WO2013075173A1 - Compounds for the treatment of hcv - Google Patents

Abstract

The present invention relates to viral polymerase inhibitors of formula (I) or salts, solvates, hydrates, racemates, enantomers or isomers thereof, in particular inhibitors of viral polymerases within the Flaviviridae family such as hepatitis C virus (HCV), processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

Description

COMPOUNDS FOR THE TREATMENT OF HCV

TECHNICAL FIELD

The present invention relates to viral polymerase inhibitors, in particular inhibitors of viral polymerases within the Flaviviridae family such as hepatitis C virus (HCV), processes for their preparation and their use in the treatment of Flaviviridae viral infections such as Hepatitis C virus (HCV) infections.

BACKGROUND

The Flaviviridae are a group of positive single-stranded RNA viruses with a genome size from 9-15 kb. The Flaviviridae consist of various genera including: Hepaciviruses (this genus contains only one species, the Hepatitis C virus (HCV), which is composed of many genotypes and subtypes); Flaviviruses (this genus includes the Dengue virus, Japanese Tick-Borne and the Yellow Fever virus and there are some additional Flaviviruses that are unclassified) and Pestiviruses (this genus includes three serotypes of bovine viral diarrhoea virus, but no known human pathogens).

Hepatitis C virus (HCV) is a major cause of viral hepatitis and has infected more than 200 million people worldwide. Hepatitis C virus has a positive-strand RNA genome enclosed in a nucleocapsid and lipid envelope. The HCV genome is approximately 9.6 kb in length and encodes a polyprotein of about 3,000 amino acids. There are at least six major genotypes, which have different geographic distributions. In the United States (US), for example, genotypes la and lb account for about 75 % of cases, and genotypes 2 and 3 for 10-20 % of cases. Significant differences are observed in the geographic distribution of HCV genotypes. For example, in Europe genotypes 2 and 3 comprise up to one half of cases whereas genotype 3 is thought to dominate in India. In addition, varied genotype distributions can be observed between countries in a particular region as well as in different areas of a given nation. In the US, HCV is the most common chronic bloodborne infection, affecting approximately 3.2 million persons. After infection with HCV, approximately 75-85% of people develop chronic infection, whilst 60-70% develop chronic liver disease. Of these, 5- 20% go on to develop cirrhosis over a period of 20-30 years, and, finally, 1-5% succumb to the consequences of chronic infection (liver cancer/cirrhosis).

Until recently, the only treatment option for HCV was 24 or 48 weeks of combination therapy consisting of weekly injections of pegylated interferon (peg-IFN) and oral ribavirin for 24 or 48 weeks. The best treatment response is seen in patients with HCV genotypes 2 and 3, in whom sustained viral response (SVR) rates of approximately 80% can be achieved with 24 weeks of therapy. Patients with HCV genotype 1 remain the most difficult to treat, with SVR rates of approximately 40% after 48 weeks of therapy. In addition to the low response rates, combination peg- IFN/ribavirin therapy is limited by serious side effects, including fatigue, influenza- like symptoms, depression and suicide with peg-IFN, and haemolytic anaemia with ribavirin. Furthermore, peg-IFN/ribavirin therapy is contra-indicated in patients who have depression, anaemia, HCV-related decompensated cirrhosis, alcohol/substance abuse and autoimmune disorders or who are pregnant.

New treatment options for HCV became available in May 2011 with the US launch of the first direct-acting antiviral (DAA) HCV drugs, telaprevir (Vertex Pharmaceuticals) and boceprevir (Merck). Both drugs are protease inhibitors and are approved for the treatment of chronic HCV genotype 1 infection in combination with peg-IFN and ribavirin. Pivotal phase 3 trials demonstrated that the addition of telaprevir or boceprevir to peg-IFN/RBV therapy achieved shortened durations of therapy and potent viral suppression, with SVR rates approaching 75% in genotype 1 treatment-naive patients and 30% to 85% in treatment-experienced patients.

However, addition of a third drug to the treatment regimen has resulted in increased adverse events. Telaprevir is associated with an increased incidence of rash and anaemia, while boceprevir is associated with anaemia and dysgeusia. Triple therapy with telaprevir or boceprevir and peg-IFN/ribavirin remains unsuitable for those intolerant to or with contraindications to peg-IFN/ribavirin therapy.

Due to the limited tolerability, efficacy, side effects, genotype coverage and concern over the emergence of resistance there is an ongoing need to find alternative agents for the treatment of HCV. The majority of compounds that are currently in development have a limited spectrum of activity against the various HCV genotypes and, in many cases, are only active against HCV genotypes lb and/or la.

The HCV genome possesses structural (core) and non-structural (NS2, NS3, NS4A, NS4B, NS5A and NS5B) proteins. The non-structural proteins are involved in viral genomic replication, with the initial synthesis of RNA carried out by NS5B RNA dependent RNA polymerase. The NS5B protein is a key target for anti-HCV therapy, as it is essential for HCV replication and has no human host equivalent. This protein has been well characterised and is a validated target for drug discovery. HCV therapy is also anticipated to evolve towards oral multidrug therapy, in which combinations of different DAA drugs with complementary mechanisms of action serve to increase viral suppression and delay or prevent the emergence of resistance.

Due to the limited tolerability, efficacy, side effects and concern over the emergence of resistance there is an ongoing need to find alternative agents for the treatment of HCV, particularly with targeted mechanisms of action such as NS5B inhibitors.

SUMMARY

The inventors have found a new class of antiviral compounds, more particularly NS5B polymerase inhibitors for the treatment of HCV infections.

Compounds of the present invention are therefore considered to be useful in treating and preventing hepatitis C infections when used on their own or in combination with one or more other antiviral agents such as ribavirin, an antiviral nucleoside, polymerase inhibitor, protease inhibitor and/or inhibitor of viral entry, assembly or egress. The combination may also additionally comprise at least one immunomodulatory agent for example an interferon or interferon derivative and/or an inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH).

It is also believed that compounds of the invention will be efficacious in combination with at least one other DAA with a different mechanism of action and a complementary resistance profile (for example an NS5A inhibitor, a nucleoside or nucleotide NS5B inhibitor or a NS3 protease inhibitor) thereby offering an alternative treatment regime for patients not eligible for or treatable with the recently approved triple combination therapy.

According to a first aspect there is provided a compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof:

(I)

wherein

— represents a single or a double-bond as the case may be; Xi is selected from S, S=0 and S(=0)₂;

R_t is H, an optional substituent, or is selected from optionally substituted Ci_ ₆alkyl, optionally substituted C2-₆alkenyl, optionally substituted C2-₆alkynyl, optionally substituted C3_₆cycloalkyl, optionally substituted C3_₆cycloalkenyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5-10-membered heteroaryl;

R₂ is selected from H or an optional substituent;

R4 and R5 are each independently selected from H and optionally substituted Ci-₆alkyl; and

R₃ is optionally substituted and is selected from C3_₆cycloalkyl, C3- ₆cycloalkenyl, 3-10-membered heterocyclyl, C6-ioaryl and 5-10-membered heteroaryl.

In a second aspect there is provided a process for producing the compound of formula (I) defined above comprising the step of coupling a compound of formula

Z is selected from OH, OCi_₆alkyl and NR4R5, preferably NR4R5; V and W are coupling partners each independently selected from halo, triflate (OTf), boronic acid (e.g. B(OH)₂) or a boronic ester (e.g. B(OR)2 wherein R is

a stannylated moiety (e.g. a stannylated alkyl group such as Sn(R)₃ wherein R is Ci-₆alkyl), C_{2- 6}alkenyl and C2-₆alkynyl groups; and

Ri, R₂, R₃, R4, R5 and Xi are as previously defined for formula (I) provided that Ri is other than H.

The compounds of formula (II) are also believed to be novel and accordingly in one embodiment there is a provided a compound of formula (II), particularly for use as a process intermediate.

The compounds of formula (I) are inhibitors of HCV. In particular, the compounds of formula (I) inhibit RNA synthesis by the RNA dependent R A polymerase of HCV (the S5B protein encoded by HCV). NS5B polymerase inhibitors have been clinically validated as potential antiviral agents for the treatment of HCV infection.

In a third aspect, there is provided a pharmaceutical agent comprising the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

There is also provided use of the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof as a pharmaceutical agent.

There is further provided the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof for use as a pharmaceutical agent.

The pharmaceutical agent may be an antiviral agent.

In a fourth aspect, there is provided a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a S5B polymerase inhibitor comprising the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

There is also provided use of the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof as a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a NS5B polymerase inhibitor.

There is further provided the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof for use as a viral polymerase inhibitor in particular a HCV polymerase inhibitor such as a NS5B polymerase inhibitor.

The compound of formula (I) may be administered in the form of a pharmaceutical composition together with a pharmaceutically acceptable carrier.

In a fifth aspect, there is provided a pharmaceutical composition comprising the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof and a pharmaceutically acceptable carrier.

According to one embodiment, the pharmaceutical composition additionally comprises a therapeutically effective amount of one or more antiviral agents such as at least one other anti-HCV agent and/or one or more immunomodulatory agents.

In a sixth aspect, there is provided a method for the treatment of a Flaviviridae viral infection such as a HCV infection which comprises administering an effective amount of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof or the pharmaceutical composition defined above to a subject diagnosed with, suffering from or at risk of developing said viral infection.

There is also provided use of the compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof or the pharmaceutical composition as defined above in the manufacture of a medicament for use in the treatment of a Flaviviridae viral infection such as a HCV infection.

There is further provided use of the compound of formula (I) or salts, N- oxides, solvates, hydrates, racemates, enantiomers or isomers thereof or the pharmaceutical composition as defined above in the treatment of a Flaviviridae viral infection such as a HCV infection.

There is still further provided the compound of the formula (I) or salts, N- oxides, solvates, hydrates, racemates, enantiomers or isomers thereof or the pharmaceutical composition defined above for use in the treatment of a Flaviviridae viral infection such as a HCV infection.

In a seventh aspect, there is provided a method of inhibiting the RNA- dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to an effective amount of the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

In an eighth aspect, there is provided a method of inhibiting HCV replication comprising exposing a cell infected with HCV to an effective amount of the compound of formula (I) defined above or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

DETAILED DESCRIPTION

The present invention relates to compounds of formula (I) which inhibit viral polymerases and are useful in the treatment of Flaviviridae viral infections, particularly, hepatitis C (HCV).

Compounds

The present invention relates to compounds of formula (I), salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof as defined above.

In one embodiment Xi is S and -— represents a double bond.

In one embodiment Ri is H. In another embodiment, i is selected from optionally substituted C_{3- 6}cycloalkyl, optionally substituted C3_₆cycloalkenyl, optionally substituted 3-10- membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5- 10-membered heteroaryl.

In a further embodiment, Ri is optionally substituted phenyl or an optionally substituted 5- or 6- membered heteroaryl. In a particular embodiment Ri is optionally substituted phenyl.

Optionally substituted 5-membered heteroaryl include optionally substituted thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazoyl, oxazolyl, isoxazolyl, oxadiazolyl, furazanyl, thiazolyl, isothiazoyl and thiadiazolyl.

Optionally substituted 6-membered heteroaryl include optionally substituted pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. In a particular embodiment Ri is optionally substituted pyridinyl.

In still another embodiment when Ri is optionally substituted such as optionally substituted phenyl or an optionally substituted 5- or 6- membered heteroaryl such as thiophenyl or pyridinyl, where suitable optional substituents include but are not limited to one or more substituents, preferably 1 to 3 substituents or 1 or 2 substituents.

In a particular embodiment Ri is phenyl substituted with 1, 2 or 3 substituents which may be the same or different.

In one embodiment the substituents on Ri are each independently selected from halo, optionally substituted

optionally substituted C2-₆alkenyl, Ci_ ealkylhalo, OH, Ci_₆alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHCi_₆alkyl, N(Ci_₆alkyl)₂, N0₂ and R₆ where Re is selected from C0₂R₇,

NHR₇, NHC(=0)R₇, NCi_₆alkylC(=0)R₇, S0₂NHC(=0)R₇ and S0₂NCi_

₆alkylC(=0)R₇ and R₇ is selected from H, optionally substituted

optionally substituted C₂_₆alkenyl, optionally substituted C₂_₆alkynyl, optionally substituted C3- ₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl, optionally substituted 5-10-membered heteroaryl and [CRsR^Rio where Rs and R9 are each independently selected from H, optionally substituted

or together with the carbon atom to which they are attached join to form a fused spirocycloalkyl such as cyclopropyl and cyclobutyl or spiroheterocyclyl ring system such as oxetane; and Rio is selected from H, optionally substituted

C0₂R4 optionally substituted C3_₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5-10- membered heteroaryl.

In one embodiment, R₇ and Rio are independently selected from optionally substituted Ci_₆alkyl, optionally substituted C3_₆cycloalkyl such as cyclopropyl and cyclobutyl, C6-ioaryl such as optionally substituted phenyl or optionally substituted 2,3-dihydroindene and optionally substituted 5-10 membered heteroaryl such as optionally substituted 6 membered heteroaryl for example 6 membered heteroaryl containing nitrogen including pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl.

In another embodiment the substituents on Ri are each independently selected from halo (particularly chloro and/or fluoro), Ci_₃alkyl (particularly methyl), Ci_ ₃alkoxy (particularly methoxy) and R6.

In a further embodiment R6 is C(=0)NHR₇ wherein R₇ is selected from Ci_ ₆alkyl, optionally substituted C₃_₆cycloalkyl (such as cyclopropyl and cyclobutyl), C₆. _loaryl (such as optionally substituted phenyl or optionally substituted 2,3- dihydroindene), optionally substituted 5-10 membered heteroaryl (such as optionally substituted 6 membered heteroaryl for example 6 membered heteroaryl containing nitrogen including pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl) and [CRsRgJRio.

In a particular embodiment R₆ is C(=0)NHR₇ and R₇ is [CRsR^Rio where Rs and R₉ are each independently selected from H, Ci_₃alkyl preferably methyl or Rg and R₉ together with the carbon atom to which they are attached join to form a cyclopropyl, cyclobutyl or oxetane spiro ring system; and Rio is selected from H, optionally substituted

CO2R4, optionally substituted C6-ioaryl (preferably optionally substituted phenyl), optionally substituted 5-10 membered heteroaryl (such as optionally substituted 6 membered heteroaryl preferably 6 membered heteroaryl containing nitrogen including pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl)

Suitable optional substituents on Rio include halo (particularly chloro and/or fluoro), Ci-₃alkyl (particularly methyl) and

(particularly methoxy).

In still a further embodiment Ri is substituted with R6 (particularly

C(=0)NHR₇ where R₇ is as previously defined) wherein Ri may be further optionally substituted with halo,

CN, NH₂, NHCi-₃alkyl, N(Ci_₃alkyl)₂ or NO2, even more preferably halo (particularly chloro and/or fluoro),

(particularly methyl) and (particularly methoxy). In one embodiment R2 is H or is an optionally substituted selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C₂-₆alkenyl, Ci_₆alkylhalo, OH, Ci_₆alkoxy, d_₆alkoxyhalo, CN, NH₂, NHCi_₆alkyl, N(Ci_₆alkyl)₂, N0₂ and R₆ wherein R₆ is selected from C0₂R₇,

NHR₇,

In a further embodiment R₂ is H.

In one embodiment R₃ is optionally substituted phenyl or an optionally substituted 6-membered heteroaryl.

In a further embodiment R₃ is optionally substituted phenyl.

In still another further embodiment R₃ is optionally substituted 6-membered heteroaryl.

Optionally substituted 6-membered heteroaryl include optionally substituted pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl. In a particular embodiment R₃ is optionally substituted pyridinyl.

In still another embodiment when ₃ is optionally substituted such as optionally substituted phenyl or an optionally substituted 6-membered heteroaryl, suitable optional substituents include but are not limited to one or more substituents, more preferably 1 to 3 or 1 or 2 substituents, particularly in the meta and/or para position(s). In a further embodiment the optional substituents are each independently selected from halo, optionally substituted Ci-₆alkyl, optionally substituted C₂_₆alkenyl, Ci_₆alkylhalo, OH, Ci_₆alkoxy, d_₆alkoxyhalo, CN, NH₂, NHCi_₆alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

and S0₂NCi_ ₆alkylC(=0)R₇.

In a particularly preferred embodiment R₃ is phenyl optionally substituted with

Ci-₃alkyl, preferably methyl or halo, preferably chloro and/or fluoro.

In one embodiment R4 is H and R5 is

preferably methyl.

In a further embodiment the compound of formula (I) is a compound of formula (la)

(la)

wherein X₂ is N, CH or C-R_a;

Yi is H or one or more Rt,;

each R_a and R_b are independently selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C2-₆ lkenyl, Ci_₆alkylhalo, OH, C^alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHC^alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

NCi_₆alkylC(=0)Ci_ ₃alkyl and S0₂NHC(=0)R₇ and S0₂NCi_₆alkylC(=0)R₇;

and— , R₂, R3, R4, R5, R6, R₇ and i are as previously defined.

In one embodiment X is N.

In another embodiment X₂ is CH.

In still another embodiment X₂ is C-R_a.

In one embodiment Y_t is H.

In another embodiment Yi is one or more R_b, preferably halo,

or

Ci_₃alkoxy.

In another embodiment the compound of formula (I) is a compound of formula

(lb)

(lb)

wherein

X₃ and X4 are each independently selected from N, CH and C-R_c;

Y₂ is H or one or more Ra;

each R. and j are independently selected from halo, optionally substituted

optionally substituted C₂_₆alkenyl,

Ci_₆alkoxyhalo, CN, NH₂, NHC^alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

NCi_₆alkylC(=0)Ci_

₆alkyl, S0₂NHC(=0)R₇ and SOzNC^alkylC^C R,;

and— , Ri, R2, R4, R5, R₇ and i are as previously defined.

In one embodiment X3 or X₄ is N and the other is CH or C-R_c.

In another embodiment X3 or X₄ is CH and the other is C-R_c.

In still another embodiment X3 and X₄ are both independently C-R_c.

In yet another embodiment X3 and X₄ are both CH.

In one embodiment Y2 is H.

In another embodiment Y2 is one or more R_d, preferably halo.

In yet another embodiment the compound of formula (I) is a compound of formula (Ic)

(Ic)

wherein— , R₂, R4, R5, R6, Xi, X₂, X3, X4, Yi and Y₂ are as previously defined.

In one embodiment with respect to the compounds of any one of formulae (I),

(la), (lb) and (Ic): Xi is S.

In a particularly preferred embodiment with respect to the compounds of any one of formulae (I), (la), (lb) and (Ic): Xi is S; and— is a double bond. In another embodiment X_t is S; and— is a single bond. The compounds with respect to any one of formulae (I), (la), (lb) and (Ic) where Xi is S may be oxidized under suitable oxidation conditions familiar to those skilled in the art to provide compounds wherein

Xi S(=0) or S(=0)2. Accordingly, in another embodiment Xi is S(=0) or S(=0)?.

In yet another embodiment of the compounds with respect to any one of formulae (I), (la), (lb) and (Ic) R4 is H and R5 is

particularly methyl.

In still another embodiment there is provided a compound selected from the group consisting of:

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide (1);

6-(4-fluorophenyl)-N-methyl-2-{3-[(2-phenylpropan-2-yl)carbamoyl]phenyl} imidazo[2, l-b][l,3]thiazole-5-carboxamide (2); 6-(4-fluorophenyl)-N-methyl-2-(3 - { [ 1 -(pyridin-2-yl)cyclopropyl]carbamoyl}phenyl) imidazo[2, l-b][l,3]thiazole-5-carboxamide (3);

6-(4-fluorophenyl)-N-methyl-2-{3-[(l-phenylcyclopropyl)carbamoyl]phenyl} imidazo[2, l-b][l,3]thiazole-5-carboxamide (4);

2-[3-(cyclopropylcarbamoyl)phenyl]-6-(4-fluorophenyl)-N-methylimidazo[2, 1 - b] [ 1 , 3 ]thiazole-5 -carboxamide (5);

2-{2-chloro-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (6);

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-fluoroplienyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (7);

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[l-(pyridin-2-yl)cyclopropyl] carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (8);

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[(lR)-l-phenylethyl]carbamoyl}phenyl) imidazo[2, l-b][l,3]thiazole-5-carboxamide (9);

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[(lS)-l-plienylethyl]carbamoyl}phenyl) imidazo[2, l-b][l,3]thiazole-5-carboxamide(10);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-phenylcyclopropyl)carbamoyl] phenyl} imidazo [2, 1 -b] [ 1 ,3 ]thiazole-5 -carboxamide (11);

6-(4-fluorophenyl)-2-{5-[(l-hydroxy-2-methylpropan-2-yl)carbamoyl]-2- methylphenyl}-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (12);

Methyl N-{3-[6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, l-b][l,3]thiazol-2- yl]-4-methylbenzoyl} -2-methylalaninate (13);

6-(4-fluorophenyl)-2-{5-[(6-hydroxy-2,3-dihydro-lH-inden-l-yl)carbamoyl]-2- methylphenyl}-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (14);

6-(4-fluorophenyl)-2-(5-{[2-(4-fluorophenyl)propan-2-yl]carbamoyl}-2-methyl phenyl)-N-methylimidazo[2,l-b][l,3]thiazole-5-carboxamide (15);

6-(4-fluorophenyl)-2-(5-{[2-(3-methoxyphenyl)propan-2-yl]carbamoyl} -2- methylphenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (16);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-methylcyclopropyl)carbamoyl] phenyl} imidazo[2,l-b][l,3]thiazole-5-carboxamide (17);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-methylcyclopropyl)carbamoyl] phenyl} imidazo[2,l-b][l,3]thiazole-5-carboxamide (18);

6-(4-fluorophenyl)-N-methyl-2-{5-[(2-phenylpropan-2-yl)carbamoyl]thiophen-3- yl } imidazo [2, 1 -b] [ 1 , 3 ] thiazole-5 -carboxamide (19) ; 6-(4-fluorophenyl)-N-methyl-2-(5-{[l-(pyridin-2-yl)cyclopropyl]carbamoyl} thiophen-3-yl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (20);

2-(5 -amino-2-methylphenyl)-6-(4-fluorophenyl)-N-methylimidazo [2, 1 - b][l,3]thiazole-5-carboxamide (21);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-methyl-2-phenylpropanoyl) amino]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide (22);

2- {5-[(cyclopropylcarbonyl)amino]-2-methylphenyl}-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (23);

2- {5-[tert-butyl(methyl)carbamoyl]-2-methylphenyl}-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (24);

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(4-methylphenyl)propan-2- yljcarbamoyl} phenyl) imidazo [2, 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (25) ;

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(pyridin-2-yl)propan-2- yljcarbamoyl} phenyl) imidazo [2, 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (26) ;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-4-[(2-phenylpropan-2- yl)carbamoyl]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide (27);

2-[4-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (28);

6-(4-fluorophenyl)-2-{2-methoxy-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl}-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (29);

N-{3-[6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, l-b][l,3]thiazol-2-yl]-4- methylbenzoyl} -2-methylalanine (30);

6-(2-chloro-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2, l-b]thiazole-5-carboxamide

(31) ;

6-(2-hydroxy-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2, 1 -b]thiazole-5 -carboxamide

(32) ;

6-(2-hydroxy-4-pyridyl)-N-methyl-l-oxo-2,3-dihydroimidazo[2, l-b]thiazole-5- carboxamide (33);

6-(4-fluorophenyl)-2-{4-methoxy-2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl}-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (34); 2-[5-(tert-butylcarbamoyl)-4-methoxy-2-methylphenyl]-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (35);

6-(4-fluorophenyl)-N-methyl-2-{2-[(2-phenylpropan-2-yl)carbamoyl]pyridin-4- yl} imidazo[2, l-b][l,3]thiazole-5-carboxamide (36); 6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-phenylcyclobutyl)carbamoyl] phenyl} imidazo[2,l-b][l,3]thiazole-5-carboxamide (37);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-methylbutan-2-yl)carbamoyl] phenyl } imidazo [2, 1 -b] [ 1 ,3 ]thiazole-5 -carboxamide (38);

2- {2-chloro-4-methoxy-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6-(4- fluorophenyl)-N-methylimidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide (39);

2-(2-chloro-4-methoxy-5- {[l-(propan-2-yl)cyclopropyl]carbamoyl}phenyl)-6-(4- fluorophenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (40);

6-(3-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-phenylpropan-2-yl)

carbamoyl]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide (41);

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(3-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (42);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(3-methyloxetan-3-yl)

carbamoyl]phenyl} imidazo [2, 1-b] [ l,3]thiazole-5-carboxamide (43);

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- { [ 1 -(pyridin-3 -yl)cyclopropyl] carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (44);

6-(4-chlorophenyl)-N-methyl-2-{2-methyl-5-[(2-phenylpropan-2-yl)

carbamoyl]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide (45);

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-chlorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (46);

2-(5-{[2-(4-chlorophenyl)propan-2-yl]carbamoyl}-2-methylphenyl)-6-(4- fluorophenyl)-N-methylimidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide (47);

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-methylpropyl)carbamoyl]phenyl} imidazo[2, 1 -b] [ 1 , 3 ]thiazole-5-carboxamide (48);

N-methyl-6-(4-methylphenyl)-2- {2-methyl-5-[(2-phenylpropan-2-yl)carbamoyl] phenyl } imidazo [2 , 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (49) ;

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-N-methyl-6-(4-methylphenyl) imidazo[2, 1 -b] [ 1 , 3 ]thiazole-5-carboxamide (50);

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-N-methyl-6-phenylimidazo[2, l- b][l, 3 ]thiazole-5 -carboxamide (51);

N-methyl-2-{2-methyl-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl}-6- phenylimidazo[2, l-b][l,3]thiazole-5-carboxamide (52);

6-(4-fluorophenyl)-N-methyl-2-{5-[(2-phenylpropan-2-yl)carbamoyl]pyridin-3-yl} imidazo[2, l-b][l,3]thiazole-5-carboxamide (53); and 6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(pyrimidin-2-yl)propan-2-yl] carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (54);

and salts, N-oxides, solvates, hydrates, racemates, enantiomers and isomers thereof.

The term

refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (z-Pr), butyl (Bu), isobutyl (z^'-Bu), sec -butyl (s- Bu), tert-butyl (z-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term

also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. "Ci_ ₄alkyl" and "Ci_₃alkyl" including methyl, ethyl, propyl, z^'sopropyl, n-butyl, zso-butyl, sec -butyl and tert-butyl are preferred with methyl being particularly preferred.

The term "C2-₆alkenyl" refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1- propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. Unless the context requires otherwise, the term "C2-₆alkenyl" also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. "C₂- ₄alkenyl" and "C2-₃alkenyl" including ethenyl, propenyl and butenyl are preferred with ethenyl being particularly preferred.

The term "C2-₆alkynyl" refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl and the like. Unless the context indicates otherwise, the term "C2-₆alkynyl" also encompasses alkynyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. C2-₃alkynyl is preferred.

The term "C3_₈cycloalkyl" refers to non-aromatic cyclic groups having from 3 to 8 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. It will be understood that cycloalkyl groups may be saturated such as cyclohexyl or unsaturated such as cyclohexenyl. C3_₆cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferred.

The terms "hydroxy" and "hydroxyl" refer to the group -OH.

The term "oxo" refers to the group =0. The term

refers to an alkyl group as defined above covalently bound via an O linkage containing 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy and pentoxy.

including methoxy, ethoxy, propoxy and butoxy are preferred with methoxy being particularly preferred.

The ter fers to a Ci-₆alkyl which is substituted with one or more halogens. ps are preferred, such as for example, -CHF₂ and - CF₃.

The ter

refers to a which is substituted with one or more halogens. Ci_₃alkoxyhalo groups are preferred, such as for example, -OCHF₂

The term "carboxylate" or "carboxyl" refers to the group -COO^" or -COOH.

The term "ester" refers to a carboxyl group having the hydrogen replaced with, for example a

group ("carboxylCi_₆alkyl" or "alkylester"), an aryl or aralkyl group ("arylester" or "aralkylester") and so on. C0₂Ci_₃alkyl groups are preferred, such as for example, methylester (CO ₂Me), ethylester (C0₂Et) and propylester (C0₂Pr) and includes reverse esters thereof (e.g. -OCOMe, -OCOEt and -OCOPr).

The term "cyano" refers to the group -CN.

The term "nitro" refers to the group -N0₂.

The term "amino" refers to the group -NH₂.

The term "substituted amino" or "secondary amino" refers to an amino group having a hydrogen replaced with, for example a

group ("Ci_₆alkylamino"), an aryl or aralkyl group ("arylamino", "aralkylamino") and so on. C 1-3 alky lamino groups are preferred, such as for example, methylamino (NHMe), ethylamino (NHEt) and propylamino (NHPr).

The term "disubstituted amino" or "tertiary amino" refers to an amino group having the two hydrogens replaced with, for example a Ci-₆alkyl group, which may be the same or different ("dialkylamino"), an aryl and alkyl group ("aryl(alkyl)amino") and so on. Di(Ci_₃alkyl)amino groups are preferred, such as for example,

dimethylamino (NMe₂), diethylamino (NEt₂), dipropylamino (NPr₂) and variations thereof (e.g. N(Me)(Et) and so on).

The term "acyl" or "aldehyde" refers to the group -C(=0)H.

The term "substituted acyl" or "ketone" refers to an acyl group having a hydrogen replaced with, for example a C_halky! group

or "alkylketone" or "ketoalkyl"), an aryl group ("arylketone"), an aralkyl group

("aralkylketone) and so on. C^alkylacyl groups are preferred.

The term "amido" or "amide" refers to the group -C(0)NH₂.

The term "aminoacyl" refers to the group -NHC(0)H.

The term "substituted amido" or "substituted amide" refers to an amido group having a hydrogen replaced with, for example a Ci_₆alkyl group ("Ci_₆alkylamido" or "Ci-₆alkylamide"), an aryl ("arylamido"), aralkyl group ("aralkylamido") and so on. Ci-₃alkylamide groups are preferred, such as for example, methylamide (- C(O)NHMe), ethylamide (-C(O)NHEt) and propylamide (-C(O)NHPr) and includes reverse amides thereof (e.g. -NHMeC(O)-, -NHEtC(O)- and -NHPrC(O)-).

The term "disubstituted amido" or "disubstituted amide" refers to an amido group having the two hydrogens replaced with, for example a Ci_₆alkyl group ("di(Ci_ ₆alkyl)amido" or "di(Ci_₆alkyl)amide"), an aralkyl and alkyl group

("alkyl(aralkyl)amido") and so on. Di(C 1-3 alky l)amide groups are preferred, such as for example, dimethylamide (-C(0)NMe₂), diethylamide (-C(0)NEt₂) and dipropylamide ((-C(0)NPr₂) and variations thereof (e.g. -C(0)N(Me)Et and so on) and includes reverse amides thereof.

The term "thiol" refers to the group -SH.

The term

refers to a thiol group having the hydrogen replaced with a

groups are preferred, such as for example, thiolmethyl, thiolethyl and thiolpropyl.

The term "thioxo" refers to the group =S.

The term "sulfmyl" refers to the group -S(=0)H.

The term "substituted sulfinyl" or "sulfoxide" refers to a sulfinyl group having the hydrogen replaced with, for example a Ci_₆alkyl group ("Ci_₆alkylsulfinyl" or "Ci_ ₆alkylsulfoxide"), an aryl ("arylsulfinyl"), an aralkyl ("aralkyl sulfinyl") and so on. Ci-₃alkylsulfinyl groups are preferred, such as for example, -SOmethyl, -SOethyl and -SOpropyl.

The term "sulfonyl" refers to the group -S0₂H.

The term "substituted sulfonyl" refers to a sulfonyl group having the hydrogen replaced with, for example a Ci_₆alkyl group

an aryl

("arylsulfonyl"), an aralkyl ("aralkylsulfonyl") and so on.

groups are preferred, such as for example, -S0₂Me, -S0₂Et and -S0₂Pr.

The term "sulfonylamido" or "sulfonamide" refers to the group -S0₂NH₂. The term "substituted sulfonamide)" or "substituted sulphonamide" refers to an sulfonylamido group having a hydrogen replaced with, for example a Ci_₆alkyl group ("sulfonylamidoCi-₆alkyl"), an aryl ("arylsulfonamide"), aralkyl

("aralkylsulfonamide") and so on. SulfonylamidoCi_₃alkyl groups are preferred, such as for example, -S0₂NHMe, -S0₂NHEt and -S0₂NHPr and includes reverse sulfonamides thereof (e.g. -NHS0₂Me, -NHS0₂Et and -NHS0₂Pr).

The term "disubstituted sufonamido" or "disubstituted sulphonamide" refers to an sulfonylamido group having the two hydrogens replaced with, for example a Ci_ ₆alkyl group, which may be the same or different ("sulfonylamidodi(Ci_₆alkyl)"), an aralkyl and alkyl group ("sulfonamido(aralkyl)alkyl") and so on. Sulfonylamidodi(Ci_ ₃alkyl) groups are preferred, such as for example, -S0₂NMe₂, -S0₂NEt₂ and -S0₂NPr₂ and variations thereof (e.g. -S0₂N(Me)Et and so on) and includes reserve sulfonamides thereof.

The term "sulfate" refers to the group OS(0)₂OH and includes groups having the hydrogen replaced with, for example a Ci_₆alkyl group ("alkylsulfates"), an aryl ("arylsulfate"), an aralkyl ("aralkylsulfate") and so on. Ci_₃sulfates are preferred, such as for example, OS(0)₂OMe, OS(0)₂OEt and OS(0)₂OPr.

The term "sulfonate" refers to the group SO₃H and includes groups having the hydrogen replaced with, for example a

group ("alkylsulfonate"), an aryl ("arylsulfonate"), an aralkyl ("aralkylsulfonate") and so on. Ci_₃Sulfonates are preferred, such as for example, S(¾Me, SOsEt and SC^Pr.

The term "aryl" refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri-cyclic ring system which may be fused or linked provided at least one ring is aromatic. The aromatic ring or ring system is generally composed of 6 to 10 carbon atoms. Examples of aryl groups include but are not limited to phenyl, biphenyl 2,3-dihydroindene, naphthyl and tetrahydronaphthyl. 6-membered aryls such as phenyl are preferred. The term "alkylaryl" refers to

such as benzyl. The term "alkoxyaryl" refers to Ci_₆alkyloxyaryl such as benzyloxy.

The term "heterocyclyl" refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which 1, 2, 3 or 4 are ring heteroatoms each heteroatom being independently selected from O, S and N.

In this context, the prefixs 3-, 4-, 5-, 6-, 7-, 8-, 9- and 10- membered denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, the term "3-10 membered heterocylyl", as used herein, pertains to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9 or 10 ring atoms. Examples of heterocylyl groups include 5-6-membered monocyclic heterocyclyls and 9-10 membered fused bicyclic heterocyclyls.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those containing one nitrogen atom such as aziridine (3 -membered ring), azetidine (4- membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5- dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5- membered rings) , piperidine, dihydropyridine, tetrahydropyridine (6-membered rings), and azepine (7-membered ring); those containing two nitrogen atoms such as imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline (dihydropyrazole) (5- membered rings), piperazine (6-membered ring); those containing one oxygen atom such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane

(tetrahydrofuran), oxole (dihydrofuran) (5-membered rings), oxane (tetrahydropyran), dihydropyran, pyran (6-membered rings), oxepin (7-membered ring); those containing two oxygen atoms such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); those containing three oxygen atoms such as trioxane (6-membered ring); those containing one sulfur atom such as thiirane (3- membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5- membered ring), thiane (tetrahydrothiopyran) (6-membered ring), thiepane (7- membered ring); those containing one nitrogen and one oxygen atom such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5- membered rings), morpholine, tetrahydrooxazine, dihydrooxazine, oxazine (6- membered rings); those containing one nitrogen and one sulfur atom such as thiazoline, thiazolidine (5-membered rings), thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur such as: oxathiole (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen and one sulfur atom such as oxathiazine (6-membered ring).

Heterocyclyls also encompass aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.

The term "aromatic heterocyclyl" may be used interchangeably with the term "heteroaromatic" or the term "heteroaryl" or "hetaryl". The heteroatoms in the aromatic heterocyclyl group may be independently selected from N, S and O. "Heteroaryl" is used herein to denote a heterocyclic group having aromatic character and embraces aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also encompasses pseudoaromatic heterocyclyls. The term "pseudoaromatic" refers to a ring system which is not strictly aromatic, but which is stabilized by means of derealization of electrons and behaves in a similar manner to aromatic rings. The term aromatic heterocyclyl therefore covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non- aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety by the aromatic ring or by a non-aromatic ring.

Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

Aromatic heterocyclyl groups may be 5-membered or 6-membered monocyclic aromatic ring systems.

Examples of 5-membered monocyclic heteroaryl groups include but are not limited to furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyls and furazanyl i.e. 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyls), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyls) and the like.

Examples of 6-membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl and the like. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (1 nitrogen), pyrazinyl, pyrimidinyl and pyridazinyl (2 nitrogens).

Aromatic heterocyclyl groups may also be bicyclic or polycyclic

heteroaromatic ring systems such as fused ring systems (including purine, pteridinyl, napthyridinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl and the like) or linked ring systems (such as oligothiophene, polypyrrole and the like). Fused ring systems may also include aromatic 5-membered or 6-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like, such as 5-membered aromatic heterocyclyls containing nitrogen fused to phenyl rings, 5-membered aromatic heterocyclyls containing 1 or 2 nitrogens fused to phenyl ring.

A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6- membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6- membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; I) a furan ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,l-b]thiazole) and imidazoimidazole (e.g.

imidazo[l,2-a]imidazole). Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.

pyrazolof l ,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[l,5- a]pyridine) groups. A further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.

Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.

Examples of heteroaryl groups containing an aromatic ring and a non- aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline,

tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[l,4]dioxine, benzo[l,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.

Examples of aromatic heterocyclyls fused to carbocyclic aromatic rings may therefore include but are not limited to benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl and the like.

The term "non-aromatic heterocyclyl" encompasses optionally substituted saturated and unsaturated rings which contain at least one heteroatom selected from the group consisting of N, S and O.

Non-aromatic heterocyclyls may be 3-7 membered mono-cyclic rings.

Examples of 5-membered non-aromatic heterocyclyl rings include 2H- pyrrolyl, 1 -pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1 -pyrrolidinyl, 2- pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2- pyrazolinyl, 3 -pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl and the like. Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihyrdopyranyl, tetrahydropyranyl, 2H pyranyl, 4H pyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4- dithianyl, 1,3,5-triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4- oxathianyl, triazinyl, 1,4-thiazinyl and the like.

Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl and the like.

Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings such as linked ring systems (for example uridinyl and the like) or fused ring systems. Fused ring systems include non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings such as phenyl, napthyl, indenyl, azulenyl, fluorenyl, anthracenyl and the like. Examples of non-aromatic 5-membered, 6-membered or 7-membered heterocyclyls fused to carbocyclic aromatic rings include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl and the like.

The term "halo" refers to fluoro, chloro, bromo or iodo.

Unless otherwise defined, the term "optionally substituted" or "optional substituent" as used herein refers to a group which may or may not be further substituted with 1, 2, 3, 4 or more groups, preferably 1, 2 or 3, more preferably 1 or 2 groups selected from the group consisting of

C2-₆alkenyl, C2-₆alkynyl, C3. scycloalkyl, hydroxyl, oxo,

aryloxy, Ci_₆alkoxyaryl, halo, Ci_₆alkylhalo (such as CF₃ and CHF₂), Ci_₆alkoxyhalo (such as OCF₃ and OCHF₂), carboxyl, esters, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketones, amides, aminoacyl, substituted amides, disubstituted amides, thiol, alkylthio, thioxo, sulfates, sulfonates, sulfinyl, substituted sulfmyl, sulfonyl, substituted sulfonyl,

sulfonylamides, substituted sulfonamides, disubstituted sulfonamides, aryl, arCi_ ₆alkyl, heterocyclyl and heteroaryl wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl and groups containing them may be further optionally substituted. Optional substituents in the case of heterocycles containing N may also include but are not limited to Ci_₆alkyl i.e. N-Ci-₃alkyl, more preferably methyl particularly N-methyl. In one embodiment the optional substituent is selected from Ci-₆alkyl, hydroxyl,

and halo.

It will be understood that suitable derivatives of aromatic heterocyclyls containing nitrogen include N-oxides thereof. The compounds of the invention may also be prepared as salts which are pharmaceutically acceptable, but it will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present invention, since these are useful as intermediates in the preparation of pharmaceutically acceptable salts.

Examples of pharmaceutically acceptable salts include salts of pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, ammonium and alkylammonium; acid addition salts of pharmaceutically acceptable inorganic acids such as hydrochloric, orthophosphoric, sulfuric, phosphoric, nitric, carbonic, boric, sulfamic and hydrobromic acids; or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulfonic, trihalomethanesulfonic, toluenesulfonic,

benzenesulfonic, isethionic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic, valeric and orotic acids. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety.

The salts may be formed by conventional means, such as by reacting the free base form of the compound with one or more equivalents of the appropriate acid.

It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms or crystal forms thereof, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with

pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide (DMF) and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein. Additionally, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds of the present invention are also considered to be disclosed herein.

It will be understood that compounds of formula (I) may possess a chiral centre and may therefore exist as an isomer such as a racemate or an R- or S- enantiomer. The compounds may therefore be used as a purified enantiomer or diastereomer, or as a mixture of any ratio thereof. The isomers may be separated conventionally by chromatographic methods or using a resolving agent. Alternatively the individual isomers may be prepared by asymmetric synthesis using chiral intermediates. Where the compound has a carbon-carbon double bond, it may occur in Z- or E- form and all isomeric forms of the compounds being included in the present invention.

Viral Polymerase Inhibition

The ability of the compounds of formula I to inhibit RNA synthesis by the

RNA dependent RNA polymerase of HCV (NS5B) can be demonstrated by any assay capable of measuring RNA dependent RNA polymerase activity. A suitable assay is described in the examples.

While the invention is described with particular reference to compounds having inhibitory activity against a HCV NS5B polymerase, it will be understood that other polymerases can, if desired, be substituted in whole or in part for the HCV polymerase herein described. For example, one microbial polymerase target is HCV NS5B polymerase which is the viral RNA-dependent RNA polymerase (RdRp) that is responsible for viral replications. HCV NS5B protein, is released from a polyprotein and is involved in the synthesis of double -stranded RNA from a single-stranded viral RNA genome. It is believed that the replication and/or reproduction of HCV virus may be inhibited or prevented through the inhibition of NS5B polymerase and suppress or prevent the formation of the double-stranded HCV RNA.

To demonstrate that the compounds of formula (I) act by specific inhibition of NS5B polymerase, the compounds may be tested for the lack of inhibitory activity in an assay measuring the activity of an RNA-dependent RNA polymerase other than HCV polymerase or in a DNA dependent RNA polymerase assay.

Pharmaceutical Compositions

The invention also provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

The pharmaceutical composition may further comprise or be administered in combination with one or more other antiviral agents such as Ribavirin (Copegus® or Rebetol®), an antiviral nucleoside inhibitor of NS5b polymerase (such as 4-amino-7- (2-C-methyl^-D-ribofuranosyl)-pyrrolo[2, l-f][l,2,4]triazine; PSI-7977; PSI-938; RG7128 or mericitabine; IDX-184; ΓΝΧ-189 and other such agents that may be developed) a non-nucleoside inhibitor of NS5b polymerase (such as GS-9190 or tegobuvir; PF-868554 or filibuvir; VX-222; IDX-375; ABT-072; ABT-333; ANA-598 or setrobuvir; BI207127; JTK-853; GS-9669; and other such agents that may be developed), a NS3/4a protease inhibitor (such as telaprevir or Incivek®; boceprevir or Victrelis®; BI-201335; TMC-435; RG-7227 or danoprevir; MK-7009 or vaniprevir; GS-9451 ; GS-9256; BMS-650032; ACH-1625; ACH-2684; MK-5172; ABT-450; IDX-320; SCH-900518 and other such agents that may be developed), an NS5A inhibitor (such as BMS-790052 (daclatasvir); GS-5885; ABT-267; PPI-461; ACH- 2928; GSK2336805 and other such agents that may be developed) and/or inhibitor of viral entry, assembly or egress. The composition may also additionally comprise at least one immunomodulatory agent for example an interferon or interferon derivative such as interferon alpha 2B (such as Intron® A interferon available from Schering Corp., Kenilworth, N.J.), pegylated interferon alpha 2A (such as Pegasys® available from Hoffmann-LaRoche, Nutley, N.J.), pegylated interferon alpha 2B (such as Peg- Intron® available from Schering Corp., Kenilworth, N.J.), consensus interferon (such as interferon alphacon-1, or Infergen® available from Valeant Pharmaceuticals, Costa Mesa, CA.), interferon alpha 2A, recombinant interferon alpha 2A (such as Roferon® available from Hoffmann-LaRoche, Nutley, N.J.), or lymphoblastoid interferon tau, and/or an inhibitor of inosine-5' -monophosphate dehydrogenase (IMPDH) and other large or small molecules known to modulate host immune responses.

Accordingly, in one embodiment of the pharmaceutical composition, the other antiviral agent is Ribavarin optionally in combination with peg/IFN.

In another embodiment, the other antiviral agent is an NS5B inhibitor, more particularly a nucleoside inhibitor such as the bicyclic nucleosides and nucleotides of the general formula described in WO2010/002877, for example, 4-amino-7-(2-C- methyl- -D-ribofuranosyl)-pyrrolo [2, 1 -fj [ 1 ,2,4]triazine.

In yet another embodiment, the other antiviral agent is an NS3/4A protease inhibitor such as telaprevir (VX-950) or Incivek®; boceprevir or Victrelis®; BI- 201335; TMC-435; G-7227 or danoprevir; MK-7009 or vaniprevir; GS-9451; GS- 9256; BMS-650032; ACH-1625; ACH-2684; MK-5172; ABT-450; IDX-320; SCH- 900518, particularly telaprevir (VX-950).

In still another embodiment, the other antiviral agent is an NS5A inhibitor such as BMS-790052 (daclatasvir); GS-5885; ABT-267; PPI-461; ACH-2928;

GSK2336805, particularly BMS-790052 (daclatasvir).

It will be understood that combined administration of the compounds of the invention with the other antiviral agent may be concurrent, sequential or separate administration.

The term "composition" is intended to include the formulation of an active ingredient with conventional carriers and excipients, and also with encapsulating materials as the carrier, to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the encapsulation carrier. Any carrier must be "pharmaceutically acceptable" meaning that it is compatible with the other ingredients of the composition and is not deleterious to a subject. The compositions of the present invention may contain other therapeutic agents as described above, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavours, etc.) according to techniques such as those well known in the art of pharmaceutical formulation (See, for example, Remington: The Science and Practice of Pharmacy, 21st Ed., 2005, Lippincott Williams & Wilkins).

The pharmaceutical composition includes those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, sub-cutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration ; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispensable granules. A solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilisers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both.

The compositions according to the present invention may thus be formulated for parenteral administration (e. g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen- free water, before use.

Pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against oxidation and the contaminating action of microorganisms such as bacteria or fungi.

The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for the compounds, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal, epidural injection or infusion.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various other ingredients such as these enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilised active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying or freeze-drying of a previously sterile-filtered solution of the active ingredient plus any additional desired ingredients.

When the active ingredients are suitably protected they may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

The amount of active compound in therapeutically useful compositions should be sufficient that a suitable dosage will be obtained. The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter: a binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound (s) may be incorporated into sustained-release preparations and formulations, including those that allow specific delivery of the active peptide to specific regions of the gut.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.

Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilising agents, and the like.

For topical administration to the epidermis the compounds according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.

Formulations suitable for topical administration in the mouth include lozenges comprising active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension.

In the case of a spray, this may be achieved for example by means of a metering atomising spray pump. To improve nasal delivery and retention the compounds according to the invention may be encapsulated with cyclodextrins, or formulated with other agents expected to enhance delivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.

The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). Conveniently the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e. g. gelatin, or blister packs from which the powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract, including intranasal formulations, the compound will generally have a small particle size for example of the order of 5 to 10 microns or less. Such a particle size may be obtained by means known in the art, for example by micronisation.

When desired, formulations adapted to give sustained release of the active ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of a HCV viral infection in living subjects having a diseased condition in which bodily health is impaired.

The invention also includes the compounds in the absence of carrier where the compounds are in unit dosage form.

Compositions comprising compounds of the invention formulated for oral delivery either alone or in combination with another HCV antiviral agent are particularly preferred.

Methods of treatment

The compounds of formula (I) may be used in the treatment of a Flaviviridae viral infection such as a HCV infection.

Generally, the term "treatment" means affecting a subject, tissue or cell to obtain a desired pharmacological and/or physiological effect and includes: (a) inhibiting the viral infection, i.e. arresting its development or further development; (b) relieving or ameliorating the effects of the viral infection, i.e. cause regression of the effects of the viral infection; (c) reducing the incidence or the viral infection or (d) preventing the infection from occurring in a subject, tissue or cell predisposed to the viral infection disease or at risk thereof, but has not yet been diagnosed with a protective pharmacological and/or physiological effect so that the viral infection does not develop or occur in the subject, tissue or cell.

The prevention of hepatitis C means, for example, administration of a pharmaceutical agent to a subject found to carry a HCV by a test and the like but without a symptom of infection, or to a subject who shows an improved disease state of hepatitis after a treatment of hepatitis C, but who still carries a HCV and is associated with a risk of recurrence of hepatitis.

The term "subject" as used herein refers to any animal, in particular mammals such as humans having a disease or condition which requires treatment with the compound of formula (I).

The term "administering" refers to providing the compound or

pharmaceutical composition of the invention to a subject suffering from or at risk of the diseases or conditions to be treated or prevented.

The term "viral infection" refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.

The term "Flaviviridae virus" refers to a virus of the family Flaviviridae, which family includes the Hepacivirus Flavivirus and Pestivirus or hepatitis C-like virus genera. A representative species of the genus of hepatitis C-like viruses is hepatitis C virus.

Dosages

The term "therapeutically effective amount" refers to the amount of the compound of formula (I) that will elicit the biological or medical response of a subject, tissue or cell that is being sought by the researcher, veterinarian, medical doctor or other clinician. In the prevention or treatment of HCV infections or diseases an appropriate dosage level will generally be about 0.01 to 500 mg per kg subject body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. The dosage may be selected, for example to any dose within any of these ranges, for therapeutic efficacy and/or symptomatic adjustment of the dosage to the subject to be treated

It will be understood that the specific dose level and frequency of dosage for any particular subject may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the subject undergoing therapy.

It will further be understood that when the compounds of the invention are to be administered in combination with one or more HCV antiviral agents the dosage forms and levels may be formulated for either concurrent, sequential or separate administration or a combination thereof.

Methods of preparation

It will be understood that unless otherwise defined each moiety having a substitutable hydrogen such as for example, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, in each occurrence as described in the general schemes and methods which follow may be optionally substituted.

It will also be understood that the particular examples which are described herein may undergo further functionalisation using methods known in the art, for example, compounds comprising amino groups or acid groups may undergo reduction amination or amide couplings respectively to form further examples of compounds of the invention.

Compounds of formula (I) may be generally synthesized via a synthetic intermediate of general formula (II) as previously described. Suitable coupling conditions will be familiar to those skilled in the art and include, but are not limited to, palladium-catalysed Suzuki, Heck and Sonogashira reactions. In one embodiment, compounds of formula (I) wherein ¾ is substituted with R₆ wherein R₆ is selected from C0₂R₇, C(=0)NHR₇, C(=0)Nd_₆alkylR₇, NHR₇, NHC(=0)R₇ and NCi_₆alkylC(=0)R7 and wherein R₇ is as previously defined, may be generally synthesized via a synthetic intermediate of eneral formula (Ila)

(Ila)

comprising the step of reacting said compound of general formula (Ila) with a reagent of general formula NH₂R₇, NH(Ci_₆alkyl)R₇, R₇-C(=0)OH or R₇-C(=0)halo under amide coupling conditions where wherein Vi is

C2-₆alkenyl- n, C2- ₆alkynyl-Rn, C3_₆cycloalkyl-Rn, C3_₆cycloalkenyl-Rn, 3-10-membered

heterocyclyl-Rii, C6-ioaryl-Rn or 5-10-membered heteroaryl-Rn wherein Rn is C(=0)OH, C(=0)halo, NH₂ or NHCi_₆alkyl and R₇ is as previously defined.

That is, compounds of formula (I) where Ri is substituted with R^ when R₆ is C(=0)NHR₇ and

may be generally synthesized via a synthetic intermediate of general formula (Ila) as defined above when Rn is C(=0)OH or C(=0)halo and the reagent is of general formula N¾R₇ or NH(Ci_₆alkyl)R₇ under amide coupling conditions. Alternatively, compounds of formula (I) where Ri is substituted with

may be generally synthesized via a synthetic intermediate of general formula (Ila) as defined above when Rn is NH2 or

and the reagent is of general formula R₇-C(=0)OH or R₇-C(=0)halo under amide coupling conditions.

Suitable amide coupling conditions will be familiar to those skilled in the art and include, but are not limited to, a coupling reagent (such as, for example, HATU, pyBOP) and a base (such as, for example, DIPEA, TEA) in an organic solvent (such as, for example, DCM, DMF).

It will be appreciated that intermediates of general formula (Ila) may be generally synthesized by reacting a compound of general formula (II) with a reagent of general formula V1-W1 under coupling conditions wherein Wi is halo, triflate (OTf), boronic acid (e.g. B(OH)₂) or a boronic ester (e.g. B(OR)₂ wherein R is Ci_ ₆alkyl), stannylated moiety (e.g. stannylated alkyl group such as Sn(R)₃ wherein R is Ci_₆alkyl moiety), C2-₆alkenyl or C2-₆alkynyl; and Vi is as previously defined. General Method(s)

Scheme 1: Synthesis of compounds of formula (I) where— represents a single or a double bond, Xj is S or may be oxidized under suitable oxidation conditions familiar to those skilled in the art, to S(=0) or S(=0)2 and Rj, R3, V, Vj, W, Wj and Z are as previously defined andR is an amide (e.g. C(=0)NHC i-ealkyl) or ester (e.g. C(=0)0 Ci-ealkyl).

Step (a): The appropriate keto ester or keto amide is brominated by reaction in an organic solvent (such as, for example, DCM) with bromine.

Step (b): The imidazothiazole is then formed by cyclisation of the appropriate bromo keto ester with an amino thiazaole in an organic solvent (such as, for example, acetone).

Step (c): The imidazothiazole is then coupled under suitable coupling conditions such as, for example, via a metal-catalysed transformation with a suitably substituted coupling partner (such as, for example, boronic acid) in the presence of a suitable catalyst (such as, for example, tetrakistriphenylphosphinepalladium(O)) and a suitable base (such as, for example, cesium carbonate) in a suitable solvent (such as, for example, dioxane)

Step (d): Amide couplings may be carried out using a primary or secondary amine (such as, for example, cumyl amine), a coupling reagent (such as, for example, HATU), and a base (such as, for example, DIPEA) in an organic solvent (such as, for example, DMF).

EXAMPLES

The invention will now be described with reference to the following non- limiting examples.

Synthetic Methods

lK NM spectra were recorded on either a Briiker Avance DRX 400, AC 200 or AM 300 spectrometer. Spectra were recorded in deuterated solvents (CDCI₃, MeOD, DMSO, CD₃CN, or Acetone) using the residual solvent peak as a reference. Chemical shifts are reported on the δ scale in parts per million (ppm) using the following conventions to assign the multiplicity: s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), m (multiplet) and prefixed br (broad). Mass spectra (ESI) were recorded on either a Micromass Platform QMS or Thermo Finnigan LCQ Advantage spectrometer. Flash chromatography was performed on 40-63 μιη silica gel 60 (Merck No. 9385). Automated flash chromatography was performed either on a Combi-

Flash™ purification system using Combi-Flash™ silica gel columns or on a Biotage SP4 purification system using either GraceResolv™ silica gel cartridges, Grace Reveleris™ C-18 reverse phase silica gel cartridges or Biotage SNAP™ C-18 reverse phase silica gel cartridges. Preparative HPLC was carried out using either a Gilson 322 pump with a Gilson 215 liquid handler and a HP 1100 PDA detector or an Agilent 1200 Series mass detected preparative LCMS using a Varian XRs C-18 100 x 21.2 mm column. Unless otherwise specified, the HPLC systems employed Phenomenex C8(2) columns using either acetonitrile or acetonitrile containing 0.06 % TFA in water, water containing 0.1 % TFA or water containing 0.1 % formic acid.

During the reactions a number of the moieties may need to be protected.

Suitable protecting groups are well known in industry and have been described in many references such as Protecting Groups in Organic Synthesis, Greene T W, Wiley- Interscience, New York, 1981.

The abbreviations used in the Examples are as follows unless indicated otherwise:

Ac: acetyl

ACN: acetonitrile

cone: concentrated

dba: dibenzylideneacetone DCM: dichloromethane

DIPEA: NN-diisopropylethylamine

DMF: NN-dimethylformamide

DMSO: dimethylsulfoxide

dppf: l, l '-bis(diphenylphosphino)ferrocene

EtOAc: ethyl Acetate

EtOH: ethanol

ESI: electrospray ionisation

h: hour(s)

HATU: 2-(7-Aza-lH-benzotriazole- 1 -yl)- 1 , 1,3,3 -tetramethyluronium hexafluorophosphate

HPLC: high performance liquid chromatography

LCMS: liquid chromatography coupled mass spectrometry

min: minute(s)

MeOH: methanol

MS: mass spectrometry

NMR: nuclear magnetic resonance

PyBOP: benzotriazol- 1 -yl-oxytripyrrolidinophosphonium hexafluorophosphate s: second(s)

SM: starting material

RT: room temperature

TEA: triethylamine

THF: tetrahydrofuran

TFA: trifluoroacetic acid

TLC: thin-layer chromatography

Example synthesis of compounds

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-ri2-phenylpropan-2- vDcarbamoyllphenyl} imidazo[2, 1-bl Γ 1 ,31thiazole-5-carboxamide (1)

Ethyl 2-bromo-3-(4-fluorophenyl)-3-oxo-propanoate (ii): To neat ethyl 3-(4- fluorophenyl)-3-oxo-propanoate (i) (5.0 g, 24 mmol) at ambient temperature was added N-bromosuccinimide (4.7 g, 26 mmol) and 4-methylbenzenesulfonic acid hydrate (0.5 g, 2 mmol). The resulting paste was stirred for 2 h then partitioned between water (50ml) and EtOAc (50 mL). The organic layer was separated, the aqueous layer extracted with EtOAc (2 x 4030 mL) and the combined organics washed with brine (40 mL), dried (MgS0₄) and concentrated to leave a colourless oil (9.2g). The crude reaction material was purified by automated flash column chromatography (Biotage-SP4) on silica (80g) eluting with EtOAc and hexane to leave the desired product (ii) as a colourless oil (6.33 g, 91%).

Ethyl 2-bromo-6-(4-fluorophenyl)imidazo[2, l-b]thiazole-5-carboxylate (iii): To a suspension of 5-bromothiazol-2 -amine (0.63 g, 3.49 mmol) in EtOH (1 mL) was added compound (ii) (1.10 g, 3.8 mmol) and the reaction mixture was heated at 75 °C for 15 h. NaHC0₃ (60 ml) was added, the aqueous layer extracted with EtOAc (3 x 60 mL) and the combined organics washed with brine (75 mL), dried (MgS0₄) and concentrated to leave a brown oil (1.56 g). The crude material was purified by reverse phase flash column chromatography eluting with ACN/water (5-100 %) to give the desired product (iii) (93 mg, 7%) as an amorphous white solid.

2-Bromo-6-(4-fluorophenyl)imidazo[2, l-b]thiazole-5-carboxylate (iv): To a solution of compound (iii) (240 mg, 0.65 mmol) in MeOH (5 mL) and THF (5 mL) was added a 2M aqueous solution of NaOH (1.5 mL). After 15 h at ambient temperature an aqueous 1M HC1 solution was added until ~ pH3 and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organics were washed with brine (20 mL), dried (MgS0₄) and concentrated to leave an amorphous brown solid (iv) (215 mg).

2- Bromo-6-(4-fluorophenyl)-N-methylimidazo[2, 1-b] [ 1, 3] ^' thiazole-5-carboxamide (v): To a solution of crude (iv) in DCM was added methanamine hydrochloride (66 mg,

0.98 mmol), followed by HATU (300 mg, 0.78 mmol) and DIPEA (290 mg, 2.3 mmol). After 16 h at ambient temperature a saturated aqueous solution of NH₄C1(30 mL) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 x 30 mL) and the combined organics were washed with brine (45 mL), dried (MgS0₄) and concentrated to leave a brown oil (330 mg). The crude material was then purified by reverse phase flash column chromatography eluting with ACN/water (5-100 %) to give the desired product (v)as an amorphous white solid (195 mg, 85%). ESI-MS m/z [M+H]⁺: 352.96/354.96. ^LH NMR (400 MHz, CD₃CN) δ 8.32 (s, 1H), 7.72 - 7.65 (m, 2H), 7.25 - 7.19 (m, 2H), 6.16 (br s, 1H), 2.74 (d, J = 4.8 Hz, 3H).

3- [6-(4-Fluorophenyl)-5-(methylcarbamoyl)imidazo[2, l-b] ' [1,3] thiazol-2-yl] benzoic acid (vi): To a degassed solution of compound (v) (8 mg, 0.02 mmol) in dioxane (1 mL) and water (0.1 mL) was added 3-borono-4-methyl-benzoic acid (6.1 mg, 0.034 mmol), dicesium carbonate (22 mg, 0.07 mmol) and Pd(dppf)Cl2.CH₂Cl2 (2 mg, 0.002 mmol) and the reaction mixture was heated in a microwave reactor for 10 min at 125°C. A saturated aqueous solution of NH₄C1 (25 ml) was added and the aqueous layer was extracted with EtOAc (3 x 25 mL) and the combined organics were washed with brine (25 mL), dried (MgS0₄) and concentrated to leave the desired product as a brown oil (vi) (15 mg) which was used directly in the next step.

6-(4-Fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl}imidazo[2,l-b] [l,3]thiazole-5-carboxamidQ (1): To a solution of crude compound (vi) (10 mg) in DCM (1 mL) at ambient temperature was added 2- phenylpropan-2-amine (5.0 mg, 0.04 mmol), followed by HATU (11 mg, 0.03 mmol) and DIPEA (1 1 mg, 0.09 mmol). After 2 h a saturated aqueous solution of NH₄C1 (30 mL) was added and the organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (15 mL), dried (MgS0₄) and concentrated to leave a brown oil (15 mg). The crude material was purified by reverse phase flash column chromatography eluting with acetonitrile/water (5-100 %) to give the desired product, Compound (1), as an amorphous white solid (4.5 mg, 38% over two steps). ESI-MS m/z [M+H] : 527.13. LH NMR (400 MHz, DMSO) δ 7.95 (s, 1H), 7.60 (s, 1H), 7.43 - 7.38 (m, 2H), 7.33 - 7.23 (m, 3H), 6.91 (d, J= 8.1 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.76 - 6.69 (m, 4H), 6.61 (t, J= 7.3 Hz, 1H), 2.20 (d, J= 4.6 Hz, 3H), 1.11 (d, J= 8.6 Hz, 6H).

The following compounds were similarly prepared to Compound 1 with variations in the boronic acid and amine component used.

2-[3-(cyclopropylcarbamoyl)phenyl]-6-(4-fluorophenyl)-N-methylimidazo[2, l- b] [ 1 , 3 ]thiazole-5 -carboxamide (5)

ESI-MS m/z [Μ+Η : 435.16. ^lH NMR (400 MHz, DMSO) δ 8.63 (t, J= 4.2 Hz, 1H), 8.56 (d, J= 9.2 u o o /

Hz, 1H), 8.10 (d, J= 4.3 Hz, 1H), 8.03 (t, J= 6.7 Hz, 1H), 7.88 - 7.80 (m, 4H), 7.59 - 7.55 (m, 1H), 7.28 (dd, J= 12.3, 5.6 Hz, 2H), 2.87 (td, J= 7.3, 3.9 Hz, 1H), 2.80 (d, J= 4.7 Hz, 3H), 0.77 - 0.71 (m, 2H), 0.61 (dd, J= 7.5, 3.8 Hz, 2H).

2- {2-chloro-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (6)

μ o o / ESI-MS m/z [M+H]^":547.10/549.09. ^lH NMR (400

MHz, CD₃CN) δ 8.55 (s, 1H), 8.03 (d, J= 2.1 Hz, 1H), 7.82 (dd, J= 8.4, 2.2 Hz, 1H), 7.77 - 7.71 (m, 2H), 7.64 (d, J= 8.4 Hz, 1H), 7.47 - 7.43 (m, 2H), CI

7.40 (br s, 1H), 7.35 - 7.28 (m, 2H), 7.28 - 7.18 (m, 3H), 6.21 (s, 1H), 2.76 (d, J= 4.8 Hz, 3H), 1.73 (s, 6H).

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-fluoroplienyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (7)

ESI-MS m/z [Μ+Η : 465.18. ^lH NMR (400 MHz, CD₃CN) δ 8.25 (s, 1H), 7.82 (s, 1H), 7.76 - 7.71 (m, 3H), 7.41 (d, J= 8.0 Hz, 1H), 7.27 - 7.21 (m, 2H),

6.66 (br s, 1H), 6.20 (br s, 1H), 2.76 (d, J= 4.8 Hz,

3H), 2.50 (s, 3H), 1.43 (s, 9H).

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[l-(pyridin-2-yl)cyclopropyl] carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (8)

ESI-MS m/z [Μ+Η : 526.09. ^lH NMR (400 MHz, CD₃CN) δ 8.47 - 8.43 (m, lH), 8.29 (s, 1H), 7.99 - 7.93 (m, 2H), 7.86 - 7.79 (m, 2H), 7.77 - 7.71 (m, 2H), 7.51 - 7.45 (m, 2H), 7.29 - 7.21 (m, 3H), 6.20

(s, 1H), 2.76 (d, J= 4.8 Hz, 3H), 2.54 (s, 3H), 1.65 - 1.61 (m, 2H), 1.42 (dd, J= 7.6, 4.5 Hz, 2H).

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-methylcyclopropyl)carbamoyl] phenyl } imidazo [2 , 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (17)

ESI-MS m/z [M+H]-: 463.16. ^lH NMR (400 MHz, CD₃CN) δ 8.25 (s, 1H), 7.82 (d, J= 1.9 Hz, 1H), 7.74 (ddd, J= 5.5, 4.4, 2.0 Hz, 3H), 7.42 (d, J= 8.0 Hz, 1H), 7.35 (s, 1H), 7.25 (dd, J= 12.4, 5.6 Hz, 2H), 6.19 (s, 1H), 2.76 (d, J= 4.8 Hz, 3H), 2.50 (s,

3H), 1.41 (s, 4H), 0.81 (t, J= 5.8 Hz, 2H), 0.64 (q, J = 4.7 Hz, 2H).

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-methylcyclopropyl)carbamoyl] phenyl } imidazo [2 , 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (18)

ESI-MS m/z [Μ+Η : 491.23. ^lH NMR (400 MHz, CD₃CN) δ 8.27 (s, 1H), 7.82 (d, J= 1.9 Hz, 1H), 7.77 - 7.71 (m, 3H), 7.42 (d, J= 8.0 Hz, 1H), 7.29 - 7.21 (m, 3H), 6.20 (s, lH), 2.76 (d, J= 4.8 Hz, 3H), 2.50 (s, 3H), 1.66 - 1.56 (m, 1H), 0.96 (d, J= 6.9

Hz, 6H), 0.82 - 0.77 (m, 2H), 0.75 - 0.71 (m, 2H).

6-(4-fluorophenyl)-N-methyl-2-{5-[(2-phenylpropan-2-yl)carbamoyl]thiophen-3- yl} imidazo[2, 1 -b] [ 1 ,3]thiazole-5-carboxamide (19)

ESI-MS m/z [Μ+Η : 519.16. ^LH NMR (400 MHz, CD₃CN) δ 8.51 (s, 1H), 8.06 (d, J= 1.4 Hz, 1H), 7.76 - 7.69 (m, 3H), 7.46 (dd, J= 8.5, 1.2 Hz, 2H),

7.36 - 7.29 (m, 3H), 7.27 - 7.19 (m, 3H), 6.19 ( br s, 1H), 2.77 (d, J= 4.8 Hz, 3H), 1.74 (s, 6H).

6-(4-fluorophenyl)-N-methyl-2-(5-{[l-(pyridin-2-yl)cyclopropyl]carbamoyl} thiophen-3-yl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (20)

ESI-MS m/z [Μ+Η : 518.10. ^lH NMR (400 MHz, CD₃CN) δ 8.49 (s, 1H), 8.46 - 8.43 (m, 1H), 8.04 - o

8.01 (m, 1H), 7.89 (br s, 1H), 7.81 (d, J= 1.4 Hz, 1H), 7.76 - 7.66 (m, 3H), 7.45 (d, J= 8.1 Hz, 1H), 7.24 (t, J= 8.9 Hz, 2H), 7.16 (dd, J= 6.5, 4.9 Hz, 1H), 6.20 ( br s, 1H), 2.76 (d, J= 4.8 Hz, 3H), 1.62 (q, J= 4.4 Hz, 2H), 1.37 (q, J= 4.4 Hz, 2H). 2-(5-amino-2-methylphenyl)-6-(4-fluorophenyl)-N-methylimidazo[2,l- b][l,3]thiazole-5-carboxamide (21)

ESI-MS m/z [M+H]-: 381.19. ^lH NMR (400 MHz, o

H₂N V^{N H} MeOD) δ 8.06 (s, 1H), 7.75 - 7.70 (m, 2H), 7.27 - 7.21 (m, 2H), 7.09 (d, J = 8.1 Hz, 1H), 6.85 (d, J= 2.4 Hz, 1H), 6.74 (dd, J= 8.2, 2.4 Hz, 1H), 2.83 (d, .7= 3.4 Hz, 3H), 2.35 (s, 3H).

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-methyl-2-phenylpropanoyl) amino]phenyl } imidazo [2, 1 -b] [ 1 ,3 ]thiazole-5-carboxamide (22)

ESI-MS m/z [Μ+Η : 527.29. ^lH NMR (400 MHz, CD₃CN) δ 8.18 (s, 1H), 7.76 - 7.69 (m, 3H), 7.65 (d, J= 2.3 Hz, 1H), 7.47 (dd, J= 8.3, 2.3 Hz, 1H), 7.45 - 7.41 (m, 2H), 7.40 - 7.34 (m, 2H), 7.30 -

7.20 (m, 4H), 6.18 ( br s, 1H), 2.75 (d, J= 4.8 Hz, 3H), 2.41 (s, 3H), 1.61 (s, 6H).

2- {5-[(cyclopropylcarbonyl)amino]-2-methylphenyl}-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (23)

ESI-MS m/z [Μ+Η : 449.25. NMR (400 MHz,

V^N'^H CD₃CN) δ 8.63 - 8.56 (m, lH), 8.21 (s, 1H), 7.78

(d, J= 2.1 Hz, 1H), 7.76 - 7.71 (m, 3H), 7.52 (dd, J = 8.3, 2.3 Hz, 1H), 7.28 (d, J= 8.2 Hz, 1H), 7.26 - 7.21 (m, 2H), 6.18 ( br s, 1H), 2.76 (d, J= 4.8 Hz, 3H), 2.43 (s, 3H), 1.68 - 1.62 (m, 1H), 0.91 - 0.86 (m, 2H), 0.83 - 0.78 (m, 2H).

2- {5-[tert-butyl(methyl)carbamoyl]-2-methylphenyl}-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide (24)

ESI-MS m/z [Μ+Η : 479.14. ^lU NMR (400 MHz, CD₃CN) δ 8.22 (s, 1H), 7.77 - 7.71 (m, 2H), 7.48 (s, 1H), 7.40 - 7.35 (m, 2H), 7.27 - 7.21 (m, 2H), 6.19 (br s, 1H), 2.86 (s, 3H), 2.76 (d, J= 4.8 Hz, 3H),

2.49 (s, 3H), 1.48 (s, 9H).

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(4-methylphenyl)propan-2- yl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (25)

6-(4-fluorophenyl)-2-{2-methoxy-5-r(2-phenylpropan-2-yl)carbamoyllphenyl}-N- methylimidazo[2. l-bl[1.31thiazole-5-carboxamide (29)

Compound (29) was similarly prepared to Compound (1) with the following modifications.

Methyl 3-f 6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, 1-b] [1 ,3] thiazol-2-yl] - 4-methoxybenzoate (ii): To a degassed solution of 2-bromo-6-(4-fluorophenyl)-N- methyl-imidazo[2, l-b]thiazole-5-carboxamide (i) (10 mg, 0.03 mmol) in dioxane (1 mL) and water (0.1 mL) was added 3-borono-4-methyl-benzoic acid (6.1 mg, 0.034 mmol), dicesium carbonate (28 mg, 0.08 mmol) and Pd(dppf)Cl2.CH₂Cl2 (2 mg, 0.003 mmol) and the reaction mixture heated in a microwave reactor for 20 min at 125 °C. A saturated aqueous solution of NH₄C1 (25 ml) was added and the aqueous layer extracted with EtOAc (3 x 25 mL), the combined organics washed with brine (25 mL), dried (MgSC^) and concentrated to leave a brown oil (15 mg). The crude material was then purified by reverse phase flash column chromatography eluting with ACN/water (5-100 %) to give compound (ii) as an amorphous white solid (3.76 mg, 30%). ESI-MS m/z [M+H]⁺: 440.12. Ή NMR (400 MHz, CD₃CN) δ 8.66 (s, 1H),

8.19 (d, J= 2.1 Hz, 1H), 8.03 (dd, J= 8.7, 2.1 Hz, 1H), 7.75 - 7.71 (m, 2H), 7.26 -

7.20 (m, 3H), 6.22 ( br s, 1H), 4.05 (s, 3H), 3.89 (s, 3H), 2.78 (d, J= 4.8 Hz, 3H). 6-(4-Fluorophenyl)-2-{2-methoxy-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl}-N- methylimidazo[2,l-b] [l,3]thiazole-5-carboxamide (29): To a solution of compound (ii) (2 mg, 0.004 mmol) in MeOH (1 mL) and THF (1 mL) was added a 2M aqueous solution of NaOH (1 mL). After 2 hours at 50 °C an aqueous 1M HC1 solution was added until ~ pH3 and the aqueous layer extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (10 mL), dried (MgS0₄) and concentrated to leave a brown oil (2 mg). To a solution of the residue in DCM (1 mL) at ambient temperature was added 2-phenylpropan-2-amine (1.0 mg, 0.006 mmol), followed by HATU (2 mg, 0.006 mmol) and DIPEA (11 mg, 0.09 mmol). After 2 h a saturated aqueous solution of NH₄C1 (30 mL) was added, the organic layer separated and the aqueous layer extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (15 mL), dried (MgS0₄) and concentrated to leave a brown oil (5 mg). The crude material was then purified by reverse phase flash column

chromatography eluting with acetonitrile/water (5-100 %) to give Compound (29) as an amorphous white solid (0.9 mg, 35 % over two steps). ESI-MS m/z [M+H] :

543.16. ^lH NMR (400 MHz, CD₃CN) δ 8.73 (s, 1H), 8.05 (d, J= 2.2 Hz, 1H), 7.84 (dd, J= 8.5, 2.0 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.49 - 7.43 (m, 2H), 7.32 (dd, J= 10.3, 5.0 Hz, 3H), 7.26 - 7.17 (m, 4H), 6.20 ( br s, 1H), 4.02 (s, 3H), 2.77 (d, J= 4.8 Hz, 3H), 1.75 (s, 6H).

N-{3-r6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, l-bi r i.31thiazol-2-yll-4- methylbenzoyll -2-methylalanine (30)

13 30

Compound (30) was prepared from the hydrolysis of Compound (13) as follows. To a solution of Compound (13) (5 mg, 0.01 mmol) in MeOH (2 mL) and THF (2 mL) was added a 2M aqueous solution of NaOH (1 mL). After 2 h at 60 °C an aqueous 1M HC1 solution was added until ~ pH3 and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (10 mL), dried (MgSO^ and concentrated to leave Compound (30) as a brown oil (4 mg). The crude material was then purified by reverse phase flash column chromatography eluting with

ACN/water (5-100 %) to obtain Compound (30) as an amorphous white solid (2.6 mg, 54%). ESI-MS m/z [M+H]⁺: 495.03. ^lH NMR (400 MHz, DMSO) δ 12.19 ( br s, 1H), 8.59 (s, 1H), 8.16 (s, 1H), 8.02 - 7.97 (m, 1H), 7.94 (s, 1H), 7.88 - 7.80 (m, 3H), 7.48 (d, J= 8.1 Hz, 1H), 7.33 - 7.26 (m, 2H), 2.77 (d, J= 4.6 Hz, 3H), 1.46 (s, 6H).

6-(2-chloro-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2.1-blthiazole-5-carboxamide 31}

tert-butyl 3-(2-chloro-4-pyridyl)-3-oxo-propanoate (i) was prepared using the method of Hogenkamp, D. J. et al. J. Med. Chem. 2007, 50, 3369-3379.

tert-butyl 2-bromo-3-(2-chloro-4-pyridyl)-3-oxo-propanoate (ii): Br₂ (40 \L, 0.78 mmol) was added dropwise to a solution of compound (i) (163 mg, 0.64 mmol) in EtOAc (1 mL) at rt. The reaction was allowed to stir for 15 mins then washed with sat. a₂S205(_aq) and the EtOAc separated. The aqueous layer was extracted further with EtOAc (lx) and the combined extracts dried before the solvent was evaporated to yield (ii) (205 mg, 96%) as a pale yellow oil which was used without further manipulation.

tert-butyl 6-(2-chloro-4-pyridyl)-2, 3-dihydroimidazo[2, l-bJthiazole-5-carboxylate (iii): Compound (ii) (205mg, 0.61mmol) was dissolved in acetone (1 mL) and 2- aminodihydrothiazole (75 mg, 0.77 mmol) added yielding initially a solution from which copious amounts of precipitate rapidly forms. The reaction was heated to 60°C for 40 mins after which time additional acetone (2 mL) was added Reaction continued for 16 hi 5 mins after which time the reaction was evaporated and the residue dissolved in sat. NaHC0₃ and EtOAc, the EtOAc layer separated and the aqueous layer further extracted with EtOAc (2x) before the combined extracts were dried and the solvent evaporated to yield the crude product (159 mg). Sample was purified on 12 g Si0₂ using EtO Ac/Heptane gradient 0-0% 3CV, 0-100% 20CV, 100- 100% 3CV and the desired fractions combined to yield the product (iii) (53.4 mg, 26%). ESI-MS m/z [M+H]⁺: 337.91. ^LH MR (CDC1₃) δ: 8.35 (dd, J = 5.2, 0.5 Hz, 1H), 7.74 (dd, / = 1.4, 0.7 Hz, 1H), 7.63 (dd, J = 5.2, 1.4 Hz, 1H), 4.51 (t, J = 7.5 Hz, 2H), 3.86 (t, J = 7.6 Hz, 2H), 1.49 (s, 9H).

6-(2-chloro-4-pyridyl)-2,3-dihydroimidazo[2, l-b]thiazole-5-carboxylic acid; 2, 2, 2- trifluoroacetic acid (iv): Compound (iii) (58 mg, 0.17 mmol) was dissolved in TFA (1 mL) and allowed to sit for 2 h 30 mins after which time the TFA was evaporated and the residue evaporated from DCM then ACN to yield the TFA salt (iv) as a white solid which was used without further manipulation.

6-(2-chloro-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2, l-b]thiazole-5-carboxamide (v): Compound (iv) (47 mg, 0.12 mmol) was suspended in DMF (500 μΐ and treated with Et(iPr)₂N (105 μί, 0.60 mmol) yielding a solution. HATU (90 mg, 0.24 mmol) was added and the reaction stirred to dissolve the HATU after which time

MeNH₂.HCl (25 mg, 0.36 mmol) was added and stirring continued for 20 mins after which time the reaction was diluted with water and the solvent evaporated to yield a solid residue. The residue was suspended in EtOAc and dissolved by addition of sat. NH₄Cl_(aq). EtOAc was separated and the aqueous extracted further with EtOAc (3x) before the combined extracts were dried and the solvent evaporated. The resultant bright yellow solid was triturated with DCM and the DCM extract purified on 12g Si0₂ using EtOAc/Heptane gradient 0-0% 3CV, 0-100% 15CV, 100-100% 10CV. The desired fractions were collected and combined to yield the desired product Compound (31) (24.5mg, 70%). ESI-MS m/z [M+H]⁺: 295.14. 'H NM (DMSO) δ: 8.39 (bq, J = 4.6 Hz, 1H), 8.36 (d, J = 5.3 Hz, 1H), 7.73 (dd, J = 1.4, 0.5 Hz, 1H), 7.66 (dd, J = 5.3, 1.5 Hz, 1H), 4.31 (t, J = 7.3 Hz, 2H), 3.95 (t, J = 7.3 Hz, 2H), 2.77 (d, J = 4.7 Hz, 3H).

6-(2-hvdroxy-4-pyridyl -N-methyl-2,3-dihvdroimidazo[2,l-blthiazole-5-carboxamide £321

Compound (31) (21mg) was dissolved in AcOH (200 μί) and heated in microwave at 210°C for 20 mins after which time the reaction was diluted with water and the solvent evaporated to yield the crude product (28.3 mg). Cone. NH_3(aq was added with some water and ACN to dissolved solid. Water/ ACN was added and evaporated several times from the sample before the residue was triturated with water to yield the desired product Compound (32) (14.2 mg, 71%) as a white solid. ESI-MS m/z

[M+H : 277.11. ^lH NMR (400 MHz, DMSO) δ 11.34 (s, 1H), 8.31 (d, J = 4.6 Hz, 1H), 7.31 (d, J = 6.9 Hz, 1H), 6.57 (d, J = 1.2 Hz, 1H), 6.44 (dd, J = 6.9, 1.7 Hz, 1H), 4.26 (t, J = 7.3 Hz, 2H), 3.92 (t, J = 7.3 Hz, 2H), 2.74 (d, J = 4.7 Hz, 3H). 6-(2-hvdroxy-4-pyridyl -N-methyl- l-oxo-2, 3-dihydroimidazor2, l-blthiazole-5- carboxamide (33)

Oxone (45 mg, 0.07 mmol) was dissolved in water (500 μΕ) and added to a cloudy mixture of Compound (32) (10 mg, 0.04 mmol) in water (500 uL) and DMF (300 uL) yielding a pale yellow solution. Reaction was continued for 10 mins then diluted with water and purified on 12g C18 using ACN/H₂0 gradient 0-0% 5CV, 0-100% 20CV, 100-100% 3CV. The desired fractions were combined and the solvent evaporated. The resultant residue was re-dissolved and evaporated from water multiple times to yield the target Compound (33) (6.9 mg, 65%) as white solid. ESI-MS m/z [M+H]⁺: 293.09. 'H NMR (400 MHz, DMSO) δ 11.70 (s, 1H), 8.30 (bq, J = 4.5 Hz, 1H), 7.80 (dd, J = 2.7, 0.6 Hz, 1H), 7.76 (dd, J = 9.5, 2.7 Hz, 1H), 6.40 (dd, J = 9.5, 0.6 Hz, 1H), 4.74 (ddd, J = 12.3, 8.2, 5.9 Hz, 1H), 4.55 (ddd, J = 12.2, 7.8, 1.6 Hz, 1H), 3.98 (dt, / = 14.1, 8.0 Hz, 1H), 3.69 (ddd, J = 14.0, 5.8, 1.7 Hz, 1H), 2.76 (d, J = 4.6 Hz, 3H).

6-(4-fluorophenyl)-2-{4-methoxy-2-methyl-5-r(2-phenylpropan-2- yl)carbamoyllphenyl}-N-methylimidazor2, l-bl[l,31thiazole-5-carboxamide (34) Compound (34) was similarly prepared to Compound (1) with the following modifications.

2-methoxy-4-methyl-N-(l -methyl- l-phenyl-ethyl)benzamide (ii): To a solution of 2- methoxy-4-methyl-benzoic acid (250 mg, 1.50 mmol) in DCM (10 mL) at ambient temperature was added 2-phenylpropan-2-amine (310 mg, 2.3 mmol) followed by HATU (690 mg, 1.8 mmol) and DIPEA. After 16 hrs the reaction mixture was diluted with DCM (30 mL) and the organic layer washed with 1M HCl(aq) (20 mL), H₂0 (20 mL), NaHC0₃ (aq) (20 mL), ¾0 (20 mL) and brine (20 mL). The organic layer was then dried (MgS0₄) and concentrated to leave the desired product ii as a colourless oil (390 mg, 92%).

5-bromo-2-methoxy-4-methyl-N-(l-methyl-l-phenyl-ethyl)benzamide (iii): To a solution of ii (280 mg, 0.99 mmol) in acetic acid (3 mL) at 0°C was added bromine (0.05 mL, 0.99 mmol). After 2 hrs the solution was converted to pH 8 upon addition of 1M NaOH(aq). Na₂S₂0₃ (aq) (30 mL) was added, the organic layer separated and the aqueous layer extracted with EtOAc (3 x 15 mL). The combined organics were washed with brine (15 mL), dried (MgSOzQ and concentrated to leave compound iii as a colourless oil (350 mg, 98%).

6-(4-fluorophenyl)-2-{4-methoxy-2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl}-N-methylimidazo[2, l-b] [l,3]thiazole-5-carboxamide (34): Compound iii (50 mg, 0.07 mmol), bisglycolatodiboron (18.7 mg, 0.08 mmol), cyclopentyl(diphenyl)phosphane; DCM; dichloropalladium; iron (10 mg, 0.01 mmol) and potassium acetate (10.2 mg, 0.10 mmol) were suspended in anhydrous 1,4- dioxane (1 mL), The mixture was degassed with Ar then stirred at 100°C for 1 h. The reaction was then cooled to room temperature, filtered and washed with dioxane (lmL). To the filtrate was added 2-bromo-6-(4-fluorophenyl)-N-methyl-imidazo[2, l- b]thiazole-5-carboxamide (15 mg, 0.04 mmol), dicesium carbonate (41.3 mg, 0.13 mmol) and cyclopentyl(diphenyl)phosphane; DCM; dichloropalladium; iron (3 mg, 0.004 mmol) followed by water (0.2 mL). The reaction mixture was degassed with Ar then heated in a microwave reactor at 125°C for 40 minutes. N¾C1 (aq) (25 ml) was added, the aqueous layer extracted with EtOAc (3 x 25 mL) and the combined organics washed with brine (25 mL), dried (MgS0₄) and concentrated to leave a brown oil (25 mg). The crude material was purified by reverse phase flash column chromatography eluting with ACN/water (5-100 %) to give the desired product, compound (34), as an amorphous white solid (7.52 mg, 20%> over two steps). ESI-MS m/z [M+H]⁺: 557.16. ¾ MR (400 MHz, DMSO) δ 8.23 (br s, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.76 - 7.71 (m, 2H), 7.48 - 7.43 (m, 2H), 7.35 - 7.30 (m, 2H), 7.26 - 7.18 (m, 3H), 7.14 (s, 1H), 6.17 (br s, 1H), 4.05 (s, 3H), 2.75 (d, J = 4.8 Hz, 3H), 2.51 (s, 3H), 1.73 (s, 6H).

Compounds 35 and 36 were similarly prepared.

The following compounds were prepared by reference to the general methods and/or Example(s) as previously described.

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(l-phenylcyclobutyl)carbamoyl] phenyl } imidazo [2, 1 -b] [ 1,3 ]thiazole-5 -carboxamide (37)

ESI-MS m/z [Μ+Η 539.17. ¾ NMR (400 MHz, CD₃CN) δ 8.25 (s, 1H), 7.89 (d, J = 1.9 Hz, 1H), 7.79 - 7.71 (m, 4H), 7.53 (dt, J = 8.3, 1.7 Hz, 2H), 7.42 (d, J = 8.0 Hz, 1H), 7.36 - 7.30 (m, 2H), 7.26 - 7.19 (m, 3H), 6.21 (s, lH), 2.76 (d, J = 4.8 Hz, 3H),

2.66 - 2.60 (m, 4H), 2.50 (s, 3H), 2.13 - 2.06 (m,

2H).

6-(4-fluorophenyl)-N-methyl-2-{2-methyl-5-[(2-methylbutan-2-yl)carbamoyl] phenyl } imidazo [2 , 1 -b] [ 1 , 3 ]thiazole-5 -carboxamide (38)

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-N-metliyl-6-phenylimidazo[2, l- b] [ l,3]thiazole-5-carboxamide (51)

ESI-MS m/z [M+H]- 447.10. ^LH NMR (CDC1₃ , 400 MHz): δ 8.39 (s, 1H ), 7.70-7.68 (m, 2H), 7.6-7.58 (m, 2H),7.52 -7.48 (m, 3H), 7. 36 (d, J = 8Hz, 1H), 5.93 (s, 1H), 5.84 (br.s, 1H), 2.85 (d, J = 5.2 Hz,

3H), 2.52 (s, 3H), 1. 48 (s, 9H).

N-methyl-2-{2-methyl-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6- phenylimidazo [2, 1 -b] [ 1 ,3 ]thiazole-5-carboxamide (52)

ESI-MS m/z [Μ+Η 509.20. ¾ NMR (CDC1₃ , 400 MHz): δ 8.4 (s, 1H), 7.81 (s, 1H), 7.73-7. 67 (m, 3H), 7.49-375.(m, 9H), 6.4 (s, 1H), 5.83 (br.s, 1H), 2.85 (d, J = 4.4 Hz, 3H), 2.52 (s, 3H), 1.84 (s, 6H).

6-(4-fluorophenyl)-N-methyl-2-{5-[(2-phenylpropan-2-yl)carbamoyl]pyridin-3-yl} imidazo[2, 1 -b] [ 1 , 3 ]thiazole-5-carboxamide (53)

ESI-MS m/z [Μ+Η 514.1. ¾ NMR (DMSO, 400 MHz): δ 9.06 (s, 1H), 8.98 (s, 1H), 8.81 (s, 1H), 8.75 (s, 1H), 8.48 (s, 1H), 8.09 (bs, 1H), 7.88-7.78 (m, 2H), 7.43 (d, J = 6.4 Hz, 1H), 7.46-7.24 (m, 5H), 7.24-7.14 (m, 1H), 2. 79 (br. s, 3H), 1.72 (s, 6H).

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(pyrimidin-2-yl)propan-2-yl] carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide (54)

ESI-MS m/z [Μ+Η 529.15. ^lB NMR (DMSO, 400 MHz): δ 8.78 (d, J = 4 Hz, 2H), 8.46 (s, 1H), 8.40 (s, 1H), 7.95 (s, 1H), 7.84 (d, J = 8 Hz, 1H), 7.72-7.64

(m, 2H), 7.40 (d, J = 8Hz, 1H), 7.26 (s, 1H), 7.25- 7.18 (m, 2H), 5.72 (brd s, 1H), 2.86 (d, J = 4Hz, 3H), 2.53 (s, 3H), 1.93 (s)

Biological Data

The in vitro and in vivo antiviral activity of the compounds of the invention may be determined using the following protocols.

HCV Polymerase Inhibition Assay HCV polymerase reactions were carried out using a modified method of Howe et ah, Antimicrobial Agents and Chemotherapy 2004 48(12): 4813-4821. Reactions contained a final concentration of, 0.5 % DMSO, 50 nM , 1b (BK) NS5bA21, 20 mM Tris-HCl pH 7.5, 5 mM MgCl₂, 5 mM MnCl₂, 3 mM DTT, 0.05 % BSA, 0.2 υ/μΐ. RNasin, 10 μg/mL Poly(rC) template, GTP (at Km) and 0.05 μθ/μΐ ³³P-GTP in a total reaction volume of 50 μ Compounds were tested in a three fold dilution series, for example starting from 50 μΜ. Reactions were initiated with the addition of GTP and terminated after 1 hour with 50 μΐ, ice cold 0.2 M EDTA. Terminated reactions were transferred to DEAE 96-well filter plates, unincorporated nucleotides washed from the filters and 50 μί scintillation fluid added prior to reading on a scintillation counter. Similarly, NS5B polymerase enzyme assays can be conducted for other serotypes using essentially the same method.

The compound concentration that reduced ³³P-GTP incorporation by 50 % (IC5₀) was calculated using non-linear regression.

Representative lb polymerase IC5₀ (μΜ) values for selected compounds of the invention in the HCV polymerase inhibition assay are listed as follows where IC5₀ (μΜ) values lie in the ranges:

A (< 0.25 μΜ): 1, 6, 8, 11, 15, 16, 25, 29, 37, 41, 45, 47, 49, 52

B (0.25 - 1.0 μΜ): 2, 3, 10, 13, 26, 34, 42, 44, 46, 53

C (1.0 - 10 μΜ): 4, 5, 7, 13, 14, 17, 18, 35, 36, 38, 39, 40, 43, 48, 50, 51, 54

HCV replicon assays

A genotype lb (Con 1) subgenomic replicon cell line based on Blight et ah,

Science 2000 290: 1972-1974, modified to express a Renilla luciferase reporter gene was used to assess antiviral activity of test compounds. Cell cultures were maintained in a sub-confluent state in DMEM with glutamine, 10% heat-inactivated foetal bovine serum (FBS) and G418 (Geneticin®).

For assay, cells were seeded at a density of 7000 cells/well into 96 well tissue culture trays in culture media lacking G418. Compounds were tested in a three fold dilution series, for example starting from 50uM. After 72 hours incubation at 37°C and 5% CO2, Renilla luciferase activity was quantified via the Promega Renilla

Luciferase or Renilla-Glo™ Luciferase Assay Systems (Promega corporation.

Similarly, replicon assays can be conducted for other HCV serotypes using essentially the same method. The compound concentration that reduced luciferase activity by 50% (EC5₀) was calculated using non-linear regression.

Representative genotype lb EC5₀ values for selected compounds of the invention are listed as follows where where EC5₀ (μΜ) values lie in the ranges:

A (< 0.25 μΜ): 1, 2, 6, 7, 8, 9, 10, 11, 13, 15, 16, 17, 18, 25, 26, 29, 34, 35, 36, 37, 38, 40, 41, 42, 44, 45, 46, 47, 49, 50, 51, 52, 53, 54

B (0.25 - 1.0 μΜ): 3, 4, 12, 39, 43, 48

C (1.0 - 10 μΜ): 5, 14, 19, 20, 23, 24

Cytotoxicity analysis

Cytotoxicity of compounds against genotype lb replicon cells was determined via metabolism of the vital dye 3-(4, 5-dimethylthiaxol-2-yl)-2,5-diphenyltetrazolium bromide (MTT, for example see Watanabe et al, Journal of Virological Methods 1994 48:257-265). Plates were prepared as described for the HCV Replicon assay and cytotoxicity of the test article was evaluated after three days. MTT was added to assay plates followed by three hour incubation at 37°C. Wells were aspirated to dryness and the formazan dye dissolved by the addition of isopropanol. Absorbance values were read at 540/690 nm). The compound concentration that reduced cell viability by 50% (CC5₀) was calculated using non-linear regression. In general, compounds of the invention displayed low cytotoxicity with CC5₀ values of > 50μΜ.

Cross-genotype HCV activity

Cross-genotypic activity of the compounds may be determined in HCV replicon assays for genotypes such as lb, la and 2a and in HCV polymerase assays for genotypes such as lb as previously described.

Combination studies in Replicon Cells

A genotype lb (Con 1) subgenomic replicon cell line based on Blight et al.,

Science 2000 290: 1972-1974, modified to express a Renilla luciferase reporter gene may be used to assess synergy of test compounds. Cell cultures were maintained in a sub-confluent state in DMEM with glutamine, 10%> heat-inactivated foetal bovine serum (FBS) and G418 (Geneticin®).

For assay, cells are seeded at a density of 7000 cells/well into 96 well tissue culture trays in culture media lacking G418. The compound concentration that reduced luciferase activity by 50% (EC5₀) is determined independently for each compound and used to set the range of concentrations for the combination experiments. Each compound is tested singly and in combination using 3-fold serial dilutions above and below the EC50. The ratio of the 2 compounds tested remained fixed across the titration range. Cytotoxicity of individual compounds is assessed independently and the titration range below the compound concentration that reduced cell viability by 50% (CC5₀). After 72 hours incubation at 37°C and 5% C0₂, Renilla luciferase activity is quantified via the Promega Renilla Luciferase Assay System.

Results are analysed and levels of synergy assessed via generation of 3D synergy plots using MacSynergy™ II (Prichard, M. N., K. R. Aseltine, and C.

Shipman, Jr. 1993. MacSynergy II. Version 1.0. User's manual. University of Michigan, Ann Arbor.).

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication, or information derived from it, or to any matter which is known, is not, and should not be taken as an acknowledgement or admission or any form of suggestion that that prior publication, or information derived from it, or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Claims

1. A compound of formula (I) or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof:

(I)

wherein

— represents a single or a double-bond;

Xi is selected from S, S=0 and S(=0)₂;

Ri is H, an optional substituent, or is selected from optionally substituted Ci_ ₆alkyl, optionally substituted C₂-₆alkenyl, optionally substituted C₂-₆alkynyl, optionally substituted C₃_₆cycloalkyl, optionally substituted C₃_₆cycloalkenyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5-10-membered heteroaryl;

R₂ is selected from H or an optional substituent;

R4 and R5 are each independently selected from H and optionally substituted Ci_₆alkyl; and

R3 is optionally substituted and is selected from C₃_₆cycloalkyl, C₃- ₆cycloalkenyl, 3-10-membered heterocyclyl, C6-ioaryl and 5-10-membered heteroaryl.

2. The compound according to claim 1 wherein Ri is selected from optionally substituted C₃_₆cycloalkyl, optionally substituted C₃_₆cycloalkenyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted Ce-io ryl and optionally substituted 5-10-membered heteroaryl.

3. The compound according to any one of claims 1 to 2 wherein Ri is optionally substituted phenyl or an optionally substituted 5- or 6- membered heteroaryl.

4. The compound according to any one of claims 1 to 3 wherein the substituents on Ri are each independently selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C₂_₆alkenyl, Ci_₆alkylhalo, OH, C^alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHCi_₆alkyl, N(Ci_₆alkyl)₂, N0₂ and R₆ wherein R₆ is selected from C0₂R₇,

and R₇ is selected from H, optionally substituted

optionally substituted C2-₆ lkenyl, optionally substituted C₂. ₆alkynyl, optionally substituted C₃.₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl, optionally substituted 5-10-membered heteroaryl and [CRsR^Rio wherein Rs and R9 are each independently selected from H, optionally substituted

or together with the carbon atom to which they are attached join to form a fused spirocycloalkyl or spiroheterocyclyl ring system; and Rio is selected from H, optionally substituted

CO2R4 optionally substituted C3- ₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5-10-membered heteroaryl wherein R₄ is as defined in claim 1.

5. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (la)

(la)

wherein X₂ is N, CH or C-R_a;

Yi is H or one or more Rt,;

each R_a and R_b are independently selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C2-₆ lkenyl, Ci_₆alkylhalo, OH, C^alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHC^alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

NCi_₆alkylC(=0)Ci_ ₃alkyl and S0₂NHC(=0)R₇ and S0₂NCi_₆alkylC(=0)R₇;

and— , R₂, R3, R4, R5, R6, R₇ and i are as defined in claim 1.

6. The compound according to any one of claims 1 to 5 wherein R is optionally substituted phenyl or an optionally substituted 6-membered heteroaryl.

7. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (lb)

(lb)

wherein

X₃ and X4 are each independently selected from N, CH and C-R_c;

Y2 is H or one or more Ra;

each R. and Rj are independently selected from halo, optionally substituted

optionally substituted C₂-₆alkenyl, Ci_₆alkylhalo, OH, C^alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHC^alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

NCi_₆alkylC(=0)Ci_ ₆alkyl, S0₂NHC(=0)R₇ and S0₂NC_walkylC(=0)R₇;

and— , Ri, R₂, R4, R5, R₇ and i are as defined in claim 1 or 4.

8. The compound according to claim 1 wherein the compound of formula (I) is a compound of formula (Ic)

(Ic)

wherein

X₂ is N, CH or C-R_a;

Yi is H or one or more Rt,;

each R_a and R_b are independently selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C₂_₆alkenyl, Ci_₆alkylhalo, OH, C^alkoxy, Ci_₆alkoxyhalo, CN,

NH₂, NHC^alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

C(=0)NHC₁_₆alkyl, C(=0)N(C₁_₅alkyl)₂, NHC(=0)C₁_₆alkyl, NC₁_₆alkylC(=0)C₁_

₃alkyl and S0₂NHC(=0)R₇ and S0₂NCi_₆alkylC(=0)R₇;

X₃ and X4 are each independently selected from N, CH and C-R_c;

Y₂ is H or one or more Ra;

each R. and Rj are independently selected from halo, optionally substituted Ci_₆alkyl, optionally substituted C₂_₆alkenyl,

OH, Ci-₆alkoxy, Ci_₆alkoxyhalo, CN, NH₂, NHd_₆alkyl, N(Ci_₆alkyl)₂, N0₂, C0₂H, C0₂Ci_₆alkyl, C(=0)NH₂,

C(=0)NHd_₆alkyl, C(=0)N(C₁_₅alkyl)₂, NHC(=0)C_!_₆alkyl, NC₁_₆alkylC(=0)C₁_ ₆alkyl, S0₂NHC(=0)R₇ and S0₂NCi_₆alkylC(=0)R₇;

and— , R₂, R4, R5, R6, R₇ and Xi are as defined in claim 1 or 4.

9. The compound according to any one of claims 1 to 8 wherein R6 is

C(=0)NHR₇ wherein R₇ is as defined in claim 4.

10. The compound according to any one of claims 1 to 9 wherein Xi is S and— is a double bond.

1 1. The compound according to any claim 1 selected from the group consisting of:

1 6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl} imidazo[2, l-b][l,3]thiazole-5-carboxamide;

2 6-(4-fluorophenyl)-N-methyl-2- {3-[(2-phenylpropan-2- yl)carbamoyl]phenyl} imidazo[2, l-b][l,3]thiazole-5-carboxamide;

3 6-(4-fluorophenyl)-N-methyl-2-(3 - { [ 1 -(pyridin-2-yl)cyclopropyl]carbamoyl} phenyl)imidazo [2, 1 -b] [ 1 ,3 ]thiazole-5-carboxamide;

4 6-(4-fluorophenyl)-N-methyl-2- {3-[(l-phenylcyclopropyl)carbamoyl]phenyl} imidazo[2, 1 -b] [ 1 ,3 ]thiazole-5 -carboxamide;

5 2-[3-(cyclopropylcarbamoyl)phenyl]-6-(4-fluorophenyl)-N-methylimidazo[2, l- b] [ 1 ,3]thiazole-5-carboxamide;

6 2- {2-chloro-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

7 2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

8 6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[l-(pyridin-2- yl)cyclopropyl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

9 6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- { [( 1 R)- 1 - phenylethyl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

10 6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[(1 S)-l- phenylethyl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

11 6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(l-phenylcyclopropyl)carbamoyl] phenyl} imidazo [2, 1 -b][ l,3]thiazole-5-carboxamide;

12 6-(4-fluorophenyl)-2- {5-[(l-hydroxy-2-methylpropan-2-yl)carbamoyl]-2- methylphenyl} -N-methylimidazo[2, 1 -b][ l,3]thiazole-5-carboxamide; methyl N- {3-[6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, 1 - b] [ l,3]thiazol-2-yl]-4-methylbenzoyl} -2-methylalaninate;

6-(4-fluorophenyl)-2- {5 -[(6-hydroxy-2, 3 -dihydro- 1 H-inden- 1 -yl)carbamoyl] -2- methylphenyl} -N-methylimidazo[2, 1 -b][ l,3]thiazole-5-carboxamide;

6-(4-fhiorophenyl)-2-(5- { [2-(4-fluorophenyl)propan-2-yl]carbamoyl} -2- methylphenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-2-(5- { [2-(3-methoxyphenyl)propan-2-yl]carbamoyl} -2- methylphenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(l-methylcyclopropyl)carbamoyl] phenyl} imidazo [2, 1 -b] [ l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[l-(propan-2- yl)cyclopropyl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide; 6-(4-fluorophenyl)-N-methyl-2- {5-[(2-phenylpropan-2-yl)carbamoyl]thiophen- 3-yl} imidazo[2, 1 -b] [ 1 ,3 ]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2-(5- {[l-(pyridin-2-yl)cyclopropyl]carbamoyl} thiophen-3-yl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

2-(5-amino-2-methylphenyl)-6-(4-fluorophenyl)-N-methylimidazo[2, 1 - b] [ 1 ,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(2-methyl-2- phenylpropanoyl)amino]phenyl}imidazo[2, l-b][l,3]thiazole-5-carboxamide; 2- {5-[(cyclopropylcarbonyl)amino]-2-methylphenyl} -6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

2- {5-[tert-butyl(methyl)carbamoyl]-2-methylphenyl} -6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- { [2-(4-methylphenyl)propan-2- yl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(pyridin-2-yl)propan-2- yl]carbamoyl}phenyl)imidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-4-[(2-phenylpropan-2- yl)carbamoyl]phenyl} imidazo[2, l-b][l,3]thiazole-5-carboxamide;

2-[4-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-2- {2-methoxy-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl}- N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

N- {3-[6-(4-fluorophenyl)-5-(methylcarbamoyl)imidazo[2, l-b][l,3]thiazol-2-yl]- 4-methylbenzoyl}-2-methylalanine;

6-(2-chloro-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2, 1 -b]thiazole-5- carboxamide;

6-(2-hydroxy-4-pyridyl)-N-methyl-2,3-dihydroimidazo[2, l-b]thiazole-5- carboxamide; and

6-(2-hydroxy-4-pyridyl)-N-methyl-l-oxo-2,3-dihydroimidazo[2, l-b]thiazole-5- carboxamide;

6-(4-fluorophenyl)-2- {4-methoxy-2-methyl-5-[(2-phenylpropan-2- yl)carbamoyl]phenyl} -N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide; 2-[5-(tert-butylcarbamoyl)-4-methoxy-2-methylphenyl]-6-(4-fluoroplienyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-[(2-phenylpropan-2-yl)carbamoyl]pyridin-4- yl } imidazo[2, 1 -b] [ 1 ,3 ]thiazole-5 -carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(l-phenylcyclobutyl)carbamoyl] phenyl} imidazo [2, 1 -b][ l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(2-methylbutan-2-yl)carbamoyl] phenyl} imidazo [2, 1 -b] [ l,3]thiazole-5-carboxamide;

2- {2-chloro-4-methoxy-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6-(4- fluorophenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

2-(2-chloro-4-methoxy-5-{[l-(propan-2-yl)cyclopropyl]carbamoyl}phenyl)-6- (4-fluorophenyl)-N-methylimidazo[2, 1 -b] [ 1 ,3]thiazole-5-carboxamide;

6-(3-fluorophenyl)-N-methyl-2- {2-methyl-5-[(2-phenylpropan-2-yl) carbamoyl]phenyl} imidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide;

2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(3-fluorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide ;

6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(3-methyloxetan-3-yl) carbamoyl]phenyl} imidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide;

6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- { [ 1 -(pyridin-3 -yl)cyclopropyl] carbamoyl}phenyl)imidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide;

6-(4-chlorophenyl)-N-methyl-2-{2-methyl-5-[(2-phenylpropan-2-yl) carbamoyl]phenyl} imidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide; 46 2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-6-(4-chlorophenyl)-N- methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

47 2-(5- {[2-(4-chlorophenyl)propan-2-yl]carbamoyl} -2-methylphenyl)-6-(4- fluorophenyl)-N-methylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

48 6-(4-fluorophenyl)-N-methyl-2- {2-methyl-5-[(2- methylpropyl)carbamoyl]phenyl} imidazo[2, 1-b] [1 ,3]thiazole-5-carboxamide;

49 N-methyl-6-(4-methylphenyl)-2-{2-methyl-5-[(2-phenylpropan-2-yl)carbamoyl] phenyl} imidazo [2, 1 -b][ l,3]thiazole-5-carboxamide;

50 2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-N-methyl-6-(4-methylphenyl) imidazo[2, 1 -b] [ 1 ,3 ]thiazole-5 -carboxamide;

51 2-[5-(tert-butylcarbamoyl)-2-methylphenyl]-N-methyl-6-phenylimidazo[2, 1 - b][l,3]thiazole-5-carboxamide;

52 N-methyl-2- {2-methyl-5-[(2-phenylpropan-2-yl)carbamoyl]phenyl} -6- phenylimidazo[2, l-b][l,3]thiazole-5-carboxamide;

53 6-(4-fluorophenyl)-N-methyl-2- {5-[(2-phenylpropan-2-yl)carbamoyl]pyridin-3- yl} imidazo[2, l-b][l,3]thiazole-5-carboxamide ; and

54 6-(4-fluorophenyl)-N-methyl-2-(2-methyl-5- {[2-(pyrimidin-2-yl)propan-2-yl] carbamoyl}phenyl)imidazo[2, 1 -b] [ l,3]thiazole-5-carboxamide;

or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof. 12. A process for producing the compound of general formula (I) according to claim 1 comprising the step of couplin a compound of formula (II):

(Π)

with a reagent of general formula i-W under coupling conditions wherein

Z is selected from OH, OCi_₆alkyl and RJ^;

V and W are coupling partners each independently selected from halo, triflate

(OTf), boronic acid, boronic ester, a stannylated moiety, C2-₆alkenyl and C2-₆alkynyl; and

Ri, R₂, R:„ R-_t, R₅, Xi and -— are as defined in claim 1 provided that Ri is other than H.

13. A process according to claim 11 wherein Ri is substituted with R5 further comprising the step(s) of forming a compound of formula (Ila) from a compound of formula (II) under coupling conditions and coupling the compound of formula (Ila) with a reagent selected from NH₂R₇, NH(Ci_₆alkyl)R₇, R₇-C(=0)OH and R₇- C(=0)halo under amide coupling conditions:

(Ila)

wherein

Xi, R2, R3 and— are as defined in claim 1 provided that Ri is not H;

Z is as defined in claim 11 ;

R₆ is selected from C0₂R₇,

NHR₇, NHC(=0)R₇ and NCi-₆alkylC(=0)R₇ wherein R₇ is selected from H, optionally substituted

optionally substituted C2-₆ lkenyl, optionally substituted C2- ₆alkynyl, optionally substituted C3_₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl, optionally substituted 5-10-membered heteroaryl and [CRsR^Rio wherein Rs and R9 are each independently selected from H, optionally substituted Ci_₆alkyl or together with the carbon atom to which they are attached join to form a fused spirocycloalkyl or spiroheterocyclyl ring system; and Rio is selected from H, optionally substituted

optionally substituted C3- ₆cycloalkyl, optionally substituted 3-10-membered heterocyclyl, optionally substituted C6-ioaryl and optionally substituted 5-10-membered heteroaryl; and

Vi is selected from Ci_₆alkyl-Rn, C2-₆ lkenyl-Rn, C2-₆alkynyl-Rn, C3- ₆cycloalkyl-Rn, C3_₆cycloalkenyl-Rn, 3-10-membered heterocyclyl-Rn, C6-ioaryl-Ru and 5-10-membered heteroaryl -Ri 1 wherein Rn is selected from C(=0)OH,

C(=0)halo, NH₂ and NHCi_₆alkyl.

14. A compound of formula (II) according to claim 12 or a compound of formula (Ila) according to claim 13.

15. A pharmaceutical agent comprising the compound of formula (I) according to any one of claims 1 to 11 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

16. The pharmaceutical agent according to claim 15 which is an antiviral agent.

17. A viral polymerase inhibitor comprising the compound of formula (I) according to any one of claims 1 to 1 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

18. The viral polymerase inhibitor according to claim 17 which is a HCV polymerase inhibitor.

19. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 1 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19 which additionally comprises a therapeutically effective amount of one or more antiviral agents and/or one or more immunomodulatory agents.

21. A method for the treatment of a Flaviviridae viral infection which comprises administering an effective amount of the compound of formula (I) according to any one of claims 1 to 11 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof, the pharmaceutical agent according to claim 15 or the pharmaceutical composition according to claim 19 to a subject diagnosed with, suffering from or at risk of developing said viral infection.

22. The method of treatment according to claim 20 wherein the Flaviviridae viral infection is a Hepatitis C virus (HCV) infection.

23. A method of inhibiting the R A-dependent RNA polymerase activity of the enzyme NS5B, encoded by HCV, comprising exposing the enzyme NS5B to an effective amount of the compound of formula (I) according to any one of claims 1 to 1 1 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.

24. A method of inhibiting HCV replication comprising exposing a cell infected with HCV to an effective amount of the compound of formula (I) according to any one of claims 1 to 11 or salts, N-oxides, solvates, hydrates, racemates, enantiomers or isomers thereof.