ZA200202723B - 5-(2-substituted-5-heterocyclylsulphonylpyrid-3-yl)-dihydropyrazolo[4,3-D]pyrimidin-7-ones as phosphodiesterase inhibitors. - Google Patents

Description

5-(2-SUBSTITUTED-5-HETEROCYCLYLSULPHONYLPYRID-3-YL)-DIHYDROPYRAZOLO[4 3-D]

PYRIMIDIN-7-ONES AS PHOSPHODIESTERASE INHIBITORS ’

Field of the Invention s This invention relates to pharmaceutically useful compounds, in particular compounds which are useful in the inhibition of cyclic guanosine 3',5" monophosphate phosphodiesterases (cGMP PDEs), such as type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases (cGMP PDES). The - compounds therefore have utility in a variety of therapeutic areas, including male erectile dysfunction (MED).

Prior Art

EP-A-0636626 relates to a class of pyrazolo[3,4-d]-pyrimidone compounds and their use as inhibitors of cGMP specific PDE. A series of 6- phenylpyrazolo[3,4-d]pyrimidinones, their synthesis and their cyclic GMP phosphodiesterase inhibitory activity are described in J. Med. Chem., 1996, 39, 1635-1644. International patent application WO 96/16657 discloses the use of certain pyrazolo[3,4-dJpyrimidinone compounds (amongst others) in the treatment of MED.

EP-A-0526004 describes certain pyrazolo[4,3-djpyrimidinone compounds as antianginal agents. International patent application WO 94/28902 discloses the use of certain pyrazolo[3,4-dJpyrimidinone compounds (amongst others) in the treatment of MED.

. ~-2--

Disclosure of the Invention

According to the present invention, there is provided a compound of general formula I: . 0]

R{ R'

X Po

N= | SN . a R

R* or a pharmaceutically or veterinarily acceptable salt and/or solvate thereof, wherein

X represents O or NR®

R' represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, C(O)OR®, C(O)NR'R'’, NR"R" and SO,NR"R')

R? represents H, halo, cyano, nitro, OR®, OC(O)R’, C(O)R’,

C(O)OR®, C(O)NR'R", NR'?R'"®, SO,NR"R'®, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R’,

C(O)OR®, C(O)NR'"R'', NR'?R™ and SO,NR'“R")

R® represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),

OR’, OC(O)R’, C(O)R®, C(O)OR°, C(O)NR"R', NR'R™ and

SO.NR"R"™)

R* représents H, halo, cyano, nitro, halo(loweralkyl), OR®, OC(O)R’,

C(O)R®, C(O)OR®, C(ONR™R', NR'?R'™, NR'Y(O)R", N[Y(O)R""].,

SOR'®. SO,R'®, C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally s substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®,

C(O)OR®, C(O)NR™R"’, NR™?R"™ and SONR'‘R")

Y represents C or S(O)

A represents lower alkylene

Z represents OR®, halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from : halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®,

C(0)OR®, C(O)NR'°R"', NR'R' and SONR"R'™)

R' and R'' independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),

OR®, OC(O)R”, C(O)R®, C(O)OR®, C(ONR'®R"**, NR'?R'®, SO,NR"R"® and NR2°S(0),R?! or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R'® and R'' may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl

R' and R'™ independently represent R'® and R'' as defined above, except that they do not represent groups that include lower alkyl,

Het or aryl, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more

C(O)NR'™R"'* and/or NR'?R"® groups .

R'2 and R™ independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR®, C(O)OR®, C(O)NRZR® and NR*R®), 50 one of R'2 or R'® may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R' and R" together represent i WO 01/27112 PCT/IB00/01430 . co = 4 - : Ca. alkylene (which alkylene group is optionally unsaturated, optionally substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR*®)

R' and R' independently represent H or lower alkyl or R' and

R', together with the nitrogen atom to which they are bound, form a heterocyclic ring

R' and R'” independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR®, C(O)OR®, C(O)NR#®R® and NR*R%) or one of R'® and R'” may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl :

R®, R®, BR’, R¢, R®, R'®, R'®, R?, R%, R®, R* and R®’ independently represent H or lower alkyl

R'® and R'® independently represent lower alkyl

R?' represents lower alkyl or aryl

R? represents H, lower alkyl, aryl, C(O)R? or S(0).R**

R? represents H, lower alkyl or aryl

R? represents lower alkyl or aryl

Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen, sulpfur and mixtures thereof which compounds are referred to together hereinafter as “the compounds of the invention”.

The term “aryl”, when used herein, includes six- to ten-membered carbocyclic aromatic groups, such as phenyl and naphthyl, which groups are optionally substituted with one or more substituents selected from aryl (which group may not be substituted by any further aryl groups), lower alkyl, Het, halo, cyano, nitro, OR’, OC(O)R’, C(O)R’, C(O)OR’

C(O)NR'™@R'*®, NR'*R"* (wherein R'* and R'* independently represent

R'2 and R' as hereinbefore defined, except that: (i) they do not represent

C(O)Het in which Het is substituted by one or more substituents that include one or more C(O)NR'®R''? and/or NR'?*R'* groups; or (ii) they do not together represent Cs; alkylene interrupted by NR?) and

SO.NR"R'™.

S oo

The term “Het”, when used herein, includes four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain one or more heteroatoms selected from nitrogen, oxygen, sulfor and mixtures thereof, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The ring systems may be monocyclic, bicyclic or fused. Each “Het” group identified herein is optionally substituted by one or more substituents selected from : halo, cyano, nitro, oxo, lower alkyl (which alkyl group may itself be optionally substituted or terminated as defined below), OR®, OC(O)R’, : 15 C(O)R®, C(O)OR®, C(O)NR'®R'"®, NR'*R'* and SO.,NR'R™. The term thus includes groups such as optionally substituted azetidinyl, pyrrolidinyl, imidazolyl, indolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxatriazolyl, thiatriazolyl, pyridazinyi, morpholinyl, pyrimidinyl, pyrazinyl, pyridinyl, quinolinyl, isoquinolinyl, piperidinyl, pyrazolyl imidazopyridinyl and piperazinyl. Substitution at Het may be at a carbon atom of the Het ring or, where appropriate, at one or more of the heteroatoms. “Het” groups may also be in the form of an N-oxide.

The heterocyclic ring that R'* and R'® (together with the nitrogen atom to which they are bound) may represent may be any heterocyclic ring that contains at least one nitrogen atom, and which ring forms a stable structure when attached to the remainder of the molecule via the essential nitrogen atom (which, for the avoidance of doubt, is the atom to which R' and R'® are attached). In this respect, heterocyclic rings that R'* and R™

. = 6 . (together with the nitrogen atom to which they are bound) may represent include four- to twelve-membered, preferably four- to ten-membered, ring systems, which rings contain at least one nitrogen atom and optionally contain one or more further heteroatoms selected from nitrogen, oxygen 5s and/or sulfur, and which rings may contain one or more double bonds or be non-aromatic, partly aromatic or wholly aromatic in character. The term thus includes groups such as azetidinyl, pyrrolidinyl, imidazolyl, indolyl, isoazoyl, oxazoyl, triazolyl, tetrazolyl, morpholinyl, piperidinyl, pyrazolyl and piperazinyl. -

The term “lower alkyl” (which includes the alkyl part of alkylHet and alkylaryl groups), when used herein, means C,. alkyl and includes methyl, ethyl, propyl, butyl, pentyl and hexyl groups. Unless otherwise specified, alkyl groups may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, and/or be substituted by one or more halo atoms. Preferred lower alkyl groups for use herein are C1.3 alkyl groups. Alkyl groups which

R, R2, R®, R*, RS, RE, R, RS, RY, RY, R". R™, R", R™ R', R'6 RY, R'®

R" R® RY RZ RZ R* R® R¥®, RY and R*® may represent, and with which R', BR? R®, R%, R™®, R"", R'3, R"™, R'®, R", aryl, alkylaryl, alkylHet and Het may be substituted, may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, be cyclic, acyclic or part cyclic/acyclic, be interrupted by one or more of oxygen, sulfur and optionally alkylated or optionally acylated nitrogen and/or be substituted by one or more halo atom. The terms “lower alkenyl” and “lower alkynyl”, when used herein, include C..s groups having one or more double or triple carbon-carbon bonds, respectively.

Otherwise, the terms “lower alkenyl” and “lower alkynyl” are defined in the same way as the term “lower alkyl”. Similarly, the term “lower alkylene”, when used herein, includes Cis groups which can be bonded at two i places on the group and is otherwise defined in the same way as “lower alkyl”. The term “acyl” includes C(O)-lower alkyl.

The terms “alkylHet” and “alkylaryl” include Ci.s alkyiHet and C6 alkylaryl.

The alkyl groups (e.g. the C..s alkyl groups) of alkylHet and alkylaryl may, when there is a sufficient number of carbon atoms, be linear or branched, be saturated or unsaturated, and/or be interrupted by oxygen. When used in this context, the terms “Het” and “aryl” are as defined hereinbefore.

Substituted alkylHet and alkylaryl may have substituents on the ring and/or on the alkyl chain.

Halo groups with which the above-mentioned groups may be substituted or terminated include fluoro, chloro, bromo and iodo.

Compounds of general formula (I) can be represented by formulae IA and iB: 0) 1 O

R { R., N \

X HN | N X HN = N=R"

NS ——

N= | N \ NZ | SN \

R

NS NS R

R* R* (1A) (1B) wherein R', R%, R®, R* and X are as defined hereinbefore.

The pharmaceutically or veterinarily acceptable salts “of the compounds of the invention which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Examples include the HCI,

. Ce } HBr, HI, sulphate or bisulphate, nitrate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, saccarate, fumarate, maleate, lactate, citrate, tartrate, gluconate, camsylate, methanesulphonate, ethanesulphonate, benzenesulphonate, p-toluenesulphonate and pamoate salts. Compounds of the invention can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali and alkaline earth metal salts, with bases. Examples include the sodium, potassium, aluminium, calcium, magnesium, zinc and diethanolamine salts. For a review on suitable pharmaceutical salts see Berge et al, J.

Pharm, Sci., 66, 1-19, 1977.

The pharmaceutically acceptable solvates of the compounds of the invention include the hydrates thereof.

Also included within the scope of the compound and various salts of the invention are polymorphs thereof.

A compound of the formula (I) contains one or more asymmetric carbon atoms and therefore exists in two or more sterecisomeric forms.

Where a compound of the formula (I) contains an alkenyl or alkenylene group, cis (E) and trans (Z) isomerism may also occur. The present invention includes the individual stereoisomers of the compounds of the formula (1) and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof. Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of the formula (I) may also be prepared from a corresponding optically pure intermediate or by resolution, such as by H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.

All stereoisomers are included within the scope of the invention.

A preferred group of compounds according to a further aspect of the invention, are compounds of formulae |, IA and IB as hereinbefore defined, wherein:

R' represents H, lower alkyl, Het, alkyiHet, or alkylaryl (which latter four groups are all optionally substituted and/or terminated with one or more substituents selected from cyano, lower alkyl, OR®, C(O)OR® or

NR'2R"); t R? represents H, halo, lower alkyl, Het or aryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents as defined hereinbefore, and preferably with NR'’R™ or

SO,NR'"R");

R? represents Cy-C, alkyl or C3-C4 cycloalkyl which are optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR’, OC(O)R’, C(O)R",

C(O)OR?, C(O)NR™R", NR'R"® and SO:NR"R");

R* represents halo, cyano, nitro, C(O)R®, C(O)OR®, C(O)NR'R"’, 2s NR™R'™, N[Y(O)R'],, NR'®Y(O)R'’, SOR'®, SO;R", C(O)AZ, lower alkyl, lower alkynyl, Het or aryl, which latter three groups are all optionally substituted and/or terminated with one or more substituents as defined hereinbefore; and wherein Y, A, Z, R® , R"', R'} R",R",R", R, R", R’,

RE R’, R?, R%, R'®, R' and Het are as herein before defined.

CL -- 10 --

Further preferred compounds herein are those in which R' represents optionally substituted lower alkyl, more preferably lower alkyl, lower alkoxy-terminated lower alkyl, NR'?R'>-terminated lower alkyl, or A- morpholino-terminated lower alkyl. Alternatively, R' may represent a 4- piperidinyl or a 3-azetidinyl group, optionally substituted at the nitrogen atom of the piperidinyl group with lower alkyl or C(O)OR®.

In such further preferred compounds of the invention, R? represents

C(O)NR'™R'', NR'2R'", lower alkyl optionally interrupted by one or more of

O, S or N, optionally substituted at N by lower alkyl or acyl, or optionally substituted aryl or Het. More preferably, when R? is interrupted lower alkyl, the interrupting atoms are one or more of O and lower alkylated-N and when RZ is aryl, it is optionally substituted phenyl or pyridyl.

Particularly preferred compounds of the invention are those in which R? represents C(O)NR'R'", NR'?R'®, C,. alkyl optionally interrupted by O or

N, optionally substituted at N by lower alkyl, optionally substituted phenyl, or optionally substituted pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazin-2- yl, pyrazol-4-yl, oxadiazol-2-yl, furan-2-yl, furan-3-yl, tetrahydrofuran-2-yl and imidazo[1,2-a)pyridin-6-yl.

In the further and particularly preferred compounds of the invention, R® may represent lower alkyl or cycloalkyl. Also, X is preferably O. -

Such further and particularly preferred compounds of the invention have

R* representing halo, lower alkyl, lower alkynyl, optionally substituted Het, optionally substituted aryl, C(O)R®, C(0)AZ, C(O)OR®, C(O)NR'R",

NR'™R" or NR'®Y(O)R"”. More preferred values for R* are C(O)R® (e.g. acetyl), halo (e.g. iodo), SOR (wherein R'® represents lower alkyl) and

C(O)NR'™R'"' (e.g. where R' and R'' independently represent H and lower alkyl and/or one of R™® and R'is lower alkoxy) or NHB, wherein B represents H, SO,CH3 or C(O)Het.

Further preferred compounds of the invention include those in which R* : s represents iodo, lower alkyl, lower alkynyl (which latter two groups are substituted and/or terminated by C(O)OR® (wherein R® represents H or

Cis alkyl), N(H)Y(O)R', N[Y(O)R'],, optionally substituted Het or

NR'™R" (wherein R'2 and R'® together represent Cas alkylene interrupted by O or N-S(O).-(optionally substituted aryl).

Compounds of the invention that are more preferred still are include those in which R* represents N(H)Y(O)R'’ (wherein R'’ represents Ci. alkyl optionally substituted and/or terminated by C(O)OH or C(O)O-lower alkyl). : 15 Preferred compounds of the invention include the compounds of

Examples 1 to 87 described hereinafter (excluding the preparative examples). More preferred compounds include the compounds of

Examples 1, 20, 22, 24, 32, 34, 44a, 44b, 44c, 63, 64, 65, 66, 67, and 85 and the compounds of Examples 5, 16, 17, 21, 26, 29, 47, 48, 49, 50, 50a, 51, 51a, 59, 68, 70, 71, 73, 74, 75, 77, 79, 80, 84, 86, 87, 89, 91, 92, 113, 114,116, 118 - 128, 130 — 136, 138, 140, 143.

Highly preferred compounds herein include the following: 5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-1-(2-methoxyethyl)-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-lodo-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7 H- pyrazolo[4,3-d]pyrimidin-7-one; 5-(2-Butoxy-5-iodo-3-pyridinyl)-2-[2-(4-morpholinyl)ethyl]-3-ethyl-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one;

tert-Buty! 4-[5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro -2H- pyrazolo[4,3-d]pyrimidin-2-yl}-1-piperidinecarboxylate; tert-Butyl 3-[5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-7-ox0-6,7-dihydro -2H- B pyrazolo[4,3-djpyrimidin-2-yl]-1-azetidinecarboxylate; 5-(2-Propoxy-5-iodo-3-pyridinyl)-3-ethyl-7-ox0-6,7-dihydro-2H-pyrazolo- [4,3-d]pyrimidin-5-yl]nicotinate; tert-Butyl [3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro- 1 H-pyrazoto[4,3-d]pyrimidin-1-ylJacetate; tert-Butyl [3-ethyi-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-

2H-pyrazolo[4,3-d]pyrimidin-2-ylJacetate; [3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-1H- : pyrazolo[4,3-d]pyrimidin-1-ylJacetic acid; [3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H- pyrazolo[4,3-d]pyrimidin-2-ylJacetic acid;

5-(2-Propoxy-5-iodo-3-pyridinyl)-1-methyl-3-propyi-1,6-dihydro-7 H- pyrazolo[4,3-d]pyrimidin-7-one; 2-[2-(Dimethylamino)ethyl}-5-(2-ethoxy-5-iodo-3-pyridinyl)-3-ethyl-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 6-Butoxy-5-[3-ethyl-2-(2-methoxyethyl)-7-oxo-6,7-dihydro-2 H-pyrazolo[4,3-

dpyrimidin-5-yl}-N-methoxy-N-methylnicotinamide; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-

7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-Acetyl-2-(2-methoxy-1-methylethoxy)-3-pyridinyl]-3-ethyl-2-(2- methoxyethyl)-2,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-

7 H-pyrazolo[4,3-d]pyrimidin-7-one;

6-Isobutoxy-N, N-dimethyl-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-

pyrazolo[4,3-d}pyrimidin-5-yl)nicotinamide;

5-(5-Glycoloyl-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7 H- pyrazolo[4,3-d]pyrimidin-7-one;

5-(5-Acetyl-2-butoxy-3-pyridinyl)-2-{2-(dimethylamino)ethyl]-3-ethyl-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-2-[2-(4-morpholinyl)ethyi]-3-ethyl-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Acetyl-2-butoxy-3-pyridiyl)-2-[2-(4-piperidinyl)ethyl}-3-ethyl-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; - tert-Butyl 4-[2-(5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro- 2H-pyrazolo[4,3-d]pyrimidin-2-yl)ethyl}-1 -piperidinecarboxylate; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -methyl-4-piperidinyl)-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; - [5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro-1H- pyrazolo[4,3-d]pyrimidin-1-yl]acetic acid; - 5-(1-Methyl-7-oxo-3-propyi-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)- — 6-propoxynicotinonitrile; 1-Methyl-5-[2-propoxy-5-(1H-tetrazol-5-yl)-3-pyridinyl]-3-propyi-1,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(3-Hydroxy-5-isoxazolyl)-2-propoxy-3-pyridinyl]-1 -methyl-3-propyl-1,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Amino-2-propoxy-3-pyridinyl)-1-methyl-3-propyl-1 ,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one; {{5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5-yl)- 6-propoxy-3-pyridinyl]Jamino}acetic acid;

N-[5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyljmethanesulfonamide;

N-[5-(1-Methyl-7-ox0-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyl}-3-oxo-3-alanine; ({[5-(1-Methyl-7-oxo-3-propy!-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinylJamino}sulfonyl)acetic acid;

N-[5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyl]alanine;

] | 14 - 5-{2-[2-(Dimethylamino)ethyl}-3-ethyl-7-oxo0-6,7-dihydro-2H-pyrazolo-[4,3- dlpyrimidin-5-yl}-6-ethoxynicotinic acid; and 5-{2-[2-(Dimethylamino)ethyl]-3-ethyl-7-oxo-6,7-dihydro-2H-pyrazolo-{4,3- d]pyrimidin-5-yl}-6-ethoxy-N-methoxy-N-methyinicotinamide.

An especially preferred group of compounds according to the present ‘invention have the general formula (I) wherein:

X represents O or NR%;

R' represents lower alkyl or alkylHet, which are optionally substituted and/or terminated with one or more substituents selected from lower alkyl, or NR'R";

R? represents lower alkyl, Het or aryl which are optionally substituted and/or terminated with one or more substituents .as defined hereinbefore;

R® represents C4-C,4 alkyl or C5-C,4 cycloalkyl which are optionally substituted and/or terminated with one or more OR® substitutents;

R* represents halo, cyano, C(O)R®, C(O)NR'R', NR™R®,

NR'®Y(O)R', SOR" or aryl, wherein said aryl group is optionally substituted and/or terminated with one or more substituents as defined herienbefore; and wherein Y, A, Z,R",R", R%R®, RR" RR’ PR,

R'® and Het are as herein before defined.

The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formulae 1, 1A and IB, and mixtures thereof, are included within the scope of the invention.

The compounds of the invention may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereomers, as well as mixtures thereof. The individual stereoisomers

-15-- i of the compounds of formulae IA and IB, as well as any mixtures thereof, are included within the scope of the invention. Diastereoisomers may be separated using conventional techniques e.g. by fractional crystallisation or chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques e.g. fractional crystallisation or HPLC. The desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation. Alternatively, the desired optical isomers may be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base. All stereoisomers are included within the scope of the invention.

Also included within the scope of the invention are radiolabelled derivatives of compounds of formulae |, IA and IB which are suitable for biological studies.

The present invention additionally provides compounds of the general formulae (IA) and (IB) or a pharmaceutically or veterinarily acceptable salts and/or solvates thereof, wherein

X represents O or NR®

R' represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl, which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, C(O)OR’, C(O)NR™R'!, NR'?R" and SO.NR"R"

R? represents H, halo, cyano, nitro, OR®, OC(O)R’, C(O)R®,

C(O)OR®, C(O)NR'R", NR'?R'®, SO:NR'R"™, lower alkyl, Het, alkyiHet, aryl or alkylaryl, which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR’, OC(O)R’, C(O)R’,

C(O)OR®, C(O)NR™R"!, NR'?R" and SO,NR"R"

R® represents H, lower alkyl, alkylHet or alkylaryl, which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),

OR®, OC(O)R’, C(O)R?, C(O)OR®, C(O)NR™R'", NR'*R" and SO.NR"R"

R* represents H, halo, cyano, nitro, halo(loweralkyl), OR®, OC(O)R’, 0 C(O)R®, C(O)OR®’, C(O)NR'™R', NR'R®™, NR™Y(O)R", SOR",

SO,R'R?, C(0)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl, which latter seven groups are ali optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR”, OC(O)R’, C(O)R®, 1s C(O)OR®, C(O)NR™R'', NR'?R" and SO.NR"R"

Y represents C or S(O), wherein one of R'® and R'” is not present when Y is S(O)

A represents lower alkylene

Z represents ORS, halo, Het or aryl, which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR", OC(O)R’, C(O)R’,

C(O)OR®, C(O)NR'R", NR'2R" and SO.NR"R"

RS, R, R’, R?, R°, R'®, R'® and R? independently represent H or lower alkyl

R' and R'' independently represent H or lower alkyl, which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl),

OR®, OC(O)R’, C(O)R®, C(O)OR®, C(O)NR'R"!, NR™*R"® and SO.NR'"R'® or Het or aryl optionally substituted with one or more of said latter eleven groups or one of R' and R'' may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl

R'? and R" independently represent H or lower alkyl or one of R' or R'™ may be C(O)Jower alkyl or C(O)Het in which Het is optionally substituted with tower alkyl

R™ and R'® independently represent H or lower alkyl or R'* and R™, 5s together with the nitrogen atom to which they are bound, form a heterocyclic ring

R'® and R" independently represent H or lower alkyl or one of R™® and R'7 may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl

Het represents an optionally substituted four to twelve membered heterocyclic group, which may be aromatic or non-aromatic, which may : contain one or more double bonds, which may be mono- or bi-cyclic and which contains one or more heteroatoms selected from N, S and O

Preparation

According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.

The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention: 1. Compounds of formulae |, IA and IB may be prepared by cyclisation of corresponding compounds of formulae I, IIA and IIB, respectively: 0

R’ H,N 1

XO 2 : N

NZ” | N )

R

R* ll

Claims (28)

Claims

1. A compound of general formula I: o R R' X XC NS

R* . 5 ora pharmaceutically or veterinarily acceptable salt and/or solvate thereof, wherein X represents O or NR® a. R' represents H, lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, C(O)OR®, C(O)NR'R'', NR'*R™ -and SO.NR"R") R? represents H, halo, cyano, nitro, OR’, OC(O)R’, C(O)R®, C(O)OR®, C(O)NR™R"", NR"R", SO,NR'R", lower alkyl, Het, alkylHet, aryl or alkylaryl (which latter five groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR’, OC(O)R’, C(O)R’, C(O)OR®, C(O)NR™R"', NR'?R" and SO.NR"R") R® represents H, lower alkyl, alkylHet or alkylaryl (which latter three groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, C(O)OR®, C(O)NRR", NR™R" and

SO.NR"R'") R* represents H, halo, cyano, nitro, halo(loweralky), OR®, OC(O)R’, 25s C(O)R®, C(O)OR®, C(O)NR™R', NR™R'™, NR'Y(O)R”, N[Y(O)R"L,

: SOR'®, SO,R', C(O)AZ, lower alkyl, lower alkenyl, lower alkynyl, Het, alkylHet, aryl, alkylaryl (which latter seven groups are all optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®,

s C(O)OR’, C(O)NR™R", NR'?R" and SO.NR'R") Y represents C or S(O) A represents lower alkylene : Z represents OR®, halo, Het or aryl (which latter two groups are both optionally substituted with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, . C(O)OR®, C(O)NR™R!!, NR'?R"® and SO.NR"‘R") R'" and R'' independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from halo, cyano, nitro, lower alkyl, halo(loweralkyl), OR®, OC(O)R’, C(O)R®, C(O)OR®, C(O)NR'®R'"®, NR'>R'’, SO,NR™R" and NR?°S(0).R®' or Het or aryl optionally substituted with one or more of said latter thirteen groups) or one of R'® and R'' may be lower alkoxy, amino or Het, which latter two groups are both optionally substituted with lower alkyl R'% and R'™ independently represent R'® and R'' as defined above, except that they do not represent groups that include lower alkyl, Het or any, when these three groups are substituted and/or terminated (as appropriate) by one or more substituents that include one or more C(O)NR'™@R'"® and/or NR'?R® groups R' and R'® independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR®, C(O)OR®, C(O)NRZR® and NR*‘R*), one of R' or R'® may be C(O)-lower alkyl or C(O)Het (in which Het is optionally substituted with lower alkyl), or R'? and R'® together represent Cs;7 alkylene (which alkylene group is optionally unsaturated, optionally

189 -- N substituted by one or more lower alkyl groups and/or optionally interrupted by O or NR®) oo ~~ R™ and R' independently represent H or lower alkyl or R™ and R', together with the nitrogen atom to which they are bound, form a heterocyclic ring R'® and R'” independently represent H or lower alkyl (which latter group is optionally substituted and/or terminated with one or more substituents selected from OR®, C(O)OR®, C(O)NRZR? and NR*R*) or one of R'® and R'” may be Het or aryl, which latter two groups are both optionally substituted with lower alkyl RS, R®, R’, R, R%, R", R"®, R?, R%, R®, R* and R®® independently represent H or lower alkyl R'® and R'? independently represent lower alkyl R?' represents lower alkyl! or aryl RZ represents H, lower alkyl, aryl, C(O)R¥ or S(0).R*® R¥ represents H, lower alkyl or aryl ~ R® represents lower alkyl or aryl R Het represents an optionally substituted four- to twelve-membered heterocyclic group, which group contains one or more heteroatoms selected from nitrogen, oxygen and/or sulfur with the provisos: () that R* is not NH; when: R' is Cy.; alkyl optionally substituted with 2s phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted by one or more substituents selected from C,.4 alkoxy; halo; CN; CF3, OCF; or Cy4 alkyl wherein said C.4 alkyl group is optionally substituted by C1. haloalkyl or C14 haloalkoxy either of which is substituted by one or more halo atoms; and R? is Cy alkyl;

. (ii) that R* is not NHz or NO; when: X is O; and R? is H, halo, optionally substituted lower alkyl, OR®, C(O)NR'R", C(O)OR®, NR'?R", NHC(0)- lower alkyl, cyano, aryl, alkylaryl, Het or alkylHet (which latter four groups are optionally substituted); and (ii) that R* is not H when: X is O; and R? is H, optionally substituted lower alkyl, OR®, C(O)NR'™R'", C(O)OR®, NR'R'®, NHC(O) - lower alkyl, cyano, aryl, alkylaryl, Het or alkylHet (which latter four groups are optionally substituted).

2. Compound as claimed in Claim 1, wherein R' represents optionally substituted lower alkyl.

3. Compound as claimed in Claim 2, wherein R' is lower alkyl, lower alkoxy-terminated lower alkyl, NR'’R'>-terminated lower alkyl, or N- morpholino-terminated lower alkyl.

4. Compound as claimed in Claim 1,wherein R' represents a 4- piperidinyl group, optionally substituted at the nitrogen atom of the piperidinyl group with lower alkyl or C(O)OR®.

5. Compound as claimed in any one of Claims 1 to 4, wherein R? represents C(O)NR'R'', NR'?R'?, lower alkyl optionally interrupted by one or more of O, S or N, optionally substituted at N by lower alkyl or acyl, or optionally substituted aryl or Het.

6. Compound as claimed in Claim 5, wherein R? represents C(O)NR'™R"', NR'R'™, Ci alkyl optionally interrupted by O or N, optionally substituted at N by lower alkyl, optionally substituted phenyl, or optionally substituted pyridin-2-yl, pyridin-3-yl, pyrimidin-5-yl, pyrazin-2-yl, pyrazol-4-yl, oxadiazol-2-yl, furan-2-yl, furan-3-yl, tetrahydrofuran-2-yl and imidazo[1,2-a]pyridin-6-yl.

191 -- N

7. Compound as claimed in any one of Claims 1 to 6, wherein R® represents lower alkyl.

s 8. Compound as claimed in any one of Claims 1 to 7, wherein X is O.

9. Compound as claimed in any one of Claims 1 to 8, wherein R* represents halo, optionally substituted Het, optionally substituted aryl, C(O)R®, C(0)AZ, C(O)OR’, C(O)NR™R"!, NR'R™ or NR'6Y(O)R".

10. Compound as claimed in Claim 9, wherein R* is COCH3 or NHB, wherein B represents H, SO,CHs or C(O)Het.

11, Compound as claimed in any one of Claims 1 to 8, wherein R* represents iodo, lower alkyl, lower alkynyl (which latter two groups are substituted and/or terminated by C(O)OR® (wherein R® represents H or Cis alkyl), N(H)Y(O)RY, N[Y(O)R']., optionally substituted Het or NR'2R"™ (wherein R'2 and R'® together represent Ca alkylene interrupted by O or N-S(O).-(optionally substituted aryl).

12. Compound as claimed in Claim 11, wherein R* represents N(H)Y(O)R" (wherein R"’ represents Cis alkyl optionally substituted and/or terminated by C(O)OH or C(O)O-lower alkyl) or lower alkynyl terminated by C(0)O-C14 alkyl.

13. Compound as claimed in Claim 1, which is: 5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7 H- pyrazolo[4,3-d]pyrimidin-7-one; : 5-(2-Butoxy-5-iodo-3-pyridinyl)-3-ethyl-1 -(2-methoxyethyi)-1,6-dihydro-7H- pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-lodo-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7 H- pyrazolo{4,3-d]pyrimidin-7-one;

5-(2-Butoxy-5-iodo-3-pyridinyl)-2-[2-(4-morpholinyl)ethyl]-3-ethyl-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; tert-Butyl 4-[5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro -2H- pyrazolo[4,3-d]pyrimidin-2-yl]-1-piperidinecarboxylate;

tert-Butyl 3-[5-(2-butoxy-5-iodo-3-pyridinyl)-3-ethyl-7-ox0-6,7-dihydro -2H- pyrazolo[4,3-d]pyrimidin-2-yl}-1-azetidinecarboxylate; 5-(2-Propoxy-5-iodo-3-pyridinyl)-3-ethyl-7-ox0-6,7-dihydro-2 H-pyrazolo- [4,3-d]pyrimidin-5-yl]nicotinate; tert-Butyl [3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-

1H-pyrazolo[4,3-d]pyrimidin-1-yl]acetate; tert-Butyl [3-ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro- 2H-pyrazolo[4,3-d]pyrimidin-2-ylJacetate, [3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-1 H- pyrazolo[4,3-d)pyrimidin-1-ylJacetic acid,

[3-Ethyl-5-(5-iodo-2-propoxy-3-pyridinyl)-7-oxo-6,7-dihydro-2H- pyrazolo[4,3-d]pyrimidin-2-yljacetic acid; 5-(2-Propoxy-5-iodo-3-pyridinyl)-1-methyl-3-propyl-1,6-dihydro-7 H- pyrazolof4,3-d]pyrimidin-7-one; 2-[2-(Dimethylamino)ethyl]-5-(2-ethoxy-5-iodo-3-pyridinyl)-3-ethyl-2,6-

dihydro-7H-pyrazolo[4,3-d}pyrimidin-7-one; 6-Butoxy-5-[3-ethyl-2-(2-methoxyethyl)-7-oxo-6,7-dihydro-2H-pyrazolo{4,3- djpyrimidin-5-yl]-N-methoxy-N-methylnicotinamide; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-

7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-Acetyl-2-(2-methoxy-1-methylethoxy)-3-pyridinyl]-3-ethyl-2-(2- methoxyethyl)-2,6-dihydro-7 H-pyrazolof4,3-d]pyrimidin-7-one; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-1-(2-methoxyethyl)-1,6-dihydro-

7 H-pyrazolo[4,3-d}pyrimidin-7-one; 6-Isobutoxy-N, N-dimethyl-5-(2-methyt-7-oxo-3-propyl-6,7-dihydro-2H- pyrazolo[4,3-d]pyrimidin-5-yl)nicotinamide;

CA 93 5-(5-Glycoloyl-2-isobutoxy-3-pyridinyl)-2-methyl-3-propyl-2,6-dihydro-7 H- pyrazolo[4,3-d]pyrimidin-7-one; : 5-(5-Acetyl-2-butoxy-3-pyridinyl)-2-[2-(dimethylamino)ethyl}-3-ethyl-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5s 5-(5-Acetyl-2-butoxy-3-pyridinyl)-2-[2-(4-morpholinyl)ethyl}-3-ethyi-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Acetyl-2-butoxy-3-pyridiyl)-2-[2-(4-piperidinyl)ethyi]-3-ethyi-2,6- dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; tert-Butyl 4-[2-(5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro-

2H-pyrazolo[4,3-ad]pyrimidin-2-yl)ethyl]-1-piperidinecarboxylate; 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-methyl-4-piperidinyl)-2,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; [5-(5-Acetyl-2-propoxy-3-pyridinyl)-3-ethyl-7-oxo-6,7-dihydro-1H- pyrazolo[4,3-d]pyrimidin-1-ylJacetic acid; 5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo{4,3-d}pyrimidin-5-yl)- 6-propoxynicotinonitrile; 1-Methyl-5-[2-propoxy-5-(1H-tetrazol-5-yl)-3-pyridinyl]-3-propyl-1,6- dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(3-Hydroxy-5-isoxazolyl)-2-propoxy-3-pyridinyl]-1-methyl-3-propyl-1,6-

dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-(5-Amino-2-propoxy-3-pyridinyl)-1-methyl-3-propyi-1,6-dihydro-7H- pyrazolof4,3-d)pyrimidin-7-one;

{{5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro- 1 H-pyrazolo[4,3-d]pyrimidin-5-yl)- 6-propoxy-3-pyridinyljJamino}acetic acid;

N-[5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyljmethanesulfonamide; N-[5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyl]-3-oxo-f-alanine; } ({{5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-

yl)-6-propoxy-3-pyridinyljamino}sulfonyl)acetic acid;

N-{5-(1-Methyl-7-oxo-3-propyl-6,7-dihydro-1 H-pyrazolo[4,3-d]pyrimidin-5- yl)-6-propoxy-3-pyridinyl]alanine; 5-(2-{2-(Dimethylamino)ethyi]-3-sthyl-7-0x0-6, 7-dihydro-2H-pyrazolo-4,3- d]pyrimidin-5-yi}-6-ethoxynicotinic acid; or 5-{2-{2-(Dimethylamino)ethyl]-3-ethyi-7-oxo-6,7-dihydro-2H-pyrazolo-{4,3- d]pyrimidin-5-yi}-6-ethoxy-A-methoxy-N-methyinicotinamide.

14. Compound as defined in any one of Claims 1 to 13 without the provisos for use as a pharmaceutical.

15. Compound as defined in any one of Claims 1 to 13 without the provisos for use as an animal medicament.

16. A formulation comprising a compound as defined in any one of Claims 1 to 13 without the provisos in admixture with a pharmaceutically or veterinarily acceptable adjuvant, diluent or carrier.

17. A formulation as claimed in Claim 16, which is a pharmaceutical formulation. oo :

18. A formulation as claimed in Claim 16, which is a veterinary formulation.

19. The use of a compound as defined in any one of Claims 1 to 13 without the provisos in the manufacture of a medicament for the curative or prophylactic treatment of a medical condition for which inhibition of cGMP PDES is desired.

20. Use of a compound as claimed in any one of Claims 1 to 13 without the provisos, for treating or preventing AMENDED SHEET }

- 195 —~ a medical condition for which inhibition of cGMP PDES is desired.

21. Use as claimed in Claim 19 or 20, wherein the condition is male erectile dysfunction (MED), impotence, female sexual dysfunction (FSD), clitoral dysfunction, female hypoactive sexual desire disorder, female sexual arousal disorder, female sexual pain disorder or female sexual orgasmic : dysfunction (FSOD),

22. A process for the preparation of a compound of formula |, as defined in Claim 1, which comprises: : (a) cyclisation of a corresponding compound of formula Il:

Ry . ley

N .

NX . _ R* oo ; oo wherein R', R?, R®, R* and X are as defined in Claim 1; (b) for compounds of formula I in which R’ represents lower alkyl, Het, aryl, Het, aryl, alkylHet or alkylaryl (which latter five groups are all optionally substituted as defined hereinbefore in respect of RY), alkylation of a corresponding compound of formula 1, in which R! represents H; (c) conversion, removal or introduction of a substituent on an aryl, ora Het, group in, or on the phenylpyridinyl, or pyrazolo, unit of, a compound of formula I; (d) conversion of one R® group to another by alkoxide exchange or amino exchange for alkoxide; (e) reaction of corresponding compounds of formulae Vili; AMENDED SHEET -

C196 -- . , O R R' > N X HN OXF x N= | N \ NS R L vill wherein L is a leaving group and R', R?, R® and X are as previously defined for compounds of formula |, with a compound containing a group R*® which is capable of exchanging for L; (f) deprotection of a protected derivative of a compound of formula |; (g) for compounds of formula I, in which R represents C(O)NR'R, and R' and R'! are as defined previously for compounds of formula |, reaction of corresponding compounds of formula |, in which R? represents C(O)OH (or a carboxylic acid derivative thereof) with a compound of formula HNR"R", in which R" and R'' are as previously defined for compounds of formula I; (h) for compounds of formula I, in which R® represents C(O)OR’, cyclisation of corresponding compounds of formula VI: 0) HN 1 N R XR? O © hk OFpel 7 0 R4 Vi 1s wherein R', R®, R* and X are as defined previously for compounds of formula 1, and R®* represents an optionally substituted lower alkyl group, as defined hereinbefore, followed by removal of the alkyl group R®™™ (if required) by hydrolysis and/or (if required) exchange with a further | : optionally substituted alkyl group; (i) for compounds of formula |, in which R? represents optionally substituted lower alkyl (which alkyl group is branched and unsaturated at s the carbon atom that is attached to the rest of the molecule), NR'*R'™, cyano, aryl or Het (which Het group is either aromatic or unsaturated at the carbon atom that is attached to the rest of the molecule), by cross- coupling of corresponding compounds of formula XXIV:

0 1 XR3 IS i ©) NTN or Hal R4 XXIV wherein Hal represents Cl, Br or I, and R', R®, R* and X are as defined in

Claim 1, using a compound of formula

RM wherein R® represents optionally substituted lower alkyl (which alkyl group is branched and unsaturated at the carbon atom that is attached to M),

1s NR'™R™, cyano, aryl or Het (which Het group is either aromatic or unsaturated at the carbon atom that is attached to M), R'? and R' are as defined in Claim 1 and M represents an optionally substituted metal or boron group, which group is suitable for cross-coupling reactions; or (j) for compounds of formulae IA and IB in which R? represents lower acyl,

lower alkoxycarbonyl or lower alkynyl, by a cross-coupling reaction between corresponding compounds of formula XXIV, respectively, as defined above, and a reagent or reagents capable of delivering the lower acyl, lower alkoxycarbonyl! or lower alkynyl group (or groups equivalent to these).

23. A compound of formula IIA, or of formula IIB, as defined in Claim 22.

24. Use as claimed in Claim 21, wherein the condition is male erectile dysfunction (MED).

25. A compound as claimed in Claim 1 or 23, substantially as herein described and exemplified.

26. A formulation as claimed in Claim 16, substantially as herein described and exemplified.

27. Use as claimed in Claim 19 or 20, substantially as herein described and exemplified. ]

28. A process as claimed in Claim 22, substantially as herein described and exemplified. : AMENDED SHEET