WO2012046030A2

WO2012046030A2 - Phosphodiesterase inhibitors

Info

Publication number: WO2012046030A2
Application number: PCT/GB2011/051872
Authority: WO
Inventors: Sylvie Gomez Bateman; Ilona Jurkiewicz; Gesine Johanna Hermann; Ian Timothy William Matthews; Jonathan Peter Kirby; Elena Hernández LÓPEZ; Manisha Samar Kulkarni; Peter Edwards; William Richard King; Howard Christopher Thomas; Mark Richard Thursz; Israel Conesa Lerma
Original assignee: Riotech Pharmaceuticals Ltd
Priority date: 2010-10-07
Filing date: 2011-10-03
Publication date: 2012-04-12
Also published as: GB201016880D0; WO2012046030A3

Abstract

The present invention relates to novel 2'5' –phosphodiesterase inhibitory compounds, to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of a variety of medical conditions.

Description

PHOSPHODIESTERASE INHIBITORS

The present invention relates to novel 2' 5 ' -phosphodiesterase inhibitory compounds, to pharmaceutical compositions comprising these compounds and to the use of these compounds in the treatment of a variety of medical conditions.

The mammalian body has an antiviral function in the form of the 2-5A system during which 2' 5 ' -phosphodiesterase is produced. In the 2-5 A system cells produce 2' 5-oligoadenylate synthetases which, in the presence of double stranded RNA, convert ATP to 2' 5 ' -linked oligoadenylates. The 2' 5 ' -linked oligoadenylates induce the activation of RNase L, a ribonuclease which, upon activation, destroys all RNA within the cell (both cellular and viral) .

The 2' 5 ' - linked oligoadenylates also give rise to the production of 2' 5 ' - phosphodiesterase and AMP as a competing reaction.

The 2-5A system is also successful in providing antitumor activity.

The 2-5 A system is activated by interferons . Interferons (IFNs) are proteins produced by the cells of the immune system in response to the presence of double-stranded RNA, a key indicator of viral infection. In the field of medicine interferons have antiviral, antiseptic and antioncogenic properties when administered as drugs and Interferon therapy is used as a treatment for many cancers (in combination with chemotherapy and radiation) and viruses such as hepatitis C. The interferons administered amplify the effect of the 2-5A system in the body by increasing the amount of RNase L produced. When used in the systemic therapy, interferons are mostly administered by an intramuscular injection.

Interferons commonly give rise to adverse side effects such as flu-like symptoms : increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness , hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Interferon therapy causes immunosuppression, in particular through neutropenia and can result in some infections manifesting in unusual ways .

It is therefore an object of the invention to provide further compounds that can amplify the effects of the 2-5 A system found in the body.

According to a first aspect of the invention there is provided a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein

Rl represents an -A-carbocyclic group or -A-heterocyclic group, Ci_ ₈alkyl, C₂.₆alkenyl, C₂.₆alkynyl, - (CH₂)_n-0- (CH₂)_m-OH, - (CH₂)_n-0- (CH₂)_m- NH₂, - (CH₂)_n-0- (CH₂)_m-NHR⁵ , - (CH₂)_n-0-(CH₂)_m-NR⁵ ₂, - (CH^-CHRR¹ , or an affinity reagent to allow cellular and gel localisation of the PDE-12 ; R2 represents an -A-carbocyclic group;

R3 represents an -A-carbocyclic group, an -A-heterocyclic group or d- ₅alkyl; and

R4 represents H, an -A-carbocyclic group or Ci_₃alkyl, wherein any one or more of said carbocyclic groups or heterocyclic groups may be optionally substituted by one or more of halogen, -OH, d- ₃alkyl, -0-C_1-3alkyl, -O-CO-R⁴, = 0 , -NH₂, -NHR⁵ , -NR⁵ ₂ or -N0₂;

A is a bond or - (CH₂)_n- ;

R and R¹ independently represent an -A-carbocyclic group, H, -NR²R³ or -NR²C-0-d.₃alkyl;

R² and R³ independently represent H, d.₃alkyl, -C-0-Ci.₅alkyl, -C-O-Ci.

₅alkylhalide or -C (0) -0-d.₅alkyl;

R⁴ represents d.₅alkyl or -CHR⁵R⁶;

R⁵ represents d.₄alkyl or d.₄alkylhalide;

R⁶ represents -NR²R³ ; and

n and m independently represent an integer from 1 to 4.

When Rl represents an -A-carbocyclic group, the carbocyclic group may be phenyl. Alternatively the carbocyclic group may be a C₃.₈ cycloalkyl group, for example a C₃ or a C₅ or a C₆ cycloalkyl group. The carbocyclic group may be unsubstituted or it may be substituted with one or more of halogen, -OH and -0-Ci_₃alkyl.

In one embodiment Rl represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl. In another embodiment Rl represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted once with halogen and the halogen may be chlorine. The halogen may be substituted at the 4 position.

In a another embodiment Rl represents an -A-carbocyclic group, A represents -(CH₂)„- and the carbocyclic group is phenyl. In this embodiment n may represent 1 or 2. In another embodiment Rl represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted once with -0-Ci_₃alkyl, for example -OCH₃. The -O-C^alkyl group, for example -OCH₃, may be substituted at the 4 position. In another embodiment Rl represents an -A-carbocyclic group, A represents represents -(CH₂)„- and the carbocyclic group is phenyl substituted once with -O-C^alkyl, for example -OCH₃. In this embodiment n may represent 1 or 2. The -O-C^alkyl group may be substituted at the 3 position, alternatively the -O-C^alkyl group may be substituted at the 4 position. The -O-C^alkyl group may be -OCH_3.

In a still further embodiment Rl represents an -A-carbocyclic group, A represents a bond. The carbocyclic group may be a C₃.₈ cycloalkyl group, for example cyclopropyl or cyclopentyl.

In a still further embodiment Rl represents an -A-carbocyclic group, A represents -(CH₂)„-, where n is 1 or 2. The carbocyclic group may be a C₃.₈ cycloalkyl group, for example a C₃ or a C₅ or a C₆ cycloalkyl group. When Rl represents an -A-heterocyclic group, the heterocyclic group may have five or six members and may include one or more of nitrogen, oxygen and sulphur or a combination thereof. When Rl represents an -A-heterocyclic group, A may represent a bond or -(CH₂)„-, where n is 1 , 2 or 3.

When Rl represents an -A-heterocyclic group, the heterocyclic group may be unsubstituted or it may be substituted with one or more Ci_₃alkyl.

In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have six members including one oxygen and one nitrogen. In this embodiment A represents -(CH₂)„- where n is 2. In this embodiment the heterocyclic group may be a morpholinyl group, for example a morpholin-4-yl group.

In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have six members including one nitrogen, for example pyridine. In this embodiment A represents -(CH₂)„- where n is 1. In this embodiment the heterocyclic group may be a pyridin-2-yl, a pyridin-3-yl or a pyridin-4-yl group. In one embodiment the heterocyclic group may have a positive charge.

In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have five members including one oxygen, for example a furan or a tetrahydrofuran. In this embodiment A represents - (CH₂)_n- where n is 1. In this embodiment the heterocyclic group may be a furan-2-yl group or a tetrahydrofuran-2-yl group. In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have five members including one oxygen and one nitrogen. In this embodiment A represents a bond. In this embodiment the heterocyclic group may be substituted with one Ci_₃alkyl, for example methyl. In this embodiment the heterocyclic group may have five members including one oxygen and one nitrogen, for example isoxazole. In this embodiment the substituted heterocyclic group may be 5-methyl- isoxazol-3-yl.

In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have five members including one nitrogen and one sulphur. In this embodiment A represents a bond. In this embodiment the heterocyclic group may have five members including one nitrogen and one sulphur, for example thiozole. The heterocyclic group may be thiazol-2-yl. In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have five members including two nitrogens, for example imidazole. In this embodiment A represents -(CH₂)„- where n is

2. In this embodiment the heterocyclic group may be imidazol-5-yl. In one embodiment when Rl represents an -A-heterocyclic group, the heterocyclic group may have five members including one nitrogen, for example pyrrolidine. In this embodiment A represents -(CH₂)„- where n is

3. In this embodiment the heterocyclic group may be substituted by = 0. In this embodiment the heterocyclic group may be pyrrolidin-l-yl substituted at position 2 by = 0.

When Rl represents a Ci.galkyl it may be straight or branched, for example -CH₃, -CH₂CH₃, -CH₂CH₂CH₂CH₃, or a branched C₅ or C₆ alkyl, more specifically it may be -CH₂CH(CH₂CH₃)₂, -CH₂CH₂CH(CH₃)₂ -CH₂CH(CH₃) (CH₂CH₃) or -(CH₂)₂CH(CH₃)₂. When Rl represents C₂.₆alkenyl, it may be C₃alkenyl, for example - CH₂CHCH₂.

When Rl represents C₂.₆alkynyl, it may be C₃alkynyl, for example - CH₂CCH.

When Rl represents - (CH₂)_n -0- (CH₂)_m-OH, n and m may each represent 2. When Rl represents - (CH₂)_n-CHRR¹ , n may represent 1 or 2. One of R and R¹ may represent H and the other may represent -NR²R³.

In one embodiment R² and R³ each represent d_₃alkyl, for example methyl.

In a further embodiment one of R² and R³ represents H and the other represents -C-0-Ci_₅alkyl, for example -COCH₃.

In a still further embodiment both of R² and R³ represent H.

In a yet further embodiment one of R² and R³ represents H and the other represents -C-O-Ci.salkylhalide, for example -COCH₂Cl.

Alternatively when Rl represents - (CH₂)_n-CHRR¹ n may represent 1. R and R¹ may each independently represent an -A-carbocyclic group, in one embodiment each of R and R¹ represents phenyl. In this embodiment A represents a bond.

Alternatively Rl may represent an affinity reagent to allow cellular and gel localisation of the PDE-12 enzyme, suitable examples of affinity reagents include Biotin, a fluorescent label and dinitrophenyl. When R2 represents an -A-carbocyclic group the carbocyclic group may be phenyl. The carbocyclic group may be unsubstituted or it may be substituted with one or more of halogen, -OH or -O-C^alkyl (for example -OCH₃) , -d.₃alkyl (for example methyl) , -NH₂, -NHR⁵ (for example _-NHCH(CH₃) (CH₂Cl)) , -NR⁵ ₂ (for example -N(CH₃)₂, -N0₂, - NOO , -O-CO-R⁴.

When R2 represents an -A-carbocyclic group, A may represent a bond.

In one embodiment R2 represents an -A-carbocyclic group, -A represents a bond and the carbocyclic group is phenyl.

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -O-C^alkyl, such as -OCH₃.

In this embodiment the phenyl may be substituted at the 3 position by one -O-C^alkyl, such as -OCH₃ and at the 4 position by -OH. Alternatively the phenyl may be substituted at the 4 position by -OH and at the 6 position by one -O-C^alkyl, such as -OCH₃. Alternatively the phenyl may be substituted at the 3 position by -OH and at the 4 position by one - 0-d.₃alkyl, such as -OCH₃. In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -N0₂. In this embodiment the phenyl may be substituted at the 3 position by -N0₂ and at the 4 position by -OH. In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -N0₂. In this embodiment the phenyl may be substituted at the 4 position by -N0₂ and at the 3 position by -OH.

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one d.₃alkyl, such as -CH₃. In this embodiment the phenyl may be substituted at the 3 position by one d.₃alkyl, such as -CH₃ and at the 4 position by -OH. In another embodiment R2 represents an -A-carbocyclic group, -A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one halogen, such as -CI. In this embodiment the phenyl may be substituted at the 3 position by one halogen, such as -CI, and at the 4 position by -OH.

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -0-d.₃alkyl, such as -OCH₃, and one -O-CO-R⁴. In this embodiment R⁴ may represent d.₅alkyl, for example C₂alkyl or C₄alkyl, such as - C(CH₃)₃.

Alternatively in this embodiment R⁴ may represent -CR⁵R⁶. R⁵ may represent d_₄alkyl, for example -CH(CH₃)₂. R⁶ may represent -NR²R³ and both R² and R³ may be hydrogen, alternatively one of R² and R³ may be hydrogen and the other may be -C(0)-0-d.₅alkyl, for example -C(0)-0- dalkyl, which may take the form -C(0)-0-C(CH₃)₃.

In this embodiment the phenyl may be substituted at the 3 position by one-0-d.₃alkyl, such as -OCH₃, and at the 4 position by one -O-CO-R⁴. In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -NH₂ group. In one embodiment the phenyl group is substituted at the 3 position by one -NH₂ group and at the 4 position by one -OH group. In another embodiment the phenyl group is substituted at the 3 position by one -OH group and at the 4 position by one _NH₂ group.

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -NHR⁵ group. In one embodiment R⁵ represents a Ci_ ₄alkylhalide group, for example -CH(CH₃) (CH₂C1) . In one embodiment the phenyl group is substituted at the 3 position by one -OH group and at the 4 position by one -NHCH(CH₃) (CH₂C1) .

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -NR⁵ ₂ group. In one embodiment R⁵ represents a C^alkyl group, for example -CH₃. In one embodiment the phenyl group is substituted at the 3 position by one -N(CH₃)₂ group and at the 4 position by one -OH group.

In another embodiment R2 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH group, for example at the 4 position.

When R3 represents an -A-carbocyclic group, the carbocyclic group may be phenyl. The carbocyclic group may be unsubstituted or it may be substituted with one or more of -OH or -O-C^alkyl (for example - OCH₃) . When R3 represents an -A-carbocyclic group, A may represent a bond.

In one embodiment R3 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl.

In another embodiment R3 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH and one -O-C^alkyl, such as -OCH₃. The substituted carboxylic group may be 4-hydroxy-3-methyoxyphenyl.

In another embodiment R3 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -0-Ci_₃alkyl, such as -OCH₃. The substituted carboxylic group may be 3- methoxyphenyl.

In another embodiment R3 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by one -OH. In this embodiment the phenyl may be substituted at the 2 position by -OH.

In another embodiment R3 represents an -A-carbocyclic group, A represents a bond and the carbocyclic group is phenyl substituted by two -0-Ci_₃alkyl groups, such as -OCH₃. The phenyl may be substituted at each of the 2 and 4 positions by a -O-C^alkyl group, such as -OCH₃

When R3 represents an -A-heterocyclic group, the heterocyclic group may have five or six members and may include one or more of nitrogen and oxygen or a combination thereof. When R3 is a heterocyclic group, A may represent a bond.

The heterocyclic group may have five members and may include oxygen. In one embodiment the heterocyclic group is furan, for example furan-2- yl, and A represents a bond.

The heterocyclic group may have six members and include nitrogen. In one embodiment the heterocyclic group is pyridine, for example pyridin- 3-yl, and A represents a bond.

When R3 represents Ci_₅alkyl, Ci.salkyl may be -CH₃ or -C(CH₃)₃. In one embodiment the compound is in accordance with formula (la) and R4 represents :

a) an -A-carbocyclic group,

b) Ci_₃alkyl, for example methyl, or

c) hydrogen.

When R4 represents an -A-carbocyclic group, the carbocylic group may be phenyl. A may represent a bond. The carbocyclic group may be unsubstituted. R4 may represent phenyl. In another embodiment the compound is in accordance with Formula (lb) and R4 represents :

a) an -A-carbocyclic group,

b) Ci_₃alkyl, for example methyl, or

c) hydrogen.

When R4 represents an -A-carbocyclic group, the carbocylic group may be phenyl. A may represent a bond. The carbocyclic group may be unsubstituted. R4 may represent phenyl.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-Ci. ₃alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents - (CH₂)_nCHRR¹ , wherein is 1 , one of R and R¹ is H and the other is -NR²R³ where R² and R³ are each d^alkyl, for example methyl. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents Ci_₈alkyl, for example -CH₂CH₂CH₂CH₃. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-carbocyclic group, wherein A represents - (CH₂)„- and n represents 1 and the carbocyclic group is phenyl. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH. In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents Ci_₈alkyl, for example -CH₂CH₂CH₂CH₃. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -NH₂ and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-heterocyclic group, the heterocyclic group has six members including one nitrogen, for example pyridin-2-yl. In this embodiment A is -(CH₂)„- where n is 1. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-Ci. ₃alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is a C₃.₈ cycloalkyl group, for example cyclopropyl. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH. In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-heterocyclic group, the heterocyclic group has six members including one nitrogen, for example pyridin-3-yl. In this embodiment A is -(CH₂)„- where n is 1. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-Ci. ₃alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-carbocyclic group, wherein A represents -(CH₂)„- and n represents 1 and the carbocyclic group is phenyl substituted once with -O-C^alkyl, for example -OCH₃. In this embodiment the -O-C^alkyl group is substituted at the 4 position. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment, in which the compound is of formula (la) , R4 represents hydrogen and R3 represents an -A-carbocyclic group, wherein A represents a bond and the carbocyclic group is phenyl. In this embodiment Rl represents an -A-carbocyclic group, wherein A represents -(CH₂)„- and n represents 1 and the carbocyclic group is phenyl substituted once with -O-C^alkyl, for example -OCH₃. In this embodiment the -O-C^alkyl group is substituted at the 3 position. In this embodiment R2 represents -A-carbocyclic group wherein A represents a bond and the carbocyclic group is phenyl, substituted in the 3 position with -O-C^alkyl (for example -OCH₃) and in the 4 position with -OH.

In one embodiment there is provided a compound of formula (la) or (lb) or a pharmaceutically acceptable salt, solvate or hydrate thereof;

wherein

Rl represents an -A-carbocyclic group or -A-heterocyclic group, Ci_ ₈alkyl, C₂.₆alkenyl, C₂.₆alkynyl, - (CH₂)_n-0- (CH₂)_m-OH or - (CH^-CHRR¹ ;

R2 represents an -A-carbocyclic group; R3 represents an -A-carbocyclic group; and

R4 represents H, an -A-carbocyclic group or C_halky!, wherein any one or more of said carbocyclic groups or heterocyclic groups may be optionally substituted by one or more of -OH, -O-Ci. ₃alkyl, = 0 , -NH₂, -NHR⁵ or -NR⁵ ₂ ;

A is a bond or - (CH₂)_n- ;

R and R¹ independently represent an H or -NR²R³ ;

R² and R³ independently represent H, d.₃alkyl or -C-O-Ci.salkyl; R⁵ represents C^alkyl or d^alkylhalide; and

n and m independently represent an integer from 1 to 4.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents phenyl substituted at position 2 with -OCH₃ , R3 represents phenyl substituted at position 4 with -CH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents phenyl substituted at position 2 with chlorine, R3 represents phenyl substituted at position 4 with -CH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 2 with -OCH₃ , R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 3 with -OH, R3 represents phenyl substituted at position 4 with -CH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 3 and position 4 with -OCH₃, R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 3 and position 4 with -OCH₃, R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 2 and position 5 with -OCH₃, R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 4 with -OH and at position 3 with -OCH₂CH₃, R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents phenyl, R2 and R3 represents 4-bromophenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 4 with -OH and at position 3 with -OCH₃, R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 4 with -OCH₂CH₃, R3 represents phenyl substituted at position 4 with - OCH₃ and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-methylphenyl, R2 represents phenyl substituted at position 3 and position 4 with -OCH₃, R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 4 with -OCH₃ , R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents phenyl, R2 represents phenyl substituted at position 3 and position 4 with -OCH₃, R3 represents phenyl substituted at position 4 with -Br and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 3 with -OCH₃ , R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 4 with -F, R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 3 with -OH, R3 represents phenyl substituted at position 4 with -OCH₃ and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-chlorophenyl, R2 represents phenyl substituted at position 4 with -OH and at position 3 with -OCH₃, R3 represents phenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents pyridin-2-yl, R2 represents phenyl substituted at position 4 with -N0₂, R3 represents 4-chlorophenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents phenyl substituted at position 3 with -N0₂, R3 represents 4-methylphenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 4 with -OH and at position 3 with -OCH₂CH3 , R3 represents methyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl substituted at position 3 with -OCH₃ , R3 represents methyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-methylphenyl, R2 represents phenyl substituted at position 3 and at position 4 with -OCH₃, R3 represents methyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents thiazol-2-yl, R2 represents phenyl, R3 represents methyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-methoxyphenyl, R2 represents 4-fluorophenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl, R3 represents 4- methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 2-methoxyphenyl; R3 represents furan-2-yl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 2-methoxyphenyl, R3 represents piridin-3-yl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 6-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 6-methoxyphenyl, R3 represents -C(CH₃)₃ and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents an -A-carbocyclic group where the carbocyclic group is 4- fluorophenyl and -A- is -CH₂-, R2 represents 2-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 2-methoxyphenyl, R3 represents -(CH₂)₃CH₃ and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 2-methoxyphenyl, R3 represents cyclobutyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents an -A-carbocyclic group where the carbocyclic group is 6- fluorophenyl and -A- is -CH₂-, R2 represents 2-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents an -A-carbocyclic group where the carbocyclic group is 3- fluorophenyl and -A- is -CH₂-, R2 represents 2-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 3-fluorophenyl, R2 represents 6-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents an -A-carbocyclic group where the carbocyclic group is 4- fluorophenyl and -A- is -(CH₂)₂-, R2 represents 6-methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl and R3 represent 4-fluorophenyl, R2 represents 2-methoxyphenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents 4-fluorophenyl, R2 represents 2-methoxyphenyl, R3 represents phenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents phenyl substituted at position 4 by -CH₂OH, R2 represents 2- methoxyphenyl, R3 represents 4-methoxyphenyl and R4 represents hydrogen. In one embodiment the compound may not have all of the following Rl represents phenyl substituted at position 4 by -CH₂OH, R2 represents 6- methoxyphenyl, R3 represents -C(CH₃)₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents pyridin-2-yl substituted at position 5 by -CH₂OH, R2 represents 6-methoxyphenyl, R3 represents -C(CH₃)₃ and R4 represents hydrogen.

In one embodiment the compound may not have all of the following Rl represents 4-bromophenyl, R2 represents phenyl, R3 represents -(CH₂)₂- 0-CH₃ and R4 represents hydrogen.

The term d.galkyl is used to refer to a linear or branched saturated hydrocarbon group having from 1 to 8 carbon atoms. The number of carbon atoms in the group can be varied by changing the numerical range indicated in this term and therefore for example C^alkyl has 1 to 3 carbon atoms in the group.

The term C₃.₈ cycloalkyl is used to refer to a saturated hydrocarbon ring having from 3 to 8 carbon atoms. The number of carbon atoms in the ring can be varied by changing the numerical range indicated in this term and therefore for example C₃.₅cycloalkyl has 3 to 5 carbon atoms in the ring.

The term C₂.₆alkenyl is used to refer to a linear or branched unsaturated, hydrocarbon group having from 2 to 6 carbon atoms and having with one or more carbon-carbon double bonds. The number of carbon atoms in the group can be varied by changing the numerical range indicated in this term and therefore for example C₄.₆alkenyl has 4 to 6 carbon atoms in the group.

The term C₂.₆alkynyl is used to refer to a linear or branched unsaturated, hydrocarbon group having from 2 to 6 carbon atoms and having with one or more carbon-carbon triple bonds. The number of carbon atoms in the group can be varied by changing the numerical range indicated in this term and therefore for example C₄.₆alkynyl has 4 to 6 carbon atoms in the group.

The term carbocyclic group is used to refer to a ring system, all of whose atoms are carbon atoms .

The term heterocyclic group is used to refer to a ring system having one or more atoms other than carbon in at least one of its rings.

The carbocyclic and heterocylic groups can include both aromatic and non-aromatic ring systems. The groups can be monocyclic or bicyclic. The groups may have from 3 to 12 ring members, for example in many cases there are 5 to 10 ring members .

Unless otherwise specified, a reference to a particular compound also includes ionic forms, salts, solvates, isomers , tautomers, N-oxides, esters, prodrugs , isotopes and protected forms thereof. All references to compounds of the formula (I) , unless context indicates otherwise, include compounds of formula (la) and (lb) . Compounds of the formula (I) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (I) include all such forms . For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula.

Where compounds of the formula (I) contain one or more chiral centres, and can exist in the form of two or more optical isomers , references to compounds of the formula (I) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers) , either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.

Where compounds of the formula (I) exist as two or more optical isomeric forms , one enantiomer in a pair of enantiomers or only one of a plurality of diastereoisomers may exhibit advantages, Accordingly, the invention provides compositions containing a compound of the formula (I) having one or more chiral centres, wherein at least 55% (e.g. at least 60% , 65%, 70% , 75% , 80%, 85%, 90% or 95%) of the compound of the formula (I) is present as a single optical isomer (e.g. enantiomer or diastereoisomer) . In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (I) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer) . The compounds of the invention include compounds with one or more isotopic substitutions , and a reference to a particular element includes within its scope all isotopes of the element. Synthesis Methods

The compounds of formula (I) can be synthesised by a variety of different routes using commercially available starting materials or materials prepared by conventional methods.

According to a further aspect of the invention, there is provided a process for preparing a compound of formula (I) , comprising the steps of:

(a)

OH

(ID (HI) (IV) (V) (i) dissolving compounds of formula (II) , (III) and (IV) , where Rl , R2 and R3 are as defined above, in acetic acid, with heating; or

(ii) dissolving compounds of formula (II) and (III) in dioxane and adding this solution to a compound of formula (IV) dissolved in dioxane, at room temperature, where Rl , R2 and R3 are as defined above; or (iii) dissolving a compound of formula (II) in dioxane and adding a compound of formula (III) and a catalytic amount of acetic acid, with heating, subsequently adding a compound of formula (II) with heating, where Rl , R2 and R3 are as defined above;

(b) dissolving the reaction product in acetic acid and adding a compound of formula (V) wherein R4 is as defined above; (c) heating the mixture;

(d) extracting and purifying the product.

In step (a) , option (i) the heating is usually at a temperature of 45-55°C, for example 50°C. The heating time may be from 18-30 hours , for example 22-26 hours , such as 24 hours. In step (a) , option (i) the reaction mixture may be stirred

In step (a) , option (ii) the reaction mixture may be stirred. The reaction may be allowed to continue for 20 minutes to 24 hours, for example for 5 to 20 hours or 10 to 15 hours .

In step (a) , option (iii) dissolving a compound of formula (II) in dioxane and adding a compound of formula (III) and a catalytic amount of acetic acid, with heating may be at a temperature of 35-45°C, for example 40°C. The heating time may be from 2-5 hours , for example 3-4 hours, such as 3.5 hours . The reaction mixture may be stirred. The heating may take place under an inert atmosphere, such as nitrogen. The acetic acid may be glacial acetic acid. The acetic acid may be added in an amount of one to four, for example two drops .

In step (a) , option (iii) subsequently adding a compound of formula (II) with heating may be at a temperature of 30-40°C, for example 35°C. The reaction may be allowed to continue for 8 to 24 hours, for example for 10 to 20 hours or 12 to 15 hours . The reaction mixture may be stirred

At the end of step (a) there may be carried out removal of the solvent and purification of the reaction product before step (b) is carried out. This has the effect of increasing purity of the reaction product. The solvent may be removed under reduced pressure, for example by vacuum, or by filtration or by evaporation.

The reaction product may be purified by trituration, for example with ether, or washing, for example with dioxane or hexane. More than one round of trituration or washing may be used.

The reaction product after solvent removal and purification of the reaction product may be a solid or a liquid.

In step (c) the mixture may be heated under reflux. The mixture may be heated under reflux for 15-60 minutes , for example 30 minutes. As an alternative the mixture may be heated to 100°C for 90-150 minutes, for example 120 minutes. As a further alternative the mixture may be heated to 80-100°C, for example 90°C under an inert atmosphere, such as nitrogen, for 120-180 minutes, for example 150 minutes.

In step (d) the product may be extracted by solvent extraction. Any solvent may be removed under reduced pressure, for example vacuum, or by filtration.

In step (d) the product may purified by one or more of washing, semi- preparative reverse phase HPLC, silica chromatograph or crystallisation. According to a further aspect there is provided an intermediate of the formula (VI) R2 \ R 1

(VI)

wherein Rl , R2 and R3 are as described in relation to formula (I) above. According to a further aspect of the invention, there is provided a process for preparing a compound of formula (VI) , comprising:

As step (a) ;

(ID (in) (IV)

(i) dissolving compounds of formula (II) , (III) and (IV) , where Rl , R2 and R3 are as defined above, in acetic acid, with heating; or

(ii) dissolving compounds of formula (II) and (III) in dioxane and adding this solution to a compound of formula (IV) dissolved in dioxane, at room temperature, where Rl , R2 and R3 are as defined above; or

(iii) dissolving a compound of formula (II) in dioxane and adding a compound of formula (III) and a catalytic amount of acetic acid, with heating, subsequently adding a compound of formula (II) with heating, where Rl , R2 and R3 are as defined above.

There may be performed a step (b) which would comprise removing the solvent and purifying the reaction product. In step (a) , option (i) the heating is usually at a temperature of 45-55°C, for example 50°C. The heating time may be from 18-30 hours , for example 22-26 hours, such as 24 hours . In step (a) , option (i) the reaction mixture may be stirred.

In step (a) , option (iii) subsequently adding a compound of formula (II) with heating may be at a temperature of 30-40°C, for example 35°C. The reaction may be allowed to continue for 8 to 24 hours , for example for 10 to 20 hours or 12 to 15 hours . The reaction mixture may be stirred

In step (b) the solvent may be removed under reduced pressure, for example by vacuum, or by filtration or by evaporation.

In step (b) the reaction product may be purified by trituration, for example with ether, or washing, for example with dioxane or hexane. More than one round of trituration or washing may be used. The reaction product of step (b) may be a solid or a liquid. Uses of the Compounds

The compounds according to the invention may be used in therapy, and this is also an embodiment of the invention. Thus, the compounds may be used to treat disorders , conditions or diseases usually targeted by RNase L in the body.

Disorders or conditions usually targeted by RNase L in the body include viral infections and oncological diseases. Thus, the compounds of the invention are used to treat diseases, disorders or conditions , including, but not limited to RNA viruses including flaviviruses . Examples include hepatitis B , hepatitis C, HIV, influenza, vaccinia virus, respiratory syncytial virus (RSV) , West Nile, Yellow Fever, Dengue Fever, Dengue Virus, bovine viral diarrhoea (BVD) virus, haematological malignancies, cancerous tumours and leukaemia.

In one embodiment, the compounds are useful in the treatment of Hepatitis C. In one embodiment, the compounds are useful in the treatment of prostate cancer.

In one embodiment the compounds are useful in the treatment of Dengue Virus.

In one embodiment the compounds are useful in the treatment of Dengue Fever.

In one embodiment the compounds are useful in the treatment of bovine viral diarrhoea (BVD) virus. The invention thus provides a method for treating or preventing these diseases or states , the method comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula (I) .

It will be appreciated that the term "treatment" and "treating" as used herein means the management and care of a patient for the purpose of combating a condition, such as a disease or a disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications , to delay the progression of the disease, disorder or condition, to alleviate or relief the symptoms and complications, and/or to cure or eliminate the disease, disorder or condition as well as to prevent the condition, wherein prevention is to be understood as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of the active compounds to prevent the onset of the symptoms or complications . The patient to be treated is preferably a mammal, in particular a human being, but it may also include animals, such as dogs , cats, cows , sheep and pigs.

In one embodiment, the compounds as described hereinbefore are used to treat or prevent viral infection, more specifically hepatitis C. In another embodiment, the compound of formula (I) is used to treat or prevent oncological diseases such as prostate cancer

Thus, in some embodiments, there is provided a use of the compounds of formula (I) in the manufacture of a medicament for the treatment or prevention of the diseases, disorders or conditions as hereinbefore described. In a further embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of the diseases , disorders or conditions as hereinbefore described.

Combination Therapies

Many diseases are treated using more than one medicament in the treatment, either concomitantly administered or sequentially administered. It is therefore within the scope of the invention to use the compounds of the invention in therapeutic methods for the treatment of one of the above mentioned diseases in combination with one another, or as an adjunct to, or in conjunction with, other established therapies normally used to in the treatment said disease. By analogy, it is also within the scope of the invention to use the compounds of the invention in combination with other therapeutically active compounds normally used in the treatment of one of the above-mentioned diseases in the manufacture of a medicament for said disease.

Examples of such combination therapies may include administration of a compound according to the present invention in combination with a medicament useful for treating viral infections or oncological diseases.

For example, the compounds may be used with other 2' 5 ' - phosphodiesterase inhibitory compounds or with compounds that activate the 2-5A system or otherwise give rise to the production of RNase L within the body.

Such combination therapy may also include administration of a compound according to the present invention together with an interferon.

Such combination therapy may also include administration of a compound according to the present invention together with ribavirin. Such combination therapy may also include administration of a compound according to the present invention together with interferon and ribavirin.

The combination treatment may be carried out in any way as deemed necessary or convenient by the person skilled in the art and for the purpose of this specification, no limitations with regard to the order, amount, repetition or relative amount of the compounds to be used in combination is contemplated. Pharmaceutical Compositions

Another purpose is to provide a pharmaceutical composition comprising the compounds of the invention. The compounds of the invention may be generally utilised as the free substance or as a pharmaceutically acceptable salt thereof.

In the present context, the term "pharmaceutically acceptable salt" is intended to indicate salts which are not harmful to the patient. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p- aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19^th Edition, Gennaro, Ed. , Mack Publishing Co. , Easton, PA, 1995.

Suitable pharmaceutical carriers include inert solid diluents or fillers , sterile aqueous solutions and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids , fatty acid amines, polyoxyethylene and water.

In addition, the compounds of the invention may form solvates with water or common organic solvents. Such solvates are also encompassed within the scope of the present invention.

Thus, in a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The composition may further comprise a buffer system, preservative(s) , tonicity agent(s) , chelating agent(s) , stabilizers and surfactants , which is well known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 20th edition, 2000. The composition may also further comprise one or more therapeutic agents active against the same disease state.

Methods to produce controlled release systems useful for compositions of the current invention include, but are not limited to, crystallization, condensation, co-crystallization, precipitation, co-precipitation, emulsification, dispersion, high pressure homogenisation, en-capsulation, spray drying, microencapsulating, coacervation, phase separation, solvent evaporation to produce microspheres , extrusion and supercritical fluid processes . General reference is made to Handbook of Pharmaceutical Controlled Release (Wise, D.L. , ed. Marcel Dekker, New York, 2000) and Drug and the Pharmaceutical Sciences vol. 99: Protein Composition and Delivery (MacNally, E.J. , ed. Marcel Dekker, New York, 2000) .

Administration of pharmaceutical compositions according to the invention may be through several routes of administration, for example, oral, rectal, nasal, pulmonary, topical (including buccal and sublingual) , transdermal, intracisternal, intraperitoneal, vaginal and parenteral (including subcutaneous , intramuscular, intrathecal, intravenous and intradermal) route. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

For topical use, sprays, creams , ointments , jellies, gels , inhalants , dermal patches , implants, solutions of suspensions , etc. , containing the compounds of the present invention are contemplated. For the purpose of this application, topical applications shall include mouth washes and gargles.

Pharmaceutical compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets , troches , dragees , pills , lozenges , powders and granules and liquid dosage forms for oral administration include solutions , emulsions, aqueous or oily suspensions , syrups and elixirs , each containing a predetermined amount of the active ingredient, and which may include a suitable excipient.

Compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, and preserving agents in order to provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically-acceptable excipients which are suitable for the manufacture of tablets . These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents , for example corn starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.

The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4, 356, 108; 4, 166,452; and 4, 265 , 874, incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatine capsules where the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatine capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions may contain the active compounds in admixture with excipients suitable for the manufacture of aqueous suspensions . Such excipients are suspending agents, for example sodium carboxymethylcellulose , methylcellulose , hydroxypropylmethylcellulose , sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide such as lecithin, or condensation products of an alkylene oxide with fatty acids , for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols , for example, heptadecaethyl-eneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides , for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients , for example, sweetening, flavouring, and colouring agents may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions . The oily phase may be a vegetable oil, for example, olive oil or arachis oil, or a mineral oil, for example a liquid paraffin, or a mixture thereof. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides , for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Syrups and elixirs may be formulated with sweetening agents , for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 , 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer' s solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conveniently employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed using synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

Parenteral administration may be performed by subcutaneous, intramuscular, intraperitoneal or intravenous injection by means of a syringe, optionally a pen-like syringe. Alternatively, parenteral administration can be performed by means of an infusion pump. A further option is a composition which may be a solution or suspension for the administration of the prolactin receptor antagonist in the form of a nasal or pulmonal spray. As a still further option, the pharmaceutical compositions containing the compound of the invention can also be adapted to transdermal administration, e.g. by needle-free injection or from a patch, optionally an iontophoretic patch, or transmucosal, e.g. buccal, administration.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions , dispersions , suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use.

The term "aqueous composition" is defined as a composition comprising at least 50 % w/w water. Likewise, the term "aqueous solution" is defined as a solution comprising at least 50 %w/w water, and the term "aqueous suspension" is defined as a suspension comprising at least 50 %w/w water. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art. Depot injectable formulations are also contemplated as being within the scope of the present invention.

When the compounds of the invention or composition thereof is used in combination with a second therapeutic agent active against the same disease state, they may conveniently be administered alone or in combination, in either single or multiple doses , sequentially or simultaneously, by the same route of administration, or by a different route.

Effective Dosages

The compounds of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended result, for example in an amount effective to treat or prevent the particular disease being treated. The compound(s) may be administered therapeutically to achieve therapeutic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated and/or eradication or amelioration of one or more of the systems associated with the underlying disorder. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realised. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art. Determination of the effective dosage is well within the capabilities of those skilled in the art.

When a compound of the invention or a pharmaceutically acceptable salt, solvate or prodrug thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.

Examples

General Synthesis Method

(ID (HI) (IV) (VI)

(VI) (V) (I)

The starting materials of formula (II) , (III) and (IV) were dissolved in a suitable amount of acetic acid and the solution was heated, for example at 50°C for 24 hours. The solvent was then removed, for example under reduced pressure (Buchi) , and the residue, which may be a solid or liquid was purified. A suitable purification process is trituration with ether once or more than once to produce the required purity of the intermediate of formula (VI) .

The intermediate of formula (VI) was dissolved in acetic acid and hydrazine monohydrate, or a derivative thereof was added. The mixture was heated, for example to reflux for 30 minutes . The solvent was removed, for example under reduced pressure (Genevac) , and the final products of formula (I) were purified. A suitable purification process is semi-preparative reverse phase HPLC. (Genesis C₁₈, 4 m, 27.5cm x 1.25cm) running a gradient of 95% water (0.1% trifluoroacetic acid) 5% acetonitrile (0.1% trifluoroactic acid) to 95% acetonitrile and 5% water over 20 minutes .

Specific Examples

1. Synthesis of 4-(4-hydroxy-3-methoxy-phenyl)-3 , 5-diphenyl-4, 5- dihydr -lH-pyrrolo[3 ,4-c]pyrazol-6-one

I ntermediate 1

a) Synthesis of 4-benzoyl-3-hydroxy-5-(4-hydroxy-3-methoxy-phi phenyl- l , 5-dihydro-pyrrol-2-one (Intermediate 1) Methyl-2,4-dioxo-4-phenylbutanoate (824mg, 4mmol) , aniline (365 1, 4mmol) and vanillin (608.6mg, 4mmol) were dissolved in glacial acetic acid (10ml) and the mixture stirred and heated to 50°C for 72 hours . The solvent was then evaporated and the residue triturated with ether to give a yellowish solid (375mg, 23.3% yield, HPLC-MS, RT 3.27min, mass 402) .

Compound 1

b) Synthesis of 4-(4-hydroxy-3-methoxy-phenyl)-3 , 5-diphenyl-4, 5- dihydro-lH-pyrrolo[3 ,4-c]pyrazol-6-one (Compound 1) 4-Benzoyl-3-hydroxy-5-(4-hydroxy-3-methoxy-phenyl)-l -phenyl- 1 , 5- dihydro-pyrrol-2-one (Intermediate 1 lOOmg, 0.25mmol) was dissolved in glacial acetic acid (2ml) followed by hydrazine hydrate (14 1, 0.275mmol) and the reaction refluxed for 30 minutes. The reaction mixture was then diluted with water (10ml) and the precipitated product was extracted into ethyl acetate (10ml) and washed with sodium hydroxide (2M, 10ml) and finally water (2x10ml) . The organic solution was dried over magnesium sulphate, filtered evaporated and further purified by reverse phase chromatography (Genesis C₁₈, 4μπι, 27.5cm x 1.25cm) running a gradient of 95% water (0.1 % trifluoroacetic acid) 5% acetonitrile (0.1% trifluoroactic acid) to 95% acetonitrile and 5% water over 20 minutes , to produce a yellow solid (55.9mg, 56.3% yield, 98% pure, Compound 1 , QC HPLC-MS, RT, 5.12min, mass 398) .

2. Synthesis of 4-{5-[3-(dimethylamino)propyl] -6-methylidene-3-phenyl- 1H 4H, 5H, 6H-pyrrolo[3 , 4-c] pyrazol-4-yl}-2-methoxyphenol

I ntermediate 2

a) Synthesis of 4-benzoyl-l-(3-dimethylamino-propyl)-3-hydroxy-5- (hydroxy-3-methoxy-phenyl)-l , 5-dihydro-pyrrol-2-one (Intermediate 2)

Vanillin (76mg, 0.5mmol) and 3-dimethylamino-l-propylamine (69 1, 0.55mmol) were dissolved in dioxane (1.0ml) and the solution was added at room temperature to a dioxane (1.0ml) solution of methyl-2,4-dioxo-4- phenylbutanoate (103mg, 0.5mmol) and stirred at room temperature. After 30 minutes the clear yellow solution had become cloudy and after overnight had become very thick. The solid was filtered and washed with a little dioxane (150mg, 100% pure, Intermediate 2) .

Compound 2

b) Synthesis of 4-{5-[3-(dimethylamino)propyl] -6-methylidene-3-phenyl- 1H, 4H, 5H, 6H-pyrrolo[3 , 4-c] pyrazol-4-yl}-2-methoxyphenol (Compound 2) . 4-Benzoyl-l-(3-dimethylamino-propyl)-3-hydroxy-5-(4-hydroxy-3- methoxy-phenyl)-l , 5-dihydro-pyrrol-2-one (Intermediate 2, 203mg, 0.5mmol) was dissolved in glacial acetic acid (2ml) and hydrazine hydrate (48 1, 0.943mmol) was added with stirring. The reaction was then heated to 100-C for two hours which showed a single peak by LC-MS (RT 3.59, mass 407) . The reaction was evaporated and re-dissolved in dichloromethane (10ml) to which was added triethylamine (6.5ml) and the solution stirred at room temperature for 2 hours evaporated down onto silica and purified by chromatography eluting with ethyl acetate, methanol and triethylamine (16: 2: 1) . The eluted material was dried down to yield off white solid (99mg, 49% yield, 100% pure, Compound 2) .

3. Synthesis of 4-{5-[3-(dimethylamino)propyl] -6-methylidene-3-phenyl- 1H, 4H, 5H, 6H-pyrrolo[3 , 4-c] pyrazol-4-yl}-2-methoxyphenol

Intermediate 3 a) Synthesis of 4-benzoyl-l-(3-butyl)-3-hydroxy-5-(4-hydroxy-3-methoxy- phenyl)-l , 5-dihydro-pyrrol-2-one (Intermediate 3) Vanillin (l . Og, 6.58mmol) was stirred and dissolved in dry dioxan (15mls) to which was added n-butylamine (0.48g, 0.65mls , 6.58mmol) followed by acetic acid (two drops) and the reaction mixture stirred and heated at 40-C under nitrogen for 3.5 hours . The schiffs base intermediate was detected (LC-MS mass 208) . Methyl-2, 4-dioxo-4- phenylpyruvate (1.35g, 6.58mmol) was added with stirring and heating to 35-C overnight. An off-white solid formed which was filtered, washed with hexane and dried in a vacuum oven. This yielded a white solid (Intermediate 3 , 2.19g, 87.25% yield, 100% pure, mass 382) .

Compound 3

b) Synthesis of 4-{5-[3-(dimethylamino)propyl] -6-methylidene-3-phenyl- 1H, 4H, 5H, 6H-pyrrolo[3 , 4-c] pyrazol-4-yl}-2-methoxyphenol (Compound 3) Intermediate 3 (1.95g, 5.11mmol) was stirred in acetic acid (lOmls) and hydrazine hydrate was added (0.28g, 5.5mmol) . This reaction mixture was then stirred and heated to 90-C under nitrogen for 150 minutes. LC- MS showed one major peak with the desired mass (278) . The mixture was poured into water (200mls) and rapidly stirred at room temperature for 30 minutes. The off-white solid was collected and washed with water and dried in a vacuum oven and re-crystallised from ethyl acetate diisopropyl ether to generate a white crystalline solid (Compound 3 , 1.25g, 65% yield, 100% pure, m.p. 119-122°C, LC-MS retention time 5.3 minutes, mass 378/755.5 , tic on silica in ethylacetate/hexane, 2: 1 , Rf 0.6) . NMR (δ, ppm, 500 MHz, DMSO-d₆,) : 0.84 (3H, s, CH₂-CH₃) ; 1.20-1.21 (2H, m, CH₂-CH₂-CH₃) ; 1.43-1.45 (2H, m, CH₂-CH₂-CH₂) ; 2.50 (1H, m, N- CHH-CH₂) ; 3.58-3.61 (1H, s, N-CHH-CH₂) ; 3.67 (3H, s, 0-CH₃) ; 5.76 (1H, s , chiral C-H) ; 6.72-6.82 (3H, m, aryl) ; 7.32-7.51 (5H, m, aryl) ; 9.08 (1H, s, O-H) ; 13.87 (1H, s, NH) .

4. Synthesis of 4-(4-hydroxy-3-methoxy-phenyl)-l-methyl-3 , 5-diphenyl- 4, 5-dihydro-lH-pyrrolo[3 ,4-c]pyrazol-6-one (Compound 4) and 4-(4- hydroxy-3-methoxy-phenyl)-2-methyl-3 , 5-diphenyl-4, 5-dihydro-lH- rrolo[3 ,4-c]pyrazol-6-one (Compound 5)

Intermediate 4 (l .Og, 2.62mmols) was suspended and stirred in acetic acid (15mls) before methyl hydrazine (0.14mls , 2.62mmols) was added. The reaction mixture was then stirred and heated (85 °C) overnight. LCMS analysis showed no starting material and the reaction mixture was poured onto ice/water (150mls) and stirred at room temperature (1 hour). The white solid was collected and dried (0.93g), analysis (LCMS) showed two peaks (same mass) and the mixture was subjected to silica chromatography eluting with ethyl acetate/hexane (2:1). This produced two products, Compound 4 (melting point 173°C-175°C, LCMS RT 3.60mins, M + H 392, 0.173g). NMR (δ, ppm,500 MHz, DMSO-d₆,) : 0.83 (3H, s, CH₂-CH₃); 1.21 (2H, m, CH₂-CH₂-CH₃); 1.42-1.43 (2H, m, CH₂-CH₂-CH₂); 2.70-2.72 (1H, m, N-CHH-CH₂); 3.54-3.57 (1H, s, N- CHH-CH₂); 3.68 (3H, s, 0-CH₃); 4.04 (3H, s, N-CH₃); 5.74 (1H, s, chiral C-H); 6.73-6.87 (3H, m, aryl); 7.25-7.52 (5H, m, aryl); 9.11 (1H, s, O-H) and Compound 5 (melting point 199°C-203°C, LCMS RT 3.43mins, M + H 392, 0.146g). NMR (δ, ppm,500 MHz, DMSO-d₆,) : 0.83 (3H, s, CH₂-CH₃); 1.17-1.20 (2H, m, CH₂-CH₂-CH₃) ; 1.40-1.42 (2H, m, CH₂-CH₂-CH₂); 2.70-2.71 (1H, m, N-CHH-CH₂); 3.60-3.64 (1H, s, N-CHH-CH₂); 3.61 (3H, s, 0-CH₃); 3.94 (3H, s, N-CH₃); 5.65 (1H, s, chiral C-H); 6.52-6.68 (3H, m, aryl); 7.32-7.36 (5H, m, aryl); 9.03 (1H, s, O-H).

5. Synthesis of 4-(4-hydroxy-3-methoxy-phenyl)-l-phenyl-3,5-diphenyl- 4,5-dihydro-lH-pyrrolo[3,4-c]pyrazol-6-one (Compound 6) and 4-(4- hydroxy-3-methoxy-phenyl)-2-phenyl-3,5-diphenyl-4,5-dihydro-lH-

Intermediate 4 (l.Og, 2.62mmols) was suspended and stirred in acetic acid (20mls) to which was added phenyl hydrazine (0.28mls, 2.62mmols) and the reaction mixture stirred with heating (90 °C) under nitrogen for 24 hours. LCMS showed the reaction had proceeded to completion and was added to ice/water (150mls) and was stirred at room temperature (1 hour) . The product was filtered and purified by silica chromatography eluting with ethyl acetate/hexane (2: 1) to afford two products, Compound 6 (melting point 123 °C-125 °C , LCMS RT 3.69, M + H 454, 0.24g) and Compound 7 (melting point 197°C-199°C , LCMS RT 4.20, M + H 454, O. l lg) .

Results

% PDE inhibition - This is a simple initial measure of the % inhibition of the enzyme ie no inhibition gives 100% substrate cleavage and 100% inhibition gives 0% substrate cleavage. Colour or fluorescence is produced, the greater the cleavage and the poorer the inhibitor. The procedure used to obtain this value for each of the compounds against which it is detailed in the table below is that of standard fluorescent transfer assay. mLOGP is the Moriguchi octanol-water partition coefficient (logP) calculated using the model developed by Moriguchi et al. (Moriguchi, 1992; Moriguchi, 1994) . clogP of a compound is the logarithm of its partition coefficient between n-octanol and water log(c_octanol/c_water) , is a well established measure of the compound's hydrophilicity.

The drug score combines druglikeness, cLogP, logS, molecular weight and toxicity risks in one handy value than may be used to judge the compound's overall potential to qualify for a drug. This value is calculated by multiplying contributions of the individual properties with the first equation:

ds is the drag score. S; are the contributions calculated directly from of cLogP, logS, molweight and druglikeness (p;) via the second equation which describes a spline curve. Parameters a and b are (1, -5) , (1, 5) , (0.012, -6) and (1, 0) for cLogP, logS, molweight and druglikeness, respectively. ¾ are the contributions taken from the 4 toxicity risk types. The ¾ values are 1.0, 0.8 and 0.6 for no risk, medium risk and high risk, respectively.

IC₅₀ values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist- IC₅₀ values are very dependent on conditions under which they are measured. The procedures used to obtain this value for each of the compounds against which it is detailed in the table below is that of standard fluorescent transfer assay and is an assay that is published in anti- viral assay journals.

Cellular Activity is measured using a standard anti-viral assay such as a plague assay or an assay to count viable live cells . In the table below the measurements were made using the PDE enzyme inhibition assay.

ADME protein binding level - a drug' s efficiency may be affected by the degree to which it binds to the proteins within blood plasma. ADME is an acronym in pharmacokinetics and pharmacology for absorption, distribution, metabolism, and excretion, and describes the disposition of a pharmaceutical compound within an organism. All of these measurements reflect how well a drug will work in a human or animal model of a particular disease.

All these drug characteristics are measured by standard HPLC/mass spectrometry and occasionally by the use of radioactive drugs for invivo profilling. HPLC/mass spectrometry and some fluorescent assays are used to study the metabolism of compounds invitro and invivo. The fluorescence assays will look at lose of activity due to metabolism and also are the compounds acting as inhibitors for metabolising enzymes, even if not metabolised themselves.

Claims

1. A compound of formula (la) or (lb) or a pharmaceutically acceptable salt, solvate or hydrate thereof;

(la) (lb)

wherein

Rl represents an -A-carbocyclic group or -A-heterocyclic group, d. ₈alkyl, C₂.₆alkenyl, C₂.₆alkynyl, -(CH₂)_n-0-(CH₂)_m-OH, -(CH₂)_n-0-(CH₂)_m- NH₂, -(CH₂)_n-0-(CH₂)_m-NHR⁵, -(CH₂)_n-0-(CH₂)_m-NR⁵ ₂, -(CH₂)_n-CHRR\ or an affinity reagent to allow cellular and gel localisation of the PDE-12;

R2 represents an -A-carbocyclic group;

R3 represents an -A-carbocyclic group, an -A-heterocyclic group or d. ₅alkyl; and

R4 represents H, an -A-carbocyclic group or d^alkyl, wherein any one or more of said carbocyclic groups or heterocyclic groups may be optionally substituted by one or more of halogen, -OH, d_ ₃alkyl, -0-d.₃alkyl, -O-CO-R⁴, = 0, -NH₂, -NHR⁵, -NR⁵ ₂ or -N0₂;

A is a bond or -(CH₂)_n-; R and R¹ independently represent an -A-carbocyclic group, H, -NR²R³ or -NR²C-0-C_1-3alkyl;

R² and R³ independently represent H, C^aikyl, -C-0-Ci.₅alkyl, -C-O-Ci. ₅alkylhalide or -C (0) -0-Ci_-5alkyl;

R⁴ represents d.₅alkyl or -CHR⁵R⁶;

R⁵ represents d_₄alkyl or d^alkylhalide;

R⁶ represents -NR²R³ ; and

n and m independently represent an integer from 1 to 4.

2. The compound of claim 1 wherein, Rl is an -A-carbocyclic group and the carbocyclic group is phenyl or a C₃.₈ cycloalkyl group.

3. The compound of claim 2 wherein, the carbocyclic group is unsubstituted or is substituted with one or more of halogen, -OH and -O- d.₃alkyl

4. The compound of claim 1 wherein, Rl is an -A-heterocyclic group and the heterocyclic group has five or six members and includes one or more of nitrogen, oxygen and sulphur or a combination thereof.

5. The compound of claim 4 wherein, the heterocyclic group is unsubstituted or is substituted with one or more d.₃alkyl.

6. The compound of any preceding claim wherein, R2 represents an - A-carbocyclic group and the carbocyclic group is phenyl.

7. The compound of claim 6 wherein, the carbocyclic group unsubstituted or is substituted with one or more of halogen, -OH or - C_{1 3}alkyl, -C_{1 3}alkyl, -NH₂, -NHR⁵ , -NR⁵ ₂, -N0₂, -NOO , -O-CO-R⁴.

8. The compound of any preceding claim wherein, R3 represents an - A-carbocyclic group and the carbocyclic group is phenyl

9. The compound of claim 8 wherein, the carbocyclic group is unsubstituted or is substituted with one or more of -OH or -0-Ci_₃alkyl.

10. The compound of any preceding claim wherein, R3 represents an - A-heterocyclic group and the heterocyclic group has five or six members and includes one or more of nitrogen and oxygen or a combination thereof.

11. The compound of any preceding claim wherein, R4 represents an - A-carbocyclic group and the carbocylic group is phenyl

12. The compound of claim 1 wherein

Rl represents an -A-carbocyclic group or -A-heterocyclic group, Ci_ ₈alkyl, C₂.₆alkenyl, C₂.₆alkynyl, -(CH₂)_n-0-(CH₂)_m-OH or -(CH^-CHRR¹ ; R2 represents an -A-carbocyclic group;

R3 represents an -A-carbocyclic group; and

R4 represents H, an -A-carbocyclic group or d^alkyl, wherein any one or more of said carbocyclic groups or heterocyclic groups may be optionally substituted by one or more of -OH, -O-Ci. ₃alkyl, = 0, -NH₂, -NHR⁵ or -NR⁵ ₂ ;

A is a bond or -(CH₂)_n-;

R and R¹ independently represent an H or -NR²R³;

n and m independently represent an integer from 1 to 4.

13. A process for preparing a compound of formula (la) or (lb) , comprising the steps of:

(a)

(ID (HI) (IV) (V)

(iii) dissolving a compound of formula (II) in dioxane and adding a compound of formula (III) and a catalytic amount of acetic acid, with heating, subsequently adding a compound of formula (II) with heating, where Rl , R2 and R3 are as defined above;

(b) dissolving the reaction product in acetic acid and adding a compound of formula (V) wherein R4 is as defined above;

(c) heating the mixture;

(d) extracting and purifying the product.

14. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 12.

15. A compound as defined in any of claims 1 to 12 for use in therapy.

16. A compound as defined in any of claims 1 to 12 for use in the prophylaxis or treatment of viral infections and oncological diseases.

17. A compound as defined in any of claims 1 to 12 for use in the prophylaxis or treatment of hepatitis B , hepatitis C , HIV, influenza, vaccinia virus, respiratory syncytial virus (RSV) , West Nile, Yellow Fever, Dengue Fever, Dengue Virus, bovine viral diarrhoea (BVD) virus , haematological malignancies, cancerous tumours and leukaemia.

18. Use of a compound as defined in any of claims 1 to 12 for the manufacture of a medicament for the prophylaxis or treatment of viral infections and oncological diseases.

19. Use of a compound as defined in any of claims 1 to 12 for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition as described herein.

20. A method for the prophylaxis or treatment of viral infections and oncological diseases, which method comprises administering to a subject in need thereof a compound of the formula (la) or (lb) as defined in any of claims 1 to 12.