ml) and extracted with dichloromethane (3 × 20 ml). The combined organic extracts were washed with brine (3X 20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was triturated with ether to give a yellow solid which was then purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 96: 4) to give the title compound as a white solid (720mg, 51%).

A sample of this product (50mg) was recrystallized from ethyl acetate to give the title compound (32mg) as colorless crystals. m.p.242-244 ℃. Delta (CDCl)₃):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(1H,s),6.63(1H,s),8.65(1H,s),8.84(1H,s),10.53(1H,s)。LRMS:m/z 494(M+1)⁺. Preparation 1524- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethyl-2-methylpyrazole-5-carboxamide

The title compound was obtained as a solid (65%) from the title compounds of preparations 23 and 138 following the procedure described in preparation 151.δ(CDCl₃):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),5.30(1H,s),6.63(1H,s),8.64(1H,s),8.83(1H,s),10.54(1H,s)。LRMS:m/z 494(M+1)⁺. Preparation of 1534- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-2-methyl-3-n-propylpyrazole-5-carboxamide

The title compound was obtained as a solid (64%) from the title compounds of preparations 23 and 136 in a similar manner to that described in preparation 151, except that an elution gradient of methanol: ethyl acetate (7: 93 to 10: 90) was used as the eluent for chromatography. Delta (CDCl)₃):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 of 1544- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-2, 3-diethylpyrazole-5-carboxamide

The title compound of preparation 137 (3.3g,16.8mmol) and triethylamine (7.5ml,54.0mmol) were added to an ice-cooled solution of the title compound of preparation 28 (6.51g,18.0mmol) in dichloromethane (100ml) and the reaction was stirred at room temperature for 18 hours. The mixture was washed successively with brine (50ml), aqueous sodium bicarbonate (2X 50ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound as a solid. Delta (CDCl)₃):1.04(3H,t),1.22(3H,t),1.50(3H,t),1.59(3H,t),2.40(2H,q),2.54(4H,m),2.91(2H,q),3.10(4H,m),4.16(2H,q),4.78(2H,q),5.30(1H,s),6.68(1H,s),8.65(1H,s),8.84(1H,s),10.05(1H,s)。LRMS:m/z 508(M+1)⁺. Preparation 155 to 157

Following a similar procedure to that described in preparation 154, the title compound from preparation 28And the appropriate amines, the preparation of the compounds having the following general formula is shown in the list prepared:1= the title compound isolated by trituration with ether. 2= ethyl acetate: methanol (94: 6) was used as eluent for chromatography. Preparation of 1584- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethyl-1-methylpyrazole-5-carboxamide

Using a method similar to that described in preparation 151, the title compound was obtained as a white solid (51%) from the title compounds of preparations 23 and 143. Delta (CDCl)₃):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(1H,br s),7.55(1H,brs),8.70(1H,s),8.83(1H,s),9.24(1H,s)。LRMS:m/z 494(M+1)⁺. Preparation of 1594- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-1-methyl-3-n-propylpyrazole-5-carboxamide

A mixture of the title compound of preparation 24 (2.0g,5.48mmol), 4-amino-1-methyl-3-N-propylpyrazole-5-carboxamide hydrochloride, EP-A-0463756(108g,4.94mmol), 1-hydroxybenzotriazole hydrate (920mg,6.87mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.15g,6.0mmol) and N-ethyldiisopropylamine (2.86ml,16.5mmol) in tetrahydrofuran (20ml) was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate (100ml) and water (50 ml). The layers were separated and dried (MgSO)₄) The organic phase was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound as a white solid (940mg, 38%). Delta (CDCl)₃):0.95(3H,t),1.02(3H,t),1.52(3H,t),1.63(2H,m),2.40(2H,q),2.54(6H,m),3.09(4H,m),4.05(3H,s),4.75(2H,q),5.81(1H,s),7.58(1H,s),8.67(1H,s),8.80(1H,s),9.25(1H,s)。LRMS:m/z 509(M+2)⁺. Preparation 1603-ethyl-4- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propylaminopyridin-3-ylcarboxamide]-2- (pyridin-2-yl) methylpyrazole-5-carboxamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (250mg,1.3mmol) was added to a solution of preparation 40(245mg,1.0mmol) and preparation 150(456mg,1.2mmol) of the title compound, N-ethyldiisopropylamine (194mg,1.5mmol) and 1-hydroxybenzotriazole hydrate (203mg,1.5mmol) in dichloromethane (10ml) and the reaction was stirred at room temperature for 16 h. The reaction was poured into ethyl acetate (30ml), washed with water (10ml) and brine (10ml), dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 94: 6) and trituration with ether to give the title compound as a white solid (242mg, 41%). Delta (CDCl)₃):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(1H,m),8.17(1H,s),8.53(1H,s),8.58(1H,d),8.64(1H,m),9.58(1H,s)。LRMS:m/z 584(M+1)⁺. Preparation of 1614- (2-ethoxy-5-nitropyridin-3-ylcarboxamide) -3-ethyl-2-methylpyrazole-5-carboxamide

Oxalyl chloride (2.6ml,30.2mmol) was added dropwise to an ice-cooled solution of the title compound of preparation 8 (1.6g,7.55mmol) and N, N-dimethylformamide (1 drop) in dichloromethane (40ml), and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure and azeotroped several times with dichloromethane.

The intermediate acid chloride was added to an ice-cooled solution of the title compound of preparation 138 (960mg,5.74mmol) and triethylamine (2.6ml,18.7mmol) in dichloromethane (40ml) and the reaction was stirred at room temperature for 2 hours. With water (20ml),The mixture was washed with brine (20ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound (2.06g, 99%). Delta (CDCl)₃):1.24(3H,t),1.61(3H,t),2.92(2H,q),3.88(3H,s),4.84(2H,q),5.27(1H,s),6.66(1H,s),9.17(1H,s),9.33(1H,s),10.57(1H,s)。LRMS:m/z 363(M+1)⁺. Preparation 1624- (5-amino-2-ethoxypyridin-3-ylcarboxamide) -3-ethyl-2-methylpyrazole-5-carboxamide

A mixture of the title compound of preparation 161 (2.06g,5.7mmol) and 10% palladium on charcoal (200mg) in ethanol (70ml) was hydrogenated at 50psi for 6h at room temperature. The reaction mixture was filtered through Arbocel , the filter pad was washed with additional ethanol, and the combined filtrates were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound (760mg, 40%) as a solid. Delta (CDCl)₃):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(1H,s),7.78(1H,s),7.96(1H,s),10.54(1H,s)。LRMS:m/z 333(M+1)⁺. Preparation 1635- (5-amino-2-ethoxypyridin-3-yl) -3-ethyl-2-methylpyrazole-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

A mixture of the title compound of preparation 162 (760mg,2.29mmol) and potassium bis (trimethylsilyl) amide (685mg,3.43mmol) in ethanol (50ml) was heated at 100 ℃ for 20 hours in a closed vessel. The cooled mixture was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound (550mg, 76%) as a solid. Delta (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(1H,s),11.17(1H,s)。LRMS:m/z 315(M+1)⁺. Preparation 1645- (5-Chlorosulfonyl-2-ethoxyPyridin-3-yl) -3-ethyl-2-methylpyrazole-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

The title compound (72%) was obtained from the title compound of preparation 163 by a similar method to that described in preparation 63. Delta (CDCl)₃) 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 of 165(R) -1-methoxy-2-propanol

Sodium methoxide (54g,1.0mol) was added in portions to ice-cooled methanol (1000ml), and the resultant solution was stirred on an ice bath for 20 minutes. (R) -1, 2-propylene oxide (58g,1mol) was added dropwise over 30 minutes, and once the addition was complete, the reaction was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and acidified with (1M) etherified hydrochloric acid with cooling, and the resulting mixture was stirred for 1 hour and then filtered. Drying (K)₂CO₃) The filtrate was filtered and evaporated under reduced pressure. The residue was heated to 70 ℃ for 30 minutes with dry calcium oxide and then distilled at atmospheric pressure to give the title compound as an oil (25.4g, 28%). P.118-120 ℃ delta (CDCl)₃):1.16(3H,d),2.28(1H,d),3.20(1H,m),3.36(1H,m),3.40(3H,s),3.97(1H,m)。[α]_D20.83 ° (c =1.02, dichloromethane). Preparation of 1664-methoxy-2-butanol

Lithium aluminium hydride (220ml,1.0M in tetrahydrofuran, 220mmol) was added dropwise over 15 min to an ice-cooled solution of 4-methoxybut-3-en-2-one (20.0g,200mmol) in tetrahydrofuran (200ml) and the reaction stirred at room temperature for 16 h. The solution was cooled again on an ice bath, water (8ml) was added dropwise, followed by 15% aqueous sodium hydroxide solution (8ml) and after a further 10 minutes, water (24ml) was added. 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 charcoal (500mg) was added and the mixture was addedHydrogenation at 60psi for 16 hours. The reaction was filtered through Arbocel  and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: an elution gradient of diethyl ether (99: 1 to 50: 50) gave the title compound (4.0g, 19%). Delta (CDCl)₃) 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 of 167N-methylcyclopropylformamide

Cyclopropanecarboxylic acid (15.83ml,200mmol) was added dropwise to a warm (40 ℃) solution of thionyl chloride (16.71ml,213mmol) in toluene (80ml) and once the addition was complete, the reaction was stirred at 80 ℃ for 2 h. The mixture was cooled on an ice bath, a solution of methylamine in tetrahydrofuran (300ml,2M,600mmol) was added and the mixture was allowed to warm to room temperature and concentrated under reduced pressure. The residue was suspended in dichloromethane (200ml), washed with saturated aqueous sodium bicarbonate (200ml), brine (200ml), dried (MgSO)₄) And evaporated under reduced pressure. The residual white solid was recrystallized from hexane/diethyl ether to give the title compound as a white crystalline solid (11.3g, 57%). Measured value: c, 58.73; h, 9.30; and N, 13.70. C₅H₉NO；0.2H₂Calculated value of O: c, 58.46; h, 9.22; and N,13.63 percent. Delta (CDCl)₃):0.70(2H,m),0.95(2H,m),1.32(1H,m),2.81(3H,d),5.73(1H,s)。LRMS:m/z 199(M+1)⁺. Preparation of 168N-cyclopropylmethyl-N-methylamine hydrochloride

A solution of the title compound of preparation 167 (7.90g,79.7mmol) in diethyl ether (75ml) was added dropwise over 5 min to a suspension of lithium aluminium hydride (3.03g,96.0mmol) in diethyl ether (100ml) and the reaction was stirred at reflux for 4 h. The cooled mixture was quenched by the successive addition of water (3ml), 10% aqueous sodium hydroxide (9ml) and water (3 ml). The resulting suspension was stirred for 5 minutes, filtered and the solid washed well with diethyl ether (100 ml). Drying (MgSO)₄) The combined filtrates were cooled on an ice bath and saturated with hydrochloric acid. Evaporating the solution under reduced pressureLiquid to give the title compound as a gum (8.7g, 90%). Delta (CDCl)₃) 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, br). Preparation 1694- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamide]-3-ethyl-2- (1-methylimidazol-2-yl) methylpyrazole-5-carboxamide

1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.2g,6.25mmol) was added to a solution of preparation 23(1.6g,4.66mmol) and preparation 89(1.2g,4.84mmol), hydroxybenzotriazole hydrate (960mg,6.2mmol) and N-ethyldiisopropylamine (2.5ml,14.5mmol) in tetrahydrofuran (15ml) and N, N-dimethylformamide (3ml) and the reaction was stirred at room temperature for 18 h. The mixture was diluted with water (100ml) and extracted with dichloromethane (3X 150 ml). Drying (Na)₂SO₄) The combined organic extracts were evaporated under reduced pressure. The residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent to give the title compound (1.42g,2.55 mmol). Delta (CDCl)₃):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,br s),5.44(2H,s),6.60(1H,br s),6.86(1H,s),7.00(1H,s),8.65(1H,s),8.82(1H,s),10.48(1H,s)。LRMS:m/z 574(M+18)⁺. Preparation 1705- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl]-3-ethyl-2- (1-methylimidazol-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4,3-d]Pyrimidin-7-ones

Following a similar procedure to that described in example 78, from the title compound of preparation 169 was obtained the title compound as a cream foam (62%). Delta (CDCl)₃):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(1H,s),8.99(1H,s),10.66(1H,s)。LRMS:m/z 556(M+1)⁺. Biological activity

The following table illustrates a series of booksIn vitro activity of the inventive compounds as cGMP PDE5 inhibitors. Watch (A)

Examples	IC₅₀(nm)
Examples	IC₅₀(nm)	10	10.1
11	10.0	10	10.1
11	10.0	18	8.9
43b	3.6	18	8.9
43b	3.6	46	8.1
48	6.9	46	8.1
48	6.9	98	7.0
99	5.7	98	7.0
99	5.7	127	7.3
153	7.2	127	7.3

Safety feature

Several compounds of the invention have been tested at doses up to 3mg/kg i.v. (mice) and at doses of 0.5mg/kg p.o. (dogs), and no adverse effects were observed.

Claims

1. A compound of formula (IA) or (IB) or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any one of its entities,wherein R is¹Is C optionally substituted by a phenyl, Het or N-linked heterocyclic group selected from piperidinyl and morpholinyl₁-C₃An alkyl group; wherein said phenyl group is substituted by one or more groups selected from C₁-C₄Alkoxy, halo, CN, CF₃、OCF₃Or C₁-C₄The substituent of the alkyl group is optionally substituted, wherein C is₁-C₄Alkyl radicals derived from C₁-C₄Haloalkyl or C₁-C₄Haloalkoxy, any of which is substituted with one or more halogen atoms; r²Is C₁-C₆An alkyl group; r¹³Is OR³Or NR⁵R⁶；R³Is formed by one or two selected from C₃-C₅Cycloalkyl, OH, C₁-C₄Alkoxy, benzyloxy, NR⁵R⁶C optionally substituted by substituents of phenyl, furyl and pyridyl₁-C₆Alkyl radical, C₃-C₆Cycloalkyl, 1- (C)₁-C₄Alkyl) piperidinyl, tetrahydrofuranyl or tetrahydropyranyl; and wherein said C₁-C₆Alkyl or said C₁-C₄Alkoxy groups may be optionally capped with haloalkyl groups; r⁴Is SO₂NR⁷R⁸；R⁵And R⁶Each independently selected from H and C₃-C₅Cycloalkyl or C₁-C₄Alkoxy-optionally substituted C₁-C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl; r⁷And R⁸Together with the nitrogen atom to which they are attached form a group consisting of one or two C₁-C₄Alkyl optionally substituted 4-R¹⁰-piperazinyl and optionally in the form of its 4-N-oxide; r¹⁰Is H; c optionally substituted by one or two substituents selected from₁-C₄Alkyl groups: OH, NR⁵R⁶、CONR⁵R⁶From C₁-C₄Alkoxy, benzodioxolyl and benzodioxacyclohexyl optionally substituted phenyl; c₃-C₆An alkenyl group; pyridyl or pyrimidinyl; and Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms optionally present in the form of its mono-N-oxide or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein any of the heterocycles are represented by C₁-C₄Alkyl radical, C₁-C₄Alkoxy or NHR¹⁵Is optionally substituted, wherein R¹⁵Is H, C₁-C₄Alkyl or C₁-C₄Alkanoyl, halo is Br, Cl, F or I.

2. The compound of claim 1, wherein R¹Is C optionally substituted by Het₁-C₂Alkyl, 2- (morpholin-4-yl) ethyl or benzyl; r²Is C₂-C₄An alkyl group; r¹³Is OR³Or NR⁵R⁶；R³Is prepared from one or two of cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR⁵R⁶C optionally substituted with substituents of phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl₁-C₄An alkyl group; a cyclobutyl group; 1-methylpiperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; r⁵And R⁶Each independently selected from H and C optionally substituted by cyclopropyl or methoxy₁-C₂Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl or morpholinyl; r⁷And R⁸Together with the nitrogen atom to which they are attached form 4-R optionally substituted by one or two methyl groups¹⁰-piperazinyl and optionally in the form of its 4-N-oxide; r¹⁰Is H; c optionally substituted by one or two substituents selected from₁-C₃Alkyl groups: OH, NR⁵R⁶、CONR⁵R⁶Phenyl optionally substituted with methoxy, benzodioxol-5-yl and benzodioxan-2-yl; an allyl group; pyridin-2-yl; pyridin-4-yl or pyrimidin-2-yl; 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.

3. The compound of claim 2, wherein R¹Is C optionally substituted by Het₁-C₂Alkyl, 2- (morpholin-4-yl) ethyl or benzyl; r²Is C₂-C₄An alkyl group; r¹³Is OR³；R³Is C optionally monosubstituted by cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl₁-C₄Alkyl, cyclobutyl, tetrahydrofuran-3-yl or tetrahydropyran-4-yl; r⁷And R⁸Together with the nitrogen atom to which they are attached form 4-R optionally in its 4-N-oxide form¹⁰-a piperazinyl group; r¹⁰Is C optionally monosubstituted by OH₁-C₃An alkyl group; 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.

4. A compound according to any one of claims 1 to 3 selected from: 3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (pyridin-2-yl) methyl-2, 6-dihydro-7H-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-piperazinol-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-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-di-hydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one; (+) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1 (R) -methylethoxy) 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) -methylethoxy) pyridin-3-yl ] -2- (6-methylpyridin-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [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-isobutoxy-5- (4-ethylpiperazin-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-ethyl-2- [1- (pyridin-2-yl) ethyl ] -2, 6-dihydro-7H-pyrazolo [4,3-d ] pyrimidin-7-one.

5. A pharmaceutical composition which comprises a compound of formula (ia) or (ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of its entities, in association with a pharmaceutically acceptable diluent or carrier.

6. A veterinary formulation which comprises a compound of formula (ia) or (ib) or a veterinarily acceptable salt thereof, or any substantial veterinarily acceptable solvate thereof, together with a veterinarily acceptable diluent or carrier.

7. A compound of formula (IA) or (IB) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of the entities thereof or a pharmaceutical composition comprising any of the foregoing for use as a medicament in the treatment of humans.

8. A compound of formula (IA) or (IB) or a veterinarily acceptable salt thereof, or a tangible, veterinarily acceptable solvate of any of them or a veterinary formulation containing any of the foregoing, for use as a medicament for the treatment of an animal.

9. The use of a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any one of the entities thereof, for the manufacture of a human medicament for the therapeutic or prophylactic treatment of a disease for which an inhibitor of cGMP PDE5 is indicated.

10. The use of a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or any one of the physical, veterinarily acceptable solvates thereof, for the preparation of a veterinary medicament for the therapeutic or prophylactic treatment of diseases for which cGMP PDE5 inhibitors are indicated.

11. Use of a compound of formula (ia) or (ib), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of any entity containing same, for the manufacture of a medicament for use in the therapeutic or prophylactic treatment of Male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labour, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, reduced vascular patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or a disease characterized by bowel motility disorders.

12. Use of a compound of formula (ia) or (ib), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate comprising any entity thereof, for the manufacture of a veterinary medicament for the therapeutic or prophylactic treatment of Male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labour, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, reduced vascular patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma, or a disease characterized by bowel motility disorders.

13. A method of treatment or prophylaxis of diseases for which an inhibitor of cGMp PDE5 is indicated in a mammal, including a human being, which method comprises administering to said mammal a therapeutically effective amount of a compound of formula (ia) or (ib) or a pharmaceutically or veterinarily acceptable salt thereof, or any entity thereof, a pharmaceutically or veterinarily acceptable solvate thereof or a pharmaceutical composition or veterinary formulation containing any of the foregoing.

14. A method of treating or preventing Male Erectile Dysfunction (MED), Female Sexual Dysfunction (FSD), premature labor, menstruation, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal's) angina, hypertension, pulmonary hypertension, congestive heart failure, arteriosclerosis, stroke, peripheral vascular disease, a condition of reduced vascular patency, chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or a condition characterised by intestinal motility disorders in a mammal (including a human being), the method comprises administering to the mammal a therapeutically effective amount of a compound of formula (ia) or (ib) or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity thereof, or a pharmaceutical composition or veterinary formulation comprising any of the foregoing.

15. A compound of formula (IIA) or (IIB):wherein Y is halo, and R¹、R²And R¹³As defined in claim 1.

16. The compound of claim 16, wherein Y is chloro.

17. A compound of formula (IVA) or (IVB):wherein R is¹、R²And R¹³As defined in claim 1.

18. A compound of formula (VA) or (VB):wherein R is¹、R²And R¹³As in the preceding claimsDefined in claim 1.

19. A compound of formula (IX A) or (IX B):wherein R is¹、R²、R⁴And R¹³As previously defined in claim 1.

20. A process for the preparation of a compound of formula (IA) or (IB):wherein R is¹Is C optionally substituted by a phenyl, Het or N-linked heterocyclic group selected from piperidinyl and morpholinyl₁-C₃An alkyl group; wherein said phenyl group is substituted by one or more groups selected from C₁-C₄Alkoxy, halo, CN, CF₃、OCF₃Or C₁-C₄The substituent of the alkyl group is optionally substituted, wherein C is₁-C₄Alkyl radicals derived from C₁-C₄Haloalkyl or C₁-C₄Haloalkoxy, any of which is substituted with one or more halogen atoms; r²Is C₁-C₆An alkyl group; r¹³Is OR³Or NR⁵R⁶；R³Is formed by one or two selected from C₃-C₅Cycloalkyl, OH, C₁-C₄Alkoxy, benzyloxy, NR⁵R⁶C optionally substituted by substituents of phenyl, furyl and pyridyl₁-C₆Alkyl radical, C₃-C₆Cycloalkyl radicals, 1- (C)₁-C₄Alkyl) piperidinyl, tetrahydrofuranyl or tetrahydropyranyl; and wherein said C₁-C₆Alkyl or said C₁-C₄Alkoxy is optionally capped with haloalkyl; r⁴Is SO₂NR⁷R⁸；R⁵And R⁶Each independently selected from H and C₃-C₅Cycloalkyl or C₁-C₄Alkoxy-optionally substituted C₁-C₄Alkyl, or together with the nitrogen atom to which they are attached form an azetidinyl group,Pyrrolidinyl, piperidinyl or morpholinyl; r⁷And R⁸Together with the nitrogen atom to which they are attached form a group consisting of one or two C₁-C₄Alkyl optionally substituted 4-R¹⁰-piperazinyl and optionally in the form of its 4-N-oxide; r¹⁰Is H, C optionally substituted by one or two substituents selected from₁-C₄Alkyl groups: OH, NR⁵R⁶、CONR⁵R⁶From C₁-C₄Alkoxy, benzodioxolyl and benzodioxacyclohexyl optionally substituted phenyl, C₃-C₆Alkenyl, pyridyl or pyrimidinyl; and Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms optionally present in the form of its mono-N-oxide or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein any of the heterocyclic groups is represented by C₁-C₄Alkyl radical, C₁-C₄Alkoxy or NHR¹⁵Is optionally substituted, wherein R¹⁵Is H, C₁-C₄Alkyl or C₁-C₄Alkanoyl with halo being Br, Cl, F or I; the process comprises reacting a compound of formula (IIA) or (IIB),wherein Y is halo, R¹、R²And R¹³As defined previously in the claims, with compounds of the formula (III),

R⁷R⁸NH (III) wherein R⁷And R⁸A pharmaceutically or veterinarily acceptable salt of the desired product, or a pharmaceutically or medically acceptable solvate of any one of its entities, is then formed, as previously defined in the claims.

21. A process for the preparation of a compound of formula (ia) or (ib) as defined in claim 20, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any entity thereof, which comprises reacting a compound of formula (va) or (vb), respectivelyWherein R is¹、R²And R¹³As previously defined for formulae (ia) and (ib) in claim 20, cyclizing to form a compound of formula (iva) or (ivb):by reaction with R⁷And R⁸R of formula (III) as defined in claim 20⁷R⁸A NH compound capable of being converted to a compound of formula (iia) or (iib) which in turn can be converted to a compound of formula (ia) or (ib) according to the process of claim 20, which can then optionally form a pharmaceutically or veterinarily acceptable salt of the desired product, or a pharmaceutically or veterinarily acceptable solvate of any one of its entities.

22. A process for the preparation of a compound of formula (IA) or (IB) as defined in claim 20, or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of any one of its entities, which process comprises cyclising a compound of formula (IX A) or (IX B), respectively,wherein R is¹、R²、R⁴And R¹³As defined in claim 20.