HK1050367B

HK1050367B - Pharmaceutically active compounds

Info

Publication number: HK1050367B
Application number: HK03102607.8A
Authority: HK
Inventors: M‧E‧邦纳吉; K‧M‧戴弗里斯; L‧J‧哈里斯; P‧C‧莱维特; J‧P‧玛希亚斯; J‧T‧纳格里; S‧D‧A‧斯特里特; A‧S‧伍德
Original assignee: 辉瑞大药厂
Priority date: 1999-10-11
Filing date: 2000-10-11
Publication date: 2005-12-09

Description

Pyrazolo [4, 3-d ] pyrimidine derivatives

Technical Field

The present invention relates to a series of pyrazolo [4, 3-d ] pyrimidin-7-ones which inhibit cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase (cGMP PDE). The compounds of the invention are particularly potent and selective inhibitors of cyclic guanosine 5 ', 5' -monophosphate phosphodiesterase (cGMP PDE5) and are therefore of utility in a variety of therapeutic areas.

Background

The compounds of the invention are of great importance for the cure or prevention of sexual dysfunction in mammals. In particular, the compounds of the invention are of interest for the treatment of sexual dysfunction in mammals, such as Male Erectile Dysfunction (MED), impotence, Female Sexual Dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder, female orgasmic dysfunction (FSOD), and sexual dysfunction due to spinal cord injury or Selective Serotonin Reuptake Inhibitor (SSRI) -induced sexual dysfunction, but clearly also for the treatment of other medical conditions where effective selective cGMP PDE5 inhibitors are indicated. Such conditions include premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, urinary incontinence, stable, unstable and variable (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced vascular patency (e.g., following Percutaneous Transluminal Coronary Angioplasty (PTCA)), peripheral vascular disease, stroke, nitrate-induced drug resistance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, ocular diseases and conditions (e.g., glaucoma, ocular neuropathy, macular degeneration, elevated intraocular pressure, retinal or arterial obstruction), and diseases characterized by gut motility disorders (e.g., Irritable Bowel Syndrome (IBS)).

Other medical conditions for which potent selective cGMP PDE5 inhibitors are useful and which can be treated with the compounds of the present invention include preeclampsia, Kawasaki syndrome, nitrate resistance, multiple sclerosis, diabetic nephropathy, neuropathy (including autonomic and peripheral neuropathy, particularly diabetic neuropathy and symptoms thereof, such as gastroparesis), peripheral diabetic neuropathy, Alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastases, alopecia areata, nut-pincer esophagus, anal fissure, hemorrhoids, hypoxic vasoconstriction, and stabilization of blood pressure during hemodialysis.

Particularly preferred disorders include MED and FSD.

PCT application PCT/IB99/00519 relates to a series of pyrazolo [4, 3-d ] pyrimidin-7-ones which inhibit cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase (cGMP PDE).

Disclosure of Invention

Accordingly, the present invention provides a compound of formula (I):

or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate thereof, wherein R¹Is C₁To C₆Alkyl or C₃To C₆Alkenyl radical, C₃To C₆Cycloalkyl or C₄To C₆Cycloalkenyl, wherein the alkyl radical may be branched or linear, wherein if R ¹Is C₁To C₃Alkyl, said alkyl is substituted with one or more of the following substituents; wherein if R is¹Is C₄To C₆Alkyl radical, C₃To C₆Alkenyl or C₃To C₆Cycloalkyl, said alkyl, alkenyl or cycloalkyl being optionally substituted by one or more of the following substituents; the two substituents are selected from:

a hydroxyl group;

C₁to C₄An alkoxy group;

C₃to C₆A cycloalkyl group;

phenyl substituted by one or more substituents selected from C₁To C₃Alkyl radical, C₁To C₄Alkoxy radical, C₁To C₄Haloalkyl, C₁To C₄Haloalkoxy, halogen, CN, NO₂、NHR¹¹、NHCOR¹²、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹Or CO₂R¹¹Wherein the haloalkyl and haloalkoxy groups contain one or more halogen atoms; NR (nitrogen to noise ratio)⁷R⁸、CONR⁷R⁸Or NR⁷COR¹¹Wherein R is⁷And R⁸Each independently selected from H, C₁To C₄Alkyl radical, C₃To C₄Alkenyl, CO₂R⁹Or SO₂R⁹Wherein said alkyl or alkenyl group may be optionally substituted by C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy substitution;

Het¹；

Het²or Het³；

Or R¹Is Het⁴Or phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from C₁To C₄Alkyl radical, C₃To C₄Alkenyl radical, C₁To C₄Alkoxy, halogen, CN, CF₃、OCF₃、NO₂、NHR¹¹、NHCOR¹²、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹、CO₂R¹¹；

R²Is C₁To C₄Alkyl radical, C₃To C₆Alkenyl or (CH)₂)_n(C₃To C₆Cycloalkyl) wherein n is 0, 1 or 2;

R¹³Is OR³Or NR⁵R⁶；

R³Is C optionally substituted by one or two substituents₁To C₆Alkyl, the substituent is selected from C₃To C₅Cycloalkyl, hydroxy, C₁To C₄Alkoxy, benzyloxy, NR⁵R⁶Phenyl, Het¹、Het²、Het³Or Het⁴In which C is₁To C₆Alkyl and C₁To C₄The alkoxy group may optionally terminate in a haloalkyl group, e.g. CF₃In which C is₃-C₅The cycloalkyl group may optionally be substituted by C₁-C₄Alkyl, hydroxy or halogen substitution;

C₃to C₆A cycloalkyl group; het¹、Het²、Het³Or Het⁴；

R⁴Is piperazin-1-ylsulfonyl with a substituent R in the 4-position of the piperazinyl group¹⁰Wherein said piperazinyl is optionally substituted by one or two C₁To C₄Alkyl substituted, and optionally in the form of its 4-N-oxide;

R⁵and R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;

R⁷and R⁸Each independently selected from H, C₁To C₄Alkyl radical, C₃To C₄Alkenyl, CO₂R⁹Or SO₂R⁹；

R⁹Is optionally covered by C₁To C₄Haloalkyl, C₁To C₄Haloalkoxy or phenyl substituted C₁To C₄Alkyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of optionally substituted with C ₁To C₄Haloalkyl or C₁To C₄Haloalkoxy substituted C₁To C₄Alkyl radical, C₁To C₄Alkoxy, halogen, CN, O₂、NHR¹¹、NHCOR¹²、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹Or CO₂R¹¹；

R¹⁰Is H; c optionally substituted by one or two substituents₁To C₄Alkyl, the substituent is selected from hydroxyl and NR⁵R⁶、CONR⁵R⁶Optionally by C₁To C₄Alkyl or C₁To C₄Alkoxy-substituted phenyl; c₃To C₆Alkenyl or Het⁴；

R¹¹Is H, C₁To C₄Alkyl radical, C₃To C₄Alkenyl, CO (C)₁To C₄Alkyl) or C₁To C₄A haloalkyl group;

R¹²is C₁To C₄Alkyl radical, C₃To C₄Alkenyl radical, C₁To C₄Haloalkyl or C₁To C₄A haloalkoxy group;

Het¹is an N-linked 4-, 5-, or 6-membered nitrogen-containing heterocyclic group, optionally containing one or more additional heteroatoms selected from S, N or O;

Het²is a C-linked 5-membered heterocyclic group containing either an O, S or N heteroatom, optionally containing one or more heteroatoms selected from N, O or S;

Het³is a C-linked 6-membered heterocyclic group containing an O or S heteroatom, optionally containing one or more heteroatoms selected from O, S or N, or Het³Is a C-linked 6-membered heterocyclyl containing three N heteroatoms;

Het⁴is a C-linked 4-, 5-, or 6-membered heterocyclyl containing one, two, or three heteroatoms selected from S, O or N;

wherein any of said heterocyclic groups Het ¹、Het²、Het³Or Het⁴May be saturated, partially unsaturated or aromatic, wherein any of said heterocyclic groups may be optionally substituted with one or more substituents selected from C₁To C₄Alkyl radical, C₃To C₄Alkenyl radical, C₁To C₄Alkoxy, halogen, CF₃、CO₂R¹¹、COR¹¹、SO₂R¹²、NHR¹¹Or NHCOR¹²And/or wherein any of said heterocyclyl groups is benzo-fused;

with the proviso that (a) if R¹Is C₁To C₃Alkyl, then Het¹Is not morpholinyl or piperidinyl, (b) if R¹Is C substituted by phenyl₁To C₃Alkyl, then the phenyl is not substituted by C₁To C₄Alkoxy, halogen, CN, CF₃、OCF₃Or C₁To C₄Alkyl substitution.

As will be recognized by the chemist, formula (I) may be represented by regioisomeric formulae (IA) and (IB). Accordingly, the present invention provides compounds of formulae (IA) and (IB):

wherein R is¹、R²、R⁴And R¹³As defined above.

In the above definitions, unless otherwise indicated, alkyl, alkoxy and alkenyl groups having three or more carbon atoms and alkanoyl groups having four or more carbon atoms may be straight-chain or branched. E.g. C₄The alkyl substituents may be in the form of n-butyl (n-butyl), iso-butyl (i-butyl), sec-butyl (sec-butyl) or tert-butyl (t-butyl). The term halogen atom includes Cl, Br, F and I. Haloalkyl and haloalkoxy are each preferably-CF ₃and-OCF₃. The term aromaticity as defined herein denotes a fully unsaturated system.

The compounds of formula (I) contain one or more asymmetric carbon atoms and thus exist in two or more stereoisomeric forms. If the compounds of the formula (I) contain alkenyl or alkenylene groups, cis (E) and trans (Z) isomerism may also occur. The invention includes individual stereoisomers of the compounds of formula (I), including individual tautomeric forms thereof, as appropriate, and mixtures thereof. Separation of the diastereomers or cis-and trans-isomers may be achieved using conventional techniques, such as fractional crystallization, chromatography or h.p.l.c. of a stereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. The individual enantiomers of the compounds of formula (I) can also be prepared from the corresponding optically pure intermediates, or by resolution of the corresponding racemates using a suitable chiral support, for example by h.p.l.c., or by fractional crystallization of the diastereomeric salts formed by reaction of the corresponding racemates with a suitable optically active acid or base, as the case may be.

All stereoisomers are included within the scope of the invention.

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

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

Pharmaceutically or veterinarily acceptable salts of the compounds of the invention containing a basic centre are for example non-toxic acid addition salts with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acids, carboxylic or organic sulphonic acids. Examples include HCl, HBr, HI, sulfate or bisulfate, nitrate, phosphate or biphosphate, acetate, benzoate, succinate, saccharate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate. The compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts with bases, specifically non-toxic alkali and alkaline earth metal salts. Examples include sodium, potassium, aluminum, calcium, magnesium, zinc and diethanolamine salts. See Berge et al j. pharm, Sci. (journal of pharmaceutical sciences), 66, 1-19, 1977 for suitable pharmaceutical salts.

Pharmaceutically acceptable solvates of the compounds of the invention include hydrates thereof.

Polymorphic forms thereof are also included within the scope of the compounds and various salts of the present invention.

A preferred group of compounds of formula (I), (IA) and (IB) is that in which R is¹Is C₁To C₆Alkyl or C₃To C₆Alkenyl, wherein the alkyl or alkenyl may be branched or straight-chain, or R¹Is C₃To C₆Cycloalkyl or C₄To C₆Cycloalkenyl radical, wherein if R¹Is C₁To C₃Alkyl, said alkyl is substituted with one or more of the following substituents; wherein if R is¹Is C₄To C₆Alkyl radical, C₃To C₆Alkenyl radical, C₃To C₆Cycloalkyl or C₄To C₆Cycloalkenyl, said alkyl, alkenyl, cycloalkyl or cycloalkenyl being optionally substituted by one or more of the following substituents;

the two substituents are selected from:

a hydroxyl group;

C₁to C₄An alkoxy group;

C₃to C₄A cycloalkyl group;

phenyl substituted by one or more substituents selected from C₁To C₃Alkyl radical, C₁To C₄Alkoxy radical, C₁To C₄Haloalkyl, C₁To C₄Haloalkoxy, halogen, CN, NO₂、NHR¹¹、NHCOR¹²、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹Or CO₂R¹¹Wherein the haloalkyl and haloalkoxy groups contain one or more halogen atoms; NR (nitrogen to noise ratio)⁷R⁸、CONR⁷R⁸Or NR⁷COR¹¹；

Het¹A group which is an N-linked 4-membered N-containing heterocyclic group;

Het²a group which is a C-linked 5-membered heterocyclic group containing either an O, S or N heteroatom, optionally containing one or more heteroatoms selected from N, O or S;

Het³A group which is a C-linked 6-membered heterocyclic group containing an O or S heteroatom, optionally containing one or more heteroatoms selected from O, S or N, or Het³A group which is a C-linked 6-membered heterocyclic group containing three N heteroatoms;

wherein R is⁷、R⁸、R¹¹And R¹²Is as defined hereinbefore;

or R¹Is Het⁴A group which is a C-linked 4-or 5-membered heterocyclic group containing one heteroatom selected from S, O or N; het⁴A group which is a C-linked 6-membered heterocyclyl containing one, two or three heteroatoms selected from S or O; het⁴A group which is a C-linked 6-membered heterocyclic group containing three nitrogen heteroatoms; it is a C-linked 6-membered heterocyclic group containing one or two nitrogen heteroatoms, which is substituted by one or more substituents selected from C₁To C₄Alkyl radical, C₁To C₄Alkoxy, CO₂R¹¹、SO₂R¹²、COR¹¹、NHR¹¹Or NHCOR¹²And optionally further comprises a heteroatom selected from S, O or N;

wherein any of said heterocyclic groups Het¹、Het²、Het³Or Het⁴Optionally saturated, partially unsaturated or aromatic, wherein any of said heterocyclic groups may optionally be substituted by one or more substituents selected from C₁To C₄Alkyl radical, C₃To C₄Alkenyl radical, C₁To C₄Alkoxy, halogen, CO ₂R¹¹、SO₂R¹²、COR¹¹Or NHR¹¹Wherein R is¹¹Is as hereinbefore defined, and/or wherein any of said heterocyclyl groups is benzo-fused;

or R¹Is phenyl substituted by one or more substituents selected from CF₃、OCF₃、SO₂R¹²Or CO₂R¹²Wherein R is¹²Is C₁To C₄Alkyl, optionally substituted by phenyl, C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy substitution, wherein the haloalkyl and haloalkoxy contain one or more halogen atoms;

R²is C₁To C₆An alkyl group;

R¹³is OR³；

R³Is C optionally substituted by one or two substituents₁To C₆Alkyl, the substituent is selected from C₃To C₅Cycloalkyl, hydroxy, C₁To C₄Alkoxy, benzyloxy, NR⁵R⁶Phenyl, furyl, tetrahydrofuryl or pyridyl wherein said C₁To C₆Alkyl and C₁To C₄The alkoxy group may optionally terminate in a haloalkyl group, e.g. CF₃(ii) a Or R³Is C₃To C₆Cycloalkyl, 1- (C)₁To C₄Alkyl) piperidinyl, tetrahydrofuranyl or tetrahydropyranyl; r⁴Is piperazin-1-ylsulfonyl with a substituent R in the 4-position of the piperazinyl group¹⁰Wherein said piperazinyl is optionally substituted by one or two C₁To C₄Alkyl substituted, and optionally in the form of its 4-N-oxide;

R⁵and R⁶Each independently selected from H and optionally C ₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl;

R¹⁰is H; can be selectively one orC substituted by two substituents₁To C₄Alkyl, the substituent is selected from hydroxyl and NR⁵R⁶、CONR⁵R⁶Optionally by C₁To C₄Alkyl or C₁To C₄Alkoxy-substituted phenyl; c₃To C₆Alkenyl or Het⁴；

With the proviso that if R¹Is C substituted by phenyl₁To C₃Alkyl, then the phenyl is not substituted by C₁To C₄Alkoxy, CN, halogen, CF₃、OCF₃Or C₁To C₄Alkyl substitution.

A further preferred group of compounds of the formulae (I), (IA) and (IB) is that in which R is¹Is C₁To C₆Alkyl, wherein the alkyl may be branched or straight chain, or R¹Is C₃To C₆Cycloalkyl, wherein if R¹Is C₁To C₃Alkyl, said alkyl is substituted with one or more of the following substituents; wherein if R is¹Is C₄To C₆Alkyl or C₃To C₆Cycloalkyl, said alkyl or cycloalkyl being optionally substituted by one or more of the following substituents;

the two substituents are selected from:

a hydroxyl group;

C₁to C₂An alkoxy group;

C₃to C₅A cycloalkyl group;

NR⁷R⁸、NR⁷COR¹¹or COR¹¹Wherein R is⁷And R⁸Each independently selected from H, C₁To C₄Alkyl or CO₂R⁹Wherein R is ⁹And R¹¹Is as defined hereinbefore;

Het¹a group which is an N-linked 4-membered N-containing heterocyclic group;

or R¹Is Het⁴A group which is a C-linked 4-or 5-membered heterocyclic group containing one heteroatom selected from S, O or N, or R¹Is Het⁴A group which is a C-linked 6-membered heterocyclyl containing one, two or three heteroatoms selected from S or O;

wherein any of said heterocyclic groups Het¹、Het²、Het³Or Het⁴May be saturated, partially unsaturated or aromatic, and may optionally be substituted by one or more substituents selected from C₁To C₄Alkyl radical, C₁To C₄Alkoxy, -CO₂R¹¹、-SO₂R¹²、-COR¹¹Or NHR¹¹Wherein R is¹¹And R¹²Is as hereinbefore defined, and/or wherein any of said heterocyclyl groups is benzo-fused;

or R¹Is phenyl substituted by one or more substituents selected from CF₃、-OCF₃、-SO₂R¹²、-COR¹¹、-CO₂R¹¹Wherein R is¹¹And R¹²Is as defined hereinbefore;

R²is C₁To C₆An alkyl group;

R¹³is OR³；

R³Is methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, i-butyl or tert-butyl, which alkyl group may optionally be substituted by one or two substituents selected from cyclopropyl, cyclobutyl, hydroxy, methoxy, ethoxy, benzyloxy, phenyl, benzyl, furan-3-yl, tetrahydrofuran-2-ylmethyl, tetrahydrofuran-3-ylmethyl, tert-butyl, and mixtures thereof, Pyridin-2-yl, pyridin-3-yl or NR⁵R⁶Wherein R is⁵And R⁶Each independently selected from H and C₁To C₂An alkyl group;

R¹⁰is H; c optionally substituted by one or two substituents₁To C₃Alkyl, the substituent is selected from hydroxyl and NR⁵R⁶、CONR⁵R⁶Wherein R is⁵And R⁶Each independently selected from H, C₁To C₄Alkyl and C₃An alkenyl group.

According to a particular embodiment, the present invention provides a compound of formula (I):

or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate thereof, wherein

R¹Is C₁To C₆Alkyl, wherein if R¹Is C₁To C₃An alkyl group, said alkyl group being substituted with a substituent selected from the group consisting of; if R is¹Is C₄To C₆Alkyl, said alkyl is optionally substituted with one substituent selected from the group consisting of: a hydroxyl group; c₁To C₄An alkoxy group; c₃To C₆A cycloalkyl group; NR (nitrogen to noise ratio)⁷R⁸；CONR⁷R^8’(ii) a A tetrahydrofuranyl group; tetrahydropyranyl and pyrazolyl; or R¹Is C₃To C₆A cycloalkyl group; azetidinyl, in which the nitrogen atom is optionally selected from hydrogen, C ₁To C₆Alkyl and C₁To C₆Substituted with alkanoyl; piperidinyl in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl radical, C₁To C₆Alkanoyl and C₁To C₆Substituted with an alkylsulfonyl group; phenyl, wherein the phenyl is optionally selected from nitro, amino, C₁To C₆Alkyl sulfonic amino and cyano; a pyridyl group; a pyrazinyl group; a thiazolyl group; pyrimidinyl optionally substituted with halo; and benzoxazolyl;

R⁷is hydrogen or C₁To C₄An alkyl group;

R⁸is C₁To C₄Alkyl radical, C₁To C₄Alkoxycarbonyl or C₁To C₄An alkylsulfonyl group;

R^8’is hydrogen or C₁To C₄An alkyl group;

R²is C₁To C₆An alkyl group;

R¹³is OR³Or pyrrolidinyl;

R³is C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical C₁To C₆Alkyl, phenyl-C₁To C₆Alkyl, pyridyl-C₁To C₆Alkyl, or tetrahydrofuryl-C₁To C₆An alkyl group; and

R⁴is piperazin-1-ylsulfonyl wherein the 4-position of the piperazinyl group is substituted by R¹⁰Is substituted in which R¹⁰Is H or C₁To C₄An alkyl group.

In a preferred version of the above embodiment, R¹Is C₁To C₆Alkyl, wherein the alkyl may be branched or straight chain, or R¹Is C₃To C₆Cycloalkyl, wherein if R¹Is C₁To C₃Alkyl, said alkyl is substituted with one of the following substituents; Wherein if R is¹Is C₄To C₆Alkyl, said alkyl is optionally substituted with one of the following substituents;

the substituents are selected from:

a hydroxyl group;

C₁to C₄An alkoxy group;

C₃to C₅A cycloalkyl group;

NR⁷R⁸or CONR⁷R^8’；

A tetrahydrofuranyl group; a tetrahydropyranyl group; a pyrazolyl group;

wherein R is⁷、R⁸And R^8’Is as defined above;

or R¹Is azetidinyl, wherein the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl and C₁To C₆Substituted with alkanoyl; piperidinyl in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl radical, C₁To C₆Alkanoyl and C₁To C₆Substituted with an alkylsulfonyl group; a pyridyl group; a pyrazinyl group; a thiazolyl group; or pyrimidinyl optionally substituted with one halogen;

R¹³is OR³(ii) a Wherein R is³Is C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical C₁To C₆Alkyl, phenyl-C₁To C₆Alkyl, pyridyl-C₁To C₆Alkyl, or tetrahydrofuryl-C₁To C₆An alkyl group.

In another preferred version of the above embodiment, R¹Is C₁To C₆Alkyl, wherein the alkyl may be branched or straight chain, or R¹Is C₃To C₆Cycloalkyl, wherein if R¹Is C₁To C₃Alkyl, said alkyl is substituted with one of the following substituents;

wherein if R is¹Is C₄To C₆Alkyl, said alkyl being optionally substituted with one of the following substituents;

The substituents are selected from:

a hydroxyl group;

C₁to C₂An alkoxy group;

C₃to C₄A cycloalkyl group;

NR⁷R⁸；

a tetrahydrofuranyl group; a tetrahydropyranyl group; a pyrazolyl group;

or R¹Is azetidinyl, wherein the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl and C₁To C₆Substituted with alkanoyl; piperidinyl in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl radical, C₁To C₆Alkanoyl and C₁To C₆Substituted with an alkylsulfonyl group; a pyridyl group; a pyrazinyl group; a thiazolyl group; or pyrimidinyl optionally substituted with one halogen.

In yet another preferred version of the above embodiment, R¹Is- (CH)₂)_n(C₃-C₅) Cycloalkyl, wherein n is 0, 1, 2 or 3; or R¹Is covered by a C₁To C₄Alkoxy-substituted methyl, ethyl, i-propyl or n-propyl, wherein the alkoxy substituent may be directly attached to any C-atom within the ethyl, i-propyl or n-propyl group;

or R¹Is C selected from iso-, n-, sec-or tert-butyl₄Alkyl optionally substituted with one substituent selected from C₁To C₄Alkoxy or C₃To C₄A cycloalkyl group;

R²is C₁To C₄An alkyl group;

R¹³is OR³Wherein R is³Is optionally covered by a C₁To C₄Alkoxy-substituted C₁To

C₄An alkyl group;

R⁴is piperazin-1-ylsulfonyl having a single substituent R at the 4-position of the piperazinyl group¹⁰，R¹⁰Is methyl or ethyl.

Preferred compounds of the invention include:

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ 2-methoxyethyl ] -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ 2-methoxyethyl ] -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (sec-butyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (iso-butyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (cyclopropylmethyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (cyclobutylmethyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-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- [ 2-methoxyethyl ] -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- [ 2-methoxy-1-methylethyl ] -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- [2- (methylamino) ethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (2-dimethylaminoethyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-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- (1-methylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2-dimethylaminoethyl-3-ethyl-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- (1-ethylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- {2- [ acetyl (methyl) amino ] ethyl } -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (1-Acetylazetidin-3-yl) -5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-lso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (2-methoxyethyl) -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -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- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-methylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-ethylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-benzyloxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-ethylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-lso-butoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-i-propoxypyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ (S) -2-sec-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ (R) -2-sec-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- { (pyridin-2-yl) methyl } pyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-sec-butyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclobutylmethyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (S) - (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (R) - (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (S) - (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-methoxyethyl) -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (R) - (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-methoxyethyl) -3-n-propyl-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- (2-hydroxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-iso-butyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-iso-butyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclobutylmethyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [2- (dimethylamino) -2-oxoethyl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidine 7-one,

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- {2- [ methyl (methylsulfonyl) amino ] ethyl } -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-Cyclobutylpropylmethyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-n-butyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (2-ethoxyethyl) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -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- (3-methoxypropyl) -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- (S) - (2-methoxypropyl) -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- (R) - (2-methoxypropyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (S) -sec-butyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-1- (2-methoxyethyl) -1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2- (R) -sec-butyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclobutyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclopentyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclopentylmethyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclohexyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (2-ethoxyethyl) -3-ethyl-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- [ (1S) -1-methyl-2-methoxyethyl) -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- [ (1R) -1-methyl-2-methoxyethyl ] -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- (3-methoxy-n-propyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

2-cyclobutyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one,

5- [ 2-n-butoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ (1S) -1-methylpropyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ (1R) -1-methylpropyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

2-n-butyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

2-cyclopropylmethyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

2-cyclobutylmethyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydro-2-furanylmethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2- (2-methoxyethoxy) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone,

5- [ 2-ethoxy-5- (4-i-propylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone, and

5- [ 2-ethoxy-5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yl) -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone.

Still further preferred is a group of compounds of formula (I), (IA) or (IB),

R¹is- (CH)₂)_n(C₃-C₆) Cycloalkyl, wherein n is 0, 1, 2 or 3; or

R¹Is formed by one or more C ₁To C₄Alkoxy-substituted methyl, ethyl, i-propyl or n-propyl, wherein the alkoxy substituent may be attached directly to any C-atom within the ethyl, i-propyl or n-propyl group other than the C-atom directly attached to the pyrazole ring;

or R¹Is C selected from iso-, n-, sec-or tert-butyl₄Alkyl optionally substituted with one or more substituents selected from C₁To C₄Alkoxy or C₃To C₄A cycloalkyl group;

R²is C₁To C₄An alkyl group;

R¹³is OR³Wherein R is³Is optionally substituted by one or two C₁To C₄Alkoxy-substituted

C₁To C₄Alkyl radical, wherein said C₁To C₄Alkyl and C₁To C₄The alkoxy group may optionally terminate in a haloalkyl group, e.g. CF₃；

R⁴Is piperazin-1-ylsulfonyl having a single substituent R at the 4-position of the piperazinyl group¹⁰And optionally in the form of its 4-N-oxide;

R¹⁰is methyl, ethyl, n-propyl or i-propyl.

A particularly preferred group of compounds of formula (I), (IA) or (IB),

R¹is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₆) Cycloalkyl, wherein n is 0; or

R¹Is-cyclopentylmethyl; or

R¹Is methyl, ethyl, i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxy, wherein the alkoxy substituent may be attached directly to any C-atom of the ethyl, i-propyl or n-propyl group other than the C-atom attached directly to the pyrazole ring; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R¹³is OR³Wherein R is³Alkyl is methyl, ethyl, n-propyl, i-butyl, n-butyl, sec-butyl or tert-butyl which may be optionally substituted by one or two methoxy, ethoxy, n-propoxy or i-propoxy groups;

R⁴is 4-methyl-, 4-ethyl-, 4-n-propyl-or 4-isopropyl-piperazin-1-ylsulfonyl.

In a highly preferred embodiment, the present invention provides a compound of formula (IB), wherein

R¹Is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₅) Cycloalkyl, wherein n is 0; or

R¹Is-cyclopentylmethyl; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R¹³is OR³Wherein R is³Alkyl is methyl, ethyl, n-propyl, i-butyl, n-butyl, sec-butyl or tert-butyl;

R⁴is 4-methyl-or 4-ethyl-piperazin-1-ylsulfonyl.

Very preferred compounds according to the invention include: 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine and salts and polymorphs thereof. Preferred salts of 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine are sulfonic acid salts, more preferably p-toluenesulfonic acid salt, benzenesulfonic acid salt, camphorsulfonic acid salt and ethanesulfonic acid salt, respectively, especially benzenesulfonic acid salt.

In a further aspect, the present invention provides a compound of formula (I):

R¹Is C₁To C₆Alkyl or C₃To C₆Alkenyl radical, C₃To C₆Cycloalkyl or C₄To C₆Cycloalkenyl, wherein the alkyl radical may be branched or straight chain, wherein

If R is¹Is C₁To C₃Alkyl, said alkyl is substituted with one or more of the following substituents;

wherein if R is¹Is C₄To C₆Alkyl radical, C₃To C₆Alkenyl or C₃To C₆Cycloalkyl, said alkyl, alkenyl or cycloalkyl being optionally substituted by one or more of the following substituents;

The two substituents are selected from:

a hydroxyl group;

C₁to C₄An alkoxy group;

C₃to C₆A cycloalkyl group;

phenyl substituted by one or more substituents selected from C₁To C₃Alkyl radical, C₁To C₄Alkoxy radical, C₁To C₄Haloalkyl, C₁To C₄Haloalkoxy, halogen, CN, NO₂、NHR¹¹、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹Or CO₂R¹¹Wherein said haloalkyl and haloalkoxy contain one or more halogen atoms, wherein R¹¹Is H, C₁To C₄Alkyl radical, C₂To C₄Alkenyl radical, C₁To C₄Alkanoyl radical, C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy, R¹²Is C₁To C₄Alkyl radical, C₂To C₄Alkenyl radical, C₁To C₄Alkanoyl radical, C₁To C₄Haloalkyl or C₁To C₄A haloalkoxy group;

NR⁷R⁸、CONR⁷R⁸or NR⁷COR¹¹Wherein R is⁷And R⁸Each independently selected from H, C₁To C₄Alkyl radical, C₂To C₄Alkenyl radical, C₁To C₄Alkoxy, CO₂R⁹、SO₂R⁹Wherein the alkyl, alkenyl or alkoxy group may be optionally substituted by C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy substituted, wherein R⁹Is optionally substituted by phenyl₁To C₄Alkyl, wherein the phenyl is optionally substituted with one or more substituents selected from the group consisting of optionally substituted with C₁To C₄Haloalkyl or C₁To C₄Haloalkoxy substituted C₁To C₄Alkyl radical, C₁To C₄Alkoxy, halogen, CN, NO ₂、NHR¹¹、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹Or CO₂R¹¹；Het¹；Het²Or Het³(ii) a Or R¹Is Het⁴Or phenyl, wherein said phenyl is optionally substituted with one or more substituents selected from C₁To C₄Alkyl radical, C₂To C₄Alkenyl radical, C₁To C₄Alkoxy, halogen, CN, CF₃、OCF₃、NO₂、NHR¹¹、NHSO₂R¹²、SO₂R¹²、SO₂NHR¹¹、COR¹¹、CO₂R¹¹；R²Is C₁To C₆Alkyl radical, C₃To C₆Alkenyl or (CH)₂)_n(C₃To C₆Cycloalkyl) wherein n is 0, 1 or 2;

R¹³is OR³Or NR⁵R⁶；

R³Is C optionally substituted by one or two substituents₁To C₆Alkyl, the substituent is selected from C₃To C₅Cycloalkyl, hydroxy, C₁To C₄Alkoxy, benzyloxy, NR⁵R⁶Phenyl, Het¹、Het²、Het³Or Het⁴In which C is₁To C₆Alkyl and C₁To C₄The alkoxy group may optionally terminate in a haloalkyl group, e.g. CF₃；C₃To C₆A cycloalkyl group; het¹、Het²、Het³Or Het⁴；

R¹⁰is H; c optionally substituted by one or two substituents ₁To C₄Alkyl, the substituent is selected from hydroxyl and NR⁵R⁶、CONR⁵R⁶Optionally by C₁To C₄Alkyl or C₁To C₄Alkoxy-substituted phenyl; c₃To C₆Alkenyl or Het⁴；

Het²is a C-linked 5-membered heterocyclic group containing a heteroatom of O, S or N, optionally containing one or more heteroatoms selected from O or S;

wherein any of said heterocyclic groups Het¹、Het²、Het³Or Het⁴May be saturated, partially unsaturated or aromatic, wherein any of said heterocyclic groups may be optionally substituted with one or more substituents selected from C₁To C₄Alkyl radical, C₂To C₄Alkenyl radical, C₁To C₄Alkoxy, halogen, CO₂R¹¹、COR¹¹、SO₂R¹²Or NHR¹¹And/or wherein any of said heterocyclyl groups is benzo-fused;

with the proviso that (a) if R¹Is C₁To C₃Alkyl, then Het ¹Is not morpholinyl or piperidinyl, (b) if R¹Is C substituted by phenyl₁To C₃Alkyl, then the phenyl is not substituted by C₁To C₄Alkoxy, halogen, CN, CF₃、OCF₃Or C₁To C₄Alkyl substitution.

In a further aspect, the present invention provides processes for the preparation of compounds of formulae (I), (IA) and (IB), their pharmaceutically and veterinarily acceptable salts and both pharmaceutically and veterinarily acceptable solvates, as described below. Those skilled in the art will appreciate that in some of the described methods, the order of the synthetic steps employed may vary, and will depend, inter alia, on factors such as: the nature of the other functional groups present in a particular reactant, the availability of key intermediates, and the protecting group strategy (if any) employed. Obviously, these factors will also influence the choice of reagents used in the synthetic steps. An illustration of the protecting group strategy is the route to the synthesis of azetidine analogues (examples 18, 19 and 20) whose precursors (preparations 63, 66 and 61, respectively) contained a tert-butyloxycarbonyl group (Boc) as the nitrogen protecting group.

It will also be appreciated that interconversion and conversion of various standard substituents or functional groups within certain compounds of formula (I), (IA) or (IB) will provide other compounds of formula (I), (IA) or (IB). Examples include alcoholate exchange at the 2-position of the 5- (pyridin-3-yl) substituent (see example 3 to example 27, example 8 to examples 28 and 29, example 21 to examples 32 and 33, example 4 to example 41, example 9 to example 43 and example 66 to example 75), amine exchange at the 2-position of the 5- (pyridin-3-yl) substituent (see example 7 to example 78), reactions on nitrogen-containing substituents, such as reductive alkylation (example 18 to example 21), acetamide formation (examples 18 and 20 to examples 22 and 24 respectively) or sulfonamide formation (preparations 68, 67 to examples 25 to 62 respectively) and reduction of nitro functionality to amino (examples 63 to 64). The deprotection and transformations described here and in the examples and preparations section can be carried out in a "one-pot" process (see for example the transformation of the compound of preparation 65 into the compound of example 26).

The following methods are illustrative of general synthetic procedures that may be taken in order to obtain the compounds of the present invention.

1. A compound of formula (I):

wherein formula (I) canAlso represented by the general formulae (IA) and (IB), wherein R¹、R²、R⁴And R¹³The definition is the same as that of the above,

can be prepared from compounds of general formula (IX):

wherein R is^PIs R¹³(i.e. OR)¹³Or NR⁵R⁶) Or X, wherein R¹³、R³、R⁵And R⁶X is a leaving group, wherein formula (IX) may be represented by formula (IXA), (IXB) or (IXC), respectively:

wherein R is¹、R²、R³、R⁴、R⁵And R⁶Wherein X is a leaving group and may be any of the formulae-NR⁵R⁶Amino or alkoxy substituted groups, wherein the intermediate compounds of formula (IXA) and (IXB) respectively may be represented by their regioisomeric formulae, as described above for the compounds of formula (I). Suitable leaving groups X for use herein include halogen, alkoxy, amino, tosylate, further groups are described in more detail below.

1.1 wherein R¹³＝NR⁵R⁶The compounds of formula (I) can be prepared by cyclisation of a compound of general formula (IXA):

wherein R is¹、R²、R⁴、R⁵And R⁶Compounds of formula (I), (IA) or (IB) as hereinbefore defined. Preferably, the cyclization is base-mediated, such thatAlkali metal salts of hindered alcohols or amines are used. For example, the desired cyclization can be carried out using an about 1-to 5-, preferably 1.2-to 3.5-fold excess of potassium tert-butoxide, potassium bis (trimethylsilyl) amide or cesium carbonate, optionally in the presence of a molecular sieve, in a suitable solvent, e.g., an inert solvent such as DMF or NHR ⁵R⁶Or mixtures thereof, optionally in the presence of about 1 molar equivalent of ethyl acetate or ethyl pivalate at the reflux temperature of the reaction mixture, or the reaction may optionally be carried out in a sealed vessel at about 100 ℃ and 130 ℃, optionally in the presence of about 1 molar equivalent of ethyl acetate or ethyl pivalate.

1.2 general synthetic route to compound (I) via reaction of compound (IXB) as depicted in scheme 1, wherein said intermediate compound (IXB) has the following general formula:

wherein R is¹、R²And R⁴Compounds of formulae (I), (IA) and (IB) as defined above, wherein X is a leaving group as defined above, are reacted^-OR³And a hydroxide trapping agent. The conversion of (IXB) to (I) can be performed in a step-wise process or a single-pot process. Numerous stepwise substitutions are possible, some of which are other subsets. They comprise

i) Cyclization (IXB to XXX) followed by substitution (XXX to I);

ii) cyclisation (IXCa to XXX) followed by replacement (XXX to I);

iii) cyclization after permutation (IXB to IXC) (IXC to I); and

iv) cyclization after replacement of (IXCa to IXC) (IXC to I), wherein compounds (XXX) and

(IXCa) has the following formula:

wherein R is¹、R²、R⁴And X is as defined above, OR^3aIs an alkoxy group which is different from the desired OR on the final compound of formula (I) ³A group, and may be OR as desired³Group replacement wherein R^3aSelected from C optionally substituted with one or two substituents₁To C₆Alkyl, the substituent is selected from C₃To C₅Cycloalkyl, hydroxy, C₁To C₄Alkoxy, benzyloxy, NR⁵R⁶Phenyl, Het¹、Het²、Het³Or Het⁴In which C is₁To C₆Alkyl and C₁To C₄The alkoxy group may optionally terminate in a haloalkyl group, e.g. CF₃In which C is₃-C₅The cycloalkyl group may optionally be substituted by C₁-C₄Alkyl, hydroxy or halogen substitution; c₃To C₆A cycloalkyl group; het¹、Het²、Het³Or Het⁴. Preferably, R^3aIs C₁To C₆An alkyl group.

In order to effect the initial displacement without significant cyclization, it is preferred to effect the reaction at a temperature in the range of from about 80 ℃ to about 90 ℃^-OR³(iv) to provide a compound of formula (IXC). Subsequent cyclization is generally carried out at a temperature greater than about 115 ℃ to provide the compound of formula (I).

In order to effect initial cyclization without significant substitution, it is preferred to effect (IXCa) and (IXCa) at a temperature greater than about 110 deg.C^-OR^3aR of (A) to (B)^3aReaction of the OH solution gives (XXX) (in (ii)). Generally in the range of about 80 ℃ to about 90 ℃ followed by the reaction with^-OR³R of (A) to (B)³And (4) replacing the OH solution to obtain the compound shown in the general formula (I).

With respect to the conversion of (IXB) to (I) (i.e., (I) above), it may be preferred to directly convert from the general formula (IXB) The compounds give compounds of the general formula (I) since the cyclization and the metathesis of this reaction can be carried out simultaneously in a "one-pot" reaction. If R is³OH has a boiling point higher than R^3aOH, and R^3aThe ambient boiling point of OH is less than about 115 ℃ (i.e., too low to allow cyclization at ambient pressure), then such a "one-pot" process can be carried out at lower pressures (i.e., near ambient pressure) than the stepwise cyclization and displacement process (i.e., (ii) above). It should be noted that it may still be necessary to compare HORs³Operating at higher boiling temperatures, i.e. at higher pressures.

In which X is OR as described in more detail below³In the case of compounds of general formula (IXC), direct cyclization gives compounds of general formula (I) which are reacted in an auxiliary base, a hydroxide scavenger and a suitable solvent R³OH or an inert solvent or a combination thereof.

The temperature for the reaction of the compound of formula (IXB) to the compound of formula (I) (e.g. to form compounds (IA) and (IB) respectively) is preferably at least about 80 ℃, more preferably from about 80 to about 130 ℃, even more preferably from about 100 to 130 ℃, most preferably from about 115 to about 125 ℃. These temperatures also apply to the transformation of compound (XXX) into (I), although the temperature may also be suitably lower in this case (e.g.about 60 ℃ C.) since no cyclisation takes place.

Preferably, from wherein X is OR³A compound of formula (IXB) (i.e. a compound of formula (IXC) as hereinbefore and hereinafter described in detail) to prepare a compound of formula (I) or (IA) or (IB) wherein

R¹Is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₆) Cycloalkyl, wherein n is 0; or

R¹Is-cyclopentylmethyl; or

R¹Is methoxy and ethoxyMethyl, ethyl, i-propyl or n-propyl substituted with n-propoxy or i-propoxy, wherein the alkoxy substituent may be attached directly to any C-atom within the ethyl, i-propyl or n-propyl group other than the C-atom directly attached to the pyrazole ring; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R¹³is OR³Wherein R is³Alkyl is methyl, ethyl, n-propyl, i-butyl, n-butyl, sec-butyl or tert-butyl, optionally substituted with one or two methoxy, ethoxy, n-propoxy or i-propoxy substituents;

R⁴is 4-methyl-, 4-ethyl-, 4-n-propyl-or 4-isopropyl-piperazin-1-ylsulfonyl.

Thus, the present invention provides in a further aspect a further process for the preparation of a compound of formula (I) or a compound of formula (IA) or (IB):

Wherein

R¹Is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₆) Cycloalkyl, wherein n is 0; or

R¹Is-cyclopentylmethyl; or

R¹Is methyl, ethyl, i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxy, wherein the alkoxy substituent may be directly attached to the ethyl, i-propyl or n-propyl group without departing from the scope of the inventionTo any C-atom other than the C-atom to which the pyrazole ring is attached; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R⁴is 4-methyl-, 4-ethyl-, 4-n-propyl-or 4-isopropyl-piperazin-1-ylsulfonyl,

the process comprises reacting a compound of formula (IXC):

wherein R is¹、R²、R³And R⁴The definition is the same as that of the above,

wherein the reaction is in^-OR³And a hydroxide trapping agent, or in the presence of a hydroxide trapping agent and an auxiliary base.

Intermediates of the general formula (IXC), more particularly (IXCA) and (IXCB), constitute a further aspect of the present invention.

A particular advantage of using a hydroxide capture agent is that it enables a higher yield of the final product (compound of general formula (I), (IA) or (IB)) to be obtained than in the same reaction in the absence of the capture agent.

Preferably, the hydroxide trapping agent is an ester. More preferably, the hydroxide trapping agent is an ester of the formula:

wherein OT is OR³Or a residue of a macroalcohol or a non-nucleophilic alcohol, or TOH is an alcohol capable of being azeotropically removed during the reaction; c (O) V is a carboxylic acid residue. For example, if OR in the compound (IXC)³Is OEt, the hydroxide trapping agent (TOC (O) V) may be, for example, ethyl acetate or ethyl pivalate. Preferably, V is C₁To C₄An alkyl group.

Preferably, X is selected from the group consisting of: -OR³(ii) a Halogen; optionally substituted arylsulfonyloxy, preferably phenylsulfonyloxy, more preferably para-e.g. with C₁-C₄Alkyl-substituted aryl (phenyl) sulfonyloxy, such as p-toluenesulfonyloxy; c₁-C₄Alkylsulfonyloxy, such as methylsulfonyloxy; nitro-or halogen-substituted benzenesulfonyloxy, preferably para-substituted, such as p-bromophenylsulfonyloxy or p-nitrophenylsulfonyloxy; c₁-C₄Perfluoroalkyl sulfonyloxy groups such as trifluoromethanesulfonyloxy; optionally substituted aroyloxy, such as benzoyloxy; c ₁-C₄Perfluoroalkanoyloxy, such as trifluoroacetyloxy; c₁-C₄Alkanoyloxy, such as acetoxy; a diazonium ion; quaternary ammonium C₁-C₄An alkylsulfonyloxy group; halosulfonyloxy, such as fluorosulfonyloxy and other fluorinated leaving groups; and diarylsulfonylamino groups, such as xylenesulfonylamino (NTs)₂)。

More preferably, X is C₁-C₆Primary or secondary alkoxy, especially C₁-C₄Alkoxy groups, such as ethoxy or methoxy.

^-OR³Both as nucleophile (displacement of the leaving group by nucleophilic substitution) and as base (causing cyclization).

^-OR³Can be produced in solution form, e.g. as salt ZOR³(wherein Z is a cation), such as a metal salt. More precisely, -OR³Will form-OR in solution in a suitable solvent³. In another embodiment, -OR³Is derived in situ from R³OH plus auxiliary base (i.e. other than-OR)³Other bases). However, in another system, ZOR may be used in a reaction system with an auxiliary base³。

As will be appreciated, the solvent in which the reaction takes place may be R³OH or an inert solvent (or a mixture of the two). By inert solvent is meant a solvent that will not generate nucleophiles under the reaction conditions, or if nucleophiles are generated, it is sufficiently hindered or unreactive so as not to substantially compete for the displacement reaction. If R is used ³OH as^-OR³The source of (b) does not essentially require a separate solvent, but an (auxiliary) inert solvent (i.e. excluding R) may be used³A solvent other than OH) as a co-solvent in the reaction.

Suitable solvents are as follows: r³OH, secondary or tertiary C₄-C₁₂Alkanol, C₃-C₁₂Cycloalkanol, tertiary C₄-C₁₂Cycloalkanol, secondary or tertiary (C)₃-C₇Cycloalkyl) C₂-C₆Alkanol, C₃-C₉Alkanones, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, diglyme, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene, 1, 2-dichlorobenzene, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.

More preferably, the solvent is R³OH, tertiary C₄-C₁₂Alkanol, tertiary C₄-C₁₂Cycloalkanol, tert (C)₃-C₇Cycloalkyl) C₂-C₆Alkanol, C₃-C₉Alkanones, 1, 2-dimethoxyethane, 1, 2-diethoxyethane, diglyme, tetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene, 1, 2-dichlorobenzene, acetonitrile, dimethyl sulfoxide, sulfolane, dimethylformamide, N-methylpyrrolidin-2-one, pyridine, and mixtures thereof.

Most preferably, the solvent is R³OH, this means^-OR³Is generated in situ, for example in the presence of an auxiliary base.

A wide range of auxiliary bases can be used in the process of the invention. Typically, these bases will not substantially react with-OR in nucleophilic substitution of X³Competition (that is to say that they will be non-nucleophilic), for example, is suitably sterically hindered.

Preferably, the auxiliary base is selected from the group consisting of sterically hindered bases, metal hydrides, metal oxides, metal carbonates and metal bicarbonates.

The sterically hindered base is advantageously a metal salt of a sterically hindered alcohol or amine.

More preferably, the auxiliary base according to the invention is selected from the group consisting of: metal salts of sterically hindered alcohols or amines, e.g. secondary or tertiary C₄-C₁₂Alkanol, C₃-C₁₂Cycloalkanol, secondary or tertiary (C)₃-C₈Cycloalkyl) C₁-C₆Alkanols, N- (secondary or tertiary C)₃-C₆Alkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, N- (C)₃-C₈Cycloalkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, di (C)₃-C₈Cycloalkyl) amines or hexamethyldisilazane; 1, 5-diazabicyclo [4, 3, 0]Non-5-ene and 1, 8-diazabicyclo [5, 4, 0]Undec-7-ene; hydrides, oxides, carbonates and bicarbonates of metals.

Even more preferably, the auxiliary base according to the invention is selected from the group consisting of: metal salts of sterically hindered alcohols or amines, e.g. tertiary C₄-C₁₂Alkanol, C₃-C₁₂Cycloalkanol, tert (C) ₃-C₈Cycloalkyl) C₁-C₆Alkanols, N- (secondary or tertiary C)₃-C₆Alkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, N- (C)₃-C₈Cycloalkyl) -N- (primary, secondary or tertiary C₃-C₆Alkyl) amine, di (C)₃-C₈Cycloalkyl) amines or hexamethyldisilazane; 1, 5-diazabicyclo [4, 3, 0]Non-5-ene and 1, 8-diazabicyclo [5, 4, 0]Undec-7-ene; hydrides, oxides, carbonates and bicarbonates of metals.

Even more preferably, the auxiliary base is selected from the sterically hindered bases of the preceding stage (i.e. all but metal hydrides, oxides, carbonates and bicarbonates).

Even more preferably, the auxiliary base is tertiary C₄-C₆A metal salt of an alcohol, for example an alkali or alkaline earth metal (e.g. Na/K) salt of t-butanol or t-pentanol, or the base is KHMDS.

Most preferably, the auxiliary base is an alkali metal salt of t-butanol (e.g., potassium t-butoxide).

ZOR³The metals of the salt and auxiliary base may be independently selected from alkali metals (lithium, sodium, potassium, rubidium, cesium) or alkaline earth metals (beryllium, magnesium, calcium, strontium, barium). Preferably, the metal is sodium, potassium, lithium or magnesium. More preferably, the metal is sodium or potassium.

To maximize the yield, it is further preferred if X is a-OR³Otherwise defined above, at least about 1 molar equivalent of an auxiliary base and-OR ³. if-OR³Also acting as a base (i.e., in the absence of an auxiliary base), that is preferably present in an amount of at least about 2 equivalents^-OR³. Suitably at least about 1 equivalent of capture agent is present (preferably at least about 2 equivalents). When X is OR³In the case of (i.e. starting from (IXC) and not (IXB)), theoretically at least 1 equivalent of a base is required, wherein the base may be-OR³Or an auxiliary base.

The temperature at which the compound of formula (IXC) is reacted to form the compound of formula (I) (e.g. to form compounds (IA) and (IB) respectively) is preferably at least about 80 ℃, more preferably from about 80 to about 130 ℃, even more preferably from about 100 to about 130 ℃, and most preferably from about 115 to about 125 ℃.

The reaction temperature at which the conversion of a compound of formula (IXB), (IXC) or (XXX) into a compound of formula (I) can be carried out depends on the solvent,^-OR³And the nature of X. If X is OR^3a(wherein OR)^3aAnd OR³Are not identical), that is to say of the formula (IXC)^a) And R³The OH compound is a solvent, preferably by reaction with XH (e.g. C)₁-C₆Alcohol) and R³OH with R at an azeotropic temperature³OH azeotropically removes XH (of course, the reaction vessel must be constructed to distill off the azeotrope). This further improves the yield and quality of the final product. For example, where X is alkoxy, preferably ethanol, is preferably present in the alcohol (i.e., XH, preferably ethanol) and R ³The conversion of compound (XXX), (IXB) or (IXC) to (I) is carried out at an azeotropic temperature of OH. If X is OR³And the solvent is R³OH, it is not necessary to remove R azeotropically³OH。

Thus, the present invention provides in a preferred embodiment a method of synthesis of a compound of formula (I), (IA) or (IB), specifically a compound of formula (I), (IA) or (IB) wherein

R¹Is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₆) Cycloalkyl, wherein n is 0; or

R¹Is- (CH)₂)_n(C₅) Cycloalkyl, wherein n is 1; or

R¹Is methyl, ethyl, i-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxyOr n-propyl, wherein the alkoxy substituent may be directly attached to any C-atom within the ethyl, iso-propyl or n-propyl group; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R⁴is 4-methyl-, 4-ethyl-, 4-n-propyl-or 4-isopropyl-piperazin-1-ylsulfonyl, wherein the process comprises reacting a compound of formula (XIB), (XIC) or (XID) with:

a) Optionally in an inert solvent, in the presence of said capture agent, with R³OH and auxiliary alkali react; or

b) At R³OH or an inert solvent or both with ZOR in the presence of the trapping agent³Reacting with auxiliary alkali; or

c) In the presence of the trapping agent, with ZOR³And R³OH or an inert solvent or both; or

d) With auxiliary bases, inert solvents or R³OH or a combination thereof with a hydroxide trapping agent for the compound of formula (IXC).

1.3 for compounds in which X is OR³And an alcohol is selected as solvent, the compound of formula (I) being preparable by cyclisation of a compound of formula (IXC):

wherein R is¹、R²、R³And R⁴Compounds of formula (I), (IA) and (IB) as defined above. In the reaction, the appropriate formula R should be employed³The OH alcohol acts as a solvent in order to avoid potential problems associated with either the 2-position alcoholate exchange of the pyridine ring or the inert solvent or both. Suitable alcohols are defined herein to mean that the alkyl chain length of the solvent alcohol should be compatible with an alkoxy group (-OR)³) The substituents being equal, e.g. if-OR³Is ethoxy, ethanol is the appropriate alcohol. Preferably, the cyclization is base-mediated, using an alkali metal salt of a hindered alcohol or amine. For example, the desired cyclization can be effected using about a 1-to 8-, preferably about a 1-to 5-, more preferably about a 1.2-to 3.5-fold excess of potassium tert-butoxide or potassium bis (trimethylsilyl) amide, optionally under suitable drying conditions, i.e. in the presence of molecular sieves or under azeotropic conditions, in the above suitable solvent, optionally in the presence of about 1 to 2 molar equivalents of a hydroxide trapping agent, such as ethyl acetate or ethyl pivalate, at the reflux temperature of the reaction mixture, or the reaction may optionally be carried out, optionally in the presence of about 1 to 2 molar equivalents of a hydroxide trapping agent, such as ethyl acetate or ethyl pivalate, at about 100 ℃ and 130 ℃ in a sealed vessel.

For where X is OR³The cyclization reaction of the compound of (IXC) is carried out under alternative reaction conditions with about 1.2 to 4.5 molar equivalents of a hindered base, such as potassium tert-butoxide or KHMDS, optionally in a sealed vessel at about 100 ℃ to about 150 ℃ in a hindered alcohol solvent, such as 3-methylpent-3-ol, rather than of the formula R³OH alcohol as a solvent, optionally in the presence of about 1 or 2 molar equivalents of ethyl acetate or ethyl pivalate.

A compound of formula (IXA) OR wherein X is OR³The compounds of formula (IXB) (i.e. compounds of formula (IXC)) of formula (VII) can be prepared by coupling a compound of formula (VII):

wherein R is¹And R²Defined as above for formula (IXA), (IXB) or (IXC),

wherein R is³、R⁴、R⁵、R⁶And X is also defined as above for formula (IXA), (IXB) or (IXC). -NR of a compound of formula (XA)⁵R⁶R in the radical⁵And/or R⁶Is H, a suitable N-protecting group strategy may be advantageously employed. Any known suitable protecting group strategy may be used.

The coupling reaction may be carried out using conventional amide bond-forming techniques, such as via an acid chloride derivative (XA) or (XB), in the presence of up to about a five-fold excess of a tertiary amine, such as triethylamine or pyridine, to act as a scavenger for the acid by-product (HY), optionally in the presence of a catalyst, such as 4-dimethylaminopyridine, in a suitable solvent, such as dichloromethane, at about 0 ℃ to about room temperature. Pyridine may also be used as a solvent for convenience.

In particular, any variant of amino acid coupling may be used. For example, an acid of formula (XA), (XB) or (XC) or a suitable salt thereof (e.g., a sodium salt) may be activated using a carbodiimide, such as 1, 3-dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminoprop-1-yl) carbodiimide, optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst, such as 4-dimethylaminopyridine, or using a halogenated triamino phosphonium salt, such as bromotris (pyrrolidinyl) phosphonium hexafluorophosphate, or using a suitable pyridinium salt, such as 2-chloro-1-methylpyridinium iodide. Either type of coupling is carried out in a suitable solvent, such as dichloromethane, tetrahydrofuran or N, N-dimethylformamide, optionally in the presence of a tertiary amine, such as triethylamine or N-ethyldiisopropylamine (for example if the compound of formula (VII) or the activating reagent is present in the form of an acid addition salt), at a temperature of from about 0 ℃ to about room temperature. Preferably, 1 to 2 molar equivalents of activating reagent and 1 to 3 molar equivalents of any tertiary amine are employed.

In a further variation, the carboxylic acid function of (XA), (XB) or (XC) may first be activated using up to about a 5% excess of a reagent such as N, N' -carbonyldiimidazole in a suitable solvent such as ethyl acetate or butan-2-one at about room temperature to about 80 ℃, and then reacting the intermediate imidate with (VII) at about 20 ℃ to about 90 ℃.

It will be appreciated that formula (VII) can also be represented by regioisomeric formulae (VIIA) and (VIIB):

wherein R is¹And R²The definition is the same as above.

Pyrazole compounds of the general formula (XIII) can be prepared according to the procedures detailed in the preparations herein and the procedures described in detail in preparations 96(a) to (h):

wherein R is^qSelected from OH and C₁-C₆Alkoxy or NR⁵R⁶Wherein R is⁵And R⁶As defined above, 4-aminopyrazole-5-carboxamide compounds of the general formula (VII), (VIIA) or (VIIB) are prepared.

By reaction with 4-R¹⁰-reaction of a piperazinyl compound, such as 4-methylpiperazine, can be obtained from carboxylic acid compounds of general formula (VIIIA), (VIIIB) or (VIIIC), respectively:

wherein R is³、R⁵And R⁶Compounds of general formula (I), (IA) and (IB) as hereinbefore defined for the preparation of compounds having general formula (XA) or (XC). The reaction may be carried out at about 0 ℃ to about room temperature, preferably in the presence of a suitable solvent, such as C₁To C₃Alkanol or dichloromethane, optionally in the presence of a suitable base, such as triethylamine, to scavenge the acid by-product (HY). If R is⁵Or R⁶Is H, then a suitable amino protecting group strategy can be employed, as detailed above.

By application with respect to the conversion of amino groups to SO₂Known methods for the radical Y, wherein Y is halogen, preferably chlorine, can be derived from compounds of general formula (XIA), (XIB) or (XIC), respectively:

Wherein R is³、R⁵、R⁶And X are as defined above for compounds of formula (I), (IA) and (IB), to prepare compounds of formula (VIIIA), (VIIIB) or (VIIIC). For example, if Y is chlorine, it is treated with an aqueous acetic acid solution of excess liquid sulfur dioxide and about three times excess copper chloride at about-15 ℃ to about room temperature by the action of about two times the excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid at about-25 ℃ to about 0 ℃. If R is¹³Containing primary or secondary amino groups, it will generally be advantageous to protect the amino group with an acid stabilizing group, such as acetyl or benzyl.

By reduction of compounds of the general formulae (XIIA), (XIIB) and (XIIC),

wherein R is³、R⁵、R⁶And X is as defined above, and the process,

compounds of formula (XIA), (XIB) and (XIC) may be prepared separately. This conversion of compounds of formulae (XIIA), (XIIB) and (XIIC) to compounds of formulae (XIA), (XIB) and (XIC) can be achieved by conventional catalytic or catalytic transfer hydrogenation processes. Typically, hydrogenation is accomplished using a Raney (RTM) nickel catalyst or a palladium catalyst, such as 10% palladium on carbon, in a suitable solvent, such as ethanol, at a hydrogen pressure of about 345kPa (50psi) to about 414kPa (60psi), at about room temperature to about 60 ℃, preferably about 40 ℃ to about 50 ℃.

Intermediates of formula (IXC) in 1.2 and 1.3 above can be prepared via a coupling reaction between a compound of formula (XB) and a compound of formula (VII), wherein the coupling can be achieved by any of the methods described above. Compounds of general formula (XB) can be prepared according to the pathway described in scheme 2.

For scheme 2, the intermediate of formula (XB) is generated from the compound of formula (XIV), the exact method depending on the leaving group X.

For compounds in which X is arylsulfonyloxy, C₁-C₄Alkylsulfonyloxy, C₁-C₄Perfluoroalkyl sulfonyloxy, aryloxy, C₁-C₄Perfluoroalkanoyloxy radical, C₁-C₄Alkanoyloxy, quaternary ammonium C₁-C₄The compound of formula (XB) of alkylsulfonyloxy or halosulfonyloxy may be formed in a suitable solvent from compound (XIV) (wherein Q ═ OH, W ═ OH) and a suitable derivatizing agent, more precisely a suitable sulfonylating agent, respectively, such as arylsulfonyl halide, C₁-C₄Alkyl sulfonyl halides, C₁-C₄Perfluoroalkanesulfonyl halides, aryl halides, C₁-C₄Perfluoroalkanoacyl halide, C₁-C₄Alkyl acyl halide, quaternary ammonium C₁-C₄Alkyl or halogen sulphonyl halides, or suitable arylating agents, e.g. aryl halides, or suitable acylating agents, e.g. C₁-C₄Perfluoroalkanohalides or C₁-C₄An alkyl halide (preferably, the halide substituent is chloride). In a proper solvent Of the agents, for example water, a compound of formula (XIV) (wherein Q ═ OH, W ═ OH) can be formed from compound (XV) (wherein P is a hydrolysable group) using a hydrolysing agent, which is preferably a hydroxide base (ideally 2 molar equivalents), more preferably a metal hydroxide, for example sodium hydroxide. The metal of the hydroxide base may be as defined above for Z (in ZOR). This will also apply to other reactions using hydroxide base/hydrolyzing agents of schemes 2 and 3 below. If P is a hydroxide-non-hydrolysable group, then suitable deprotection strategies should be employed in accordance with standard literature practice.

A compound of formula (XB) wherein X ═ chlorine can be generated from a compound of formula (XIV) (i.e. a compound of formula (XV)) wherein Q ═ Cl and W ═ P (e.g. OEt) and a hydroxide base (ideally 1 molar equivalent), e.g. sodium hydroxide, preferably in a suitable solvent, e.g. water and a deprotecting agent.

Preferably, the deprotecting agent used here according to the invention is a hydrolysing agent, more preferably a hydroxide nucleophile, advantageously a hydroxide base (ideally 1 molar equivalent), such as sodium hydroxide, preferably in a suitable solvent, such as water.

In a suitable solvent, e.g. water, from (XIV) (wherein Q ═ NH ₂W ═ OH) and nitrous acid can yield compounds of formula (XB) in which X ═ diazonium. From compounds of formula (XIV) (wherein Q ═ NH)₂W ═ P, e.g. OEt) and a deprotecting agent, e.g. a hydroxide base, e.g. sodium hydroxide, can yield a compound of formula (XIV) (wherein Q ═ NH)₂And W ═ OH). Formation of intermediate (XIV) (Q ═ NH) from (XV) and an aminating agent, e.g. ammonia, in a suitable solvent, e.g. water₂W ═ P, e.g., OEt).

Preferably in the presence of a base (ideally 2 molar equivalents), such as triethylamine, in a suitable solvent from (XIV) (where Q ═ NH₂W ═ OH) and a suitable derivatizing agent, preferably a suitable sulfonylating agent, such as an arylsulfonyl halide, preferably arylsulfonyl chloride (ideally at least 2 molar equivalents), can form a compound of formula (XB) in which X ═ diarylsulfonamido.

In a suitable solvent, e.g. water, from (XIV) (wherein Q ═ C₁-C₆(preferably C)₁-C₄) Primary or secondary alkoxy, W ═ P, e.g. OEt) and deprotecting agents (when P ═ OEt), preferably hydroxide bases, e.g. sodium hydroxide, can form compounds in which X ═ C₁-C₆(preferably C)₁-C₄) A primary or secondary alkoxy group of the formula (XB). From (XV) and the appropriate alcoholate OR in a suitable solvent, for example toluene ^-Can produce the compound of formula (XIV) (wherein Q ═ C)₁-C₆(preferably C)₁-C₄) Primary or secondary alkoxy, W ═ P, e.g. OEt), where R is C₁-C₆Alkyl, more preferably C₁-C₄Primary or secondary alkyl groups, for example sodium ethoxide. Most preferably P ═ X (where X is alkoxy) as this avoids the trans-esterification problem.

The compound of formula (XV) may be produced by reaction of a compound of formula (XVI) with a mono-N-substituted piperazinyl group, optionally in the presence of a complementary base which does not irreversibly react with the sulfonyl chloride moiety, such as triethylamine, preferably in a suitable solvent, such as toluene, wherein the mono-substituent R¹⁰The definition is the same as above. "D" in the compounds (XV) and (XVI) is Cl or Br. If there is more than one equivalent of monosubstituted piperazine, the monosubstituted piperazine may also be a base. Preferably about 2 equivalents are used.

If a complementary base is used, it should not react with the sulfonyl chloride moiety (e.g., an oxide, carbonate or bicarbonate of a metal) or react with the sulfonyl chloride moiety in such a way that it remains active against nucleophilic attack (e.g., a tertiary amine such as triethylamine). Amine NH (R)³)(R⁴) May also act as a base, in which case preferably more than one equivalent is present, more preferably about 2 equivalents (or more).

The compound of formula (XVI) can be formed from the compound of formula (XX) in the presence of a chlorinating or brominating agent, such as thionyl chloride or thionyl bromide, more preferably in the presence of a halogenation catalyst, still more preferably thionyl chloride or thionyl bromide, in the presence of dimethylformamide. Thionyl chloride/bromine can also act as a solvent, but more preferably the reaction takes place in other suitable solvents, such as toluene. In this case only a stoichiometric amount of thionyl chloride/bromine will be required, preferably at least 2 molar equivalents, more preferably at least 5 molar equivalents.

It is possible to perform the four-step conversion of (XX) to (XB) in a single cascade step, without isolation of the intermediate product, all using the same solvent (hereinafter "cascade solvent"). Thus if X is alkoxy (-OR)³Groups), the steps (XX) to (XB) can be stacked together using a single solvent, such as a water-immiscible inert organic solvent. More preferably a hydrocarbon solvent (e.g. toluene, xylene, anisole, chlorobenzene, hexane, heptane, octane, nonane, decane, cyclohexane, methylcyclohexane) or an ether (e.g. dibutyl ether, diphenyl ether) or a ketone (e.g. methyl isobutyl ketone, methyl ethyl ketone) or an ester (e.g. ethyl acetate, butyl acetate) or dimethylformamide. More preferably a hydrocarbon solvent (e.g., toluene, xylene, anisole, chlorobenzene, octane, nonane, decane, methylcyclohexane) or an ether (e.g., dibutyl ether, diphenyl ether) or an ester (e.g., ethyl acetate, butyl acetate). Even more preferably, the nesting solvent is toluene.

The intermediate of formula (XX) is generated from the compound of formula (XVII) in the presence of a reagent which will generate the carboxylic acid protecting group (P) (i.e.generate a-COP group). Preferably, the reagent is an esterifying agent to form a carboxylic acid ester (where, for example, P will be an alkoxy group and the protective generator will be an alcohol), such as C₁-C₆The carboxylic acid ester, which will be carried through the reaction scheme, is hydrolyzed under basic conditions to the carboxylic acid function of compound (XB). Most preferably, the esterification agent is ethanol. Additional solvents may also be suitable, such as toluene.

In the presence of a sulfonylating agent, more preferably comprising SO₃Desirably at least 1 molar equivalent SO₃) E.g. SO₃In organic solvents (e.g. THF, dioxane and heptane) or aprotic solvents (e.g. nitrobenzene, nitromethane, 1, 4-dioxane, dichloromethane) or in the absence ofThe intermediate of formula (XVII) is generated from 2-hydroxynicotinic acid or a salt thereof in an organic acid (e.g. sulfuric acid) or a liquid carboxylic acid (e.g. acetic acid) or THF or heptane. Even more preferably, the sulfonylating agent is oleum (SO in sulfuric acid)₃) For example about 20% to 30% oleum.

The compound of formula (IXB) is generated by reaction of the intermediate of formula (XB) with the compound of formula (VII) in the presence of a coupling agent, e.g., N' -carbonyldiimidazole, and a suitable solvent, e.g., ethyl acetate, as detailed above.

The preparation of the compound of the formula (VII) is described below.

In a preferred embodiment of scheme 2, X is-OR³Alkoxy, whereby Q in compound (XIV) represents OR³. Preferably, OR³Is C₁To C₆Alkoxy, more preferably C₁To C₄Primary or secondary alkoxy, especially ethoxy. Although the general procedure of scheme 2 is applicable to other leaving groups as well.

This preferred embodiment of scheme 2 is illustrated in scheme 3. In scheme 3, an intermediate of formula (XB) is generated from a compound of formula (XIV) by removing protecting group P with a deprotecting agent in the presence of a hydroxide base, such as sodium hydroxide, preferably in a suitable solvent, such as water and toluene, advantageously by saponification.

At appropriate C₁-C₆Alcoholate nucleophiles (-OR)³) In the presence of (e.g. primary or secondary alcoholates), preferably of the formula ZOR³Wherein the metal (Z) is as defined above for ZOR, e.g. sodium ethoxide, preferably in a suitable solvent, e.g. toluene or R³OH, wherein R³OH is as defined above, preferably ethoxy, and the intermediate of formula (XIV) is formed from the compound of formula (XV). D in the compounds of formulae (XV) and (XVI) is Cl or Br, more preferably D is Cl.

Preferably in the presence of a base, e.g. triethylamine or an excess of N-R ¹⁰Piperazine, preferably in a suitable solvent, such as toluene, by the formula (XVI)) Compounds and N-R¹⁰The reaction of piperazine produces an intermediate of formula (XV).

The intermediate of formula (XVI) is formed from the compound of formula (XX) in the presence of a chlorinating or brominating agent, such as thionyl chloride or bromine, preferably thionyl chloride or bromine/dimethylformamide, which define the same procedure as scheme 2 above. The former can also act as a solvent, but more preferably the reaction takes place in other suitable solvents, such as toluene. In this case only a stoichiometric amount of thionyl chloride/bromine will be required, preferably at least 2 molar equivalents, more preferably at least 5 molar equivalents.

The intermediate of formula (XX) is generated from the compound of formula (XVII) in the presence of a reagent which will generate the carboxylic acid protecting group (P) (i.e.generate a-COP group). Preferably, the reagent is an esterifying agent to form a carboxylic ester, e.g. C₁-C₆The carboxylic acid ester, which will be carried through the reaction scheme, is hydrolyzed under basic conditions to the carboxylic acid function of compound (XB). Most preferably, the esterification agent is ethanol. Additional solvents, such as toluene, may be used as appropriate.

The intermediate of formula (XVII) is generated from 2-hydroxynicotinic acid and a sulfonylating agent, for example 30% oleum.

It is still possible to perform the four-step conversion of (XX) to (XB) in a single telescopic (teleselected) step (as described above) in the same reaction tank, without isolation of the intermediate product, all with the same solvent (herein called "telescopic solvent"). The list of solvents described in connection with scheme 2 can be applied directly here. Most preferably, the solvent is toluene.

For example, after compound (XVI) is produced, excess chlorinating/brominating agent can be azeotropically removed at the azeotropic temperature of the agent and the solvent for the intussusception. After compound (XV) is formed, the HBr/HCl (i.e., HD) salt formed can be washed or filtered from the reaction vessel (with water) and the remaining aqueous solvent (if used) and some of the overlap solvent removed azeotropically. In the formation of compound (XIV), if used to introduce OR³The alcoholate(s) are dissolved in a solvent (e.g. ethanol), which can also be mixed with someThe capping solvent is removed azeotropically. If a solid alcoholate is used, the latter azeotropic step is not required. Most preferably, the nesting solvent used in all of the nesting steps of scheme 3 is toluene.

It will be appreciated that, in accordance with the present invention, salts of the compounds of schemes 1 to 3 can be formed by converting the relevant compound (in situ or as a separate step) to a salt thereof. Acid addition salts of the compounds of formula (I) can also be formed according to the present invention.

1.4 obviously, with respect to R therein¹³Is OR³By developing the cyclisation and alcoholate exchange process described in sections 1.2 and 2.1 herein, it may be particularly advantageous to generate compounds of formula (I), (IA) or (IB) directly from compounds of general formula (IXCa) in a "one-pot reaction" in which the 2-alkoxy group of the 5- (pyridin-3-yl) substituent in the former is different from the latter. Alternative alcohols (R) should be used for this purpose³OH), wherein the alcohol-R³The alkyl chain of the group being different from-R on the starting compound of formula (IXCa)^3aA group. If used to provide an alternative 2-alkoxy (-OR)³) Too rare or expensive to be useful as a reaction solvent, it would be appropriate to use a suitable alternative as a reaction solvent, e.g. 1, 4-dioxane, to the desired alcohol (R)^3aOH) is sufficient to effect the desired conversion, typically from about 1 to about 2 molar equivalents. (IXCa) and R^3aThe definition is the same as above.

2. In a further generally applicable process, a compound of formula (I), (IA) OR (IB) may be prepared from an "alternatively" compound of formula (I), (IA) OR (IB), wherein the process may comprise different-ORs³Interconversion of radicals, X and-OR³Interconversion of radicals OR-OR ³and-NR⁵R⁶Interconversion of radicals, in which X, R³And NR⁵R⁶The definition is the same as above.

2.1 As mentioned above, certain compounds of formula (I), (IA) and (IB) can be interconverted by inducing an alcoholate exchange or displacement at the 2-position of the 5- (pyridin-3-yl) substituent. This can be done as followsThe appropriate alcohol (formula R) is now added^3aOH, wherein R^3aAlkyl is as defined above and is different from R on the starting materials (I), (IA) or (IB)³Group) is treated with an alkali metal salt of a sterically hindered alcohol or amine in order to form the desired alkoxide anion, which is then reacted with the reactant. Typically, from about 1 to about 8, more preferably from about 5 to about 8, especially from about 4 to about 8, molar equivalents of potassium bis (trimethylsilyl) amide are combined with the desired alcohol (formula R) as solvent in a two-step process^3aOH) at about 80 ℃ to about 100 ℃ for about 25 minutes to about 1 hour, then adding a compound of formula (IA) or (IB), and heating the reaction mixture at about 100 ℃ to about 130 ℃ for about 6 to about 24 hours. Alternatively, in a single-step process, the reactants 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, potassium t-butoxide, or cesium carbonate in the desired alcohol as solvent at from about 80 ℃ to about 130 ℃. A hydroxide trapping agent may optionally be included in such an alkoxide exchange reaction.

2.2 alternatively, wherein R¹³is-OR³Certain compounds of formula (I), (IA) or (IB) can be obtained from compounds of formula (XXX):

wherein R is¹、R²、R⁴As defined above, X is other than-OR³Any other group, reacted at-OR³Optionally in the presence of a hydroxide trap as defined above.

2.3 in a further alternative synthesis, wherein R¹³Is NR⁵R⁶The compounds of the general formula (I), (IA) or (IB) can be prepared directly from the compounds of the general formula (I), (IA) or (IB) in which R is¹³＝OR³The compound of the general formula (I) is produced. If R is¹³Is OR³The reaction may be carried out in the presence of an excess of a non-nucleophilic base, such as a sterically hindered amine or a suitable inorganic base, in a suitable solvent,the reaction mass is used in excess of R⁵R⁶NH or a suitable acid addition salt thereof. In general, R is used⁵R⁶NH as the free base, and an about 3-fold excess (of reactant) of potassium bis (trimethylsilyl) amide (KHMDS) in Dimethylformamide (DMF) as the solvent at about 100 deg.C. Alternatively, excess R may be used⁵R⁶The reaction is carried out in the presence of about 50% excess copper (II) sulfate as solvent, at a reflux temperature up to the reaction medium. If the desired amino substituent on a compound of formula (I), (IA) or (IB) is-NR⁵R⁶And R is ⁵Or R⁶One of which is H, can be exchanged by refluxing in DMF with the appropriate amine and copper (II) sulfate penta-or hepta-hydrate or anhydrous copper (II) sulfate or KHDMS. Usually, in order to exchange OR³The radical being alternatively of the formula NHR⁵R⁶Amines, e.g. wherein R⁵Or R⁶A compound selected from aliphatic or cyclic amines, optionally including oxygen (e.g., morpholine), then the reaction is preferably carried out by treatment with the appropriate amine and about 3 equivalents of potassium bis (trimethylsilyl) amide in DMF at 100 ℃ for about 18 hours.

3. In a further alternative process, compounds of formula (I) may be prepared from compounds of formula (IIA) or (IIC), respectively:

wherein Y is halogen, preferably chlorine, R¹、R²、R³、R⁵And R⁶Defined as above for the formulae (IXA) and (IXC),

reacting it with 4-R¹⁰-reaction of a piperazinyl compound, as described for the preparation of compounds of formulae (XA) and (XB) from compounds of formulae (VIIA) and (VIIIB), respectively.

Alternatively, a compound of formula (I), (IA) or (IB) may also be prepared from a compound of formula (IIB):

wherein R is¹、R²、R⁴And X is as defined above, and the process,

reacting it with 4-R¹⁰Reaction of the piperazinyl compound, optionally followed by a hydroxide trap and-OR^3-The metathesis reaction is carried out in the presence of (a) as detailed above for the preparation of compound (I) from compound (IXB) or (XXX).

3.1 Compounds of formula (IIA), (IIB) or (IIC) can be prepared from compounds of formula (IVA) or (IVB) or (IVC), respectively:

wherein R is¹、R²、R³、R⁵、R⁶And X is as defined above, and the process,

using known techniques for converting amino groups to SO₂Processes for the radical Y, wherein Y is also defined as above for formula (IIA), (IIB) and (IIC). Such reactions have been described previously as the preparation of compounds of formula (VIIIA) and (VIIIB) from compounds of formula (XIA) and (XIB), respectively.

The compounds of formula (IVA) or (IVB) or (IVC) can be prepared by cyclisation of a compound of formula (VA) or (VB) or (VC), respectively:

wherein R is¹、R²、R³、R⁵、R⁶And X are as defined above, wherein the cyclisation conditions are similar to those described above for the compounds of general formula (IXA), (IXB) or (IXC).

The compounds of formula (VA) or (VB) or (VC) can be prepared by reduction of a compound of formula (VIA) or (VIB) or (VIC), respectively:

wherein R is¹、R²、R³、R⁵、R⁶And X is as defined above for compounds of general formulae (VA), (VB) and (VC),

the preparation of compounds of formula (XIA) or (XIB) from compounds of formula (XIIA) or (XIIB), respectively, is described in detail above by conventional catalytic or catalytic transfer hydrogenation processes.

The compounds of formula (VIA), (VIB) or (VIC) may be prepared by reaction of a compound of formula (VII) as defined above with a compound of formula (XIIA) or (XIIB) or (XIIC), respectively:

Wherein R is³、R⁵、R⁶And X is as defined above for a compound of formula (VIA) or (VIB) or (VIC). Also, as detailed above, when NR is⁵R⁶When primary or secondary amino groups, conventional amine protecting group strategies are preferred for (XIIA). The coupling reaction is analogous to the reaction of (VII) with a compound of formula (XA) or (XB) or (XC), as described herein.

3.2 Compounds of formula (IIA) or (IIB) or (IIC) can be prepared from compounds of formula (IVA) or (IVB) or (IVC), respectively, as described above, wherein said compounds of formula (IVA) or (IVB) or (IVC) can be prepared by direct cyclisation of compounds of formula (VIA) or (VIB) or (VIC), respectively:

wherein R is¹、R²、R³、R⁵、R⁶And X is as defined above, wherein said directingThe conditions for the cyclisation are similar to those described previously for the cyclisation of a compound of formula (IXA) or (IXB) or (IXC), wherein the cyclisation is followed by reduction of the resulting intermediate according to the method described previously, to provide a compound of formula (IVA) or (IVB) or (IVC) from a compound of formula (VA) or (VB) or (VC).

Compounds of formula (XIIC) wherein X is Cl may be prepared by nitration of 2-hydroxynicotinic acid, followed by esterification, followed by chlorination of the appropriately protected nicotinic acid and subsequent ester hydrolysis.

Compounds of formula (XIIIC) (i.e. wherein X is-OR) may be prepared analogously to the previous methods³A compound of the general formula (XIIIB).

4. A further generally applicable synthetic route to compounds of formula (I), (IA) or (IB) involves the incorporation of R in the final step of the synthesis¹And (4) a substituent. Thus, compounds of formula (I), (IA) or (IB) may be prepared by carrying out the reaction of formula (I) using one or more of a number of well known methods^a)、(IA^a) Or (IB)^a) Alkylation of compounds wherein R¹Is hydrogen, R²、R¹³And R⁴The above formulae (I), (IA) and (IB) are defined, for example, by:

(i) in the presence of a suitable base, optionally in the presence of sodium iodide or potassium iodide, at a temperature of about-70 ℃ to about 100 ℃, with a compound of formula R¹J compound reaction, wherein R¹Defined above for formula (I), (IA) and (IB), J is a suitable leaving group, e.g. halogen, preferably chlorine, bromine or iodine, C₁-C₄An alkylsulfonyloxy, trifluoromethanesulfonyloxy or arylsulfonyloxy group (e.g. benzenesulfonyloxy or p-toluenesulfonyloxy). Preferably, the alkylation is carried out at about room temperature to about 120 ℃. Suitable base-solvent combinations may be selected from:

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

(b) hydroxides of sodium or potassium, or C of sodium or potassium₁To C₄Alcoholate, and C₁To C₄Alkanol, water or mixtures thereof;

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

(d) Mixtures of tetraalkylammonium halides or hydroxides, and aqueous sodium or potassium hydroxides with dichloromethane, 1, 2-dichloroethane or chloroform under phase transfer catalysis.

Generally, an excess of about 10% sodium hydride is added to a solution of the reactants in a suitable solvent, such as anhydrous tetrahydrofuran, a solution of cesium carbonate in Dimethylformamide (DMF) is used, and the resulting anion is then used with an excess of about 10% of the desired R¹And J, processing.

(ii) By the classical Mitsunobu method, with formula R¹Reaction of OH compound, wherein R¹Compounds of the general formulae (I), (IA) and (IB) as defined above. Typical reaction conditions involve the reaction between a triarylphosphine and an azodicarboxylic acid bis (C) ₁To C₄) The reactants are treated with the alkanol in the presence of the alkyl ester in a suitable solvent, such as tetrahydrofuran or 1, 4-dioxane, at about-5 ℃ to about room temperature.

(iii) With the formula R in the presence of a suitable catalyst system, for example copper (II) acetate, or under so-called "Goldberg" conditions¹M compound reaction, wherein R¹Represents optionally substituted phenyl, Het²、Het³Or Het⁴Wherein the Het group is aromatic or partially unsaturated at the C atom to which M is attached, wherein M represents an optionally substituted metal or boron group, wherein the metal or boron group is suitable for a cross-coupling reaction (of a metal or boron compound), e.g. dihydroxyBorane. Such cross-coupling is preferably carried out in the presence of a suitable base (e.g. pyridine) and a drying agent (typically 4A molecular sieve) in a suitable solvent, such as dichloromethane or N-methylpyrrolidine, optionally under microwave irradiation.

(iv) Under conditions suitable for cross-coupling of halogenated compounds with formula R¹Reaction of a compound of E, wherein E is halogen, preferably bromine, R¹(iv) is as defined in (iii). The reaction is typically carried out in the presence of a suitable catalyst system (e.g., a palladium catalyst), in the presence of a suitable base, such as sodium t-butoxide, in a suitable solvent, such as toluene, under heating, typically at about 70 ℃.

4.1 thus, when R¹(ii) when not hydrogen, under the same conditions as used for the conversion of a compound of formula (IXA), (IXB) or (IXC) to a compound of formula (I), (IA) or (IB), respectively¹Is hydrogen and R²、R³、R⁵、R⁶、R⁴And X is as defined above for a compound of formula (IXA), (IXB) or (IXC)^a) Or (IXB)^a) Or (IXC)^a) The compound can be obtained wherein R¹Is hydrogen and R²、R¹³And R⁴A compound of formula (I) as defined above for a compound of formula (I), (IA) or (IB)^a)、(IA^a) Or (IB)^a) The reaction mixture was then acidified to a pH of about 6.

4.2 in a further alternative, generally applicable synthetic route, the compounds of the invention may be prepared by cyclisation of a compound of formula (IXA), (IXB) or (IXC) from which it is derived^a)、(IXB^a) Or (IXC)^a) Obtained from a compound in which R¹Is hydrogen, R²、R³、R⁵、R⁶、R⁴And X are as defined above, using one or more of a number of well known methods, e.g. as described above for formula (I)^a)、(IA^a) Or (IB)^a) Compounds detailed for the conversion to compounds of general formula (I), (IA) or (IB).Any of the foregoing methods for such universal transformations may be used. Preferred conversion conditions are from about 1.0 to 1.3 equivalents of sodium hydride in tetrahydrofuran solvent at from about-78 ℃ to about room temperature and from about 1.1 to 2.3 equivalents of alkylating agent, from about 60 ℃ to about 70 ℃ using about 2.2 equivalents of cesium carbonate as base, dimethylformamide as solvent and about 1.1 equivalents of alkylating agent at about 60 ℃.

5. In a still further alternative synthesis, R may be derived therefrom via a suitable alkylation reaction¹⁰A compound of formula (I) which is H gives a compound of formula (I), (IA) or (IB), for example by reaction with an alkyl halide and a suitable base, for example cesium carbonate and methyl chloride.

In a preferred process for the preparation of the compounds according to the invention, compounds of the general formula (VIIB) are prepared from compounds of the general formula (XIIIB) according to the process detailed in preparations 96(a) to (h). These compounds of the formula (VIIB) are coupled with a compound of the formula (XC) prepared as detailed in preparation examples 29 and 96(i) to provide a compound of the formula (IXC) prepared as detailed in preparation example 95. The compound of formula (IXC) is then cyclized, preferably under basic conditions, following the detailed procedure of examples 8 and 102 to form a compound wherein R¹³Is OR³A compound of the general formula (IB).

4-aminopyrazole-5-carboxamides of the formulae (VII), (VIIA) and (VIIB), pyrazoles of the formula (XIII), carboxylic acids of the formulae (XA), (XB), (XIIA), (XIIB), (XIIC) and (X) or of the formula R¹J and R¹The E compounds, if neither commercially available nor described subsequently, can be obtained by conventional synthetic procedures analogous to those described in the preparation examples, starting from readily available starting materials using appropriate reagents and reaction conditions, according to standard textbooks on organic chemistry or the literature precedent.

Furthermore, the person skilled in the art will know variations and alternatives to the methods described in the examples and preparations section below in order to obtain a compound defined by formula (I), (IA) or (IB).

Pharmaceutically acceptable acid addition salts of compounds of formula (I), (IA) or (IB) containing a basic centre may also be prepared in a conventional manner. For example, acid addition salts of compounds of formula (I), more specifically IA and IB, may be formed by reacting a compound of formula (I) with an equimolar amount or excess of the appropriate acid, neat or in a suitable solvent. The salt may then be precipitated from the solution and isolated by filtration, or the reaction solvent may be stripped off by conventional means, for example by evaporation under vacuum. Exemplary salts that can be used in schemes 1 to 3 are given in PCT/IB 99/00519. Examples of salts of compounds IA and IB are p-toluenesulfonate, benzenesulfonate, camphorsulfonate and ethanesulfonate, respectively.

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

The invention also includes all suitable isotopic variations of the compound of formula (I) or a pharmaceutically acceptable salt thereof. Isotopic variations of the compounds of formula (I) or pharmaceutically acceptable salts thereof are defined as those in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of formula (I) and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Certain isotopic variations of the compounds of formula (I) and pharmaceutically acceptable salts thereof, e.g. having a radioisotope incorporated therein, e.g.³H or¹⁴Those of C are useful in drug and/or substrate tissue distribution studies. Tritium, i.e.³H. And carbon-14, i.e.¹⁴C isotopes are particularly preferred because of their ease of preparation and detection. Further, with compounds such as deuterium, i.e. with²Substitution of isotopes such as H may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. Isotopic variations of the compounds of formula (I) and pharmaceutically acceptable salts thereof according to the present invention can generally be prepared by conventional procedures, for example by the methods illustrated or described in the examples and preparations below, and using appropriate isotopic variations of suitable reagents.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), (IA) or (IB) which may be prepared prior to the final deprotection stage may not be pharmacologically active per se, but may in some instances also be administered orally or parenterally and metabolised in vivo to form pharmacologically active compounds of the invention. Such derivatives may therefore be referred to as "prodrugs". Furthermore, certain compounds of formula (I), (IA) or (IB) may act as prodrugs for other compounds of formula (I), (IA) or (IB).

All derivatives and prodrugs of the protected compounds of formula (I), (IA) or (IB) are included within the scope of the present invention. Suitable Protecting Groups for use in the present invention may be found in the "Protecting Groups", p.j.kocienski eds, Thieme, New York, 1994, see especially chapter 4, page 118-154 for carboxyl Protecting Groups; and "protective groups in Organic Synthesis" (protecting groups in Organic Synthesis), 2 nd edition, T.W.Greene & P.G.M.Wutz Wiley-Interscience (1991), see especially chapter 5 for carboxyl protecting groups. Examples of suitable prodrugs of the compounds of the invention are described in Drugs of today, Vol.19, 9, 1983, PP 499-538 and Topics in chemistry, chapter 31, PP 306-316.

The biological activity of the compounds of the invention was determined by the following test methods.

Phosphodiesterase (PDE) inhibition activity

The compounds of the present invention are potent and selective cGMP PDE5 inhibitors. By passingMeasuring IC₅₀Value (concentration of compound required for 50% inhibition of enzymatic activity) in vitro PDE inhibitory activity against cyclic guanosine 3 ', 5' -monophosphate (cGMP) and cyclic adenosine 3 ', 5' -monophosphate (cAMP) phosphodiesterase was determined.

The required PDE enzymes are isolated from a variety of sources, including human cavernosa, human and rabbit platelets, human ventricles, human skeletal muscle, and bovine retina, essentially using the methods of w.j.thompson and m.m.appleman (Biochem. (biochemistry), 1971, 10, 311). Specifically, cGMP-specific PDEs (PDE5) and cGMP-inhibiting cAMP PDEs (PDE3) are obtained from human sponge tissue, human platelets, or rabbit platelets; cGMP-stimulating PDE (PDE2) was obtained from human sponge; calcium/calmodulin (Ca/CAM) -dependent PDE (PDE1) was obtained from the human ventricle; cAMP-specific PDEs (PDE4) are obtained from human skeletal muscle; the photoreceptor PDE (PDE6) is obtained from bovine retina. Phosphodiesterase 7-11 was produced from full-length human recombinant clones transfected into SF9 cells.

The measurements were carried out using a modification of the "batch" method of w.j.thompson et al (Biochem. (biochemistry), 1979, 18, 5228), using a scintillation proximity assay for the direct detection of AMP/GMP, using a modification of the protocol described by Amersham plc, under the product designation TRKQ 7090/7100. In summary, the effects of PDE inhibitors were studied at various inhibitor concentrations and in the presence of small amounts of substrate (at-1/3K) _mAn unlabeled species of cGMP or cAMP at a concentration of [ 2 ], [³H]3: 1 ratio of labels) and determining the fixed amount of enzyme so that IC is obtained₅₀K_i. Assay buffer (20mM Tris-HCl pH 7.4, 5mM MgCl) was added₂1mg/ml bovine serum albumin) to a final assay volume of 100 μ l. The reaction was initiated with enzyme and incubated at 30 ℃ for 30-60 minutes to give a substrate turnover of < 30% and stopped with 50. mu.l of yttrium silicate SPA beads (containing 3mM each of the unlabeled cyclic nucleotides PDE 9 and 11). The plate was sealed again, shaken for 20 minutes, then the beads were allowed to settle in the dark for 30 minutes, then in a TopCount plate reader (Packard, Merid)en, CT). Conversion of the radioactivity units to% Activity of uninhibited control (100%), on inhibitor concentration and inhibitor IC₅₀Values are plotted, the latter being obtained using the "Fit Curve", Microsoft Excel extension. These test results show that the compounds of the present invention are potent and selective cGMP-specific PDE5 inhibitors.

Preferred compounds of the invention, for example those of examples 3-12, 14-17, 19, 21-30, 32, 33, 35-46, 48-59, 61, 62, 65-75, 77, 79-102, IC for the PDE5 enzyme₅₀Values are less than about 10 nM. More preferred compounds, such as those of examples 3-12, 14, 15, 17, 23-30, 32, 33, 35-46, 48, 50-59, 61, 62, 65, 69-74, 79-102, IC for the PDE5 enzyme ₅₀Values were less than about 5 nM. Particularly preferred compounds, for example those of examples 4-10, 15, 17, 23-28, 30, 32, 33, 35-42, 44, 45, 46, 50, 52-56, 58, 59, 61, 62, 65, 69-74, 79-93, 96, 98-102, IC for the PDE5 enzyme₅₀Values were less than about 2 nM.

Particularly preferred herein are compounds, IC's for the PDE5 enzyme₅₀Values of less than about 10, more preferably less than about 5, most preferably less than about 2nM, and selectivity for the PDE5 enzyme over the PDE6 enzyme of greater than 10-fold, more preferably greater than 50-fold, more preferably greater than 100-fold, especially greater than 200-fold.

Functional Activity

Functional activity was determined in vitro by determining the ability of the compounds of the invention to enhance the relaxing effect of sodium nitroprusside on rabbit sponge tissue strips prior to induction of contraction as described in s.a.balard et al (british. journal of pharmacology), 1996, 118 (suppl), abstract 153P.

In vivo Activity

Compounds were screened in anesthetized dogs using a method based on Trigo-Rocha et al (neuroourol and Urodyn., 1994, 13, 71) to determine their ability to enhance the intracavernosal pressure rise induced by intracavernosal injection of sodium nitroprusside after i.v. administration.

The compounds of formula (I), (IA) or (IB), their pharmaceutically acceptable salts and both pharmaceutically acceptable solvates may be administered alone, but in human therapy will generally be administered in admixture with suitable pharmaceutical excipients, diluents or carriers, the ingredients being selected with regard to the intended route of administration and standard pharmaceutical practice. For example, the compounds of formula (I), (IA) or (IB) or salts or solvates thereof may be administered orally, buccally or sublingually in the form of tablets, capsules (including soft gel capsules), ovules, elixirs, solutions or suspensions, which may contain flavouring or colouring agents for immediate, delayed, modified or controlled release, e.g. sustained, dual or pulsed release applications. The compounds of the invention may also be administered via intracavernosal injection. The compounds of the invention may also be administered via fast-dispersing or fast-dissolving dosage forms, high-energy-dispersing dosage forms or coated granules. Pharmaceutical formulations suitable for the compounds of the present invention may be in coated or uncoated dosage form, as desired.

Such tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate, glycine and starch (preferably corn, potato or tapioca starch), disintegrants such as sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricants such as magnesium stearate, stearic acid, glycerol behenate and talc may be included.

Solid compositions of a similar type may also be employed as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the compounds of formula (I), (IA) or (IB) may be combined with various sweetening or flavoring agents, coloring matter or dyes, with emulsifying and/or suspending agents, and with diluents such as water, ethanol, propylene glycol or glycerin, and combinations thereof.

Modified release and pulsatile release dosage forms may contain excipients such as those detailed with respect to immediate release dosage forms, and excipients that additionally act as release rate modifiers, which are coated and/or included on and/or in the drug body. Release rate modifiers include, but are not limited to, hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, ethyl cellulose, cellulose acetate, polyoxyethylene, xanthan gum, Carbomer, ammonio methacrylate copolymer, hydrogenated castor oil, carnauba wax, paraffin wax, cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer, and mixtures thereof. Modified release and pulsatile release dosage forms may contain one or a combination of release rate modifying excipients. The release rate modifying excipient may be present within the dosage form, i.e., within the matrix, and/or on the dosage form, i.e., on the surface or coating.

The fast dispersing or dissolving dosage form (FDDF) may contain the following ingredients: aspartame, acesulfame potassium, citric acid, croscarmellose sodium, crospovidone, ascorbic acid, ethyl acrylate, ethylcellulose, gelatin, hydroxypropyl methylcellulose, magnesium stearate, mannitol, methyl methacrylate, mint flavors, polyethylene glycol, fumed silica, silicon dioxide, sodium starch glycolate, sodium stearyl fumarate, sorbitol, xylitol. The term dispersion or dissolution as used herein to describe FDDF depends on the solubility of the drug substance used, and a fast dispersing dosage form can be prepared if the drug substance is insoluble, or a fast dissolving dosage form can be prepared if the drug substance is soluble.

The compounds of the invention may also be administered parenterally, for example intracavernosally, intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques. For such parenteral administration, it is preferred to use them in the form of sterile aqueous solutions which may contain other substances, for example, enough salts or glucose to render the solution isotonic with blood. The aqueous solution should be suitably buffered if necessary (preferably, pH from 3 to 9). Suitable parenteral formulations are readily prepared under sterile conditions using standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dosage level of a compound of formula (I), (IA) or (IB), or a salt or solvate thereof, will generally be from 10 to 500mg (single or multiple doses).

Thus, for example, a tablet or capsule of a compound of formula (I), (IA) or (IB), or a salt or solvate thereof, may contain from 5mg to 250mg of the active compound for single administration or for simultaneous administration of two or more, as the case may be. In any event, the physician will determine the actual dosage which will be most suitable for any individual patient and will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the general case. There may of course be specific cases where higher or lower dosage ranges are also worth, and are within the scope of the invention. The skilled artisan will also appreciate that in the treatment of certain conditions, including MED and FSD, the compounds of the invention may be employed on an "as needed" basis (i.e., as needed or desired).

EXAMPLE 10mg tablet

Composition% w/w

Besylate 13.038 from example 103^*

Lactose 62.222

Starch 20.740

Croscarmellose sodium 3.000

Magnesium stearate 1.000

^*The amount is adjusted according to the pharmaceutical activity.

Such tablets may be prepared by standard methods, such as direct compression or wet or dry granulation. The tablet cores may be coated with a suitable coating.

The compounds of the invention may also be administered intranasally or by inhalation, suitably in the form of a dry powder inhaler or aerosol for release from a pressurised container, pump, nebuliser, or nebuliser, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as 1, 1, 2, 2-tetrafluoroethane (HFA 134A trademark) or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA 227EA trademark)), carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by a valve providing a release dose. The pressurised container, pump, spray or atomiser may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as the solvent, and may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of formula (I), (IA) or (IB) and a suitable powder base such as lactose or starch.

Aerosol or dry powder formulations are preferably arranged so as to contain from 1 to 50mg per dose or "puff" of the compound of formula (I), (IA) or (IB) for delivery to the patient. The total daily dose of the aerosol will be in the range 1 to 50mg, and may be administered once, or more usually in multiple doses throughout the day.

The compounds of the invention may also be formulated for release via an atomizer. Formulations suitable for use in an atomizer device contain the following ingredients as solubilizers, emulsifiers or suspending agents: water, ethanol, glycerol, propylene glycol, low molecular weight polyethylene glycol, sodium chloride, fluorocarbons, polyethylene glycol ethers, sorbitan trioleate, oleic acid.

Alternatively, the compounds of formula (I), (IA) or (IB), or salts or solvates thereof, may be administered in the form of a suppository or pessary, or they may be administered topically in the form of a lotion, solution, cream, ointment or dusting powder. The compounds of formulae (IA) and (IB) or salts or solvates thereof may also be administered transdermally. The compounds of formula (I), (IA) or (IB) or salts or solvates thereof may also be administered transdermally, for example using a skin patch. They may also be administered by the ocular, pulmonary or rectal route.

For ophthalmic use, the compounds may be formulated as micronized suspensions in isotonic, pH adjusted, sterile saline, or preferably as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as benzalkonium chloride. Alternatively, it may be formulated as an ointment, for example a petrolatum ointment.

For topical application to the skin, the compounds of formula (I), (IA) or (IB), or salts or solvates thereof, may be formulated into a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, suitable lotions or creams may be formulated, suspended or dissolved in a mixture of, for example, one or more of the following: mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The compounds of formula (I), (IA) or (IB) may also be used in combination with cyclodextrins. Cyclodextrins are known to form entrapped and non-entrapped complexes with drug molecules. The formation of drug-cyclodextrin complexes can modify the solubility, dissolution rate, bioavailability, and/or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful in most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrins may also be used as auxiliary additives, such as carriers, diluents or solubilisers. alphA-, betA-and gammA-cyclodextrins are the most commonly used, suitable examples being described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

Oral administration of the compounds of the invention is generally the preferred route for humans, e.g. most suitable in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen for an average human MED is 5 to 250mg of the compound, as appropriate. In situations where the recipient suffers from swallowing disorders or impaired absorption of the drug following oral administration, the drug may be administered parenterally, sublingually or buccally.

With respect to veterinary use, a reasonably acceptable formulation of a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof, is administered in accordance with normal veterinary practice and the veterinarian will determine the dosing regimen and route of administration which will be most appropriate for the particular animal.

It is understood that all references herein to treatment include curative, palliative and prophylactic treatment.

Further, the present invention provides a pharmaceutical composition comprising a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or prodrug thereof, in association with a pharmaceutically acceptable diluent or carrier.

There is further provided a veterinary formulation comprising a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof, in association with a veterinarily acceptable diluent or carrier.

The present invention also provides a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or prodrug thereof, or a pharmaceutical composition comprising any of the foregoing, for use as a human medicament.

There is additionally provided a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof or a veterinarily acceptable solvate or prodrug thereof, or a veterinary formulation containing any of the foregoing, for use as a medicament for animals.

In a further aspect, the present invention provides the use of a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or solvate or prodrug thereof, for the manufacture of a medicament for human use, for the cure, alleviation or prevention of medical conditions for which an inhibitor of cGMP PDE5 is indicated. There is further provided the use of a compound of formula (I), (IA) or (IB), or a suitable salt, solvate or prodrug thereof, in the manufacture of a medicament for the treatment of a medical condition where inhibition of cGMP PDE5 is required.

There is also provided the use of a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof, for the manufacture of a medicament for use in an animal for the cure, alleviation or prevention of a medical condition for which an inhibitor of cGMP PDE5 is indicated.

Furthermore, the present invention provides the use of a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate or prodrug thereof, for the manufacture of a human medicament for the treatment, alleviation or prevention of Male Erectile Dysfunction (MED), impotence, Female Sexual Dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female pain disorder, Female Sexual Orgasmic Dysfunction (FSOD), sexual dysfunction due to spinal cord injury, Selective Serotonin Reuptake Inhibitor (SSRI) -induced sexual dysfunction, premature labour, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet, urinary incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, Atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, stroke, nitrate-induced drug resistance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, ocular diseases and conditions, diseases characterized by intestinal motility disorders, preeclampsia, kawasaki syndrome, nitrate resistance, multiple sclerosis, diabetic nephropathy, neuropathy (including autonomic and peripheral neuropathy, particularly diabetic neuropathy and symptoms thereof, such as gastroparesis), alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastases, alopecia areata, nut-pincer esophagus, anal fissure, hemorrhoids, hypoxic vasoconstriction or stabilization of blood pressure during hemodialysis. Particularly preferred disorders include MED and FSD.

Also provided is the use of a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof, for the manufacture of a medicament for use in an animal for the treatment, alleviation or prevention of Male Erectile Dysfunction (MED), impotence, Female Sexual Dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female pain disorders, female orgasmic dysfunction (FSOD), sexual dysfunction resulting from spinal cord injury, Selective Serotonin Reuptake Inhibitor (SSRI) -induced sexual dysfunction, premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, urinary incontinence, stable, unstable and variability (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive disease, coronary artery disease, congestive heart failure, pulmonary disease, congestive heart failure, Atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, stroke, nitrate-induced drug resistance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, ocular diseases and conditions, diseases characterized by intestinal motility disorders, preeclampsia, kawasaki syndrome, nitrate resistance, multiple sclerosis, diabetic nephropathy, neuropathy (including autonomic and peripheral neuropathy, particularly diabetic neuropathy and symptoms thereof, such as gastroparesis), alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastases, alopecia areata, nut-pincer esophagus, anal fissure, hemorrhoids, hypoxic vasoconstriction or stabilization of blood pressure during hemodialysis. Particularly preferred disorders include MED and FSD.

In addition, the present invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated in an animal, including a human, which method comprises administering to said animal a therapeutically effective amount of a compound of formula (I), (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate or prodrug thereof, or a pharmaceutical or veterinary formulation containing any of the foregoing.

Still further, the present invention provides a method of treating or preventing Male Erectile Dysfunction (MED), impotence, Female Sexual Dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder, female orgasmic dysfunction (FSOD), sexual dysfunction due to spinal cord injury, Selective Serotonin Reuptake Inhibitor (SSRI) -induced sexual dysfunction, premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, urinary incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, atherosclerosis, conditions of reduced vascular patency, peripheral vascular disease, stroke, nitrate-induced drug resistance, bronchitis, allergic asthma, inflammatory bowel disease, chronic asthma, allergic rhinitis, ocular diseases and conditions, diseases characterized by intestinal motility disorders, preeclampsia, kawasaki syndrome, nitrate resistance, multiple sclerosis, diabetic nephropathy, neuropathy (including autonomic and peripheral neuropathy, particularly diabetic neuropathy and symptoms thereof, such as gastroparesis), alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastases, alopecia areata, nut-shaped esophagus, anal fissure, hemorrhoids, hypoxic vasoconstriction or stabilization of blood pressure during hemodialysis, the method comprises administering to the animal a therapeutically effective amount of a compound of formula (I), (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate or prodrug thereof, or a pharmaceutical or veterinary formulation comprising any of the foregoing.

In a still further aspect, the present invention provides a combination of a compound of formula (I), (IA) or (IB) and a compound which is otherwise useful for inhibiting PDE5, wherein the combination is useful for the treatment or prevention of Male Erectile Dysfunction (MED), impotence, Female Sexual Dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female arousal disorder, female pain disorder, female orgasmic dysfunction (FSOD), sexual dysfunction resulting from spinal cord injury, Selective Serotonin Reuptake Inhibitor (SSRI) -induced sexual dysfunction, premature labor, dysmenorrhea, Benign Prostatic Hyperplasia (BPH), bladder outlet obstruction, urinary incontinence, stable, unstable and variability (Prinzmetal) angina, hypertension, pulmonary hypertension, chronic obstructive disease, coronary artery disease, congestive heart failure, atherosclerosis, pulmonary hypertension, chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, or stroke in an animal, including a human being, Conditions of reduced vascular patency, peripheral vascular disease, stroke, nitrate-induced drug resistance, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, ocular diseases and conditions, diseases characterized by gut motility disorders, preeclampsia, kawasaki syndrome, nitrate resistance, multiple sclerosis, diabetic nephropathy, neuropathy (including autonomic and peripheral neuropathy, particularly diabetic neuropathy and symptoms thereof, such as gastroparesis), alzheimer's disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastases, alopecia areata, nut-pincer esophagus, anal fissure, hemorrhoids, hypoxic vasoconstriction or stabilization of blood pressure during hemodialysis.

The invention also includes any novel intermediate described herein, such as those of formulas (IXA), (IXB), (VIIA), (VIIB), (VIII), (VIIIA), and (X).

The invention additionally encompasses the co-administration of a cGMP PDE5 inhibitor of the general formula (I), wherein the co-administration can be simultaneous, sequential or co-administration with:

(a) one or more naturally occurring or synthetic prostaglandins or esters thereof. Prostaglandins suitable for use herein include, for example, alprostadil, prostaglandin E₁Prostaglandin E₀13, 14-dihydroprostaglandin E₁Prostaglandin E₂Epostinol, natural, synthetic and semi-synthetic prostaglandins and derivatives thereof, including those described in US 6,037,346 issued 3.14.2000, hereby incorporated by reference, PGE₀、PGE₁、PGA₁、PGB₁、PGF_1α19-hydroxy PGA₁19-hydroxy PGB₁、PGE₂、PGB₂19-hydroxy PGA₂19-hydroxy PGB₂、PGE_3αCarboprost, tromethamine dinoprost, tromethamine, dinoprostone, lipoprost, gemeprost, meprost, sulprostone, tiaprost and moxiselide; and/or

(b) One or more alpha-adrenergic receptor antagonist compounds, also known as alpha-adrenergic receptors or alpha-blockers. Compounds suitable for use herein include: the alpha-adrenergic receptors described in PCT application WO 99/30697, published on 14.6.1998, the disclosure of which is incorporated herein by reference, including the selective alpha-adrenergic receptors ₁-adrenergic receptor or alpha₂-adrenergic receptors and non-selective adrenergic receptors, suitably alpha₁-adrenergic receptors include: phentolamine, phentolamine mesylate, trazodone, alfuzosin, indoramine, naftopidil, tamsulosin, dapiprazole, phenoxybenzamine, idazoxan, efacryn, yohimbine, rauwolfia alkaloid, Recordati 15/2739, SNAP 1069, SNAP 5089, RS 17053, SL 89.0591, doxazosin, terazosin, abanoquine, and prazosin; alpha from US 6,037,346(14/03/2000)₂-the blockers diphenylamin, tolazoline and tramazosin; the α -adrenergic receptors described in the following US patents: 4,188,390, respectively; 4,026,894, respectively; 3,511,836, respectively; 4,315,007, respectively; 3,527,761, respectively; 3,997,666, respectively; 2,503,059, respectively; 4,703,063, respectively; 3,381,009, respectively; 4,252,721 and 2,599,000, each of which is incorporated herein by reference; alpha is alpha₂-adrenergic receptors include: clonidine, papaverine hydrochloride, optionally in the presence of cariotonic agents, such as pirxamine; and/or

(c) One or more NO-donor (NO-agonist) compounds. NO-donor compounds suitable for use herein include organic nitrates, such as mono-, di-or tri-nitrates, or organic nitrates, including glycerol dinitrate (also known as nitroglycerin), isosorbide mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate, erythritol tetranitrate, Sodium Nitroprusside (SNP), 3-morpholino sydnonimine, S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-N-glutathione (SNO-GLU), N-hydroxy-L-arginine, amyl nitrate, linsidomine chloride hydrate, (SIN-1) S-nitroso-N-cysteine, diazeniumdiolate (NONO), 1, 5-pentane dinitrate, L-arginine, ginseng, zizphi structures, molsidomine, Re-2047, nitrosylated maxisylate derivatives, such as NMI-678-11 and NMI-937 as described in published PCT application WO 00/12075; and/or

(d) One or more potassium channel openers. Potassium channel openers suitable for use herein include nicorandil, chromancalin, levochromancalin, limacarin, pinadil, cliazoxide, minoxidil, charybdotoxin, glyburide, 4-aminopyridine, BaCl₂(ii) a And/or

(e) One or more dopaminergic agents. Dopaminergic compounds suitable for use herein include D₂Agonists, such as pramipexole, apomorphine; and/or

(f) One or more vasodilators. Vasodilators suitable for use herein include nimodipine, pinadil, cyclanoate, isoxsuprine, chlorpromazine, haloperidol, Rec15/2739, trazodone, pentoxifylline; and/or

(g) One or more thromboxane a2 agonists; and/or

(h) One or more CNS active agents; and/or

(i) One or more ergot alkaloids. US patent 6,037,346 issued 3/14/2000 describes suitable ergot alkaloids including acetylaminorbyl, bromoergoline, bromoergourea, cyanoergoline, ergonitrile, disulerine, ergonovine maleate, ergotamine tartrate, ethergine, ergonitrile, ergodiethylamine, mesulergine, metergoline, nicergoline, pergolide, proligel, proterguride, terguride; and/or

(k) One or more compounds that modulate the action of atrial natriuretic peptides (also known as atrial natriuretic peptides), such as inhibitors or neutral endopeptidases; and/or

(l) One or more angiotensin converting enzyme inhibiting compounds, such as enapril, and angiotensin converting enzyme inhibitors in combination with neutral endopeptidases, such as omapatrilat; and/or

(m) one or more angiotensin receptor antagonists, such as losartan; and/or

(n) one or more NO-synthase substrates, such as L-arginine; and/or

(o) one or more calcium channel blockers, such as amlodipine; and/or

(p) one or more endothelin receptor antagonists and inhibitors or endothelin converting enzymes; and/or

(q) one or more cholesterol lowering agents, such as statins and fibrates; and/or

(r) one or more antiplatelet and antithrombotic agents, such as tPA, uPA, warfarin, hirudin and other thrombus inhibitors, heparin, thromboplastin activator inhibitors; and/or

(s) one or more insulin sensitizers, such as rezulin, and hypoglycemic agents, such as glipizide; and/or

(t) L-DOPA or carbidopa; and/or

(u) one or more acetylcholinesterase inhibitors, such as donezipil; and/or

(v) One or more steroidal or non-steroidal anti-inflammatory agents.

Drawings

FIG. 1 shows scheme 1 mentioned in the present specification.

FIG. 2 shows scheme 2 mentioned in the present specification.

FIG. 3 shows scheme 3 mentioned in the present specification.

Detailed Description

The following examples and preparations illustrate the synthesis of the compounds of the present invention and intermediates used therein. A large number of the compounds included in the preparations are compounds of formula (I), (IA) or (IB) and are therefore examples of compounds according to the invention.

1H Nuclear Magnetic Resonance (NMR) spectra were recorded using a Varian Unity300 or Varian Inova 400 spectrometer, consistent with the proposed structure in all cases. The characteristic chemical drift (δ) is given in parts per million downfield from tetramethylsilane using conventional abbreviations to represent the major peaks: for example, s is a singlet, d is a doublet, t is a triplet, q is a quartet, m is a multiplet, and br is a broad peak.

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

Room temperature means 20 to 25 ℃.

Example 1

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ 2-methoxyethyl ] -3-n-propyl-2.6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 28 (560mg, 1.04mmol) and potassium tert-butoxide (292mg, 2.4mmol) in ethanol (20ml) was heated in a sealed vessel at 100 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated and dried (MgSO)₄) And evaporated under reduced pressure. The crude product is subjected to silica gel column chromatographySpectrum purification using an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) gave the title compound, 220 mg.

Measured value: c, 52.65; h, 6.43; n, 18.39.C₂₃H₃₃N₇O₅S；0.3H₂O calculated C, 53.16; h, 6.40; n, 18.87 percent.

δ(CDCl₃)：1.02(3H，t)，1.58(3H，t)，1.84(2H，m)，2.28(3H，s)，2.52(4H，m)，3.01(2H，t)，3.15(4H，m)，3.30(3H，s)，3.90(2H，t)，4.45(2H，t)，4.77(2H，q)，8.62(1H，s)，9.02(1H，s)，10.61(1H，s).

LRMS：m/z 520(M+1)⁺

Example 2

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ 2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 27 (420mg, 0.80mmol) and potassium bis (trimethylsilyl) amide (240mg, 1.20mmol) in ethanol (40ml) was heated in a sealed vessel at 100 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 130 mg.

δ(CDCl₃)：1.40(3H，t)，1.58(3H，t)，2.27(3H，s)，2.50(4H，m)，3.10(6H，m)，3.30(3H，s)，3.92(2H，t)，4.45(2H，t)，4.75(2H，q)，8.62(1H，d)，9.02(1H，d)，10.65(1H，s).

LRMS：m/z 506(M+1)⁺

Example 3

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ 2-methoxyethyl ] -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 30 (740mg, 1.34mmol) and potassium bis (trimethylsilyl) amide (321.5mg, 1.61mmol) in ethanol (40ml) was heated in a sealed vessel at 100 ℃ for 18 hours. TLC analysis showed that starting material remained, so additional potassium bis (trimethylsilyl) amide (321.5mg, 1.61mmol) was added and the reaction was continued for 18 hours. The cooled mixture was concentrated under reduced pressure, the residue partitioned between water and ethyl acetate, and the layers were separated. The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 150 mg.

δ(CDCl₃)：1.02(6H，m)，1.58(3H，t)，1.83(2H，m)，2.41(2H，q)，2.56(4H，m)，3.01(2H，t)，3.14(4H，m)，3.29(3H，s)，3.90(2H，t)，4.44(2H，t)，4.75(2H，q)，8.61(1H，s)，9.02(1H，s)，10.61(1H，s).

LRMS：m/z 534(M+1)⁺

Example 4

2- (sec-butyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 39 (400mg, 0.75mmol), potassium bis (trimethylsilyl) amide (298mg, 1.50mmol) and ethyl acetate (73. mu.l, 0.75mmol) in ethanol (10ml) was heated in a sealed vessel at 120 ℃ for 12 hours. Allowing the cooled mixture to stand Partition between ethyl acetate and aqueous sodium bicarbonate and separate the layers. The organic phase was dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent to give the title compound, 164 mg.

δ(CDCl₃)：0.79(3H，t)，1.02(3H，t)，1.38(3H，t)，1.56(6H，m)，1.90(1H，m)，2.21(1H，m)，2.41(2H，q)，2.57(4H，m)，2.98-3.18(6H，m)，4.41(1H，m)，4.75(2H，q)，8.61(1H，s)，9.02(1H，s)，10.58(1H，s).

Examples 5 to 9

Following a similar procedure to that described in example 4, the following table example compounds having the general structure:

the 1 ═ is purified by ethyl ether trituration

2-additional recrystallization from ethyl acetate

Example 10

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (tetrahydrofuran-2-yl) methyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 42 (250mg, 0.44mmol), potassium bis (trimethylsilyl) amide (132mg, 0.66mmol) and ethyl acetate (40. mu.l, 0.41mmol) in 3-methyl-3-pentanol (4ml) was heated at 120 ℃ for 18 hours in a sealed vessel. TLC analysis showed that the starting material remained, so additional potassium bis (trimethylsilyl) amide (132mg, 0.66mmol) was added, and the reaction was heated under reflux for further 24 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 60 mg.

δ(CDCl₃)：1.03(3H，t)，1.40(3H，t)，1.58(3H，t)，1.84(3H，m)，2.08(1H，m)，2.41(2H，q)，2.56(4H，m)，3.14(6H，m)，3.70-3.90(2H，m)，4.30-4.50(3H，m)，4.75(2H，q)，8.62(1H，s)，9.02(1H，s)，10.62(1H，s).

LRMS：m/z 546(M+1)⁺

Example 11

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [2- (pyrazol-1-yl) ethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 48 (300mg, 0.52mmol), potassium bis (trimethylsilyl) amide (320mg, 1.57mmol) and ethyl acetate (50. mu.l, 0.52mmol) in ethanol (40ml) was heated at 130 ℃ for 18 hours in a sealed vessel. The cooled mixture was concentrated under reduced pressure, the residue partitioned between water and dichloromethane, and the layers were separated. The aqueous phase was extracted with dichloromethane and the combined organic solutions were dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 90: 10) and triturated with ethyl acetate to give the title compound as a white solid, 80 mg.

δ(CDCl₃)：1.01(3H，t)，1.18(3H，t)，1.57(3H，t)，2.41(2H，q)，2.58(6H，m)，3.14(4H，m)，4.77(6H，m)，6.08(1H，m)，6.96(1H，d)，7.57(1H，d)，8.62(1H，d)，9.00(1H，d)，10.67(1H，s).

LRMS：m/z 556(M+1)⁺

Example 12

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [2- (methylamino) ethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 54 (130mg, 0.24mmol) and potassium bis (trimethylsilyl) amide (58mg, 0.29mmol) in ethanol (6ml) was heated in a sealed vessel at 130 ℃ for 16 hours. The cooled mixture was concentrated under reduced pressure, and the residue was suspended in sodium bicarbonate solution (15ml) and extracted with ethyl acetate (3X 15 ml). The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The remaining gum was purified twice by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (89: 10: 1) as eluent and ethyl acetate: methanol: diethylamine (78: 20: 2) repeatedly as eluent to give the title compound, 32mg, as a beige foam.

δ(CDCl₃)：1.02(3H，t)，1.41(3H，t)，1.58(3H，t)，2.41(2H，q)，2.56(7H，m)，3.10(6H，m)，3.27(2H，t)，4.47(2H，t)，4.77(2H，q)，8.61(1H，s)，9.00(1H，s)，10.50-10.80(1H，brs).

LRMS：m/z 519(M+1)⁺

Examples 13 to 15

Following a similar procedure to that described in example 12, the following table example compounds having the general structure:

the eluent is dichloromethane to methanol

Example 16

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-methylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 53 (470mg, 0.86mmol) and potassium bis (trimethylsilyl) amide (600mg, 3.0mmol) in ethanol (45ml) was heated at 130 ℃ for 16 hours. The cooled mixture was concentrated under reduced pressure, the solution was diluted with aqueous sodium bicarbonate to pH8 and extracted with ethyl acetate (3 ×). The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (91.75: 7.5: 0.75) as eluent to give the title compound, 170 mg.

δ(CDCl₃)：1.02(3H，t)，1.38(3H，t)，1.58(3H，m)，2.40(2H，q)，2.50(3H，s)，2.57(4H，m)，3.01(2H，q)，3.16(4H，m)，3.79(2H，t)，3.90(2H，t)，4.78(2H，q)，5.12(1H，m)，8.62(1H，d)，9.01(1H，d)，10.62(1H，s).

Example 17

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2-dimethylaminoethyl-3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 55 (150mg, 0.27mmol) and potassium bis (trimethylsilyl) amide (109mg, 0.55mmol) in n-butanol (5ml) was heated in a sealed vessel at 120 ℃ for 16 hours. The cooled mixture was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (90: 10) as eluent to give the title compound as a white foam, 27 mg.

δ(CDCl₃)：1.02(6H，m)，1.42(3H，t)，1.57(2H，m)，1.95(2H，m)，2.30(6H，s)，2.41(2H，q)，2.57(4H，m)，2.90(2H，t)，3.05(2H，q)，3.16(4H，m)，4.40(2H，t)，4.66(2H，t)，8.61(1H，d)，9.01(1H，t)，10.60(1H，s).

Example 18

2- (azetidin-3-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

To a solution of the title compound of preparation 63 (350mg, 0.57mmol) in dichloromethane (3ml) was added trifluoroacetic acid (3ml), and the reaction was stirred at room temperature for 21/2 hours. The reaction was concentrated under reduced pressure and the residual gum was triturated with ether several times. The resulting suspension was sonicated for one minute, then the solid was filtered, washed with ether and dried to give the title compound as a white foam, 280 mg.

Measured value: c, 42.82; h, 4.80; n, 14.92.C₂₃H₃₂N₈O₄S；2CF₃CO₂H；H₂O calculated C, 42.52; h, 4.76; n, 14.69 percent.

δ(DMSOd₆)：1.14(3H，m)，1.21(3H，t)，1.34(3H，t)，2.70-3.44(12H，m)，4.47(6H，m)，5.68(1H，m)，8.24(1H，s)，8.74(1H，s)，9.14-9.30(2H，m)，12.02(1H，s).

Example 19

2- (azetidin-3-yl) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (1-methylbutoxy) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

Following a similar procedure as described in example 18, the title compound was obtained from preparation 66 as an off-white powder (51%).

δ(DMSOd₆)：0.86(3H，t)，1.07-1.46(12H，m)，2.41-3.50(12H，m)，4.49(4H，m)，5.38(1H，m)，5.68(1H，m)，8.26(1H，s)，8.74(1H，s)，9.00(1H，m)，9.26(1H，m)，11.96(1H，s).

Example 20

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl ] -3-ethyl-2- [2- (methylamino) ethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

Following a similar procedure to that described in example 18, the title compound was obtained as a white solid (79%) from preparation 61 and trifluoroacetic acid.

δ(DMSOd₆)：0.94(3H，t)，1.12(3H，m)，1.26(3H，t)，1.73(2H，m)，2.41(6H，m)，2.60(3H，s)，2.68-3.60(7H，m)，4.39(2H，t)，4.60(2H，t)，8.23(1H，s)，8.57(2H，m)，8.74(1H，s)，11.94(1H，s).

Example 21

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-ethylazetidin-3-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of example 18 (215mg, 0.28mmol), acetaldehyde (17.3. mu.l, 0.31mmol), acetic acid (16. mu.l, 0.28mmol) and triethylamine (7.9. mu.l, 0.28mmol) in tetrahydrofuran (6ml) was added sodium triacetoxyborohydride (81mg, 0.38mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous sodium bicarbonate (30ml) and the mixture was extracted with ethyl acetate (2X 30 ml). The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The residual gum was purified by column chromatography on silica gel using dichloromethane: methanol (90: 10) as eluent to give the title compound, 120 mg.

δ(CDCl₃)：1.04(6H，m)，1.38(3H，t)，1.58(3H，t)，2.41(2H，q)，2.57(4H，m)，2.68(2H，q)，3.01(2H，q)，3.15(4H，m)，3.76(2H，m)，3.95(2H，m)，4.76(2H，q)，5.16(1H，m)，8.63(1H，d)，9.02(1H，d)，10.68(1H，s).

Example 22

2- (1-Acetylazetidin-3-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of example 18 (43mg, 0.056mmol) and triethylamine (8.5mg, 0.086mmol) in dichloromethane (2ml) was added acetyl chloride (6mg, 0.076mmol), and the reaction systemStirred at room temperature for 36 hours. The mixture was treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (2 ×). The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The residual gum was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (97: 3 to 95: 5) to give the title compound, 19 mg.

δ(CDCl₃)：1.02(3H，t)，1.38(3H，t)，1.60(3H，t)，1.98(3H，s)，2.42(2H，q)，2.58(4H，m)，3.02(2H，q)，3.16(4H，m)，4.50(2H，m)，4.59(1H，m)，4.78(2H，q)，5.05(1H，m)，5.31(1H，m)，8.62(1H，d)，9.01(1H，d)，10.70(1H，s).

Example 23

2- (1-acetylpiperidin-4-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (30%) was obtained from the compound of preparation 68 and acetyl chloride following the procedure described for example 22.

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.56(3H，t)，2.00(2H，m)，2.17(3H，s)，2.23-2.44(4H，m)，2.55(4H，m)，2.78(1H，m)，3.09(6H，m)，3.27(1H，m)，4.06(1H，m)，4.50(1H，m)，4.70-4.90(3H，m)，8.62(1H，d)，9.02(1H，d)，10.60(1H，s).

Example 24

2- {2- [ acetyl (methyl) amino ] ethyl } -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (74%) was obtained from the compound of example 20 and acetyl chloride following the procedure described for example 22.

δ(CDCl₃)：1.02(3H，t)，1.14(3H，t)，1.40(3H，t)，1.99(2H，m)，2.06(3H，s)，2.42(2H，q)，2.57(4H，m)，2.80(3H，s)，3.01(2H，q)，3.16(4H，m)，3.93(2H，t)，4.50(2H，t)，4.62(2H，t)，8.62(1H，d)，9.04(1H，d)，10.66(1H，s).

Example 25

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [1- (methylsulfonyl) piperidin-4-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (33%) was obtained from preparation 68 and methanesulfonic anhydride following a similar procedure as described in example 22.

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.58(3H，t)，2.10(2H，m)，2.40(2H，q)，2.56(6H，m)，2.90(3H，s)，3.00-3.20(8H，m)，4.01(2H，m)，4.21(1H，m)，4.78(2H，q)，8.62(1H，d)，9.01(1H，s)，10.61(1H，s).

Example 26

2- (1-Acetylazetidin-3-yl) -5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 65 (28mg, 0.043mmol) in dichloromethane (0.5ml) was added trifluoroacetic acid (0.5ml), and the solution was stirred at room temperature for 21/2 hours. The mixture was evaporated under reduced pressure and the residue was triturated with ether several times. The resulting precipitate was filtered off, washed with diethyl ether and dried to give a beige solid.

To a solution of this intermediate in dichloromethane (3ml) and triethylamine (61. mu.l, 0.44mmol) was added acetyl chloride (16. mu.l, 0.22mmol) and the reaction was stirred at room temperature for 16 h. Saturated aqueous sodium hydrogencarbonate (10ml) was added to the solution, and the mixture was extracted with ethyl acetate. The combined organic extracts were dried (MgSO) ₄) Evaporation under reduced pressure gave a gum. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (98: 2 to 95: 5) to give the title compound, 7 mg.

δ(CDCl₃)：1.02(6H，m)，1.38(3H，t)，1.57(2H，m)，1.94(5H，m)，2.40(2H，q)，2.47(4H，m)，3.02(2H，q)，3.14(4H，m)，4.50(2H，m)，4.59(1H，m)，4.67(2H，m)，5.06(1H，m)，5.31(1H，m)，8.62(1H，d)，9.01(1H，d)，10.68(1H，s).

Example 27

5- [ 2-lso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (2-methoxyethyl) -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of example 3 (80mg, 0.15mmol) in 2-methyl-n-propanol (5ml) was added potassium bis (trimethylsilyl) amide (149.7mg, 0.75mmol) and the reaction was stirred at 120 ℃ for 18 h. The cooled mixture was concentrated under reduced pressure, and the residue was suspended in water (10ml) and extracted with ethyl acetate (3X 10 ml). The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a solid, 67 mg.

Measured value：C，54.92；H，7.08；N，16.92.C₂₆H₃₉N₇O₅S；0.7H₂O calculated C, 54.38; h, 7.09; n, 17.07%

δ(CDCl₃)：1.03(6H，m)，1.14(6H，d)，1.83(2H，m)，2.30(1H，m)，2.41(2H，q)，2.55(4H，m)，3.01(2H，t)，3.13(4H，m)，3.30(3H，s)，3.90(2H，t)，4.46(4H，m)，8.61(1H，s)，9.01(1H，s)，10.60(1H，s).

LRMS：m/z 562(M+1)⁺

Examples 28 to 33

Following a procedure similar to that described in example 27, the following table example compounds of the general structure:

Wherein for examples 28 and 29, R²Is n-propyl, R for examples 30 to 33²Is ethyl.

Example 34

5- [ 2-lso-butoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of example 2 (155mg, 0.31mmol) in 2-methyl-n-propanol (10ml) was added potassium bis (trimethylsilyl) amide (306mg, 1.54mmol), and the reaction system was stirred at reflux for 24 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a solid, 88 mg.

Measured value: c, 52.45; h, 6.43; n, 17.33.C₂₄H₃₅N₇O₅S；1.1H₂O calcd for C, 52.08; h, 6.77; n, 17.71 percent

δ(CDCl₃)：1.14(6H，d)，1.41(3H，t)，2.30(4H，m)，2.52(4H，m)，3.07(2H，q)，3.15(4H，m)，3.30(3H，s)，3.92(2H，t)，4.46(4H，m)，8.62(1H，s)，9.03(1H，s).

LRMS：m/z 534(M+1)⁺

Examples 35 to 40

Following a similar procedure to that described in example 34, the following table example compounds of the general structure were prepared from the title compound of example 8 and the appropriate alcohol:

purification was performed using an elution gradient of ethyl acetate: methanol (95: 5 to 90: 10) followed by trituration with ether.

EXAMPLE 41

2- (sec-butyl) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A solution of the title compound from example 4 (129mg, 0.25mmol) in 2-methoxyethanol (10ml) was heated at 110 ℃ for 15 minutes and then cooled. Potassium bis (trimethylsilyl) amide (249mg, 1.50mmol) was added to the solution, and the reaction was stirred at 130 ℃ for 22 hours. The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate and the layers were separated. The organic phase was dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent to give the title compound as a yellow foam, 59 mg.

δ(CDCl₃)：0.79(3H，t)，1.03(3H，t)，1.39(3H，t)，1.60(3H，d)，1.90(1H，m)，2.22(1H，m)，2.41(2H，q)，2.57(4H，m)，2.97-3.18(6H，m)，3.57(3H，s)，3.85(2H，m)，4.40(1H，m)，4.78(2H，m)，8.62(1H，s)，8.98(1H，s)，10.76(1H，s).

LRMS：m/z 548(M+1)⁺

Example 42

2-cyclobutylmethyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was obtained as a white solid (64%) from example 7 and 2-methoxyethanol following the procedure described for example 41.

δ(CDCl₃)：1.01(3H，t)，1.40(3H，t)，1.80-1.98(5H，m)，2.05(2H，m)，2.40(2H，q)，2.54(4H，m)，3.00(2H，m)，3.15(4H，m)，3.55(3H，s)，3.83(2H，t)，4.30(2H，d)，4.76(2H，t)，8.60(1H，s)，8.96(1H，d)，10.74(1H，brs).

Example 43

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2- (2-methoxy-1-methylethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was obtained as a yellow foam (57%) from example 9 title compound and 2-methoxyethanol following the procedure described for example 41.

δ(CDCl₃)：1.02(3H，t)，1.38(3H，t)，1.59(3H，d)，2.41(2H，q)，2.56(4H，m)，3.05(6H，m)，3.22(3H，s)，3.56(3H，s)，3.72(1H，m)，3.84(2H，m)，3.96(1H，dd)，4.71(1H，m)，4.78(2H，m)，8.61(1H，s)，8.97(1H，s)，10.78(1H，brs).

Example 44

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) sulfonylpyridin-3-yl ] -2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

And

example 45

A mixture of the title compound of example 8 (250mg, 0.48mmol) and potassium bis (trimethylsilyl) amide (480mg, 2.41mmol) in 1-methoxy-2-propanol (20ml) was stirred at 120 ℃ for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane to methanol (100: 0 to 95: 5) to give a white solid. The material was purified by HPLC using a Chiralpak AD 250 column, purified in hexanes: isopropanol (85: 15) with 1% diethylamine as eluent gave the title compound of example 44, 49mg,

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.50(3H，m)，2.42(2H，q)，2.57(4H，m)，3.06(2H，m)，3.15(4H，m)，3.30(3H，s)，3.55(3H，s)，3.64(1H，m)，3.76(1H，m)，3.92(2H，t)，4.45(2H，t)，5.60(1H，m)，8.60(1H，s)，8.90(1H，s)，10.80

(1H，s).

LRMS：m/z 564(M+1)⁺

and example 45 the title compound, 39 mg.

δ(CDCl₃)：1.04(3H，t)，1.40(3H，t)，1.50(3H，d)，2.42(2H，q)，2.57(4H，m)，3.07(2H，q)，3.16(4H，m)，3.29(3H，s)，3.56(3H，s)，3.64(1H，m)，3.75(1H，m)，3.90(2H，t)，4.45(2H，t)，5.60(1H，m)，8.60(1H，s)，8.90(1H，s)，10.80

(1H，s).

LRMS：m/z 564(M+1)⁺

Example 46

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-methoxyethyl) -3-n-propyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

And

example 47

A mixture of the title compound of example 3 (345mg, 0.65mmol) and potassium bis (trimethylsilyl) amide (645mg, 3.24mmol) in 1-methoxy-2-propanol (2.5ml) was stirred at 110 ℃ for 16 h. The cooled mixture was diluted with ethyl acetate, washed with aqueous ammonium chloride, then water and dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol (97: 3) as eluent to give a yellow gum. The material was purified by HPLC using a Chiralpak AD 250 column, purified in hexanes: isopropanol (85: 15) with 1% diethylamine as eluent gave the title compound of example 46, 17mg,

δ(CDCl₃)：1.02(6H，m)，1.50(3H，d)，1.81(2H，m)，2.41(2H，q)，2.56(4H，m)，3.00(2H，m)，3.14(4H，m)，3.28(3H，s)，3.55(3H，s)，3.62-3.78(2H，m)，3.90(2H，t)，4.44(2H，t)，5.60(1H，m)，8.60(1H，s)，8.89(1H，s)，10.80(1H，s).

LRMS：m/z 578(M+1)⁺

and example 47 the title compound, 64 mg.

δ(CDCl₃)：1.01(6H，m)，1.48(3H，d)，1.81(2H，m)，2.40(2H，q)，2.54(4H，m)，2.99(2H，t)，3.10(4H，m)，3.27(3H，s)，3.51(3H，s)，3.60-3.76(2H，m)，4.87(2H，t)，4.44(2H，t)，5.59(1H，m)，8.60(1H，s)，8.86(1H，s).

LRMS：m/z 578(M+1)⁺

Example 48

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxy-1-methylethoxy) pyridin-3-yl ] -2- (2-hydroxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

And

example 49

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-hydroxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 60 (120mg, 0.2mmol) in 1-methoxy-2-propanol (10ml) was added potassium bis (trimethylsilyl) amide (200mg, 1.0mmol), and the reaction system was heated at reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 90: 10) to give the title compound of example 48, 8mg,

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.50(3H，d)，2.41(2H，q)，2.58(4H，m)，3.10(7H，m)，3.58(3H，s)，3.70(2H，m)，4.20(2H，m)，4.40(2H，m)，5.59(1H，m)，8.61(1H，d)，8.88(1H，d)，10.90(1H，s).

LRMS：m/z 550(M+1)⁺

and example 49 the title compound was a white solid.

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.58(3H，t)，2.41(2H，q)，2.56(4H，m)，2.87(1H，brs)，3.02-3.19(6H，m)，4.22(2H，m)，4.42(2H，t)，4.77(2H，q)，8.62(1H，s)，9.02(1H，s)，10.66(1H，s).

LRMS：m/z 506(M+1)⁺

Example 50

2- (2-ethoxyethyl) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 70 (250mg, 0.45mmol) in 2-methoxyethanol (5ml) was added potassium bis (trimethylsilyl) amide (359mg, 1.8mmol), and the reaction system was heated at reflux for 6 hours. TLC analysis showed that starting material remained, so additional potassium bis (trimethylsilyl) amide (90mg, 0.45mmol) was added to the cooled mixture and the reaction was stirred under reflux for an additional 4 hours. The cooled mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane: methanol (95: 5) as eluent. The product was triturated with ether and pentane to give the title compound as a crystalline solid, 75 mg.

Measured value: c, 52.88; h, 6.59; n, 17.39.C₂₅H₃₇N₇O₆S calculated C, 53.27; h, 6.62; n, 17.39%

d(CDCl₃)：1.02(3H，t)，1.12(3H，t)，1.40(3H，t)，2.41(2H，q)，2.57(5H，m)，3.06(2H，q)，3.15(4H，m)，3.42(2H，q)，3.57(3H，s)，3.85(2H，t)，3.94(2H，t)，4.44(2H，t)，4.78(2H，t)，8.61(1H，s)，8.98(1H，s)，10.78(1H，s).

Example 51

2- (iso-butyl) -3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 40 (958mg, 1.84mmol) in 2-methoxyethanol (20ml) was added potassium bis (trimethylsilyl) amide (732mg, 3.68mmol), and the reaction was stirred at 120 ℃ for 16 hours. The cooled mixture was concentrated under reduced pressure, the residue was dissolved in water (25ml), and the pH was adjusted to 2 with hydrochloric acid (2N). The solution was washed with ethyl acetate, neutralized and the resulting precipitate was filtered off. The solid was dissolved in ethyl acetate, evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent to give the title compound, 53 mg.

δ(CDCl₃)：0.97(6H，d)，1.40(3H，t)，2.28(4H，m)，2.52(4H，m)，3.02(2H，q)，3.16(4H，m)，3.57(3H，s)，3.86(2H，t)，4.10(2H，d)，4.78(2H，t)，8.61(1H，d)，8.98(1H，d)，10.79(1H，s).

LRMS：m/z 534(M+1)⁺

Example 52

2- (iso-butyl) -3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 36 (1.0g, 1.89mmol) in 2-methoxyethanol (8ml) was added potassium bis (trimethylsilyl) amide (1.85g, 9.35mmol), and the reaction was stirred at 120 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure and the residue partitioned between water (200ml) and dichloromethane (200 ml). The resulting precipitate was filtered off and the layers were separated. The aqueous phase was extracted with dichloromethane (2X 200ml) and the combined organic solutions were evaporated under reduced pressure to give a cream solid. The separated solids were combined and purified by silica gel column chromatography using dichloromethane: methanol (90: 10) as eluent to give the title compound as a pale yellow solid, 220 mg.

δ(CDCl₃)：0.95(6H，d)，1.05(3H，t)，1.40(3H，d)，2.40(3H，m)，2.55(4H，m)，3.00(2H，q)，3.10(4H，m)，3.55(3H，s)，3.85(2H，t)，5.05(2H，d)，4.80(2H，t)，8.60(1H，s)，8.95(1H，s)，10.80(1H，s).

LRMS：m/z 549(M+1)⁺

Example 53

2-cyclobutylmethyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

Using a similar procedure as described in example 52, the title compound was obtained from preparation 41 and 2-methoxyethanol as an off-white solid (31%).

δ(CDCl₃)：1.41(3H，t)，1.88(4H，m)，2.07(2H，m)，2.26(3H，s)，2.52(4H，m)，3.00(3H，m)，3.15(4H，m)，3.57(3H，s)，3.86(2H，m)，4.33(2H，d)，4.79(2H，t)，8.62(1H，s)，8.98(1H，s)，10.75(1H，s).

Example 54

5- [ 2-lso-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (1-methylpiperidin-4-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 52 (90mg, 0.156mmol), potassium bis (trimethylsilyl) amide (156mg, 0.78mmol) and ethyl acetate (14mg, 0.156mmol) in isopropanol (12ml) was stirred in a sealed vessel at 130 ℃ for 6 hours. The cooled reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution (60ml) and extracted with ethyl acetate (60 ml). Combining the organic phaseThe extract was dried (MgSO₄) Evaporation under reduced pressure gave a gum. The crude product was purified by column chromatography on silica eluting with methylene chloride: methanol: 0.88 ammonia (92.6: 6.6: 0.6) to give the title compound as a beige foam, 36 mg.

δ(CDCl₃)：1.01(3H，t)，1.12(6H，d)，1.39(3H，t)，1.94(2H，m)，2.15(2H，m)，2.22-2.44(6H，m)，2.55(6H，m)，3.02(4H，m)，3.14(4H，m)，4.22(1H，m)，4.43(2H，d)，8.60(1H，d)，9.00(1H，d)，10.54(1H，s).

Examples 55 to 58

Following a procedure similar to that described in example 54, the following example compounds of the general formula:

example 59

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -1- [2- (dimethylamino) -2-oxoethyl ] -3-ethyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

And

example 60

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [2- (dimethylamino) -2-oxoethyl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To preparation 59 the title compound (145mg, 0.30mmol) in tetrahydrofuran (2 ml)) To the solution was added sodium hydride (13mg, 60% suspension in mineral oil, 0.33mmol) and the solution was stirred for 30 minutes. 2-chloro-N, N-dimethylacetamide (40mg, 0.034mmol) was added and the reaction was stirred at room temperature for 16 hours, then at 60 ℃ for another 16 hours. The cooled mixture was treated with aqueous sodium bicarbonate (15ml) and extracted with ethyl acetate (2X 15 ml). The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (96.5: 3.5) as eluent and ethyl acetate: diethylamine (90: 10) repeatedly as eluent to give the title compound of example 59, 20mg,

δ(CDCl₃)：1.03(6H，t)，1.41(3H，t)，1.59(2H，m)，1.95(2H，m)，2.41(2H，q)，2.57(4H，m)，3.00(5H，m)，3.15(7H，m)，4.66(2H，t)，5.44(2H，s)，8.63(1H，d)，9.10(1H，d)，10.85(1H，s).

And example 60 the title compound, 45 mg.

δ(CDCl₃)：1.01(6H，t)，1.42(3H，t)，1.55(2H，m)，1.94(2H，m)，2.40(2H，q)，2.55(4H，m)，3.00(5H，m)，3.14(7H，m)，4.64(2H，t)，5.19(2H，s)，8.61(1H，d)，9.01(1H，d)，10.58(1H，s).

Example 61

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- {2- [ methyl (methylsulfonyl) amino ] ethyl } -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 62 (76mg, 0.117mmol) in dichloromethane (1ml) was added trifluoroacetic acid (1ml), and the solution was stirred at room temperature for 21/2 hours. The mixture was evaporated under reduced pressure, the residue was triturated thoroughly with ether, the resulting precipitate was filtered and dried to give a white powder.

To a solution of this intermediate in dichloromethane (2ml) and triethylamine (65. mu.l, 0.47mmol) was added methanesulfonyl chloride (20. mu.l, 0.26mmol) and the reaction was stirred at room temperature for 11/2 hours. The mixture was treated with saturated aqueous sodium bicarbonate (10ml) and extracted with ethyl acetate (2X 10 ml). The combined organic extracts were dried (MgSO)₄) Evaporation under reduced pressure gave a gum. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (96: 4) as eluent to give the title compound as a beige foam, 30 mg.

δ(CDCl₃)：1.02(6H，t)，1.42(3H，t)，1.54(2H，m)，1.94(2H，m)，2.41(2H，q)，2.57(4H，m)，2.65(3H，s)，2.80(3H，s)，3.13(6H，m)，3.76(2H，t)，4.52(2H，t)，4.67(2H，t)，8.62(1H，d)，9.04(1H，d)，10.68(1H，s).

Example 62

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [1- (methylsulfonyl) pyridin-4-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

Using a similar procedure as described in example 61, the title compound was obtained from preparation 67 and methanesulfonyl chloride as a white solid (34%).

δ(CDCl₃)：1.01(6H，t)，1.40(3H，t)，1.55(2H，m)，1.95(2H，m)，2.08(2H，m)，2.42(2H，q)，2.57(6H，m)，2.90(3H，s)，3.01-3.18(8H，m)，4.01(2H，m)，4.42(1H，m)，4.66(2H，t)，8.62(1H，d)，9.01(1H，d)，10.60(1H，s).

Example 63

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (4-nitrophenyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a suspension of the title compound of preparation 49 (200mg, 0.33mmol) and ethyl acetate (50. mu.l, 0.51mmol) in ethanol (5ml) was added potassium bis (trimethylsilyl) amide (134mg, 0.67mmol), and the reaction mixture was heated in a sealed vessel at 120 ℃ for 12 hours. The cooled reaction was concentrated under reduced pressure, the residue partitioned between ethyl acetate and water, and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic solutions were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent to give the title compound as a yellow oil, 10 mg.

δ(CDCl₃)：1.02(3H，t)，1.36(3H，t)，1.60(3H，t)，2.41(2H，q)，2.57(4H，m)，3.17(6H，m)，4.78(2H，q)，7.82(2H，d)，8.42(2H，d)，8.66(1H，d)，9.07(1H，d)，10.78(1H，brs).

LRMS：m/z 583(M+1)⁺

Example 64

2- (4-aminophenyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a suspension of iron powder (29mg, 0.52mmol) and ammonium chloride (45mg, 0.85mmol) in water (2ml) was added a solution of the title compound of example 63 (100mg, 0.17mmol) in methanol (2ml) and the reaction was heated at 60 ℃ for 1 h. The cooled mixture was filtered and the filtrate evaporated under reduced pressure to give the title compound as a pale brown solid, 93 mg.

δ(CDCl₃)：1.02(3H，t)，1.26(3H，t)，1.59(3H，t)，2.41(2H，q)，2.57(4H，m)，3.03(2H，q)，3.16(4H，m)，3.94(2H，s)，4.77(2H，q)，6.78(2H，d)，7.27(2H，d)，8.63(1H，d)，9.07(1H，d)，10.66(1H，s).

LRMS：m/z 553(M+1)⁺

Example 65

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- {4- [ (methylsulfonyl) amino ] phenyl } -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To an ice-cooled solution of the title compound of example 64 (93mg, 0.17mmol) in pyridine (2ml) was added methanesulfonyl chloride (15. mu.l, 0.19mmol), and the reaction system was warmed to room temperature and stirred for 90 minutes. TLC analysis showed that starting material remained, so additional methanesulfonyl chloride (15. mu.l, 0.19mmol) was added and the reaction stirred for an additional hour. The reaction was quenched by addition of aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO)₄) And concentrated under reduced pressure. The residual solid was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (90: 10: 1) as eluent, followed by repeated elution with dichloromethane: methanol: 0.88 ammonia (95: 5: 1) to give the title compound, 36 mg.

δ(CDCl₃)：1.03(3H，t)，1.34(3H，t)，1.59(3H，t)，2.42(2H，q)，2.58(4H，m)，3.14(9H，m)，4.78(2H，q)，6.92(1H，s)，7.44(2H，d)，7.58(2H，d)，8.65(1H，d)，9.07(1H，d)，10.75(1H，s).

LRMS：m/z 631(M+1)⁺

Example 66

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2-phenyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a mixture of the title compound of preparation 58 (250mg, 0.54mmol), copper (II) acetate monohydrate (145mg, 0.72mmol), phenylboronic acid (132mg, 1.08mmol) and 4A molecular sieve (392mg) in dichloromethane (5ml) was added pyridine (0.1ml, 1.08mmol), and the reaction was stirred at room temperature for 4 days. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.5) as eluent, with ethyl ether: trituration with hexane. The resulting solid was filtered and purified from isopropanol: recrystallization from dichloromethane gave the title compound as a solid, 200 mg.

δ(CDCl₃)：1.02(3H，t)，1.47(3H，t)，1.60(3H，t)，2.42(2H，q)，2.58(4H，m)，3.10(2H，q)，3.17(4H，m)，4.76(2H，q)，7.40(1H，m)，7.51(2H，m)，7.80(2H，d)，8.67(1H，d)，9.16(1H，s)，10.90(1H，s).

LRMS：m/z 538(M+1)⁺

Example 67

2- (4-cyanophenyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 58 (100mg, 0.22mmol), copper (II) acetate monohydrate (58mg, 0.29mmol), 4-cyanophenylboronic acid (63mg, 0.44mmol) and 4-molecular sieve (156mg) in pyridine (1ml) and N-methylpyrrolidine (1ml) was irradiated with full power microwaves for 3X 10 seconds and then for 2X 20 seconds. The mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent. The product was prepared from dichloromethane: recrystallization from isopropanol gave the title compound, 45 mg.

δ(CDCl₃)：1.03(3H，t)，1.49(3H，t)，1.62(3H，t)，2.42(2H，q)，2.58(4H，m)，3.08(2H，q)，3.17(4H，m)，4.58(2H，q)，7.79(2H，d)，8.14(2H，d)，8.70(1H，d)，9.16(1H，d)，11.09(1H，s).

LRMS：m/z 563(M+1)⁺

Example 68

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (pyridin-2-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

To a solution of the title compound of preparation 58 (200mg, 0.43mmol) in toluene (3ml) were added tris (dibenzylideneacetone) dipalladium (O) (8mg, 0.009mmol), R-BINAP (8mg, 0.013mmol), sodium tert-butoxide (41mg, 0.43mmol) and 2-bromopyridine (50. mu.l, 0.52mmol), and the reaction system was heated at 70 ℃ for 16 hours. The cooled mixture was evaporated under reduced pressure and the residue was filtered through silica gel using dichloromethane: methanol (80: 20) as eluent. The product was purified by reverse phase HPLC on silica gel using acetonitrile: an elution gradient of 0.1% aqueous trifluoroacetic acid (5: 95 to 85: 15) gave the title compound as a solid, 13 mg.

δ(CDCl₃)：1.36(3H，t)，1.48(3H，t)，1.57(3H，t)，3.00(2H，m)，3.14(6H，m)，3.70(2H，m)，3.96(2H，m)，4.77(2H，q)，7.52(1H，m)，8.15-8.26(2H，m)，8.69(2H，m)，8.92(1H，d)，10.80-11.00(1H，s).

LRMS：m/z 539(M+1)⁺

Example 69

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (pyrazin-2-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

To a solution of the title compound of preparation 58 (500mg, 1.08mmol) in N, N-dimethylformamide (10ml) was added cesium carbonate (353mg, 1.09mmol), and further 2-chloropyrazine (100. mu.l, 1.12mmol), and the reaction system was heated at 120 ℃ for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (98: 2: 1) as eluent. The product was further purified by silica gel reverse phase HPLC using acetonitrile: an elution gradient of 0.1% aqueous trifluoroacetic acid (5: 95 to 50: 50) gave the title compound, 86 mg.

δ(CDCl₃)：1.38(6H，2xt)，1.58(3H，t)，2.98-3.22(6H，m)，3.54(2H，q)，3.76(2H，m)，4.00(2H，m)，4.78(2H，q)，8.57-8.74(3H，m)，8.98(1H，d)，9.57(1H，s).

LRMS：m/z 540(M+1)⁺

Example 70

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (thiazol-2-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one trifluoroacetate

The title compound (7%) was obtained from preparation 58 and 2-bromothiazole following a similar procedure as described in example 69.

δ(CD₃OD)：1.28-1.41(6H，m)，1.48(3H，t)，3.20-3.34(6H，m)，3.34-3.60(6H，m)，4.65(2H，q)，7.59(1H，d)，7.78(1H，d)，8.58(1H，d)，8.78(1H，d).

LRMS：m/z 545(M+1)⁺

Example 71

2- (6-chloropyrimidin-4-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To an ice-cooled solution of the title compound of preparation 58 (250mg, 0.54mmol) in tetrahydrofuran (5ml) was added sodium hydride (22mg, 60% dispersion in mineral oil, 0.55mmol), and the solution was warmed to room temperature. 4, 6-dichloropyrimidine (80mg, 0.54mmol) was added and the reaction stirred at 65 ℃ for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent. The product was triturated with dichloromethane to give the title compound as a pale yellow solid, 5 mg.

δ(CDCl₃)：1.02(3H，t)，1.40(3H，t)，1.60(3H，t)，2.42(2H，q)，2.58(4H，m)，3.16(4H，m)，3.62(2H，q)，4.78(2H，q)，8.40(1H，s)，8.67(1H，d)，8.97(1H，s)，9.10(1H，d)，10.79(1H，s).

LRMS：m/z 574，576(M+1)⁺

Example 72

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (pyrimidin-2-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (8%) was obtained from the compound of preparation 58 and 2-chloropyrimidine following a similar procedure as described in example 71.

Measured value: c, 53.33; h, 5.36; n, 23.12.C₂₄H₂₉N₉O₄S calculated C, 53.42; h, 5.42; and N, 23.36 percent.

δ(CDCl₃)：1.03(3H，t)，1.37(3H，t)，1.59(3H，t)，2.41(2H，q)，2.58(4H，m)，3.17(4H，m)，3.55(2H，q)，4.78(2H，q)，7.42(1H，m)，8.64(1H，d)，8.95(2H，d)，9.11(1H，d)，10.73(1H，s).

LRMS：m/z 540(M+1)⁺

Example 73

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -3-ethyl-2- (pyrimidin-2-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To an ice-cooled tetrahydrofuran (4ml) solution of the title compound of preparation 69 (200mg, 0.41mmol) was added sodium hydride (19mg, 60% dispersion in mineral oil, 0.48mmol), and the solution was stirred for 30 minutes. 2-Chloropyrimidine (56mg, 0.48mmol) was added and the reaction was heated at reflux for 18 h. The mixture was evaporated under reduced pressure and the residue was diluted with water and extracted with dichloromethane. The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 31 mg.

δ(CDCl₃)：1.02(3H，t)，1.36(3H，t)，2.42(2H，q)，2.58(4H，m)，3.18(4H，m)，3.50(2H，q)，3.58(3H，s)，3.88(2H，t)，4.80(2H，t)，7.42(1H，m)，8.64(1H，d)，8.95(2H，d)，9.02(1H，d)，10.82(1H，s).

LRMS：m/z 570(M+1)⁺

Example 74

2- (1, 3-benzoxazol-2-yl) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (35%) was obtained from the compound of preparation 69 and 2-chlorobenzoxazole following a similar procedure as described in example 73.

δ(CDCl₃)：1.02(3H，t)，1.50(3H，t)，2.42(2H，q)，2.58(4H，m)，3.18(4H，m)，3.59(3H，s)，3.62(2H，q)，3.87(2H，t)，4.80(2H，t)，7.43(2H，m)，7.64(1H，m)，7.80(1H，m)，8.65(1H，d)，9.02(1H，d)，10.98(1H，s).

LRMS：m/z 609(M+1)⁺

Example 75

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2-phenyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the compound from example 66 (200mg, 0.37mmol) in 2-methoxyethanol (10ml) was added potassium bis (trimethylsilyl) amide (294mg, 1.47mmol), and the reaction system was heated under reflux for 18 hours. The mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (97: 3: 0.5) as eluent. The product was prepared from dichloromethane: recrystallization from isopropanol afforded the desired compound as a white solid, 82 mg.

Measured value: c, 57.06; h, 5.83; n, 17.27.C ₂₇H₃₅N₇O₅S calculated value C, 57.13; h, 5.86; n, 17.27%.

δ(CDCl₃)：1.02(3H，t)，1.46(3H，t)，2.42(2H，q)，2.57(4H，m)，3.16(2H，q)，3.17(4H，m)，3.56(3H，s)，3.84(2H，t)，4.58(2H，t)，7.38(1H，m)，7.48(2H，m)，7.80(2H，m)，8.64(1H，m)，9.04(1H，m)，11.10(1H，brs).

LRMS：m/z 568(M+1)⁺

Example 76

5- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -1- (2-methoxyethyl) -3-n-propyl-1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 57 (440mg, 0.82mmol) and potassium bis (trimethylsilyl) amide (196mg, 0.98mmol) in ethanol (15ml) was heated in a sealed vessel at 100 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (20ml) and brine (10ml), and the layers were separated. The organic phase was separated and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as 275mg as a pale yellow solid.

δ(CDCl₃)：1.02(3H，t)，1.60(3H，t)，1.86(2H，m)，2.29(3H，s)，2.52(4H，m)，2.95(2H，t)，3.16(4H，m)，3.35(3H，s)，3.87(2H，t)，4.78(4H，m)，8.64(1H，s)，9.09(1H，s)，10.81(1H，s).

LRMS：m/z 520(M+1)⁺

Example 77

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-1- (2-methoxyethyl) -1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 56 (1.02g, 1.9mmol) and potassium tert-butoxide (533mg, 4.75mmol) in ethanol (40ml) was heated in a sealed vessel at 100 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (50ml) and brine (25ml), and the layers were separated. The organic phase was washed with brine (25ml) and dried (MgSO) ₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: methanol (100: 0 to 90: 10) to give the title compound, 698mg, as a pale yellow solid.

Measured value: c, 53.00; h, 6.39; n, 18.87C₂₃H₃₃N₇O₅S calculated value C, 53.16; h, 6.40; n, 18.87%

δ(CDCl₃)：1.03(3H，t)，1.40(3H，t)，1.59(3H，t)，2.41(2H，q)，2.57(4H，m)，3.00(2H，q)，3.15(4H，m)，3.35(3H，s)，3.88(2H，t)，4.78(4H，m)，8.63(1H，s)，9.09(1H，s)，10.83(1H，s).

LRMS：m/z 520(M+1)⁺

Example 78

2-cyclobutylmethyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (pyrrolidin-1-yl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound from example 7 (200mg, 0.38mmol) and copper sulfate pentahydrate (74mg, 0.30mmol) in pyrrolidine (4ml) was heated at reflux for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel twice with an elution gradient of dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a pale brown solid, 109 mg.

δ(CDCl₃)：1.04(3H，m)，1.38(3H，t)，1.90(8H，m)，2.10(2H，m)，2.37-2.68(5H，m)，3.00(2H，q)，3.14(4H，m)，3.42(4H，m)，4.32(2H，d)，8.00(1H，s)，8.58(1H，s).

LRMS：m/z 555(M+1)⁺

Example 79

2-cyclobutyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the compound of preparation 83 (440mg, 0.83mmol), potassium bis (trimethylsilyl) amide (500mg, 2.51mmol) and ethyl acetate (100. mu.l, 1.0mmol) in ethanol (10ml) was heated in a sealed vessel at 120 ℃ for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 263 mg.

¹Hnmr(CDCl₃，300MHz)δ：1.01(3H，t)，1.35(3H，t)，1.58(3H，t)，1.96(2H，m)，2.38-2.60(8H，m)，2.98(4H，m)，3.14(4H，m)，4.76(2H，q)，4.96(1H，m)，8.61(1H，d)，9.02(1H，d)，10.59(1H，s).

LRMS：m/z 516(MH⁺)

Example 80

2-cyclopentyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a suspension of the compound of preparation 84 (243mg, 0.45mmol) in ethanol (5ml) was added potassium bis (trimethylsilyl) amide (450mg, 2.25mmol) and the mixture was heated in Reactifinal for 24 h at 100 ℃. TLC analysis showed that starting material remained, so additional potassium bis (trimethylsilyl) amide (250mg, 1.25mmol) and ethyl acetate (3 drops) were added and the reaction was heated at 111 ℃ for 18 hours. The cooled mixture was partitioned between ethyl acetate and sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with ethyl acetate (2 ×), the combined organic solutions were washed with brine and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using methanol: dichloromethane (2: 98) as eluent, triturated with ether to give the title compound as a white powder, 55 mg.

¹Hnmr(CDCl₃，400MHz)δ：1.02(3H，t)，1.39(3H，t)，1.55(3H，t)，1.72(2H，m)，2.05(2H，m)，2.17(2H，m)，2.30(2H，m)，2.40(2H，q)，2.56(4H，m)，3.04(2H，q)，3.16(4H，m)，4.76(2H，q)，4.82(1H，m)，8.61(1H，s)，9.02(1H，s)，10.55(1H，s).

LRMS：m/z 530.8(MH⁺)

Measured value: c, 57.17; h, 6.65; n, 18.14.C₂₅H₃₅N₇O₄S calculated value C, 56.69; h, 6.66; n, 18.51 percent.

Example 81

2-cyclopentylmethyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was obtained as a white powder in 41% yield from the compound of preparation 85 following a similar procedure as described in example 80.

¹Hnmr(CDCl₃，400MHz)δ：1.01(3H，t)，1.30(4H，m)，1.40(3H，t)，1.54(5H，m)，1.70(2H，m)，2.40(2H，q)，2.56(4H，m)，2.63(1H，m)，3.02(2H，q)，3.12(4H，m)，4.20(2H，d)，4.74(2H，q)，8.61(1H，d)，9.03(1H，d)，10.60(1H，s).

LRMS：m/z 547.7(MH⁺)

Example 82

2-cyclohexyl-5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was obtained as a white solid in 35% yield from the compound of preparation 86 following a similar procedure as described in example 80.

¹Hnmr(CDCl₃，400MHz)δ：1.02(3H，t)，1.30-1.50(6H，m)，1.58(3H，t)，1.78(1H，m)，1.98(4H，m)，2.22(2H，m)，2.41(2H，q)，2.55(4H，m)，3.05(2H，q)，3.16(4H，m)，4.23(1H，m)，4.75(2H，q)，8.61(1H，s)，9.01(1H，s)，10.54(1H，s).

LRMS：m/z 548.8(MH⁺)

Measured value: c, 57.23; h, 6.96; n, 17.54.C₂₆H₃₇N₇O₄S calculated value C, 57.44; h, 6.86; n, 18.03 percent.

Example 83

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (2-ethoxyethyl) -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the compound of preparation 70 (170mg, 0.30mmol) and ethyl acetate (30mg, 0.33mmol) in ethanol (5ml) was added potassium bis (trimethylsilyl) amide (256mg, 1.28mmol), and the reaction system was heated at 130 ℃ for 6 hours. The cooled mixture was evaporated under reduced pressure and the residual yellow solid was purified by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent. The product was triturated with isopropyl ether and then purified again by column chromatography using an elution gradient of dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 20 mg.

¹Hnmr(CDCl₃，400MHz)δ：1.00(3H，t)，1.10(3H，t)，1.40(3H，t)，1.54(3H，t)，2.40(2H，q)，2.50(4H，m)，3.05(2H，q)，3.10(4H，m)，3.40(2H，q)，3.90(2H，t)，4.42(2H，t)，4.70(2H，q)，8.60(1H，s)，9.00(1H，s)，10.60(1H，s).

LRMS：m/z 535(MH⁺)

Measured value: c, 53.97; h, 6.64; n, 18.14.C₂₄H₃₅N₇O₅S calculated C, 54.02; h, 6.61; n, 18.37 percent.

Example 84

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ (1S) -1-methyl-2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the compound of preparation 90 (1.20g, 2.17mmol) and ethyl acetate (200. mu.l, 2.02mmol) in ethanol (40ml) was added bis (trimethyl)Silyl) potassium amide (2.10g, 10.5mmol), and the reaction was heated in a sealed vessel at 130 ℃ for 6 hours. The cooled mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate and water and neutralized by addition of solid carbon dioxide. The layers were separated, the aqueous phase was extracted with ethyl acetate and the combined organic solutions were dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (99: 1 to 96: 4) and the product crystallized from diethyl ether/pentane to give the title compound, 250 mg.

¹Hnmr(CDCl₃，300MHz)δ：1.02(3H，t)，1.39(3H，t)，1.58(6H，m)，2.41(2H，q)，2.56(4H，m)，3.08(6H，m)，3.22(3H，s)，3.74(1H，m)，3.98(1H，m)，4.74(3H，m)，8.62(1H，d)，9.02(1H，d)，10.58(1H，s).

Measured value: c, 53.79; h, 6.61; n, 18.26.C₂₄H₃₅N₇O₅S calculated C, 54.02; h, 6.61; n, 18.38 percent.

Example 85

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- [ (1R) -1-methyl-2-methoxyethyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was obtained as a crystalline solid in 17% yield from the compound of preparation 89 following a similar procedure as described in example 84.

¹Hnmr(CDCl₃，300MHz)δ：1.02(3H，t)，1.39(3H，t)，1.58(6H，m)，2.40(2H，q)，2.55(4H，m)，3.08(6H，m)，3.22(3H，s)，3.70(1H，m)，3.98(1H，m)，4.72(3H，m)，8.61(1H，d)，9.02(1H，d)，10.58(1H，s).

LRMS：m/z 534.4(MH⁺)

Measured value: c, 53.67; h, 6.62; n, 18.27.C₂₄H₃₅N₇O₅S calculated C, 54.02; h, 6.61; n, 18.38 percent.

Example 86

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (3-methoxy-n-propyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the compound of preparation 88 (200mg, 0.36mmol) in 3-methyl-3-pentanol (4ml) was added potassium bis (trimethylsilyl) amide (145mg, 0.72mmol), and the reaction system was heated at 130 ℃ for 10 hours, followed by cooling. The mixture was evaporated under reduced pressure and the residue was purified twice by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent to give the title compound, 40 mg.

¹Hnmr(CDCl₃，400MHz)δ：1.00(3H，t)，1.40(3H，t)，1.57(3H，t)，2.20(2H，m)，2.42(2H，m)，2.60(4H，m)，3.03(2H，q)，3.15(4H，m)，3.30(3H，s)，3.35(2H，t)，4.40(2H，t)，4.72(2H，q)，8.60(1H，s)，9.00(1H，s)，10.60(1H，brs).

LRMS：m/z 535(MH⁺)

Example 87

2-cyclobutyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The compound of preparation 83 (238mg, 0)45mmol) and a mixture of potassium bis (trimethylsilyl) amide (450mg, 2.25mmol) in 2-methoxyethanol (5ml) were stirred at reflux for 6 h. The cooled mixture was partitioned between ethyl acetate and sodium bicarbonate solution and the layers were separated. The organic phase was washed with brine and dried (MgSO) ₄) And evaporated under reduced pressure. The residual orange oil was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent to give the title compound as an incompletely white foam, 150 mg.

¹Hnmr(CDCl₃，300 MHz)δ：1.00(3H，t)，1.38(3H，t)，1.85-2.05(2H，m)，2.40(2H，q)，2.45(2H，m)，2.54(4H，m)，2.90-3.05(4H，m)，3.15(4H，m)，3.55(3H，s)，3.80(2H，m)，4.74(2H，m)，4.95(1H，m)，8.60(1H，s)，8.98(1H，s)，10.75(1H，s).

LRMS：m/z 546.4(MH⁺)

Measured value: c, 54.53; h, 6.59; n, 17.77.C₂₅H₃₅N₇O₅S calculated C, 55.03; h, 6.47; and N, 17.97 percent.

Examples 88 to 92

Following a procedure similar to that described in example 87, the following compounds of general structure were prepared from the corresponding pyrazole carboxamide and 2-methoxyethanol:

further purification by trituration with diethyl ether

2-is purified by ethyl ether development

Example 93

5- [ 2-n-butoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

To a solution of the compound of preparation 27 (162mg, 0.31mmol) in n-butanol was added potassium bis (trimethylsilyl) amide (123mg, 0.62mmol), and the reaction mixture was heated at 120 ℃ for 18 hours. The cooled mixture was concentrated under reduced pressure and the residual yellow oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol: 0.88 ammonia (98: 2: 0.2 to 95: 5: 0.5). The product was triturated with ether to give the title compound as a white solid, 78 mg.

¹Hnmr(CDCl₃，300MHz)δ：1.03(3H，t)，1.41(3H，t)，1.54(2H，m)，1.94(2H，m)，2.28(3H，s)，2.51(4H，m)，3.07(2H，m)，3.14(4H，m)，3.30(3H，s)，3.95(2H，t)，4.46(2H，t)，4.67(2H，t)，8.63(1H，m)，9.04(1H，m)，10.60(1H，m).

Measured value: c, 53.64; h, 6.64; n, 18.15.C₂₄H₃₅N₇O₅S calculated C, 54.02; h, 6.61; n, 18.37 percent.

Example 94

3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ (1S) -1-methylpropyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

To the compound of preparation 93 (500mg, 0.96 mmol)) To a solution of potassium bis (trimethylsilyl) amide (960mg, 4.8mmol) in 2-methoxyethanol (15ml) was added, and the reaction system was heated at 130 ℃ for 5 hours. The cooled reaction mixture was partitioned between ethyl acetate and water, and the mixture was neutralized with solid carbon dioxide. The layers were separated and the organic phase was washed with water and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient elution of dichloromethane: methanol (99: 1 to 96: 4) to give an oil. This was triturated with ether to give the title compound as a white powder, 170 mg.

¹Hnmr(CDCl₃，400MHz)δ：0.80(3H，t)，1.40(3H，t)，1.60(3H，d)，1.90(1H，m)，2.20(1H，m)，2.22(3H，s)，2.50(4H，m)，3.00(2H，m)，3.10(4H，m)，3.58(3H，s)，3.80(2H，m)，4.40(1H，m)，4.80(2H，m)，8.60(1H，s)，9.00(1H，s)，10.70(1H，s).

LRMS：m/z 534.6(MH⁺)

Measured value: c, 54.20; h, 6.68; n, 18.39.C₂₄H₃₅N₇O₅S calculated C, 54.08; h, 6.71; n, 18.40 percent.

[α]_D+26.0 ° (c ═ 0.1, methanol).

Example 95

3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- [ (1R) -1-methylpropyl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

The title compound was obtained as a white powder in 23% yield from the compound of preparation 94 and 2-methoxyethanol following a similar procedure as described for example 94.

LRMS：m/z 534.6(MH⁺)

Example 96

2-n-butyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

The title compound was obtained as a solid in 54% yield from the compound of preparation 91 and 2-methoxyethanol following a similar procedure as described in example 95.

¹Hnmr(CDCl₃，400MHz)δ：0.95(3H，t)，1.40(5H，m)，1.97(2H，m)，2.35(3H，s)，2.58(4H，m)，3.01(2H，q)，3.18(4H，m)，3.56(3H，s)，3.85(2H，t)，4.28(2H，t)，4.78(2H，t)，8.62(1H，d)，8.98(1H，d)，10.75(1H，s).

LRMS：m/z 535(MH⁺)

Example 97

2-cyclopropylmethyl-3-ethyl-5- [2- (2-methoxyethoxy) -5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

The title compound was obtained as a solid in 41% yield from the compound of preparation 92 and 2-methoxyethanol following a similar procedure as described for example 95.

¹Hnmr(CDCl₃，400MHz)δ：0.46(2H，m)，0.62(2H，m)，1.40(4H，m)，2.27(3H，s)，2.50(4H，m)，3.05(2H，q)，3.16(4H，m)，3.57(3H，s)，3.84(2H，t)，4.20(2H，d)，4.58(2H，t)，8.61(1H，d)，8.98(1H，d)，10.77(1H，s).

LRMS：m/z 532.2(MH⁺)

Example 98

2-cyclobutylmethyl-3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (tetrahydro-2-furanylmethoxy) pyridin-3-yl ] -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

A mixture of the compound from example 7 (200mg, 0.38mmol) and potassium bis (trimethylsilyl) amide (371mg, 1.86mmol) in tetrahydrofuran methanol (2.5ml) was heated at reflux for 18 h. The cooled mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 90: 10). The product was recrystallized from ether to give the title compound, 20 mg.

¹Hnmr(CDCl₃，300MHz)δ：1.01(3H，t)，1.40(3H，t)，1.75-2.18(10H，m)，2.40(2H，q)，2.55(4H，m)，3.00(3H，m)，3.15(4H，m)，3.88(1H，m)，4.16(1H，m)，4.30(2H，d)，4.38(1H，m)，4.59(1H，m)，4.75(1H，m)，8.60(1H，d)，8.98(1H，d)，10.73(1H，s).

LRMS：m/z 587(MH⁺)

Example 99

3-ethyl-5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -2- (2-methoxyethoxy) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

The title compound was obtained as a solid following a similar procedure as described in example 98 from the compound of example 8 and 2-methoxyethanol.

¹Hnmr(CDCl₃，300MHz)δ：1.02(6H，m)，1.84(2H，m)，2.42(2H，q)，2.56(4H，m)，3.01(2H，t)，3.15(4H，m)，3.29(3H，s)，3.57(3H，s)，3.88(2H，m)，4.44(2H，t)，4.78(2H，t)，8.61(1H，s)，8.98(1H，s)，10.76(1H，s).

LRMS：m/z 564(MH⁺)

Example 100

5- [ 2-ethoxy-5- (4-i-propylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

To a cooled (-20 ℃ C.) solution of preparation 82 amine (400mg, 1.12mmol) in acetic acid (5ml) and concentrated hydrochloric acid (5ml) was added sodium nitrite (116mg, 1.68mmol) and the solution was allowed to warm to room temperature over 4 hours. The solution was then cooled again to-15 ℃ and liquid sulphur dioxide (3ml) was added, followed by a solution of copper (II) chloride (450mg, 3.34mmol) in water (2ml), the solution stirred for 2 hours and then allowed to warm to room temperature. The reaction system was diluted with water and extracted with dichloromethane (100 ml). The combined organic extracts were dried (Na)₂SO₄) Concentrated under reduced pressure and the residue azeotroped with toluene. The product was dissolved in ethanol (5ml), N-isopropylpiperazine (500. mu.l, 3.56mmol) was added and the reaction was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure and the crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (96: 4: 0.5) as eluent. The resulting pale yellow solid was prepared from isopropyl ether: dichloro-methyl Recrystallization from alkane gave the title compound, 211 mg.

¹Hnmr(CDCl₃，300MHz)δ：1.00(6H，2xs)，1.40(3H，t)，1.56(3H，t)，2.60(4H，m)，2.66(1H，m)，3.08(6H，m)，3.27(3H，s)，3.92(2H，t)，4.45(2H，t)，4.75(2H，q)，8.61(1H，d)，9.02(1H，d)，10.61(1H，s).

LRMS：m/z 534.5(MH⁺)

Measured value: c, 54.00; h, 6.69; n, 18.24.C₂₄H₃₅N₇O₅S calculated C, 54.02; h, 6.61; n, 18.37 percent.

Example 101

5- [ 2-ethoxy-5- (4-n-propylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (2-methoxyethyl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

Following the procedure described for example 100, the title compound was obtained in 21% yield from preparation 82 amine and n-propylpiperazine (prepared from the hydrobromide salt in the presence of excess triethylamine).

¹Hnmr(CDCl₃，300MHz)δ：0.84(3H，t)，1.40(3H，t)，1.55(5H，m)，2.30(2H，m)，2.55(4H，m)，3.08(6H，m)，3.28(3H，s)，3.94(2H，t)，4.44(2H，t)，4.75(2H，q)，8.62(1H，d)，9.03(1H，d)，10.61(1H，s).

LRMS：m/z 534.4(MH⁺)

Example 102

1- (6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl) -4-ethylpiperazine ethyl acetate solvate

To prepare the compound of example 8, a mixture of N- [ 3-carbamoyl-5-ethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] -2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinamide (1.18kg, 2.2mol), potassium tert-butoxide (500g, 4.4mol) and ethyl acetate (193g) in ethanol (11.8L) was heated at 120 ℃ for 20 hours. The reaction mixture was then concentrated under reduced pressure and a total of about 10L of solvent was distilled off. To the residue was added water (2.9L) and the mixture was stirred at room temperature while adding aqueous HCl until pH 7.5. Ethyl acetate (7.5L) was added and the biphasic mixture was warmed to 55 ℃. The organic phase was separated and the aqueous phase was extracted with additional ethyl acetate (3.0L). The organic phases were combined and distilled at atmospheric pressure to a final volume of 4L. The precipitated solid was granulated at 5 ℃ for 1 hour, filtered, washed with ethyl acetate (1.2L) and dried under vacuum. 1- (6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl) -4-ethylpiperazine was obtained as a pale yellow crystalline solid, 877g, 78%.

m.p. 157 ℃. found: c, 52.65; h, 6.46;

N，17.76.C₂₃H₃₃N₇O₅S.0.2 C₂H₅CO₂CH₃calculated C, 53.21; h, 6.49; n, 18.25 percent.

δ(CDCl₃)：1.07(3H，t)，1.42(3H，t)，1.61(3H，t)，2.44(2H，q)，2.57(4H，m)，3.08(2H，q)，3.15(4H，m)，3.32(3H，s)，3.92(2H，q)，4.48(2H，q)，4.77(2H，q)，8.65(1H，d)，9.06(1H，d).

The spectra also had a signal corresponding to the ethyl acetate solvate.

LRMS：m/z＝520(M+1)⁺

Example 103

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine

10g (0.019mol) of the ethyl 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine acetate solvate of the compound of example 8 and example 102 were charged with 12ml/g (120mls) of ethanol containing 16% water. The slurry was heated to reflux to give a solution, and 6ml/g (60mls) was distilled off under atmospheric pressure. The solution was then cooled to room temperature and crystallization occurred at 40 ℃. The slurry was then cooled to 5-10 ℃, granulated for 30 minutes, then filtered and washed with 2ml/g (20mls) of ethanol. The moist solid was dried under vacuum at 55-60 ℃ overnight to give a white crystalline solid.

(yield 7.6g, 76%). melting point 162-165 ℃.

δ(CDCl₃)：1.05(3H，t)，1.42(3H，t)，1.58(3H，t)，2.43(2H，q)，2.57(4H，t)，3.09(2H，t)，3.15(4H，t)，3.30(3H，s)，3.93(2H，t)，4.48(2H，t)，4.90(2H，q)，8.65(1H，d)，9.05(1H，d)，10.65(1H，s).

In the method of example 103, the compounds of examples 8 and 102 can be prepared using water and pharmaceutically acceptable alcohols such as methanol, ethanol, propanol, butanol and mixtures thereof.

Example 104

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine benzenesulfonate

170g (0.33mol) of the compound 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine from example 103 were charged, 10ml/g (1.7 l) of water/2-butanone (4% v/v) were added and the mixture was warmed to reflux. To the refluxing solution was added over 30 minutes an aqueous solution of benzenesulfonic acid (23mls, giving a 70% w/w solution). Stripping 5.3ml/g (0.9L) of 2-butanone, displacement and cooling of the slurry. The slurry was cooled to 5-10 ℃ and granulated for 2 hours, then filtered and washed with 2ml/g (0.3 l) of 2-butanone. The salt was dried overnight at 55-60 ℃ under vacuum to give a white crystalline solid. The yield was 215g, 96.4%. Mpt242-244 ℃.

δ(DMSO)：1.17(3H，t)，1.28(3H，t)，1.35(3H，t)，2.73(2H，q)，2.97(2H，q)，3.2(3H，s)，3.58(2H，t)，3.78(3H，t)，3.81(2H，t)，4.49(2H，t)4.51(2H，q)，7.29-7.33(3H，m)，7.57-7.60(2H，m)，8.28(1H，d)，8.73(1H，d)，9.13(1H，s)，11.90(1H，s).

Powder X-ray diffraction (PXRD) patterns of the salt having a melting point of 242-244 deg.C were determined using a Siemens D5000 powder X-ray diffractometer equipped with a theta-theta goniometer, an automatic light divergence slit, a second monochromator and a scintillation counter. The sample was rotated while being irradiated with copper K- α 1X-ray (wavelength: 1.5046 a) which had been filtered through a graphite monochromator (λ: 0.15405nm) with an X-ray tube and operated at 40 kV/mA.

Table I illustrates the major peaks (in degrees θ) of the PXRD pattern.

TABLE I

Angle of rotation	Strength%	Angle of rotation	Strength%	Angle of rotation	Strength%
Angle of rotation	Strength%	Angle of rotation	Strength%	Angle of rotation	Strength%	2-θ°	％	2-θ°	％	2-θ°	％
						2-θ°	％	2-θ°	％	2-θ°	％
						4.208	8.6	22.294	91.9	34.952	5.5
7.292	52.5	22.708	13.4	35.497	5.6	4.208	8.6	22.294	91.9	34.952	5.5
7.292	52.5	22.708	13.4	35.497	5.6	8.153	12.6	23.414	12.6	35.830	5.4
8.422	4.1	23.682	4.7	36.507	4.5	8.153	12.6	23.414	12.6	35.830	5.4
8.422	4.1	23.682	4.7	36.507	4.5	9.426	10.2	24.132	4.6	36.816	8.4
10.957	100.0	24.361	13.3	37.047	16.0	9.426	10.2	24.132	4.6	36.816	8.4
10.957	100.0	24.361	13.3	37.047	16.0	12.645	11.4	24.554	12.9	37.641	5.5
14.150	18.6	24.844	6.9	38.362	8.7	12.645	11.4	24.554	12.9	37.641	5.5
14.150	18.6	24.844	6.9	38.362	8.7	14.639	3.1	24.902	7.6	38.582	17.7
14.928	2.7	25.444	15.2	39.203	8.8	14.639	3.1	24.902	7.6	38.582	17.7
14.928	2.7	25.444	15.2	39.203	8.8	15.080	4.9	25.854	43.0	40.549	7.8
15.363	1.8	26.054	16.4	41.277	6.7	15.080	4.9	25.854	43.0	40.549	7.8
15.363	1.8	26.054	16.4	41.277	6.7	16.070	4.5	26.369	12.5	41.487	11.9
16.245	5.4	27.016	9.5	42.376	8.4	16.070	4.5	26.369	12.5	41.487	11.9
16.245	5.4	27.016	9.5	42.376	8.4	16.351	11.4	27.706	4.8	42.759	7.1
16.892	33.9	28.302	7.2	43.450	8.0	16.351	11.4	27.706	4.8	42.759	7.1
16.892	33.9	28.302	7.2	43.450	8.0	17.554	35.1	28.504	10.9	44.400	4.5
18.178	11.8	28.998	4.0	45.043	8.3	17.554	35.1	28.504	10.9	44.400	4.5
18.178	11.8	28.998	4.0	45.043	8.3	18.562	3.2	29.615	16.1	45.888	6.2
18.903	3.0	30.197	5.2	46.393	6.2	18.562	3.2	29.615	16.1	45.888	6.2
18.903	3.0	30.197	5.2	46.393	6.2	19.174	3.1	31.039	12.5	46.897	7.3
19.591	31.6	31.445	7.7	48.197	7.8	19.174	3.1	31.039	12.5	46.897	7.3
19.591	31.6	31.445	7.7	48.197	7.8	20.392	43.3	32.094	6.5	48.373	7.9
20.598	6.8	32.611	6.4	49.163	5.3	20.392	43.3	32.094	6.5	48.373	7.9
20.598	6.8	32.611	6.4	49.163	5.3	20.965	12.8	32.734	9.3	50.501	6.0
21.136	7.8	33.014	6.5	50.619	5.9	20.965	12.8	32.734	9.3	50.501	6.0
21.136	7.8	33.014	6.5	50.619	5.9	21.485	32.9	33.110	7.2	52.248	14.6
22.000	24.0	33.740	3.5	52.746	5.7	21.485	32.9	33.110	7.2	52.248	14.6
22.000	24.0	33.740	3.5	52.746	5.7			34.255	3.4	54.668	5.1

When prepared via an alternative route, the melting point of the same sulfonate salt as defined by the PXRD pattern described in Table I is in the range of 235-246 deg.C (measured using a Perkin Elmer DSC7 with a heating rate of 20 deg.C/min).

Example 104

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine p-toluenesulfonate

5g (0.0096mol) of the compound 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine from example 103 were charged and 10ml/g (50mls) of ethanol were added and the mixture was warmed to reflux. To the refluxed solution was added 1.86g (0.0097mol) of p-toluenesulfonic acid in 10mls of ethanol over 15 seconds. The solution was allowed to cool and granulated at < r.t. for 1 hour. The slurry was filtered and washed with 3ml/g (15mls) ethanol. The salt was dried overnight at 55-60 ℃ under vacuum to give a white crystalline solid. The yield was 6.12g, 92.3%. Mpt 208 ℃.

δ(DMSO)：1.18(3H，t)，1.28(3H，t)，1.36(3H，t)，2.28(3H，s)，2.78(2H，q)，2.99(2H，q)，3.23(4H，t)3.25(3H，s)，3.55(2H，t)，3.80(2H，t)，3.82(2H，t)，4.51(2H，t)，4.53(2H，q)，7.11(2H，d)，7.47(2H，d)，8.30(1H，d)，8，73(1H，d)，9.2(1H，s)，11.90(1H，s).

Example 105

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine (+) -camphorsulfonate

3g (0.006mol) of the compound 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine from example 103 are charged with 10ml/g (30mls) of 2-butanone/water (4% v/v) and the mixture is brought to reflux. To the refluxing solution was added 1.48g (0.006mol) (+) -camphorsulfonic acid in 5mls 2-butanone and 1ml aqueous solution in < 1 minute. 3.3ml/g (10mls) was azeotroped, the solution was cooled and crystallization occurred at about 45 ℃. The slurry was cooled to 5-10 ℃ and granulated for 0.5 h, then filtered and washed with 5ml/g (15mls) of 2-butanone. The salt was dried overnight at 55-60 ℃ under vacuum to give a white crystalline solid. (yield 3.4g, 77%.) Mpt 222-.

δ(DMSO)：0.75(3H，s)，1.03(3H，s)，1.18(3H，t)，1.28(3H，t)，1.36(3H，t)，1.20-1.40(2H，m)，1.79-198(3H，m)，2.2-2.3(1H，m)，2.5-2.62(2H，m)，2.78(2H，q)，2.99(2H，q)，3.02(1H，d)，3.23(4H，t)3.25(3H，s)，3.55(2H，t)，3.79(2H，t)，3.82(2H，t)，4.51(2H，t)，4.50(2H，q)，8.29(1H，d)，8.73(1H，d)，9.33(1H，s)，11.85(1H，s).

Example 106

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine (+/-) -camphorsulfonate

17g (0.033mol) of the compound 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine from example 103 are charged and 10ml/g (170mls) of ethanol are added and the mixture is warmed to reflux. To the refluxing solution was immediately added 7.75g (0.035mol) of racemic camphorsulfonic acid in 30mls of ethanol. The solution was allowed to cool and crystallisation occurred at 65-66 ℃. The slurry was cooled to 5-10 ℃ and granulated for 1 hour, then filtered and washed with 3ml/g (51mls) of ethanol. The salt was dried overnight at 55-60 ℃ under vacuum to give a white crystalline solid. (yield 22.1g, 89.8%)

δ(DMSO)：0.75(3H，s)，1.03(3H，s)，1.18(3H，t)，1.28(3H，t)，1.36(3H，t)，1.20-1.40(2H，m)，1.79-198(3H，m)，2.2-2.3(1H，m)，2.5-2.62(2H，m)，2.78(2H，q)，2.99(2H，q)，3.02(1H，d)，3.23(4H，t)，3.25(3H，s)，3.55(2H，t)，3.79(2H，t)，3.82(2H，t)，4.51(2H，t)，4.50(2H，q)，8.29(1H，d)，8.73(1H，d)，9.33(1H，s)，11.85(1H，s).

Example 107

1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine ethanesulfonate

5g (9.6mmol) of the title compound 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] as described in example 102 are charged]Pyrimidin-5-yl]-3-pyridylsulfonyl } -4-ethylpiperazine, 10ml/g (0.05 l) of ethanol were added and the temperature was raised to reflux. To the refluxed solution was added a solution of 1.1g (10.5mmol) of ethanesulfonic acid in 2ml of ethanol. The slurry was cooled and crystallized at 26-30 ℃. The slurry was granulated, filtered and washed with 2ml/g (0.01 l) ethanol. The salt was dried overnight at 55-60 ℃ under vacuum to give a white crystalline solid. The yield was 5.2g, 86.1%. Mpt 205 ℃. delta. (CDCl)₃)：1.16(3H，t)，1.39(3H，t)，1.41(3H，t)，1.52(3H，t)，2.73(2H，q)，3.03(2H，t)，3.09(2H，q，3.16(2H，t)，3.30(3H，s)，3.35(2H，t)，3.65(2H，t)，3.89(2H，t)，3.90(2H，q)，4.46(2H，t)，4.71(2H，q)，8.63(1H，d)，8.71(1H，d)，10.76(1H，s)，11.29(1H，s).

Biological activity

The following table illustrates some of the compounds of the invention as cGMP PDEs₅In vitro activity of inhibitors and their relative cGMP PDE₆For cGMP PDE₅Selectivity of (2).

cGMP PDE₅IC of₅₀Measurements are based on data generated by human sponge body tissue, for rod cGMP PDE₆IC of₅₀The measurements are based on data generated by bovine retinal tissue, with regard to cGMP PDE ₅For cGMP PDE₆Is based on IC₅₀ PDE₅/IC₅₀ PDE₆。

Watch (A)

Examples	IC₅₀(nM)	Selectivity (PDE 5/6)
Examples	IC₅₀(nM)	Selectivity (PDE 5/6)	5	1.0	-
8	1.68	223.8	5	1.0	-
8	1.68	223.8	17	0.90	254.1
22	6.4	325.3	17	0.90	254.1
22	6.4	325.3	24	1.52	134.9
27	0.85	161	24	1.52	134.9
27	0.85	161	53	1.09	-
60	0.45	343.7	53	1.09	-

Preparation example 1

3-ethyl-1- (2-methoxyethyl) -4-nitropyrazole-5-carboxamide and

preparation example 2

3-ethyl-2- (2-methoxyethyl) -4-nitropyrazole-5-carboxamide

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO 98/49166) (1.7g, 8.8mmol), 2-bromoethyl methyl ether (0.85ml, 8.85mmol) and cesium carbonate (2.9g, 9.0mmol) in N, N-dimethylformamide (20ml) was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate (125ml) and brine (100 ml). The phases were separated and the organic layer was dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate/methanol (97: 3) as eluent to give the title compound of preparation 1, 831mg,

δ(DMSOd₆)：1.19(3H，t)，2.82(2H，q)，3.20(3H，s)，3.68(2H，t)，4.22(2H，t)，8.18(1H，s)，8.38(1H，s).

LRMS：m/z 260(M+18)⁺and preparation 2 the title compound, 793 mg.

δ(CDCl₃)：1.18(3H，t)，2.98(2H，q)，3.22(3H，s)，3.70(2H，t)，4.28(2H，t)，7.65(1H，s)，7.94(1H，s).

LRMS：m/z 243(M+1)⁺

Preparation example 3

1- (2-methoxyethyl) -4-nitro-3-n-propylpyrazole-5-carboxamide

And

preparation example 4

2- (2-methoxyethyl) -4-nitro-3-n-propylpyrazole-5-carboxamide

A mixture of 4-nitro-3-N-propyl-1H-pyrazole-5-carboxamide (WO 98/49166) (7.3g, 37.0mmol), 2-bromoethyl methyl ether (3.85ml, 41.0mmol) and cesium carbonate (24.0g, 74.0mmol) in N, N-dimethylformamide (300ml) was heated at 70 ℃ for 4 hours. The cooled mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (100ml) and brine (100ml), and the phases were separated. The aqueous layer was extracted with ethyl acetate (2X 100ml) and the combined organic solutions were dried (Na) ₂SO₄) And evaporated under reduced pressure. The residue was triturated with ether and the resulting precipitate was filtered and dried to give some of the N2 isomer. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: methanol (100: 0 to 99: 1). The product of preparation 3 was suspended in diethyl ether, the mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound of preparation 3, 1.07g,

δ(CDCl₃)：1.00(3H，t)，1.74(2H，m)，2.88(2H，t)，3.35(3H，s)，3.78(2H，t)，4.47(2H，t)，6.06(1H，s)，7.24(1H，s).

LRMS：m/z 257(M+1)⁺

further N2 isomer (preparation 4) was obtained amounting to 3.85 g.

δ(DMSOd₆)：1.04(3H，t)，1.68(2H，m)，2.98(2H，t)，3.30(3H，s)，3.79(2H，t)，4.29(2H，t)，5.85(1H，s)，7.35(1H，s).

LRMS：m/z 257(M+1)⁺

Preparation example 5

2- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl-3-ethyl-4-nitropyrazole-5-carboxamide

3-ethyl-4-nitro-1H-pyrazole-5-formamide (WO 98/49166) (4.9g, 26.6mmol),A mixture of cesium carbonate (21.0g, 64.5mmol) and (2-bromoethoxy) -tert-butyldimethylsilane (7.0g, 29.0mmol) in acetonitrile (400ml) was heated at 80 ℃ for 20 h. The cooled mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (200ml) and water (100ml), and the layers were separated. The organic phase was extracted with water (3X 50ml) and dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using ethyl acetate as eluent and repeated elution gradients of pentane over ethyl acetate (50: 50 to 0: 100) to give some of the desired compounds. The crude product containing the N1 and N2 isomers was triturated with pentane and the resulting precipitate filtered and dried to give the title compound as a solid (1.7 g total).

δ(CDCl₃)：-0.05(6H，s)，0.81(9H，s)，1.28(3H，t)，3.08(2H，q)，4.03(2H，t)，4.24(2H，t)，5.80(1H，s)，7.34(1H，s).

LRMS：m/z 343(M+1)⁺

Preparation example 6

3-iodo-1-azetidinecarboxylic acid tert-butyl ester

Reacting 3- [ (methylsulfonyl) oxy group]A mixture of tert-butyl-1-azetidinecarboxylate (Synlett., 1998, 379) (5.0g, 19.9mmol) and potassium iodide (16.5g, 99.4mmol) in N, N-dimethylformamide (25ml) was heated at 100 ℃ for 42 h. The cooled mixture was partitioned between water and ethyl acetate and the layers were separated. The organic phase was dried (MgSO)₄) Concentrated under reduced pressure and the residue azeotroped with xylene. The crude product was purified by column chromatography on silica gel using dichloromethane as eluent to give the title compound, 3.26 g.

δ(CDCl₃)：1.43(9H，s)，4.28(2H，m)，4.46(1H，m)，4.62(2H，m)，LRMS：m/z 284(M+1)⁺

Preparation example 7

3- [3- (aminocarbonyl) -5-ethyl-4-nitropyrazol-1-yl ] -1-azetidinecarboxylic acid tert-butyl ester

Esters of phenyl or naphthyl

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO 98/49166) (6.59g, 35.8mmol), cesium carbonate (12.25g, 37.6mmol) and the title compound of preparation 6 (10.3g, 37.6mmol) in N, N-dimethylformamide (60ml) was heated at 60 ℃ for 3 days. The cooled reaction system was poured into a 2% aqueous sodium bicarbonate solution (250ml) and extracted with ethyl acetate (1X 230ml, 1X 100 ml). The combined organic extracts were dried (MgSO)₄) And evaporated under reduced pressure. The residual oil was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: pentane (50: 50 to 100: 0) to give the N1-isomer (5.0g) and the title compound of preparation 7, 4.1 g.

δ(CDCl₃)：1.25(3H，t)，1.46(9H，s)，2.96(2H，q)，4.37(2H，m)，4.44(2H，m)，5.06(1H，m)，5.82(1H，s)，6.63(1H，s).

Preparation example 8

Benzyl 2- [3- (aminocarbonyl) -5-ethyl-4-nitropyrazol-1-yl ] ethyl (methyl) carbamate

Following a similar procedure as described in preparation 7, starting from 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (WO 98/49166) and methanesulfonic acid 2- [ (benzyloxy) carbonyl (methyl) amino]Ethyl ester (j.med.chem. (journal of medicinal chemistry), 37, 23, 1994, 3977) was obtained (25%). Delta (CDCl)₃)

: (rotamers in a ratio of 0.42: 0.58), 1.03 and 1.20(3H, t), 2.69 and 2.87(2H, q), 2.80 and 2.92(3H, s), 3.72(2H, m), 4.20 and 4.33(2H, t), 5.02 and 5.14(2H, s), 5.86(1H, m), 7.35(6H, m).

Preparation example 9

4-amino-3-ethyl-2- (2-methoxyethyl) pyrazole-5-carboxamide

A mixture of the title compound of preparation 2 (500mg, 2.07mmol) and 10% palladium on carbon (50mg) in ethanol (20ml) was hydrogenated at 50psi and room temperature for 18 h. The reaction mixture was filtered through Arbocel and the filtrate was evaporated under reduced pressure to give the title compound as a white solid.

δ(DMSOd₆)：1.03(3H，t)，2.57(2H，q)，3.20(3H，s)，3.63(2H，t)，4.09(2H，t)，4.39(2H，s)，6.90(1H，s)，7.01(1H，s).

LRMS：m/z 213(M+1)⁺

Preparation examples 10 to 12

Following a procedure similar to that described for preparation 9, the compounds of the general structure:

preparation example 13

Benzyl 2- [ 4-amino-3- (aminocarbonyl) -5-ethylpyrazol-1-yl ] ethyl (methyl) carbamate

A mixture of the title compound of preparation 8 (1.92g, 5.28mmol), iron powder (3.04g) and water (2.5ml) in acetic acid (50ml) was stirred at room temperature for 25 minutes. The reaction mixture was filtered through Arbocel and the filtrate was slowly poured into saturated sodium bicarbonate solution (400 ml). The pH of the solution was adjusted to 8 with solid sodium carbonate and the solution was then extracted with ethyl acetate (2X 350 ml). The combined organic extracts were dried (MgSO)₄) Evaporation under reduced pressure gave the title compound, 1.5 g.

δ(CDCl₃): (rotamers in a ratio of 0.46: 0.54), 1.00 and 1.14(3H, t), 2.38 and 2.50(2H, q), 2.68 and 2.80(3H, s), 3.63(2H, m), 3.95(2H, s), 4.04 and 4.17(2H, t), 5.10 and 5.14(2H, s), 5.14(1H, s), 6.53(1H, s), 7.36(5H, m).

Preparation example 14

4-amino-3-ethyl-1- (2-methoxyethyl) pyrazole-5-carboxamide

Obtained (95%) from the title compound of preparation 1 by a similar procedure to that described for preparation 9, purification by column chromatography using dichloromethane: methanol (90: 10) as eluent.

δ(CDCl₃)：1.26(3H，t)，2.58(2H，q)，3.37(3H，s)，3.60(2H，s)，3.82(2H，t)，4.50(2H，t).

LRMS：m/z 213(M+1)⁺

Preparation example 15

4-amino-1- (2-methoxyethyl) -3-n-propylpyrazole-5-carboxamide

Obtained as a solid (99%) from the title compound of preparation 3 using the procedure described for preparation 9.

δ(CDCl₃)：0.95(3H，t)，1.63(2H，m)，2.48(2H，t)，3.30(3H，s)，3.78(2H，t)，4.46(2H，t).

LRMS：m/z 227(M+1)⁺

Preparation example 16

Pyridine-2-amino-5-sulfonic acid

To fuming sulfuric acid (320g) was added 2-aminopyridine (80g, 0.85mol) dropwise over 30 minutes, and the resulting solution was heated at 140 ℃ for 4 hours. After cooling, the reaction was poured onto ice (200g) and the mixture was stirred in an ice/salt bath for an additional 2 hours. The resulting suspension was filtered and the solid washed with ice water (200ml) and cold IMS (200ml) and dried under suction to give the title compound as a solid, 111.3 g.

LRMS：m/z 175(M+1)⁺

Preparation example 17

Pyridine-2-amino-3-bromo-5-sulfonic acid

To a solution of the title compound of preparation 16 (108g, 0.62mol) in water (600ml) was added dropwise bromine (99g, 0.62mol) over one hour under steady reflux. Once the addition was complete, the reaction was cooled and the resulting mixture was filtered. The solid was washed with water and dried under suction to give the title compound, 53.4 g.

δ(DMSOd₆，300MHz)：8.08(1H，s)，8.14(1H，s).

LRMS：m/z 253(M)⁺

Preparation example 18

Pyridine-3-bromo-2-chloro-5-sulfonyl chloride

To an ice-cooled solution of the title compound of preparation 17 (25.3g, 100.0mmol) in aqueous hydrochloric acid (115ml, 20%) was added dropwise a solution of sodium nitrite (7.6g, 110.0mmol) in water (30ml) maintaining the temperature below 6 ℃. The reaction was stirred at 0 ℃ for 30 minutes and at room temperature for another hour. The reaction mixture was evaporated under reduced pressure and the residue was dried under vacuum at 70 ℃ for 72 hours. A mixture of the solid, phosphorus pentachloride (30.0g, 144.0mmol) and phosphorus oxychloride (1ml, 10.8mmol) was heated at 125 ℃ for 3 hours and then cooled. The reaction mixture was poured onto ice (100g) and the resulting solid was filtered and washed with water. The product was dissolved in dichloromethane and dried (MgSO ₄) Evaporation under reduced pressure gave the title compound as a yellow solid, 26.58 g.

δ(CDCl₃，300MHz)：8.46(1H，s)，8.92(1H，s).

Preparation example 19

3-bromo-2-chloro-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

To an ice-cooled solution of the title compound of preparation 18 (23.0g, 79.0mmol) in dichloromethane (150ml) was added dropwise a solution of 1-ethylpiperazine (11.3ml, 89.0mmol) and triethylamine (12.5ml, 89.0mmol) in dichloromethane (150ml), and the reaction system was stirred at 0 ℃ for one hour. The reaction mixture was concentrated under reduced pressure and the residual brown oil was purified by column chromatography on silica gel using an elution gradient of dichloromethane: methanol (99: 1 to 97: 3) to give the title compound as an orange solid, 14.5 g.

δ(CDCl₃，300MHz)：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 example 20

3-bromo-2-chloro-5- (4-methylpiperazin-1-ylsulfonyl) pyridine

To a solution of the title compound of preparation 18 (10.0g, 34.5mmol) in ethanol (200ml) was added dropwise N-methylpiperazine (7.65ml, 69.0mmol) and the reaction was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, the residue partitioned between dichloromethane (200ml) and water (100ml) and the layers separated. The organic phase was dried (Na)₂SO₄) Evaporation under reduced pressure gave the title compound, 10.53g, as a yellow solid.

δ(CDCl₃)：2.28(3H，s)，2.51(4H，m)，3.14(4H，m)，8.24(1H，s)，8.67(1H，s).

Preparation example 21

3-bromo-2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridine

A mixture of the title compound of preparation 19 (6.60g, 17.9mmol) and sodium ethoxide (6.09g, 89.55mmol) in ethanol (100ml) was heated at reflux for 18 h and then cooled. The reaction mixture was concentrated under reduced pressure, the residue partitioned between water (100ml) and ethyl acetate (100ml), and the layers were separated. The aqueous phase was extracted with ethyl acetate (2X 100ml) and the combined organic solutions were dried (MgSO₄) Evaporation under reduced pressure gave the title compound as a brown solid, 6.41 g.

Measured value: c, 41.27; h, 5.33; n, 11.11.C₁₃H₂₀BrN₃O₃S calculated C, 41.35; h, 5.28; n, 10.99 percent.

δ(CDCl₃，300MHz)：1.06(3H，t)，1.48(3H，t).2.42(2H，q).2.56(4H，m)，3.09(4H，m)，4.54(2H，q)，8.10(1H，s)，8.46(1H，s).

LRMS：m/z 378，380(M+1)⁺

Preparation example 22

3-bromo-2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridine

A mixture of the title compound of preparation 20 (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 hours. The reaction mixture was concentrated under reduced pressure, the residue partitioned between ethyl acetate (150ml) and brine (50ml), and the layers were separated. The organic phase was dried (Na)₂SO₄) Filtered and evaporated under reduced pressure to give the title compound, 9.1 g.

δ(CDCl₃)：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 example 23

Pyridine-2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) -3-carboxylic acid ethyl ester

A mixture of the title compound of preparation 21 (6.40g, 16.92mmol), triethylamine (12ml, 86.1mmol) and tris (triphenylphosphine) palladium (O) in ethanol (60ml) was heated at 100 ℃ under 200psi carbon monoxide for 18 h and then cooled. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (100: 0 to 97: 3) to give the title compound as an orange oil, 6.2 g.

δ(CDCl₃，300MHz)：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 example 24

Pyridine-2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) -3-carboxylic acid ethyl ester

Obtained (85%) as an orange solid from the title compound of preparation 22 using a similar procedure as described for preparation 23.

δ(CDCl₃)：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 example 25

Pyridin-2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) -3-carboxylic acid

A mixture of the title compound of preparation 23 (4.96g, 13.35mmol) and aqueous sodium hydroxide (25ml, 2N, 50.0mmol) in ethanol (25ml) was stirred at room temperatureStirred for 2 hours. The reaction mixture was concentrated under reduced pressure to half its volume, washed with ether and acidified to pH5 with 4N hydrochloric acid. The aqueous solution was extracted with dichloromethane (3X 30ml) and the combined organic extracts were dried (MgSO₄) Evaporation under reduced pressure gave the title compound as a tan solid, 4.02 g.

δ(DMSOd₆，300MHz)：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 example 26

Pyridine-2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) -3-carboxylic acid hydrochloride

To a solution of the title compound of preparation 24 (7.57g, 21.0mmol) in dioxane (150ml) was added sodium hydroxide solution (21ml, 2M, 42.0mmol) 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 with hydrochloric acid to pH 2. The solution was evaporated under reduced pressure, the residue was again suspended in hot ethanol, filtered and the filtrate was evaporated again to give the title compound, 5.46 g.

δ(DMSOd₆)：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 example 27

4- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (2-methoxyethyl) pyrazole-5-carboxamide

To an ice-cooled solution of the title compound of preparation 26 (522mg, 1.43mmol) and N, N-dimethylformamide (1 drop) in dichloromethane (20ml) was added oxalyl chloride (500ml, 5.73mmol) dropwise, and the reaction was stirred for 2 hours. The mixture was concentrated under reduced pressure and azeotroped several times with dichloromethane to afford the intermediate acid chloride. A solution of this product in dichloromethane (20ml) was added to a solution of the title compound of preparation 9 (250mg, 1.18mmol) and triethylamine (500ml, 3.18mmol) in dichloromethane (20ml) and the reaction was stirred at room temperature for 18 h. The mixture was washed with water and dried (Na) ₂SO₄) And evaporated under reduced pressure. The residue was subjected to silica gel column chromatography using an elution gradient of methylene chloride: methanol (100: 0 to 95: 5) to give the title compound, 428 mg.

δ(CDCl₃)：1.20(3H，t)，1.59(3H，t)，2.28(3H，s)，2.50(4H，m)，2.95(2H，m)，3.10(4H，m)，3.36(3H，s)，3.80(2H，t)，4.25(2H，t)，4.78(2H，q)，5.26(1H，s)，6.65(1H，s)，8.65(1H，s)，8.85(1H，s)，10.51(1H，s).

LRMS：m/z 524(M+1)⁺

Preparation example 28

4- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -2- (2-methoxyethyl) -3-n-propylpyrazole-5-carboxamide

The title compound was obtained as a white solid (79%) from the title compounds of preparation 10 and 26 following the procedure described for preparation 27.

δ(CDCl₃)：0.92(3H，t)，1.58(5H，m)，2.24(3H，s)，2.47(4H，m)，2.90(2H，t)，3.10(4H，m)，3.35(3H，s)，3.78(2H，t)，4.23(2H，t)，4.78(2H，q)，5.42(1H，brs)，6.68(1H，brs)，8.62(1H，d)，8.82(1H，d)，10.48(1H，s).

LRMS：m/z 538(M+1)⁺

Preparation example 29

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (2-methoxyethyl) pyrazole-5-carboxamide

To a solution of the title compound of preparation 25 (7.25g, 21.1mmol) and the title compound of preparation 9 (4.45g, 20.9mmol), 1-hydroxybenzotriazole hydrate (3.71g, 27.4mmol) and N-diisopropylethylamine (10.96ml, 63.3mmol) in dichloromethane (70ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (5.26g, 27.4mmol) and the reaction was stirred for 18 h. The reaction mixture was diluted with dichloromethane (100ml), washed with water (100ml), saturated aqueous sodium bicarbonate (100ml) and brine (100ml), dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound as a foam, 10.05 g.

δ(CDCl₃)：1.03(3H，t)，1.20(3H，t)，1.58(3H，t)，2.40(2H，q)，2.54(4H，m)，2.95(2H，q)，3.10(4H，m)，3.37(3H，s)，3.80(2H，t)，4.26(2H，t)，4.78(2H，q)，5.27(1H，s)，6.66(1H，s)，8.65(1H，s)，8.85(1H，s)，10.51(1H，s).

LRMS：m/z 538(M+1)⁺

Preparation example 30

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -2- (2-methoxyethyl) -3-n-propylpyrazole-5-carboxamide

To a solution of the title compound of preparation 25 (1.0g, 2.65mmol) and the title compound of preparation 10 (600mg, 2.65mmol), 1-hydroxybenzotriazole hydrate (465mg, 3.45mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (660mg, 3.45mmol) in dichloromethane (20ml) was added N-diisopropylethylamine (0.92ml, 5.3mmol), and the reaction was stirred for 18 hours. The reaction mixture was washed with brine and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 740 mg.

δ(CDCl₃)：0.94(3H，t)，1.03(3H，t)，1.59(5H，m)，2.40(2H，q)，2.54(4H，m)，2.92(2H，t)，3.11(4H，m)，3.37(3H，s)，3.80(2H，t)，4.25(2H，t)，4.78(2H，q)，5.26(1H，s)，6.66(1H，s)，8.65(1H，s)，8.83(1H，s)，10.48(1H，s).

LRMS：m/z 552(M+1)⁺

Preparation example 31

2- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

Obtained as a white solid (67%) from the title compounds of preparations 25 and 11 following a similar procedure to that described for preparation 27.

δ(CDCl₃)：0.00(6H，s)，0.85(9H，s)，1.04(3H，t)，1.22(3H，t)，1.57(3H，t)，2.40(2H，q)，2.53(4H，m)，2.94(2H，q)，3.10(4H，m)，4.02(2H，t)，4.19(2H，t)，4.78(2H，q)，5.39(1H，s)，6.66(1H，s)，8.64(1H，s)，8.83(1H，s)，10.49(1H，s).

LRMS：m/z 638(M+1)⁺

Preparation example 32

Benzyl 2- {3- (aminocarbonyl) -4- [ ({ 2-ethoxy-5- [ (4-ethyl-1-piperazinyl) sulfonyl ] -3-pyridyl } carbonyl) amino ] -5-ethylpyrazol-1-yl } ethyl (methyl) carbamate

To a solution of the title compound of preparation 25 (1.5g, 4.5mmol) and the title compound of preparation 13 (1.7g, 4.95mmol), 1-hydroxybenzotriazole hydrate (833mg, 5.44mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.28g, 6.68mmol) in dichloromethane (50ml) was added triethylamine (1.0ml, 7.2mmol), and the reaction was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, the residue partitioned between saturated aqueous sodium bicarbonate and ethyl acetate, and the layers were separated. The aqueous phase was extracted with ethyl acetate (2X 50ml), the organic solutions combined and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give the title compound, 3.0 g.

δ(CDCl₃)：1.00-1.20(6H，m)，1.58(3H，t)，2.40(2H，q)，2.54(4H，m)，2.70-2.91(5H，m)，3.10(4H，m)，3.70(2H，m)，4.16-4.32(2H，m)，4.79(2H，q)，5.12(2H，m)，5.24(1H，s)，6.62(1H，s)，7.37(5H，m)，8.64(1H，s)，8.82(1H，s)，10.50(1H，s).

Preparation example 33

2- (1-tert-butoxycarbonylazetidin-3-yl) -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

The title compound (72%) was obtained from the title compounds of preparation examples 25 and 12 following a similar procedure as described for preparation 32.

δ(CDCl₃)：1.01(3H，t)，1.19(3H，t)，1.47(9H，s)，1.58(3H，t)，2.40(2H，q)，2.54(4H，m)，2.86(2H，q)，3.10(4H，m)，4.38(2H，m)，4.41(2H，m)，4.79(2H，q)，5.10(1H，m)，5.30(1H，brs)，6.77(1H，br s)，8.63(1H，d)，8.82(1H，d)，10.57(1H，s).

Preparation example 34

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -1H-3-ethylpyrazole-5-carboxamide

To a solution of the title compound of preparation 25 (21.7g, 62.9mmol), 1-hydroxybenzotriazole hydrate (10.1g, 66.0mmol) and triethylamine (13.15ml, 94.3mmol) in dichloromethane (240ml) was added a solution of 3-ethyl-1H-pyrazole-5-carboxamide (WO 98/49166) (9.2g, 59.8mmol) in N, N-dimethylformamide (60 ml). 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (13.26g, 69.2mmol) was added and the reaction stirred at room temperature for 6 hours. The dichloromethane was removed under reduced pressure, the remaining solution was poured into ethyl acetate (400ml), and the mixture was washed with aqueous sodium bicarbonate (400 ml). The resulting crystalline precipitate was filtered, washed with ethyl acetate and dried under vacuum to give the title compound as a white powder, 22 g.

δ(CDCl₃+1drop DMSOd₆)0.96(3H，t)，1.18(3H，t)，1.50(3H，t)，2.25-2.56(6H，m)，2.84(2H，q)，3.00(4H，m)，4.70(2H，q)，5.60(1H，br s)，6.78(1H，brs)，8.56(1H，d)，8.76(1H，d)，10.59(1H，s)，12.10-12.30(1H，s).

LRMS：m/z 480(M+1)⁺

Preparation example 35

4- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -1H-3-ethylpyrazole-5-carboxamide

To an ice-cold solution of the title compound of preparation 26 (10.0g, 27.0mmol) and N, N-dimethylformamide (160. mu.l) in dichloromethane (150ml) was added oxalyl chloride (9.5ml, 108mmol) dropwise and once the addition was complete, the reaction was stirred at room temperature for 51/2 hours. The mixture was evaporated under reduced pressure and the residue azeotroped with toluene to give a yellow solid. To a solution of the intermediate acid chloride (10.5g, 27.3mmol) and 4-amino-3-ethyl-1H-pyrazole-5-carboxamide (WO 98/49166) (4.2g, 27.3mmol) in dichloromethane (150ml) was added triethylamine (11.2ml, 81.0mmol), and the reaction was stirred at room temperature for 18 hours. The mixture was diluted with water and the layers were separated. The aqueous phase was extracted with dichloromethane (2 ×), and the combined organic solutions were dried (Na) ₂SO₄) And evaporated under reduced pressure. The crude product was triturated with ether and the resulting solid filtered to give the title compound, 10.1 g.

δ(CDCl₃)：1.21(3H，t)，1.59(3H，t)，2.26(3H，s)，2.50(4H，m)，2.94(2H，q)，3.10(4H，m)，4.79(2H，q)，5.50(1H，brs)，6.80(1H，brs)，8.64(1H，d)，8.84(1H，d)，10.65(1H，s).

Preparation example 36

2-iso-butyl-4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

To a solution of the title compound of preparation 34 (750mg, 1.56mmol) and cesium carbonate (1.12g, 3.44mmol) in N, N-dimethylformamide (15ml) was added 1-bromo-2-methylpropane (187. mu.l, 1.72mmol)The reaction was stirred at 60 ℃ for 18 hours. The cooled mixture was partitioned between water and ethyl acetate and the layers were separated. The organic layer was dried (MgSO₄) Concentrated under reduced pressure and azeotroped with toluene to give a solid. The product was recrystallized from diethyl ether to give the title compound as a white solid, 152 mg.

δ(CDCl₃)：0.96(6H，d)，1.02(3H，t)，1.19(3H，t)，1.58(3H，t)，2.26(1H，m)，2.40(2H，q)，2.52(4H，m)，2.94(2H，q)，3.10(4H，m)，3.88(2H，d)，4.78(2H，q)，5.25(1H，s)，6.65(1H，s)，8.64(1H，d)，8.83(1H，d)，10.54(1H，s).

LRMS：m/z 536(M+1)⁺

Preparation examples 37 to 41

Following a procedure similar to that described for preparation 36, the following compounds of the general formula were prepared from the title compound of preparation 34 and the appropriate bromide compound:

preparation example 42

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (tetrahydrofuran-2-yl) methylpyrazole-5-carboxamide

Ice-cold preparation example 34 title compound (2)0g, 4.18mmol) of N, N-dimethylformamide (40ml) cesium carbonate (1.63g, 5.0mmol) was added and the solution was stirred for 30 minutes. Tetrahydrofuryl bromide (0.6ml, 5.28mmol) was added and the reaction was heated at 60 ℃ for 72 hours. The cooled mixture was evaporated under reduced pressure and the residue partitioned between water and dichloromethane. The phases were separated and the organic layer was dried (MgSO ₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 1.20 g.

δ(CDCl₃)：1.01(3H，t)，1.18(3H，t)，1.58(3H，t)，1.70-2.12(4H，m)，2.40(2H，q)，2.54(4H，m)，2.97(2H，m)，3.10(4H，m)，3.74-3.94(2H，m)，4.16(2H，m)，4.32(1H，m)，4.78(2H，q)，5.32(1H，brs)，6.64(1H，brs)，8.63(1H，s)，8.82(1H，s)，10.50(1H，s).

LRMS：m/z 564(M+1)⁺

Preparation example 43

Methanesulfonic acid 2-methoxy-1-methylethyl ester

To an ice-cooled solution of 1-methoxy-2-propanol (3ml, 30.7mmol) and triethylamine (10.27ml, 73.7mmol) in dichloromethane (150ml) was added dropwise methanesulfonyl chloride (2.86ml, 36.9mmol), and the reaction was stirred at room temperature for 18 hours. The mixture was washed with water, then 2M hydrochloric acid and dried (MgSO)₄) Evaporation under reduced pressure gave the title compound as a yellow oil, 5.24 g.

δ(CDCl₃)：1.39(3H，d)，3.03(3H，s)，3.39(3H，s)，3.46(2H，m)，4.88(1H，m).

LRMS：m/z 186(M+18)⁺

Preparation example 44

Methanesulfonic acid 2- [ (tert-butoxycarbonyl) (methyl) amino ] ethyl ester

To an ice-cold solution of tert-butyl 2-hydroxyethyl (methyl) carbamate (synth. commun., 1993, 23(17), 2443) (4.5g, 25.7mmol) in pyridine (40ml) was added methanesulfonyl chloride (2.98ml, 38.6mmol) and the reaction was stirred for 2 hours. The solution was poured into water (150ml) and extracted with ethyl acetate (2X 50 ml). The combined organic extracts were washed with 10% aqueous citric acid and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate to pentane (34: 66 to 40: 60) to give the title compound, 1.0 g.

δ(CDCl₃)：1.46(9H，s)，2.96(3H，s)，3.02(3H，s)，3.56(2H，m)，4.34(2H，m).

Preparation example 45

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (1-methyl-2-methoxyethyl) pyrazole-5-carboxamide

To a solution of the title compound of preparation 34 (700mg, 1.46mmol) in tetrahydrofuran (10ml) was added sodium hydride (64mg, 60% dispersion in mineral oil, 1.6mmol), and the solution was stirred for 10 minutes. The title compound of preparation 43 (270mg, 1.60mmol) was added and the reaction was stirred at 60 ℃ for 3 days. The cooled mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic solutions were dried (MgSO)₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol (98: 2) as eluent to give the title compound as whiteColor foam, 310 mg.

δ(CDCl₃)：1.02(3H，t)，1.22(3H，m)，1.50(3H，d)，1.59(3H，t)，2.40(2H，q)，2.55(4H，m)，2.92(2H，m)，3.10(4H，m)，3.30(3H，s)，3.60(1H，m)，3.78(1H，m)，4.57(1H，m)，4.78(2H，q)，5.25(1H，brs)，6.68(1H，brs)，8.64(1H，s)，8.83(1H，s)，10.48(1H，s).

LRMS：m/z 552(M+1)⁺

Preparation example 46

2- (1-tert-butoxycarbonylpiperidin-4-yl) -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

The title compound (43%) was obtained from preparation 34 and tert-butyl 4- [ (methylsulfonyl) oxy ] -1-piperidinecarboxylate (WO 93/19059) following the procedure described for preparation 45.

δ(CDCl₃)：1.02(3H，t)，1.23(3H，t)，1.49(9H，s)，1.57(3H，m)，1.93(2H，m)，2.16(2H，m)，2.40(2H，q)，2.54(4H，m)，2.82-2.97(4H，m)，3.10(4H，m)，4.30(3H，m)，4.79(2H，q)，5.23(1H，s)，6.65(1H，s)，8.63(1H，d)，8.82(1H，d)，10.57(1H，s).

Preparation example 47

2- {2- [ (tert-butoxycarbonyl) (methyl) amino ] ethyl } -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

The title compound was prepared from the title compounds of preparations 34 and 44 following a procedure similar to that described for preparation 45. The crude product was purified by column chromatography on silica gel using ethyl acetate diethylamine (95: 5) as eluent to give the title compound, 30%.

δ(CDCl₃)：1.02(3H，t)，1.20(3H，t)，1.46(9H，s)，1.57(3H，t)，2.40(2H，q)，2.53(4H，m)，2.88(3H，s)，3.10(4H，m)，3.58(1H，m)，3.64(2H，m)，4.22(2H，m)，4.30(1H，m)，4.79(2H，q)，5.24(1H，s)，6.65(1H，s)，8.62(1H，d)，8.82(1H，d)，10.53(1H，s).

Preparation example 48

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- [2- (pyrazol-1-yl) ethyl ] pyrazole-5-carboxamide

To an ice-cooled solution of the title compound of preparation 34 (1.0g, 2.09mmol) in tetrahydrofuran (25ml) was added sodium hydride (88mg, 60% dispersion in mineral oil, 2.19mmol), and the solution was stirred for one hour. 1- (2-chloroethyl) pyrazole (WO 98/49166) (410mg, 3.14mmol) was added and the reaction was heated at reflux for 18 h. The cooled mixture was concentrated under reduced pressure, the residue partitioned between water and ethyl acetate, and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic solutions were dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 300 mg.

δ(CDCl₃)：1.02(6H，m)，1.58(3H，t)，2.40(2H，q)，2.56(6H，m)，3.10(4H，m)，4.50(2H，t)，4.63(2H，t)，4.78(2H，q)，6.20(1H，m)，7.06(1H，m)，7.58(1H，m)，8.63(1H，d)，8.80(1H，d)，10.46(1H，s).

Preparation example 49

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (4-nitrophenyl) pyrazole-5-carboxamide

To a cooled (-78 deg.C.) solution of the title compound of preparation 34 (1.0g, 2.08mmol) in tetrahydrofuran (10ml) was added sodium hydride (80mg, 80% dispersion in mineral oil, 2.67mmol) and the mixture was slowly warmed to room temperature. 4-Fluoronitrobenzene (0.5ml, 4.7mmol) was added and the reaction was heated at 65 ℃ for 72 hours. The cooled mixture was partitioned between aqueous ammonium chloride and ethyl acetate and the layers were separated. The aqueous phase was extracted with ethyl acetate and the combined organic solutions were washed with water, brine and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 95: 5) to give the title compound, 630 mg.

δ(CDCl₃)：0.93(6H，m)，1.52(3H，t)，2.32(2H，m)，2.44(4H，m)，2.98(6H，m)，4.72(2H，q)，5.96(1H，s)，6.76(1H，s)，7.62(2H，d)，8.32(2H，d)，8.58(1H，d)，8.75(1H，d)，10.63(1H，s).

LRMS：m/z 601(M+1)⁺

Preparation example 50

2- [ 3-dimethylamino-n-propyl ] -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

To an ice-cooled solution of 3-dimethylamino-1-propanol (6g, 58.2mmol) and triethylamine (9.7ml, 69.8mmol) in dichloromethane (200ml) was added methanesulfonyl chloride (4.95ml, 64.0mmol), and the reaction was stirred at room temperature for 16 hours. Subjecting the mixture to acetic acid The ethyl ester was partitioned with aqueous sodium bicarbonate and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic solutions were dried (Na)₂SO₄) And evaporated under reduced pressure. The residue was immediately purified by column chromatography on silica gel using dichloromethane: methanol (90: 10) as eluent to give an oily solid, 1.5 g. It was immediately re-dissolved in dichloromethane (3ml), filtered and the filtrate diluted with tetrahydrofuran (10 ml).

To an ice-cooled solution of the title compound of preparation 34 (760mg, 1.59mmol) in tetrahydrofuran (15ml) was added sodium hydride (70mg, 60% dispersion in mineral oil, 1.75mmol) portionwise, and once the addition was complete, the solution was stirred at room temperature for one hour. The mesylate solution prepared above was then added and the reaction was stirred at 70 ℃ for 16 hours. The cooled mixture was poured into saturated sodium bicarbonate solution (120ml) and extracted with ethyl acetate (2X 100 ml). The combined organic extracts were dried (Na)₂SO₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (89: 10: 1) as eluent to give the title compound, 140 mg.

δ(CDCl₃)：1.02(3H，t)，1.21(3H，t)，1.58(3H，t)，2.32(6H，s)，2.40(2H，q)，2.54(4H，m)，2.78(2H，t)，2.92(2H，q)，3.08(4H，m)，4.18(2H，t)，4.78(2H，q)，5.25(1H，s)，6.66(1H，s)，8.64(1H，s)，8.83(1H，s)，10.54(1H，s).

Preparation example 51

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (piperidin-4-yl) pyrazole-5-carboxamide bis (trifluoroacetic acid) salt

To a solution of the title compound of preparation 46 (309mg, 0.47mmol) in dichloromethane (4ml) was added trifluoroacetic acid (3ml), and the solution was stirred for 21/2 hours. The reaction was evaporated under reduced pressure and the residue was triturated thoroughly with ether. The resulting solid was sonicated in ether for 1 min, the resulting precipitate filtered and dried to give the title compound as a white solid, 278 mg.

δ(DMSOd₆)：1.15(6H，m)，1.46(3H，t)，2.04(2H，m)，2.20(2H，m)，2.40-2.84(6H，m)，3.00-3.22(6H，m)，3.25-3.60(4H，m)，3.76(1H，m)，4.62(4H，m)，7.27(1H，s)，7.40(1H，s)，8.41(2H，m)，8.70(2H，m)，10.24(1H，s).

Preparation example 52

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (1-methylpiperidin-4-yl) pyrazole-5-carboxamide

To a solution of the title compound of preparation 46 (320mg, 0.48mmol) in dichloromethane (2ml) was added trifluoroacetic acid (1.5ml), and the solution was stirred at room temperature for 21/2 hours. The reaction mixture was evaporated under reduced pressure and the residue was triturated thoroughly with ether and dried under vacuum to give a white solid.

To a solution of the intermediate amine in dichloromethane (8ml) was added formaldehyde (217. mu.l, 37% aqueous solution, 2.90mmol) and the solution was stirred vigorously for 30 minutes. Acetic acid (88. mu.l, 1.69mmol) was added and the solution stirred for an additional 30 minutes, then sodium triacetoxyborohydride (169mg, 0.80mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction mixture was poured into an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (91.75: 7.5: 0.75) as eluent to give the title compound, 70 mg.

δ(CDCl₃)：1.02(3H，t)，1.22(3H，t)，1.58(3H，t)，1.92(2H，m)，2.14(2H，m)，2.25-2.45(7H，m)，2.54(4H，m)，2.91(2H，q)，2.99-3.16(6H，m)，4.08(1H，m)，4.78(2H，q)，5.11(1H，brs)，6.65(1H，brs)，8.63(1H，d)，8.83(1H，d)，10.53(1H，s).

Preparation example 53

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- (1-methylazetidin-3-yl) pyrazole-5-carboxamide

To a solution of the title compound of preparation 33 (700mg, 1.1mmol) in dichloromethane (3.5ml) was added trifluoroacetic acid (2.5ml), and the solution was stirred at room temperature for 21/2 hours. The reaction mixture was evaporated under reduced pressure and the residue was triturated thoroughly with ether and dried under vacuum. The solid was suspended in saturated aqueous sodium bicarbonate, extracted with ethyl acetate and the combined organic extracts evaporated under reduced pressure.

To a solution of the intermediate amine in dichloromethane (8ml) was added formaldehyde (280. mu.l, 37% aqueous solution, 4.4mmol) and the solution was stirred vigorously for 30 minutes. Acetic acid (53. mu.l, 1.1mmol) was added and the solution stirred for an additional 30 minutes, then sodium triacetoxyborohydride (238mg, 1.12mmol) was added and the reaction stirred at room temperature for 16 hours. The reaction mixture was poured into an aqueous sodium hydrogencarbonate solution (30ml) and extracted with ethyl acetate (2X 30 ml). The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (91.75: 7.5: 0.75) as eluent to give the title compound, 470 mg.

δ(CDCl₃)：1.01(3H，t)，1.18(3H，t)，1.58(3H，t)，2.40(2H，q)，2.48(3H，s)，2.54(4H，m)，2.85(2H，q)，3.10(4H，m)，3.59(2H，t)，3.82(2H，t)，4.79(2H，q)，4.96(1H，m)，5.32(1H，brs)，6.79(1H，brs)，8.64(1H，d)，8.82(1H，d)，10.52(1H，s).

Preparation example 54

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- [2- (methylamino) ethyl ] pyrazole-5-carboxamide

A mixture of the title compound of preparation 32 (250mg, 0.37mmol) and 10% palladium on carbon (35mg) in methanol (3ml) was hydrogenated at 60psi at room temperature for 16 h. The reaction mixture was filtered through Arbocel _, the filter pad was washed with methanol, and the combined filtrates were evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol: 0.88 ammonia (90: 10: 0 to 89: 10: 1) to give the title compound (135mg, 68%) as a white foam.

δ(CDCl₃)：1.02(3H，t)，1.20(3H，t)，1.60(3H，t)，2.40(2H，q)，2.48(3H，s)，2.52(4H，m)，2.94(2H，q)，3.10(6H，m)，4.22(2H，t)，4.79(2H，q)，5.28(1H，s)，6.67(1H，s)，8.64(1H，s)，8.83(1H，s)，10.54(1H，s).

Preparation example 55

2- [2- (dimethylamino) ethyl ] -4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

To an ice-cooled solution of the title compound of preparation 34 (1.0g, 2.1mmol) in tetrahydrofuran (25ml) was added sodium hydride (88mg, 60% dispersion in mineral oil, 2.2mmol) portionwise, and the solution was stirred for 30 minutes.

2-dimethylaminoethyl chloride hydrochloride (451mg, 3.15mmol) was treated with saturated aqueous sodium bicarbonate and the mixture was extracted with dichloromethane (2X 15 ml). The combined extracts were concentrated to a volume of about 2ml at room temperature under reduced pressure and the solution was diluted with tetrahydrofuran (10 ml). This was then added to the previously prepared solution and the reaction system was heated under reflux for 20 hours. The cooled mixture was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate (100 ml). The organic extracts were evaporated under reduced pressure and the residual foam was purified by column chromatography on silica gel using ethyl acetate: diethylamine (95: 5) as eluent to give the title compound, 300 mg.

δ(CDCl₃)：1.02(3H，t)，1.22(3H，t)，1.59(9H，m)，2.40(2H，q)，2.54(4H，m)，2.78(2H，t)，2.94(2H，q)，3.09(4H，m)，4.19(2H，t)，4.78(2H，q)，5.25(1H，s)，6.65(1H，s)，8.62(1H，s)，8.83(1H，s)，10.54(1H，s).

Preparation example 56

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-1- (2-methoxyethyl) pyrazole-5-carboxamide

The title compound (70%) was obtained from the title compounds of preparation examples 25 and 14 following a similar procedure as described for preparation 27.

δ(CDCl₃)：1.04(3H，t)，1.27(3H，t)，1.59(3H，t)，2.42(2H，q)，2.57(4H，m)，2.72(2H，q)，3.12(4H，m)，3.38(3H，s)，3.85(2H，t)，4.55(2H，t)，4.77(2H，q)，5.57(1H，s)，7.92(1H，s)，8.68(1H，s)，8.86(1H，s)，9.82(1H，s).

LRMS：m/z 538(M+1)⁺

Preparation example 57

4- [ 2-ethoxy-5- (4-methylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -1- (2-methoxyethyl) -3-n-propylpyrazole-5-carboxamide

A mixture of the title compound of preparation 26 (585mg, 1.77mmol) and the title compound of preparation 15 (300mg, 1.32mmol), 1-hydroxybenzotriazole hydrate (189mg, 1.40mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (267mg, 1.40mmol) and N-ethyldiisopropylamine (0.39ml, 2.25mmol) in dichloromethane (20ml) was stirred at room temperature for 18 h. The mixture was washed with brine (10ml) and then with water (10ml) and extracted with hydrochloric acid (1M, 3X 20 ml). The combined acidic extracts were neutralised with sodium bicarbonate solution and the aqueous solution extracted with dichloromethane (3X 30 ml). The combined organic extracts were dried (Na) ₂SO₄) Evaporation under reduced pressure gave the title compound as a white solid, 446 mg.

δ(CDCl₃)：0.97(3H，t)，1.67(5H，m)，2.28(3H，s)，2.50(4H，m)，2.65(2H，t)，3.10(4H，m)，3.37(3H，s)，3.82(2H，t)，4.52(2H，t)，4.76(2H，q)，5.57(1H，s)，7.87(1H，s)，8.67(1H，s)，8.85(1H，s)，9.77(1H，s).

LRMS：m/z 538(M+1)⁺

Preparation example 58

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

To a solution of the title compound of preparation 34 (10.0g, 20.8mmol) and ethyl acetate (2ml, 20mmol) in ethanol (160ml) was added potassium bis (trimethylsilyl) amide (8.28g, 41.6mmol), and the reaction mixture was heated in a sealed vessel at 120 ℃ for 12 hours. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 5: 0.5) as eluent to give the title compound, 3.75 g.

δ(CDCl₃)：1.03(3H，t)，1.42(3H，t)，1.60(3H，t)，2.42(2H，q)，2.58(4H，m)，3.02(2H，q)，3.16(4H，m)，4.78(2H，q)，8.66(1H，d)，9.08(1H，d)，11.00(1H，s)11.05-11.20(1H，brs).

LRMS：m/z 462(M+1)⁺

Preparation example 59

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 34 (500mg, 1.04mmol) and potassium bis (trimethylsilyl) amide (436mg, 2.19mmol) in n-butanol (12ml) was heated in a sealed vessel at 130 ℃ for 16 hours. The cooled mixture was poured into saturated aqueous sodium bicarbonate, extracted with ethyl acetate and the combined organic extracts were dried (MgSO ₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (96: 4) as eluent to give the title compound, 128 mg.

δ(CDCl₃)：1.04(6H，m)，1.42(3H，t)，1.59(2H，m)，1.96(2H，m)，2.46(2H，m)，2.60(4H，m)，3.01(2H，q)，3.19(4H，m)，4.70(2H，t)，8.64(1H，d)，9.03(1H，d)，11.09(1H，s).

LRMS：m/z 490(M+1)⁺

Preparation example 60

2- (2- { [ tert-butyl (dimethyl) silyl ] oxy } ethyl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 31 (2.02g, 3.17mmol) and potassium bis (trimethylsilyl) amide (950mg, 4.76mmol) in 3-methyl-3-pentanol (50ml) was stirred at reflux for 8 hours. The cooled mixture was concentrated under reduced pressure, the residue suspended in ethyl acetate (100ml), washed with water (50ml) and brine (50ml), and dried (MgSO)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using a gradient eluting with dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 124 mg.

δ(CDCl₃)：-0.08(6H，s)，0.81(9H，s)，1.02(3H，t)，1.40(3H，t)，1.57(3H，t)2.41(2H，q)，2.56(4H，m)，3.14(6H，m)，4.15(2H，t)，4.40(2H，t)，4.74(2H，q)，8.62(1H，s)，9.03(1H，s)，10.68(1H，s).

LRMS：m/z 620(M+1)⁺

Preparation example 61

2- {2- [ (tert-butoxycarbonyl) (methyl) amino ] ethyl } -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2-n-propoxypyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of example 14 (100mg, 0.16mmol) and potassium bis (trimethylsilyl) amide (161mg, 0.81mmol) in n-propanol (3ml) was heated at 100 ℃ for 16 h. The cooled reaction mixture was poured into saturated sodium bicarbonate solution (20ml), extracted with ethyl acetate (2X 30ml) and the combined organic extracts evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent to give the title compound, 71 mg.

δ(CDCl₃)：1.03(3H，t)，1.14(3H，t)，1.41(3H，t)，1.45(9H，s)，2.00(2H，m)，2.42(2H，q)，2.58(7H，m)，3.01(2H，q)，3.16(4H，m)，3.78(2H，t)，4.46(2H，m)，4.63(2H，t)，8.63(1H，d)，9.04(1H，d)，10.66(1H，brs).

Preparation example 62

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- {2- [ (tert-butoxycarbonyl) (methyl) amino ] ethyl } -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of example 14 (123mg, 0.20mmol), potassium bis (trimethylsilyl) amide (198mg, 1.0mmol) and ethyl acetate (18mg, 0.20mmol) in n-butanol (12ml) was heated at 110 ℃ for 8 hours in a sealed vessel. The cooled mixture was poured into saturated aqueous sodium bicarbonate (60ml), extracted with ethyl acetate (2X 60ml) and the combined organic extracts dried (MgS 0)₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (97: 3) as eluent to give the title compound as a beige foam, 36 mg.

δ(CDCl₃)：1.02(6H，t)，1.40(3H，t)，1.45(9H，s)，1.55(2H，m)，1.95(2H，m)，2.41(2H，q)，2.58(7H，m)，3.01(2H，q)，3.16(4H，m)，3.78(2H，t)，4.45(2H，m)，4.67(2H，t)，8.63(1H，d)，9.03(1H，d)，10.64(1H，s).

Preparation example 63

2- (1-butoxycarbonylazetidin-3-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 33 (1.3g, 2.05mmol) and potassium bis (trimethylsilyl) amide (490mg, 2.46mmol) in ethanol (35ml) was heated in a sealed vessel at 130 ℃ for 16 hours. The cooled mixture was concentrated under reduced pressure, the residue was dissolved in water (15ml), the solution was neutralized with hydrochloric acid (2N), and saturated sodium bicarbonate was then added. The aqueous solution was extracted with dichloromethane (5X 30ml) and the combined organic extracts were dried (MgSO ₄) And evaporated under reduced pressure. The residual gum was purified by column chromatography on silica gel using ethyl acetate: diethylamine (96: 4) as eluent to give the title compound, 350 mg.

δ(CDCl₃)：1.02(3H，t)，1.38(3H，t)，1.48(9H，s)，1.58(3H，t)，2.40(2H，q)，2.57(4H，m)，3.02(2H，q)，3.14(4H，m)，4.37(2H，t)，4.42(2H，m)，4.77(2H，q)，5.25(1H，m)，8.64(1H，s)，8.81(1H，s)，10.57(1H，s).

Preparation 64

2- (1-butoxycarbonylpiperidin-4-yl) -5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound was prepared from the title compound of preparation 46 following a procedure similar to that described for preparation 63. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent to give the title compound (62%).

δ(CDCl₃)：1.03(3H，t)，1.38-1.60(15H，m)，1.94(2H，m)，2.41(4H，m)，2.57(4H，m)，2.90(2H，m)，3.10(6H，m)，4.26-4.48(3H，m)，4.77(2H，q)，8.62(1H，d)，9.02(1H，d)，10.60(1H，s).

Preparation example 65

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (1-tert-butoxycarbonylazetidin-3-yl) -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (67%) was obtained from preparation 63 and n-butanol following a similar procedure to that described for preparation 61.

δ(CDCl₃)：1.02(6H，t)，1.38(3H，t)，1.48(9H，s)，1.57(2H，m)，1.96(2H，m)，2.41(2H，q)，2.57(4H，m)，3.02(2H，q)，3.15(4H，m)，4.39(2H，m)，4.68(4H，m)，5.26(1H，m)，8.62(1H，m)，9.02(1H，m)，10.67(1H，s).

Preparation example 66

2- (1-tert-butoxycarbonylazetidin-3-yl) -5- [5- (4-ethylpiperazin-1-ylsulfonyl) -1-methylbutoxypyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 63 (100mg, 0.16mmol) and potassium bis (trimethylsilyl) amide (157mg, 0.79mmol) in (R) -pentan-2-ol (1ml) was heated at 120 ℃ for 4 days. The cooled mixture was suspended in saturated aqueous sodium bicarbonate (35ml) and extracted with ethyl acetate (2X 35 ml). The combined organic extracts were dried (MgSO) ₄) And evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane: methanol: 0.88 ammonia (95: 4.7: 0.3) as eluent to give the title compound, 14 mg.

δ(CDCl₃)：1.02(6H，m)，1.38(3H，t)，1.48(12H，m)，1.80(1H，m)，1.98(1H，m)，2.42(2H，q)，2.58(4H，m)，3.02(2H，q)，3.16(4H，m)，4.40(2H，t)，4.67(2H，m)，5.25(1H，m)，5.62(1H，m)，8.62(1H，s)，9.02(1H，s)，10.70(1H，s).

Preparation example 67

5- [ 2-n-butoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -2- (1-tert-butoxycarbonylpiperidin-4-yl) -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

The title compound (69%) was obtained from the title compound of preparation 46 and n-butanol by following a similar procedure to that described in preparation 62.

δ(CDCl₃)：1.01(6H，t)，1.34-1.60(14H，m)，1.93(4H，m)，2.41(4H，m)，2.57(4H，m)，2.90(2H，m)，3.00-3.20(6H，m)，4.38(3H，m)，4.66(2H，t)，8.61(1H，d)，9.00(1H，s)，10.58(1H，s).

Preparation example 68

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-2- (piperidin-4-yl) -2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one bis (trifluoroacetic acid) salt

A solution of the title compound of preparation 64 (48mg, 0.075mmol) in trifluoroacetic acid (0.5ml) in dichloromethane (0.5ml) was stirred at room temperature for 21/2 h. The mixture was concentrated under reduced pressure and the residue was triturated thoroughly with ether. The solid was then sonicated in ether for one minute, the resulting precipitate filtered and dried to give the title compound, 54 mg.

δ(DMSOd₆)：1.16(3H，t)，1.22-1.38(6H，m)，2.10(2H，m)，2.38(2H，m)，3.00(2H，q)，3.07-3.54(14H，m)，4.50(2H，q)，5.85(1H，m)，8.24(1H，s)，8.44(1H，brs)，8.74(2H，m)，11.90(1H，s).

Preparation example 69

5- [5- (4-ethylpiperazin-1-ylsulfonyl) -2- (2-methoxyethoxy) pyridin-3-yl ] -3-ethyl-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one

A mixture of the title compound of preparation 58 (1.0g, 2.2mmol) and potassium bis (trimethylsilyl) amide (2.16g, 10.8mmol) in 2-methoxyethanol (20ml) was heated at reflux for 18 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a gradient eluting from dichloromethane: methanol (100: 0 to 90: 10) to give the title compound, 860 mg.

δ(CDCl₃)：1.03(3H，t)，1.42(3H，t)，2.43(2H，q)，2.59(4H，m)，3.02(2H，q)，3.18(4H，m)，3.59(3H，s)，4.80(2H，t)，8.63(1H，d)，9.00(1H，d)，11.25(1H，brs).

LRMS：m/z 492(M+1)⁺

Preparation example 70

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -2- (2-ethoxyethyl) -3-ethylpyrazole-5-carboxamide

To a mixture of the title compound of preparation 34 (1.0g, 2.09mmol) and cesium carbonate (816mg, 2.50mmol) in N, N-dimethylformamide (20ml) was added 2-bromoethyl ether (0.28ml,2.50mmol) and the reaction system stirred at 60 ℃ for 12 h. The mixture was diluted with water (100ml) and extracted with ethyl acetate (2X 100 ml). The combined organic extracts were dried (MgSO)₄) Evaporated under reduced pressure and the residue azeotroped with toluene. The crude product was triturated with ether and the resulting solid filtered and dried to give the title compound as a crystalline solid, 550 mg.

d(DMSOd₆)：0.92(3H，t)，1.10(6H，m)，1.44(3H，t)，2.30(2H，q)，2.42(4H，m)，2.80(2H，q)，2.96(4H，m)，3.40(2H，q)，3.78(2H，t)，4.24(2H，t)，4.63(2H，q)，7.29(1H，s)，7.40(1H，s)，8.40(1H，d)，8.66(1H，d)，10.40(1H，s).

LRMS：m/z 552(M+1)⁺

Preparation 71

4-Cyclopentylmethyl 4-methylbenzenesulfonate

To a solution of cyclopentanemethanol (1ml, 9.25mmol) in diethyl ether (25ml) was added p-toluenesulfonyl chloride (2.12g, 11.1mmol) and the solution was cooled in an ice/salt bath. Freshly ground potassium hydroxide (4.7g, 83.3mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 hours. The reaction was diluted with water, the phases separated and the aqueous layer extracted with ether. The combined organic solutions were dried (MgSO) ₄) Evaporation under reduced pressure gave the title compound as a clear oil, 2.18 g.

¹Hnmr(CDCl₃，400MHz)δ：1.20(2H，m)，1.55(4H，m)，1.74(2H，m)，2.20(1H，m)，2.43(3H，s)，3.92(2H，d)，7.36(2H，d)，7.80(2H，d).

LRMS：m/z 277(MNa⁺)

Preparation example 72

Methanesulfonic acid tetrahydro-2H-pyran-4-yl ester

To an ice-cold solution of tetrahydro-2H-pyran-4-ol (2.0g, 19.6mmol) and triethylamine (3.56ml, 25.5mmol) in dichloromethane (20ml) was added dropwise methanesulfonyl chloride (1.82ml, 23.5mmol) over 10 minutes, and the reaction was stirred at room temperature for 72 hours. The reaction system was washed with saturated aqueous sodium bicarbonate (10ml) and dried (MgSO)₄) Evaporation under reduced pressure gave an orange oil which solidified on standing, 3.1 g.

¹Hnmr(CDCl₃，400MHz)δ：1.88(2H，m)，2.03(2H，m)，3.01(3H，s)，3.55(2H，m)，3.95(2H，m)，4.90(1H，m).

LRMS：m/z 198(MNH4)⁺

Measured value: c, 39.90; h, 6.74.C₆H₁₂O₄S calculated value C, 39.99; h, 6.71 percent.

Preparation example 73

Cyclohexylmethane sulfonate

The title compound was prepared according to the procedure described for Tetrahedron 41, 17, 1985, 3447.

Preparation example 74

Methanesulfonic acid (1R) -1-methylpropyl ester

To an ice-cooled solution of (R) -2-butanol (4.0ml, 43.5mmol) and triethylamine (6.65ml, 47.8mmol) in dichloromethane (70ml) was added dropwise methyl acetate over 30 minutesSulfonic anhydride (8.33g, 47.8mmol) in dichloromethane (30 ml). The reaction was then allowed to warm to room temperature and stirred for 18 hours. The mixture was then washed with water, 2N hydrochloric acid and then dried (Na)₂SO₄) Evaporation under reduced pressure gave the title compound as a pale yellow oil, 7.0 g.

¹Hnmr(CDCl₃，300MHz)δ：0.98(3H，t)，1.40(3H，d)，1.62-1.80(2H，m)，3.00(3H，s)，4.76(1H，m).

Preparation example 75

Methanesulfonic acid (1S) -1-methylpropyl ester

Following the procedure described for preparation 74, the title compound was obtained as an oil in 54% yield from (S) -2-butanol and methanesulfonic anhydride.

¹Hnmr(CDCl₃，300MHz)δ：0.96(3H，t)，1.38(3H，d)，1.60-1.76(2H，m)，2.96(3H，s)，4.70(1H，m).

Preparation example 76

(2R) -1-methoxypropan-2-ol

Sodium methoxide (54g, 1.0mol) was added portionwise to ice-cooled methanol (1000ml), and the resulting solution was stirred in an ice bath for 20 minutes. (R) -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, acidified with 1M volatile hydrochloric acid under ice-cooling, and the resulting mixture was stirred for one hour and then filtered. The filtrate is dried (K)₂CO₃) Filtered and evaporated under reduced pressure. The residue was heated to 70 ℃ for 30 minutes on dry calcium oxide and then on a large scaleDistillation under atmospheric pressure gave the title compound as an oil, 25.4 g.

b.p.118-120℃

¹Hnmr(CDCl₃，300MHz)δ：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]_D-20.83 ° (c ═ 1.02, dichloromethane)

Preparation example 77

Methanesulfonic acid (1R) -2-methoxy-1-methylethyl ester

To a solution of the alcohol of preparation 76 (5.0g, 55mmol) in dichloromethane (100ml) was added triethylamine (8.5ml, 61mmol) and the solution was cooled in an ice/acetone bath. A solution of methanesulfonic anhydride (10.64g, 61mmol) in dichloromethane (50ml) was added dropwise over 30 min, and the reaction was stirred at room temperature for 18 h. The reaction mixture was washed with water and 2M hydrochloric acid and then dried (Na) ₂SO₄) Evaporation under reduced pressure gave the title compound, 2.77 g.

¹Hnmr(CDCl₃，300MHz)δ：1.39(3H，d)，3.03(3H，s)，3.38(3H，s)，3.44(2H，m)，4.87(1H，m).

Preparation example 78

Methanesulfonic acid (1S) -2-methoxy-1-methylethyl ester

S (-) -propylene oxide (17.58g, 0.30mol) was added dropwise over 45 minutes to a freshly prepared solution of sodium (7.0g, 0.30mol) in methanol (100ml) and the mixture was stirred at room temperature for 18 hours. The reaction was diluted with pentane (150ml) and acetic acid (17ml, 0.30mol) was added slowly. The resulting mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residual oil was distilled at 30Torr, and the fraction boiling at 30 ℃ was collected to give 3.3g of an oil containing about 30% methanol.

To a solution of this oil in dichloromethane (60ml) was added triethylamine (5.56ml, 0.04mol) and the solution was cooled in ice. A solution of methanesulfonic anhydride (7.03g, 0.04mol) in dichloromethane (30ml) was added dropwise over 30 minutes, and the reaction was stirred at room temperature for 18 hours. The mixture was washed with water and 2M hydrochloric acid and then dried (MgSO)₄) Evaporation under reduced pressure gave the title compound, 3.3g, which was used without further purification.

¹Hnmr(CDCl₃)，300MHz)δ：1.39(3H，d)，3.03(3H，s)，3.38(3H，s)，3.44(2H，m)，4.87(1H，m).

Preparation example 79

2-ethoxy-5-nitro-3-pyridinecarboxylic acid

A suspension of 2-ethoxy-3-pyridinecarboxylic acid (16.4g, 98mmol) and cesium carbonate (32g, 98mmol) in N, N-dimethylformamide (240ml) was stirred at room temperature for 2 hours. Ethyl iodide (7.85ml, 98mmol) was added and the reaction stirred for an additional 24 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between aqueous sodium carbonate (100ml) and ethyl acetate (100 ml). The phases were separated and the aqueous layer was extracted with ethyl acetate (2X 100 ml). The combined organic solution was washed with brine and dried (Na) ₂SO₄) Evaporation under reduced pressure gave ethyl ester, 18.0g, as a pale yellow oil.

To an ice-cooled solution of this oil (4.66g, 22.3mmol) in trifluoroacetic anhydride (50ml) was added ammonium nitrate (5.36g, 66mmol) in portions and the reaction was stirred at room temperature for 18 hours. The reaction mixture was carefully poured into ice water (200ml) and the resulting suspension was stirred for one hour. The precipitate was filtered off, washed with water and dried under suction to give the nitro ester as a solid, 3.29 g.

To a solution of this solid (5.1g, 20mmol) in ethanol (100ml) was added dropwise an aqueous sodium hydroxide solution (4ml, 5N, 20mmol) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue was suspended in water (50ml) and acidified to pH3 with hydrochloric acid. The aqueous solution was extracted with ethyl acetate (3X 100ml), the combined organic layers were washed with brine (100ml) and dried (Na)₂SO₄) Evaporation under reduced pressure gave a beige solid. The crude product was recrystallized from ethyl acetate/hexane to give the title compound, 3.32g, as beige crystals.

¹Hnmr(CDCl₃，300MHz)δ：1.55(3H，t)，4.78(2H，q)，9.17(1H，s)，9.23(1H，s).

Preparation example 80

4- (2-ethoxy-5-nitropyridin-3-ylcarboxamido) -3-ethyl-2- (2-methoxyethyl) pyrazole-5-carboxamide

A mixture of preparation 79 acid (4.46g, 21.0mmol), preparation 9 pyrazole (4.15g, 19.6mmol), 1-hydroxybenzotriazole hydrate (3.51g, 26.0mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.98g, 26.0mmol) and N-ethyldiisopropylamine (10.38ml, 60.0mmol) in dichloromethane (110ml) was stirred at room temperature for 18 h. The reaction was diluted with dichloromethane (100ml) and washed successively with water (70ml), 10% aqueous sodium bicarbonate (70ml) and brine (70ml) and then dried (Na) ₂SO₄) And concentrated under reduced pressure. The residual yellow solid was purified by column chromatography on silica gel using dichloromethane: methanol (95: 5) as eluent. The product was recrystallized from ethyl acetate to give the title compound as a pale yellow crystalline solid, 3.96 g.

¹Hnmr(CDCl₃，400MHz)δ：1.21(3H，t)，1.59(3H，t)，2.94(2H，q)，3.35(3H，s)，3.80(2H，t)，4.27(2H，t)，4.83(2H，q)，5.29(1H，brs)，6.62(1H，brs)，9.15(1H，d)，9.32(1H，d)，10.51(1H，brs).

LRMS：m/z 407.5(MH⁺)

Measured value: c, 50.21; h, 5.39; n, 20.66.C₁₇H₂₂N₆O₆Calcd for C, 50.24; h, 5.46; and N, 20.68 percent.

Preparation example 81

4- (5-amino-2-ethoxypyridin-3-ylcarboxamido) -3-ethyl-2- (2-methoxyethyl) pyrazole-5-carboxamide

A mixture of the nitro compound of preparation 80 (3.86g, 9.50mmol) and 10% palladium on carbon (200mg) in dichloromethane (75ml) and ethanol (25ml) was hydrogenated at 50psi and room temperature for 2 h. The mixture was diluted with dichloromethane then filtered through Solkafloc @, and the filtrate evaporated under reduced pressure to give the title compound, 3.63 g.

¹Hnmr(DMSOd₆，400MHz)δ：1.06(3H，t)，1.37(3H，t)，2.75(2H，q)，3.23(3H，s)，3.72(2H，t)，4.24(2H，t)，4.39(2H，q)，5.02(2H，brs)，7.25(1H，brs)，7.37(1H，brs)，7.70(2H，m)，10.33(1H，s).

LRMS：m/z 377.2(MH⁺)

Preparation example 82

5- (5-amino-2-ethoxypyridin-3-yl) -3-ethyl-2- (2-methoxyethyl) pyrazole-2, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidinone

A mixture of the amine from preparation 81 (2.53g, 6.72mmol) and potassium bis (trimethylsilyl) amide (5.56g, 27.9mmol) in ethanol (50ml) was heated in a sealed vessel at 120 ℃ for 8 h. The cooled mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using an elution gradient of ethyl acetate: ethanol (100: 0 to 96: 4) to give the title compound, 1.96 g.

¹Hnmr(CDCl₃，400MHz)δ：1.40(3H，t)，1.51(3H，t)，3.06(2H，q)，3.30(3H，s)，3.57(2H，brs)，3.90(2H，t)，4.45(2H，t)，4.55(2H，q)，7.77(1H，d)，8.18(1H，d)，11.03(1H，brs).

LRMS：m/z 359.1(MH⁺)

Preparation example 83

2-cyclobutyl-4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethylpyrazole-5-carboxamide

To a solution of the compound of preparation 34 (1.8g, 3.76mmol) in N, N-dimethylformamide (40ml) was added cesium carbonate (2.7g, 8.31mmol) followed by cyclobutylbromide (388. mu.l, 4.13mmol), and the reaction mixture was stirred at 60 ℃ for 3 days. The cooled solution was partitioned between ethyl acetate and sodium bicarbonate solution and the layers were separated. The aqueous phase was extracted with ethyl acetate (3 ×), and the combined organic solutions were dried (MgSO)₄) And evaporated under reduced pressure. The residual yellow solid was triturated with ether to give the title compound as a pale yellow powder, 762 mg.

¹Hnmr(CDCl₃)，400MHz)δ：1.00(3H，t)，1.20(3H，t)，1.57(3H，t)，1.88(2H，m)，2.40(4H，m)，2.52(4H，m)，2.70(2H，m)，2.82(2H，q)，3.08(4H，m)，4.78(3H，m)，5.24(1H，brs)，6.75(1H，brs)，8.62(1H，s)，8.81(1H，s)，10.50(1H，s).

Preparation examples 84 to 88

Following a similar procedure to that described in preparation 83, a compound of the following general structure was prepared from the compound of preparation 34 and the appropriate alkylating agent:

the product was purified by column chromatography eluting with methylene chloride in methanol (97: 3).

Preparation example 89

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- [ (1R) -1-methyl-2-methoxyethyl ] pyrazole-5-carboxamide

To a solution of the compound of preparation 34 (2.0g, 4.17mmol) in N, N-dimethylformamide (30ml) was added cesium carbonate (3.00g, 9.20mmol), and the mixture was stirred for 30 minutes. Methanesulphonate (0.77g, 4.58mmol) from preparation 78 was added and the reaction stirred at 60 ℃ for 8 hours. The cooled mixture was partitioned between ethyl acetate and water and the pH adjusted to 8 with solid carbon dioxide. The layers were separated. The aqueous phase was extracted with ethyl acetate (2 ×), and the combined organic extracts were dried (Na) ₂SO₄) And evaporated under reduced pressure. Purifying the crude product by silica gel column chromatographyAn elution gradient of methanol: dichloromethane (1: 99 to 8: 92) gave the title compound, 300 mg.¹Hnmr(CDCl₃，300MHz)δ：1.02(3H，t)，1.23(3H，t)，1.48(3H，d)，1.58(3H，t)，2.40(2H，q)，2.52(4H，m)，2.90(2H，m)，3.08(4H，m)，3.30(3H，s)，3.60(1H，m)，3.78(1H，m)，4.56(1H，m)，4.78(2H，q)，5.30(1H，brs)，6.66(1H，brs)，8.63(1H，d)，8.82(1H，d)，10.48(1H，s).

LRMS：m/z 552.3(MH⁺)

Preparation example 90

4- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-ylcarboxamido ] -3-ethyl-2- [ (1S) -1-methyl-2-methoxyethyl ] pyrazole-5-carboxamide

The title compound was obtained as an oil in 52% yield from the compound of preparation 34 and the mesylate of preparation 77 following the procedure described for preparation 89.

¹Hnmr(CDCl₃，300MHz)δ：1.01(3H，t)，1.22(3H，t)，1.48(3H，d)，1.58(3H，t)，2.40(2H，q)，2.54(4H，m)，2.90(2H，m)，3.08(4H，m)，3.30(3H，s)，3.61(1H，m)，3.78(1H，m)，4.56(1H，m)，4.78(2H，q)，5.25(1H，brs)，6.66(1H，brs)，8.63(1H，d)，8.82(1H，d)，10.48(1H，s).

LRMS：m/z 552.4(MH⁺)

Preparation examples 91 to 94

Following a similar procedure to that described in preparation 83, a compound of the following general structure was prepared from the compound of preparation 35 and the appropriate alkylating agent:

the 1 ═ is purified by silica gel column chromatography eluting with methylene chloride methanol (100: 0 to 98: 2).

Preparation example 95

2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinic acid

(a) 2-hydroxy-5-sulfonicotinic acid

2-Hydroxynicotinic acid (27kg, 194.2mol) was added dropwise over 1 hour to 30% oleum (58.1kg) at 50 ℃. This resulted in an exotherm to 82 ℃. The reaction mixture was further heated to 140 ℃. After 12 hours at this temperature, the contents of the kettle were cooled to 15 ℃ and filtered. The filter cake was then resuspended in acetone (33kg) at room temperature, filtered, and dried to give the title compound (35.3kg, 83%) as a white solid. The decomposition temperature is 273 ℃.

δ(DMSO_d6)：7.93(1H，d)，8.42(1H，d).m/z

(found value: 220[ M + H ]]⁺，100％.C₆H₆NO₆S calculated value 220.17).

(b) 2-hydroxy-5-sulfonicotinic acid ethyl ester

2-hydroxy-5-sulfonicotinic acid (500g, 2.28mol) was dissolved in ethanol (2.5L) with stirring and heated to 80 ℃. After 30 minutes, 0.5L of solvent was distilled off and then replaced with fresh ethanol (0.5L) and heated back to 80 ℃. After a further 60 minutes, 1.0L of solvent was distilled off, replaced by fresh ethanol (1.0L) and heated back to 80 ℃. After another 60 minutes, 1.0L of the solvent was distilled off, and the reaction system was cooled to 22 ℃ and stirred for 16 hours. Filtering the precipitated solidsThe body was washed with ethanol (0.5L) and dried under vacuum at 50 ℃ to give the title compound (416g, 74%) as a white solid. Decomposition temperature 237 ℃ Delta (DMSO)_d6): 1.25(3H, t), 4.19(2H, q), 7.66(1H, d), 8.13(1H, d). M/z (found: 248[ M + H ]]⁺， 100％.C₈H₁₀NO₆S calculated value 248.22).

(c) 2-chloro-5-chlorosulfonylnicotinic acid ethyl ester

Ethyl 2-hydroxy-5-sulfonicotinate (24.7g, 0.1mol) was suspended with stirring in thionyl chloride (238g, 2.0mol) and dimethylformamide (1.0 ml). The reaction mixture was then heated to reflux for 2.5 hours. Most of the thionyl chloride was removed in vacuo and the residual thionyl chloride was azeotroped with toluene to give the crude title compound (30.7g, 108%) as a yellow oil. d (CDCl) ₃): 1.46(3H, t), 4.50(2H, q), 8.72(1H, d), 9.09(1H, d). it was used directly in the following step.

(d) 2-chloro-5- (4-ethyl-1-piperazinylsulfonyl) nicotinic acid ethyl ester

Crude ethyl 2-chloro-5-chlorosulfonylnicotinate (30.7g, assuming 0.1mol) was dissolved in ethyl acetate (150ml) with stirring, followed by cooling with ice. A solution of N-ethylpiperazine (11.4g, 0.1mol) and triethylamine (22.5g, 0.22mol) in ethyl acetate (50ml) was carefully added thereto over 30 minutes, maintaining the internal temperature below 10 ℃. Once the addition was complete, the reaction was allowed to warm to 22 ℃ and stirred for 1 hour. The solid was filtered off and the remaining filtrate was concentrated in vacuo to give the crude title compound (37.1g, 103%) as a crude yellow gum. Delta (CDCl)₃)：1.10

(3H, t), 1.42(3H, M), 2.50(2H, M), 2.60(4H, M), 3.19(4H, M), 4.43(2H, q), 8.40(1H, d), 8.80(1H, d). M/z (found: 362[ M + H ] M/z)]⁺，100％.C₁₄H₂₁C_lN₃O₄S calculated value 362.85).

(e) 2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinic acid ethyl ester

A solution of ethyl 2-chloro-5- (4-ethyl-1-piperazinylsulfonyl) nicotinate (36.1g, 0.1mol) in ethanol (180ml) was cooled to 10 ℃ with stirring. Sodium ethoxide (10.2g, 0.15mol) was added in portions, maintaining the temperature below 20 ℃. The reaction mixture was then stirred at ambient temperature for 18 hours. The precipitate was filtered off, and water (180ml) was added to the filtrate. The filtrate was then heated to 40 ℃ for 1 hour. The ethanol (180ml) was then distilled off at ambient pressure and the remaining aqueous solution was cooled to ambient temperature. The precipitated solid was then filtered off, washed with water and dried under vacuum at 50 ℃ to give the title compound (12.6g, 34%) as a beige solid. M.p.66-68 ℃. delta. (cDCl) ₃): 1.04(3H, t), 1.39(3H, t), 1.45(3H, t), 2.41(2H, q), 2.52(4H, M), 3.08(4H, M), 4.38(2H, q), 2.57(2H, q), 8.38(1H, d), 8.61(1H, d). M/z (found: 372[ M + H, q ])]⁺，100％.C₁₆H₂₆N₃O₅S calculated value 372.46).

(f) 2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinic acid

Ethyl 2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinate (10.2g, 0.0275mol) was dissolved in toluene (50ml), to which was added a solution of sodium hydroxide (1.1g, 0.0275mol) in water (20 ml). The two-phase mixture was then stirred vigorously at ambient temperature overnight. The aqueous phase was separated and concentrated hydrochloric acid was added to adjust the pH to 5.6. The precipitated product was suspended under ice cooling for 15 minutes, filtered, washed with water and dried under vacuum at 50 ℃ to give the title compound as an incompletely white solid. Mpt 206-₃): 1.25(3H, t), 1.39(3H, t), 2.82(2H, q), 3.03(4H, M), 3.25(4H, M), 4.50(2H, q), 8.25(1H, d), 8.56(1H, d). M/z (found: 344[ M + H ])]⁺，100％.C₁₄H₂₂N₃O₅S calculated value 344.38).

This step 95(f) has been described in preparation example 23 of PCT/IB99/00519 (incorporated herein by reference).

Preparation example 96

N- [ 3-carbamoyl-5-ethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] -2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinamide

(a) 3-Ethyl-1H-pyrazole-5-carboxylic acid ethyl ester

To a stirred solution of 2, 2-dimethoxybutane (10g, 84.7mmol) in CH at 0 ℃ under nitrogen₂Cl₂To the solution (50ml) was added pyridine (13.7ml, 169.5 mmol). The reaction mixture was kept at 0 ℃ and trichloroacetyl chloride (18.9ml, 169.5mmol) in CH was added over 1 hour with constant stirring₂Cl₂(35ml) solution. As the reaction proceeded, a yellow-orange solution began to precipitate as a white solid. The reaction mixture was allowed to warm to room temperature over 20 hours. The reaction mixture was diluted with ethanol (150ml), cooled again to 0 ℃ and then treated with a solution of hydrazine hydrate (8.2ml, 169.5mmol) in ethanol (35ml) for 30 minutes. The reaction system was heated to 50 ℃ and the solvent was distilled off at atmospheric pressure. The temperature was increased until the heating temperature reached 78 ℃. Reflux was maintained for an additional 2 hours and then cooled to room temperature. The reaction mixture was diluted with water (250ml) and ethanol was removed by evaporation under reduced pressure. The obtained mixture is substituted by CH₂Cl₂Extraction (3X 200 ml). The combined organics were dried (MgSO)₄) Filtered and evaporated under reduced pressure to give the title compound as a brown oil, 12.05g, 85%.

¹H NMR(300MHz，CDCl₃)：δ＝1.20(3H，t)，1.28(3H，t)，2.67(2H，q)，4.29(2H，q)，6.55(1H，s)，12.56(1H，s).

LRMS m/z＝167.1[M-H]⁺，C₈H₁₂N₂O₂Calculated 168.2.

(b) 3-ethyl-1H-pyrazole-5-carboxylic acid

To a stirred suspension of the title compound (66.0g, 0.39mol) of preparation 96(a) in methanol was added dropwise an aqueous solution (10M, 100ml, 1.0mol) of sodium hydroxide, and the resulting solution was heated under reflux for 4 hours. The cold reaction mixture was concentrated under reduced pressure to about 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 by suction to give the title compound (34.1 g). Delta (DMSO) _d6)：1.13(3H，t)，2.56(2H，q)，6.42(1H，s).

(c) 4-nitro-3-n-propyl-1H-pyrazole-5-carboxylic acid

Oleum (17.8ml) was added to stirred, ice-cooled fuming nitric acid (16.0ml), the resulting solution was heated to 50 ℃ and then 3-n-propyl-1H-pyrazole-5-carboxylic acid (chem. pharm. Bull. (chemical and pharmaceutical bulletin), 1984, 32, 1568; 16.4g, 0.106mol) was added in portions over 30 minutes while keeping the reaction temperature below 60 ℃. The resulting solution was heated at 60 ℃ for 18 hours, cooled, and then poured onto ice. The white precipitate was collected, washed with water and dried by suction to give the title compound (15.4 g).

m.p.170-172 ℃, found: c, 42.35; h, 4.56; n, 21.07.C₇H₉N₃O₄Calcd C, 42.21; h, 4.55; n, 21.10%. Delta (DMSO)_d6)：0.90(3H，t)，1.64(2H，m)，2.83(2H，m)，14.00(1H，s).

(d) 3-ethyl-4-nitro-1H-pyrazole-5-carboxylic acid

Obtained as a brown solid (64%) from the title compound of preparation 96(b) by a method similar to preparation 96 (c).

δ(DMSO_d6)：1.18(3H，t)，2.84(2H，m)，13.72(1H，s).

(e) 4-nitro-3-n-propyl-1H-pyrazole-5-carboxamide

A solution of the title compound of preparation 96(c) (15.4g, 0.077mol) in thionyl chloride (75ml) was heated at reflux for 3 hours, then the cold reaction mixture was evaporated under reduced pressure. The residue was azeotroped with tetrahydrofuran (2X 50ml), followed by suspension in tetrahydrofuran (50ml), and the suspension was stirred, 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 was triturated with water and dried by suction to give the title compound (14.3 g).

m.p.197-199 ℃ measured: c, 42.35; h, 5.07; n, 28.38.C₇H₁₀N₄O₃Calcd C, 42.42; h, 5.09; n, 28.27%. delta. (DMSO)_d6)：0.90(3H，t)，1.68(2H，m)，2.86(2H，t)，7.68(1H，s)，8.00(1H，s).

(f) 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide

Obtained as a white solid (90%) from the title compound of production 96(d) by a method similar to production 96 (e). Delta (DMSO)_d6)：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)⁺.

(g) (i) 5-Ethyl-1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxamide

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (2.5kg, 13.6mol), sodium carbonate (1.8kg, 17.0mol) and 2-bromoethylmethyl ether (1.98kg, 14.2mol) in THF (22.5L) and water (2.5L) was heated under reflux and stirred for 20 hours. The mixture was cooled to ambient temperature and CH was added₂Cl₂(67.5L) and water (22.5L). The resulting organic and aqueous layers were separated. CH for aqueous phase₂Cl₂(22.5L) and the combined organic solutions were distilled at atmospheric pressure and replaced with ethyl acetate (33L) to a final volume of 17L. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (2.5L). 5-Ethyl-1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxamide was obtained as a white crystalline solid, 2.10kg, 57%.

m.p. 140 ℃. found: c, 44.46; h, 5.79; n, 23.01.C ₉H₁₄N₄O₄Calcd C, 44.63; h, 5.79; n, 23.14 percent.

δ(CDCl₃)：1.18(3H，t)，2.98(2H，q)，3.22(3H，s)，3.77(2H，t)，4.28(2H，q)，6.03(1H，s)，7.36(1H，s).

LRMS：m/z＝243(M+1)⁺

(g) (ii) 5-Ethyl-1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxamide

A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25g, 0.136mol), sodium carbonate (18g, 0.17mol) and sodium iodide (20.4g, 0.136mol) was suspended in methyl ethyl ketone (125ml) at room temperature. 2-Bromoethylmethyl ether (12.8ml, 0.142mol) was added and the mixture was heated to reflux and stirred for 70 h. The mixture was cooled to ambient temperature and water (250ml) was added. The resulting slurry was warmed to reflux, held at that temperature for 30 minutes, and then cooled to room temperature. The resulting precipitate was granulated at room temperature for 3 hours, filtered and dried in vacuo to give 5-ethyl-1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid, 24.3g, 74%. Data are reported in preparation 96(g) (i).

(h) 4-amino-5-ethyl-1- (2-methoxyethyl) -1H-pyrazole-3-carboxamide

A mixture of 5-ethyl-1- (2-methoxyethyl) -4-nitro-1H-pyrazole-3-carboxamide (20g, 82.6mmol) and 5% Pd/C (1g) in methanol (200ml) was stirred in a sealed vessel at 50psi/25 ℃ for 15H. At the end of the reaction, the mixture was filtered through Arbocel and the filter cake was washed with methanol. The methanol solution was distilled off at atmospheric pressure and replaced with ethyl acetate to a final volume of 100 ml. The cooled mixture was granulated at ambient temperature for 2 hours, filtered and washed with ethyl acetate (20ml) to give 4-amino-5-ethyl-1- (2-methoxyethyl) -1H-pyrazole-3-carboxamide as a white crystalline solid, 15g, 88%.

m.p. 131 ℃. found: c, 50.75; h, 7.62; n, 26.38.C₉H₁₆N₄O₂Calcd for C, 50.94; h, 7.55; n, 26.42 percent.

δ(CDCl₃)：1.20(3H，t)，2.63(2H，q)，3.32(3H，s)，3.74(2H，t)，3.95(2H，s)，4.15(2H，t)，5.27(1H，s)，6.59(1H，s).

LRMS：m/z＝213(M+1)⁺

(i) N- [ 3-carbamoyl-5-ethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] -2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinamide

2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinic acid (2.31kg, 6.73mol) was suspended in ethyl acetate (16.2L) and 1, 1-carbonyldiimidazole (1.09kg, 6.73mol) was added at room temperature. The reaction mixture was heated at 45 ℃ for 40 minutes, then the reaction system was stirred at reflux for another 40 minutes. After cooling to ambient temperature, 4-amino-5-ethyl-1- (2-methoxyethyl) -1H-pyrazole-3-carboxamide (1.5kg, 7.06mol) was added to the cooled mixture and the reaction was stirred under reflux for a further 15 hours. The mixture was cooled, filtered and the filter cake was washed with 90% water/10% ethyl acetate (2ml/g) to give N- [ 3-carbamoyl-5-ethyl-1- (2-methoxyethyl) -1H-pyrazol-4-yl ] -2-ethoxy-5- (4-ethyl-1-piperazinylsulfonyl) nicotinamide as an incompletely white crystalline solid, 3.16kg, 88%. m.p. 156 ℃.

Measured value: c, 51.33; h, 6.56; n, 18.36.C₂₃H₃₅N₇O₆S calculated C, 51.40; h, 6.53; n, 18.25 percent.

δ(CDCl₃)：1.04(3H，t)，1.22(3H，t)，1.60(3H，t)，2.44(2H，q)，2.54(4H，m)，2.96(2H，q)，3.12(4H，m)，3.36(3H，s)，3.81(2H，t)，4.27(2H，t)，4.80(2H，q)，5.35(1H，s)，6.68(1H，s)，8.66(1H，d)，8.86(1H，d)，10.51(1H，s).

LRMS：m/z＝539(M+1)⁺

In addition, according to the present invention, intermediate compounds (XIV) and (XB) (as depicted in schemes 2 and 3) can be prepared from the commercially available starting material (2-hydroxynicotinic acid) in better yields than the corresponding reaction procedure in PCT/IB 99/00519. For example, compound (XIV) was produced in 14.5% yield in preparation 18 of PCT/IB99/00519 (i.e., from the reaction procedures of preparations 1, 3, 5, 7 and 18), whereas the same compound was produced according to the present invention in 23% yield (see preparation 95). More preferably, all or part of the reaction sequence used to form compounds (XIV) and (XB) can be stacked together according to the present invention to provide better yields. Thus, compound (XB) was prepared in 35% yield (see preparation 95 herein) where X is OEt. Furthermore, the reaction scheme of the present invention is safer and more economical to operate, and involves fewer steps (and process time) in the case of a cascade process.

It will be appreciated that the formation of the compounds of formula (XB) and (XIV) from (XV), respectively, is a separate invention, preferably prepared from 2-hydroxynicotinic acid, as described herein. Likewise, each of the steps of schemes 2 and 3 (and the nesting step) are independent inventions, although in preferred aspects, the compounds of formulae (I), (IA) and (IB) are prepared from nicotinic acid according to schemes 2 and 3.

Thus in a further aspect of the invention, the compound of formula (XVII) is formed in a solvent, in SO₃In the presence of (a), reacting 2-hydroxynicotinic acid or a salt thereof.

Claims

1. A compound of formula (I):

R¹Is C₁To C₆Alkyl, wherein if R¹Is C₁To C₃An alkyl group, said alkyl group being substituted with a substituent selected from the group consisting of; if R is¹Is C₄To C₆Alkyl, said alkyl is optionally substituted with one substituent selected from the group consisting of: a hydroxyl group; c₁To C₄An alkoxy group; c₃To C₆A cycloalkyl group; NR (nitrogen to noise ratio)⁷R⁸；CONR⁷R^8’(ii) a A tetrahydrofuranyl group; tetrahydropyranyl and pyrazolyl; or R¹Is C₃To C₆A cycloalkyl group; azetidinyl, in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl and C₁To C₆Substituted with alkanoyl; piperidinyl in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl radical, C₁To C₆Alkanoyl and C₁To C₆Substituted with an alkylsulfonyl group; phenyl, wherein the phenyl is optionally selected from nitro, amino, C₁To C₆Alkyl sulfonic amino and cyano; a pyridyl group; a pyrazinyl group; a thiazolyl group; pyrimidinyl optionally substituted with halo; and benzoxazolyl;

R⁷is hydrogen or C₁To C₄An alkyl group;

R^8’is hydrogen or C ₁To C₄An alkyl group;

R²is C₁To C₆An alkyl group;

R¹³is OR³Or pyrrolidinyl;

R⁴is piperazin-1-ylsulfonyl wherein the 4-position of the piperazinyl group is substituted by R¹⁰Is substituted in which

R¹⁰Is H or C₁To C₄An alkyl group.

2. A compound according to claim 1, wherein R¹Is C₁To C₆Alkyl, wherein the alkyl may be branched or straight chain, or R¹Is C₃To C₆A cycloalkyl group,

wherein if R is¹Is C₁To C₃Alkyl, said alkyl is substituted with one of the following substituents;

wherein if R is¹Is C₄To C₆Alkyl, said alkyl is optionally substituted with one of the following substituents;

the substituents are selected from:

a hydroxyl group;

C₁to C₄An alkoxy group;

C₃to C₅A cycloalkyl group;

NR⁷R⁸or CONR⁷R^8’；

A tetrahydrofuranyl group; a tetrahydropyranyl group; a pyrazolyl group;

wherein R is⁷、R⁸And R^8’Is as defined in claim 1;

or R¹Is azetidinyl, wherein the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl and C₁To C₆Substituted with alkanoyl; piperidinyl in which the nitrogen atom is optionally selected from hydrogen, C₁To C₆Alkyl radical, C₁To C₆Alkanoyl and C₁To C₆Substituted with an alkylsulfonyl group; a pyridyl group; a pyrazinyl group; a thiazolyl group; or pyrimidinyl optionally substituted with one halogen; r ¹³Is OR³(ii) a Wherein R is³Is C₁To C₆Alkyl radical, C₁To C₆Alkoxy radical C₁To C₆Alkyl, phenyl-C₁To C₆Alkyl, pyridyl-C₁To C₆Alkyl, or tetrahydrofuryl-C₁To C₆An alkyl group.

3. A compound according to claim 2, wherein R¹Is C₁To C₆Alkyl, wherein the alkyl may be branched or straight chain, or R¹Is C₃To C₆Cycloalkyl, wherein if R¹Is C₁To C₃Alkyl, said alkyl is substituted with one of the following substituents; wherein if R is¹Is C₄To C₆Alkyl, said alkyl being optionally substituted with one of the following substituents;

the substituents are selected from:

a hydroxyl group;

C₁to C₂An alkoxy group;

C₃to C₄A cycloalkyl group;

NR⁷R⁸；

a tetrahydrofuranyl group; a tetrahydropyranyl group; a pyrazolyl group;

4. A compound according to claim 3, wherein

R¹Is- (CH)₂)_n(C₃-C₅) Cycloalkyl, wherein n is 0, 1, 2 or 3; or

R¹Is covered by a C₁To C₄Alkoxy-substituted methyl, ethyl, i-propyl or n-propyl, wherein the alkoxy substituent may be directly attached to any C-atom within the ethyl, i-propyl or n-propyl group;

or R¹Is C selected from iso-, n-, sec-or tert-butyl₄Alkyl, optionally substituted with one substituentThe substituents are selected from C₁To C₄Alkoxy or C₃To C₄A cycloalkyl group;

R²is C₁To C₄An alkyl group;

R¹³is OR³Wherein R is³Is optionally covered by a C₁To C₄Alkoxy-substituted C₁To C₄An alkyl group;

5. A compound according to claim 4, having general formula (IA) or (IB):

wherein R is¹Is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₅) Cycloalkyl, wherein n is 0; or

R¹Is- (CH)₂)_n(C₅) Cycloalkyl, wherein n is 1; or

R¹Is methyl, ethyl, i-propyl or n-propyl substituted by methoxy, ethoxy, n-propoxy or i-propoxy, wherein the alkoxy substituent may be attached directly to any C-atom within the ethyl, i-propyl or n-propyl group; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R¹³Is OR³Wherein R is³Alkyl is methyl, ethyl, n-propyl, i-butyl, n-butyl, sec-butyl or tert-butyl which is optionally substituted by one methoxy, ethoxy, n-propoxy or i-propoxy group;

R⁴is 4-methyl-or 4-ethyl-piperazin-1-ylsulfonyl.

6. A compound according to claim 5, having the general formula (IB):

R¹is- (CH)₂)_n(C₃-C₄) Cycloalkyl, wherein n is 1 or 2; or

R¹Is- (CH)₂)_n(C₃-C₅) Cycloalkyl, wherein n is 0; or

R¹Is- (CH)₂)_n(C₅) Cycloalkyl, wherein n is 1; or

R¹Is iso-, n-, sec-or tert-butyl;

R²is C₂To C₄An alkyl group;

R⁴is 4-methyl-or 4-ethyl-piperazin-1-ylsulfonyl.

7. A compound according to any of claims 1 to 4 selected from:

5- [ 2-ethoxy-5- (4-ethylpiperazin-1-ylsulfonyl) pyridin-3-yl ] -3-ethyl-1- (2-methoxyethyl) -1, 6-dihydro-7H-pyrazolo [4, 3-d ] pyrimidin-7-one, or

and pharmaceutically acceptable salts or polymorphs thereof.

8. A compound according to claim 1 selected from 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine and salts thereof.

9. A compound according to claim 1 which is 1- { 6-ethoxy-5- [ 3-ethyl-6, 7-dihydro-2- (2-methoxyethyl) -7-oxo-2H-pyrazolo [4, 3-d ] pyrimidin-5-yl ] -3-pyridylsulfonyl } -4-ethylpiperazine.

10. A pharmaceutical composition which comprises a compound of formula (I), (IA) or (IB) as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate or prodrug, according to any one of claims 1 to 9, in association with a pharmaceutically acceptable diluent or carrier.

11. A veterinary formulation comprising a compound of formula (I), (IA) or (IB) as defined in any one of claims 1 to 9 or a veterinarily acceptable salt, or a veterinarily acceptable solvate or prodrug according to any one of claims 1 to 9 in association with a veterinarily acceptable diluent or carrier.

12. Use of a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or prodrug thereof, according to any one of claims 1 to 9, for the manufacture of a human medicament for the cure or prevention of a medical condition for which a type 5 cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase inhibitor is indicated.

13. Use of a compound of formula (I), (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof according to any one of claims 1 to 9 for the manufacture of a medicament for animals for the cure, alleviation or prevention of medical conditions in which a type 5 cyclic guanosine 3 ', 5' -monophosphate phosphodiesterase inhibitor is indicated.

14. Use of a compound of formula (I), (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or prodrug thereof, according to any one of claims 1 to 9, for the manufacture of a human medicament for the cure, alleviation or prevention of male erectile dysfunction, impotence, female sexual dysfunction, clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction.

15. Use of a compound of formula (I), (IA) or (IB) or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate or prodrug thereof according to any one of claims 1 to 9 for the manufacture of a veterinary medicament for the cure, alleviation or prevention of male erectile dysfunction, impotence, female sexual dysfunction, clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic dysfunction.

16. A compound of formula (IX):

wherein R is^PR as defined in claim 1¹³Or R is^PIs a leaving group X, i.e. may be of the formula-NR⁵R⁶Any radical substituted by amino or alkoxy of, R¹，R²And R⁴As defined in claim 1, R⁵And R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached, forms azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

17. A process for the preparation of a compound of formula (I):

wherein R is¹、R²、R¹³And R⁴The definition of the method is the same as that of claim 1,

the process comprises the cyclisation of a compound of formula (IX):

wherein R is^PIs R¹³Or R is^PIs a leaving group X, i.e. may be of the formula-NR⁵R⁶Any radical substituted by amino or alkoxy of, R ¹、R²、R⁴And R¹³As defined in claim 1, R⁵And R⁶Each independently of the otherIs selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, wherein the cyclization is base-mediated using an alkali metal salt of a sterically hindered alcohol or amine,

wherein said cyclization reaction is optionally followed by the formation of a pharmaceutically or veterinarily acceptable salt of the desired product or a pharmaceutically or veterinarily acceptable solvate or prodrug of the desired product.

18. A process for the preparation of a compound of formula (I):

wherein R is¹、R²And R⁴As defined in claim 1, R¹³OR as defined in claim 1³The process comprising the conversion of a compound of formula (XXX):

wherein X is a leaving group, i.e. may be of the formula-NR⁵R⁶Any radical substituted by amino or alkoxy of, R⁵And R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, R¹、R²And R⁴The definition of the method is the same as that of claim 1,

wherein said conversion reaction is optionally followed by the formation of a pharmaceutically or veterinarily acceptable salt of the desired product or a pharmaceutically or veterinarily acceptable solvate or prodrug of the desired product.

19. A compound of general formula (XXX):

wherein R is¹、R²And R⁴As defined in claim 1, wherein X is a leaving group, i.e. a group of the formula-NR⁵R⁶Any radical substituted by amino or alkoxy of, R⁵And R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached, forms azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

20. A process for preparing a compound of formula (I) from a compound of formula (IXB) via the following actions:

i) (IXB) cyclization to (XXX) followed by substitution from (XXX) to (I);

ii) cyclization from (IXCa) to (XXX), followed by replacement from (XXX) to (I);

iii) a permutation from (IXB) to (IXC) followed by a cyclization from (IXC) to (I); and

iv) a substitution from (IXCa) to (IXC) followed by a cyclization from (IXC) to (I), wherein compounds (XXX) and (IXCa) have the following general formula:

wherein R is¹、R²And R⁴Definition of claim 1, OR^3aIs an alkoxy group which is different from the desired OR on the final compound of formula (I)³A group, and may be OR as desired³Group replacement wherein R^3aSelected from optionally substituted C₁To C₆Alkyl, X is a leaving group, i.e. may be of the formula-NR ⁵R⁶Any radical substituted by amino or alkoxy of, R⁵And R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, and wherein compounds (IXB) and (IXC) have the general formula:

wherein R is¹、R²、R³And R⁴As defined in claim 1, X is a leaving group, i.e. may be of the formula-NR⁵R⁶Any radical substituted by amino or alkoxy of, R⁵And R⁶Each independently selected from H and optionally C₃To C₅Cycloalkyl or C₁To C₄Alkoxy-substituted C₁To C₄Alkyl, or together with the nitrogen atom to which they are attached form azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, or

v) (IXB) is directly cyclized to (I).