WO2009034390A1

WO2009034390A1 - Heterocyclic derivatives and their use in treating hepatitis c

Info

Publication number: WO2009034390A1
Application number: PCT/GB2008/050817
Authority: WO
Inventors: Malcolm Clive Carter; Stuart Cockerill; Stephen Sean Flack; Christopher James Wheelhouse
Original assignee: Arrow Therapeutics Ltd
Current assignee: Arrow Therapeutics Ltd
Priority date: 2007-09-14
Filing date: 2008-09-12
Publication date: 2009-03-19
Anticipated expiration: 2010-03-14

Abstract

Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or alleviating HCV, formula (I): wherein R1, R2, R4, Y1, Y2, Y3, A, B and W are as defined in the specification.

Description

NOVEL COMPOUNDS 033

The present invention relates to a series of compounds which are useful in treating or preventing a hepatitis C viral (HCV) infection. The present invention provides, in a first embodiment, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or alleviating HCV

wherein:

Ri is a moiety -A₁, -Li-Ai, -A₁-A/, -Li-Ai-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NR⁷-, -NR -CO-, -NR⁷- CO-NR⁷⁷-, -NR⁷- or -(C₁-C₂ alkylene)-NR⁷- moiety, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C₁-C₄ alkyl;

R₂ represents H, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or halogen;

R₄ is a moiety -A₄, -L₄-A₄, -A₄-A₄ ⁷, -L₄-A₄-A₄ ⁷ or -A₄-L₄-A₄ ⁷;

W represents ethynyl or a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety being unsubstituted or substituted by Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy or halogen; Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N;

each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- to 10- 5 membered heteroaryl, 5- to 10- membered heterocyclyl or C₃-Cs carbocyclyl moiety;

each Li and L₄ is the same or different and represents a C₁-C₄ alkylene or a Ci-C₄ hydroxy alky lene group; o the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and

the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ beings unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C₄ alkyl)-Xi, -CO₂R⁷, -SO₂NRV, -S(O)₂-R⁷, -CONR⁷R⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CO- NR⁷-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and -CO-O-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(Ci-C₄ alkyl)-X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano, nitro ando -NR⁷R⁷⁷, wherein Xi is -CO₂R⁷, -SO₂-R⁷, -NR⁷-CO₂-R⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷ or -SO₂- NR⁷R⁷⁷, each X₂ is the same or different and is cyano, nitro or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents Ci-C₄ alkyl. 5 As used herein, a Ci-C₄ alkyl moiety is a linear or branched alkyl moiety containing from 1 to 4 carbon atoms, such as a Ci-C₃ or Ci-C₂ alkyl moiety. Examples of Ci-C₄ alkyl moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. For the avoidance of doubt, where two alkyl moieties are present in a substituent, the alkyl moieties may be the same or different. o As used herein, a Ci-C₄ alkylene or Ci-C₂ alkylene group is any divalent linear or branched Ci-C₄ or Ci-C₂ alkyl moiety. Linear Ci-C₄ alkylene groups are methylene, ethylene, n-propylene and n-butylene groups. Branched C₁-C₄ alkylene groups include -CH(CH₃)-, -CH(CH₃)-CH₂- and -CH₂-CH(CH₃)-.

As used herein, a C1-C4 hydroxyalkylene group is a said C1-C4 alkylene group which is substituted by a single hydroxy group. Particular C1-C4 hydroxyalkylene groups are branched C1-C4 alkylene groups carrying a hydroxy substituent, which is preferably located on a terminal carbon atom.

As used herein, a halogen is chlorine, fluorine, bromine or iodine. A halogen is typically fluorine, chlorine or bromine.

As used herein, a C1-C4 alkoxy moiety is a said C1-C4 alkyl moiety attached to an oxygen atom. A preferred Ci -C₄ alkoxy moiety is me thoxy. A Ci-C₄ hydroxyalkyl moiety is a said C1-C4 alkyl moiety substituted by a single hydroxyl moiety. Preferred hydroxyalkyl moieties are Ci-C₂ hydroxyalkyl moieties, for example -CH(OH)-CH₃ and -CH₂OH.

A C1-C4 haloalkyl or C1-C4 haloalkoxy moiety is a said C1-C4 alkyl or C1-C4 alkoxy moiety substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy moieties are perhaloalkyl and perhaloalkoxy moieties such as -CX₃ and -OCX₃ wherein X is a said halogen atom, for example chlorine or fluorine. A particular haloalkyl moiety is -CF₃. A particular haloalkoxy moiety is -OCF₃. In one embodiment, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C₂ alkyl)-Xi, -CO₂R⁷⁷⁷, -SO₂R⁷⁷⁷, -SO₂NR⁷R⁷⁷⁷, -CONR⁷R⁷⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-SO₂-R⁷⁷⁷ and -CO-NR⁷-(Ci-C₂ alkyl)-NR⁷R⁷⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(Ci-C₂ alkyl)-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein Xi is -CO₂R⁷⁷⁷, -NR⁷-CO₂-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷ or -SO₂NR⁷R⁷⁷⁷, each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ are the same or different and represent hydrogen or C1-C4 alkyl and each R⁷⁷⁷ is the same or different and represents C1-C4 alkyl.

In another embodiment, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH₂-Xi, -CO₂-R⁷⁷⁷, -SO₂R⁷⁷⁷, -SO₂NR⁷R⁷⁷⁷, -CONR⁷R⁷⁷⁷, -NR⁷-C0- R⁷⁷⁷, -NR⁷-SO₂-R⁷⁷⁷ and -CO-NR⁷-(Ci-C₂ alkyl)-NR⁷R⁷⁷⁷ and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein Xi is -CO₂R⁷⁷⁷, -NR⁷-CO₂-R⁷⁷⁷ or -SO₂NR⁷R⁷⁷⁷, each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ are the same or different and represent hydrogen or C₁-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents C1-C4 alkyl.

In another embodiment, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH₂-Xi, -CO₂-R⁷⁷⁷, -SO₂NR⁷R⁷⁷⁷, -CONR⁷R⁷⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷- SO₂-R⁷⁷⁷ and -CO-NR⁷-(Ci-C₂ alkyl)-NR⁷R⁷⁷⁷ and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein Xi is -CO₂R⁷⁷⁷, -NR⁷-CO₂-R⁷⁷⁷ or -SO₂NR⁷R⁷⁷⁷, each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ are the same or different and represent hydrogen or C₁-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents C1-C4 alkyl. In another embodiment, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R4 are unsubstituted or substituted by SO₂-R⁷⁷⁷, halogen or C1-C4 alkoxy wherein R⁷⁷⁷ represents C₁-C₄ alkyl.

As used herein, a 5- to 10-membered heteroaryl moiety is a monocyclic 5- to 10- membered aromatic ring, containing at least one heteroatom, for example 1 , 2 or 3 heteroatoms, selected from O, S and N. Typically a 5- to 10-membered heteroaryl moiety is a 5- to 6-membered heteroaryl moiety. Examples include imidazolyl, isoxazolyl, pyrrolyl, thienyl, thiazolyl, furanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and triazolyl moieties. A 5- to 10- membered heteroaryl moiety is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a phenyl ring. In another embodiment, it is a non-fused 5- to 6- membered ring as defined above.

A said fused or non-fused heteroaryl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C ₁-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, and each R⁷ and R⁷⁷ is the same or different and represents hydrogen or C₁-C₄ alkyl. In another embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci -C₂ haloalkyl, C1-C2 haloalkoxy and hydroxy. As used herein, a 5- to 10-membered heterocyclyl moiety is a monocyclic non- aromatic, saturated or unsaturated C5-C10 carbocyclic ring, in which at least one, for example 1, 2 or 3, carbon atoms in the ring are replaced with a moiety selected from O, S, SO, SO₂ and N and optionally incorporating one or more carbonyl (C=O) groups. Typically, it is a saturated Cs-Cioring (preferably a Cs-C₆ ring) in which 1, 2 or 3 of the carbon atoms in the ring are replaced with a moiety selected from O, S, SO₂ and NH and incorporating up to two CO moieties.

In one embodiment, a heterocyclyl moiety is a 5- to 6- membered ring. Examples include azetidinyl, pyrazolidinyl, piperidyl, piperidin-2,6-dionyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S, S- dioxothiomorpholinyl, 1,3-dioxolanyl, 1 ,4-dioxanyl, pyrrolidinyl, imidazolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl, tetrahydrothienyl, dithiolanyl, thiazolidinyl, oxazolidinyl, tetrahydropyranyl and pyrazolinyl moieties. Typically, these examples of heterocyclyl moieties are selected from piperidyl, piperidin-2,6-dionyl, piperidin-2-onyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, S, S- dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2-onyl, pyrrolidin-2-onyl, tetrahydrofuranyl and tetrahydropyranyl.

A 5- to 10- membered heterocyclyl moiety is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a phenyl ring. In another embodiment, it is a non-fused 5- to 6- membered ring as defined above.

A said fused or non- fused heterocyclyl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by (a) an unsubstituted -SO₂R⁷⁷⁷ or -SO₂-NR⁷R⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci -C₂ haloalkyl, Ci-C₂ haloalkoxy, C₁- C4 hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Q- C₄ alkyl and each R⁷⁷⁷ is C₁-C₄ alkyl. In another embodiment, it is unsubstituted or substituted by (a) an unsubstituted -SO₂-(C ₁-C₄ alkyl) or -SO₂-NR⁷R⁷⁷ substituent, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C₁-C₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy and hydroxy. In another embodiment, it is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C4 alkyl) or -SO₂-N(Ci-C4 alkyl)₂ substituent and/or (b) 1 or 2 unsubstituted substituents selected from C1-C4 alkyl and hydroxy substituents.

In a further embodiment of the invention, a said fused or non- fused heterocyclyl moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂R⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or C₁-C₄ alkyl and each R⁷⁷⁷ is C₁-C₄ alkyl. More typically, it is unsubstituted or substituted by (a) an unsubstituted -SO₂-(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy and hydroxy. Most typically, it is unsubstituted or substituted by (a) an unsubstituted -SO₂-(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from C1-C4 alkyl and hydroxy substituents. In a further embodiment of the invention, a said fused or non- fused heterocyclyl moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from - CH₂-X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, and each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy and hydroxy. Most preferably, said preferred substituents are selected from C₁- C₄ alkyl and hydroxy substituents.

For the avoidance of doubt, although the above definitions of heteroaryl and heterocyclyl groups refer to an "N" moiety which can be present in the ring, as will be evident to a skilled chemist the N atom will be protonated (or will carry a substituent as defined above) if it is attached to each of the adjacent ring atoms via a single bond. A said phenyl group is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused or fused to a 5- to 6- membered heteroaryl or heterocyclyl ring.

A said fused or non- fused phenyl group is unsubstituted or substituted as set out above. When a said phenyl group is fused to a phenyl, heteroaryl or heterocyclyl ring, the fused moiety is typically unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C₂ haloalkyl, Ci-C₂ alkyl and hydroxy groups. In one embodiment, the fused moiety is unsubstituted or substituted by a halogen or Ci-C₂ haloalkyl substituent. As used herein, a C₃-Cs carbocyclic moiety is a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 8 carbon atoms. In one embodiment, it is a saturated hydrocarbon ring (i.e. a cycloalkyl moiety) having from 3 to 7 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. In another embodiment, it is a C₃-C₆ carbocyclic moiety. A C₃-Cs carbocyclyl group is optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. In one embodiment, it is non-fused.

A said fused or non- fused carbocyclyl moiety is unsubstituted or substituted as set out above. In one embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, and each R⁷ and R⁷⁷ is the same or different and represents hydrogen or C₁-C₄ alkyl. In another embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C₁-C₄ alkyl, cyano and Ci-C₂ haloalkyl substituents. In one embodiment, the Ai moiety represents a non-fused 5- to 6- membered heterocyclyl or C₃-Cs carbocyclyl group, or a phenyl or 5- to 6- membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. In another embodiment, it is a non-fused group or an indazolyl, indolyl, benzimidazolyl, benzo[l,3]dioxolanyl, lH-benzo[d]imidazol-2(3H)- onyl, benzothiazolyl or quinoxalinyl group. In another embodiment, it is a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[l,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, lH-benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group.

Ai is substituted or unsubstituted as set out above. However, when Ai is other than a non-fused phenyl ring, it is typically unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH₂-X₂, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C 1-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷, wherein each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, and each R⁷ and R⁷⁷ is the same or different and represents hydrogen or C1-C4 alkyl. In one embodiment, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C₁- C₂ haloalkyl, Ci-C₂ haloalkoxy and hydroxy.

Typically, the A/ moiety represents a non-fused phenyl, C₃-Cs carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. In one embodiment, the A/ moiety represents a phenyl, oxazolyl, piperazinyl, triazolyl, piperidinyl, piperidin-2- onyl, piperidin-2,6-dionyl, morpholinyl, pyrrolidinyl, pyrazolyl, isoxazolyl, cyclohexyl, thiomorpholinyl or S,S-dioxothiomorpholinyl group. In another embodiment, the A/ moiety represents a morpholino, piperazinyl or S, S- dioxothiomorpholinyl group. In one embodiment, A/ is a piperazinyl moiety. In one embodiment, A/ is a S, S- dioxothiomorpholinyl moiety.

In one embodiment, the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-R⁷⁷⁷ or -SO₂NR⁷R⁷⁷ substitutent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C1-C4 hydroxyalkyl, hydroxy and -NR⁷R⁷⁷, wherein each R⁷ and R⁷⁷ are the same or different and are selected from hydrogen and C1-C4 alkyl and R /// represents Ci-C alkyl. In another embodiment, the Ai moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₄ alkyl) or -SO₂-NR⁷R⁷⁷ substituent, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C₁-C₄ alkyl, and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, Ci-C₂ alkyl, Ci-C₂ haloalkyl and Ci-C₂ hydroxyalkyl.

In a further embodiment of the invention, the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-R⁷⁷⁷ substitutent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy and -NR⁷R⁷⁷, wherein each R⁷ and R⁷⁷ are the same or different and are selected from hydrogen and C₁-C₄ alkyl and each R⁷⁷⁷ represents C₁-C₄ alkyl. In another embodiment, the A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SC>2-(Ci-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C₁-C₂ alkyl, Ci-C2 haloalkyl and C₁-C₂ 5 hydroxy alkyl.

In a further embodiment of the invention, the A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy and -NR⁷R⁷⁷, wherein each R⁷ and R⁷⁷ are the same or different and are selected from hydrogen and Ci-C₄0 alkyl. In another embodiment, the A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, Ci-C₂ alkyl, Ci-C₂ haloalkyl and Ci-C₂ hydroxyalkyl.

In one embodiment, the A/ moiety represents a group

wherein R is Ci-C₄ alkyl, -S(O)₂-R⁷ or -S(O)₂-NR⁷R⁷⁷ wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl. Preferably, R is Ci-C₄ alkyl or -SO₂-(Ci-C₄ alkyl). o In one embodiment, the A₄ moiety is a non-fused 5- to 6- membered heterocyclyl or C3-C8 carbocyclyl group, or a phenyl or 5- to 6- membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. In one embodiment, the A₄ moiety represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C₃-Cs carbocyclyl group, or a5 phenyl group which is optionally fused to a 5- to 6- membered heteroaryl group. In another embodiment, the A₄ moiety represents phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-Cs cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S, S- dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl. In anothero embodiment, the A₄ moiety represents phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, cyclopropyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl.

In one embodiment, the A4 moiety is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO₂R⁷⁷⁷ and -CONR⁷R⁷⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, -NR⁷R⁷⁷⁷, C₁- C4 haloalkyl, C1-C4 haloalkoxy and cyano, wherein R⁷ represents hydrogen or C1-C4 alkyl and R⁷⁷⁷ represents C₁-C₄ alkyl. In another embodiment, the A₄ moiety is unsubstituted or substituted by (a) a single unsubstituted -CONR⁷R⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR⁷R⁷⁷⁷, C1-C4 alkyl, C₁-C₂ alkoxy, C1-C2 haloalkyl and cyano, wherein R⁷ is hydrogen or C1-C4 alkyl and R⁷⁷⁷ represents C1-C4 alkyl. In one embodiment, the A4 moiety is unsubstituted.

In one embodiment, the A₄ ⁷ moiety represents a non- fused phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C₃-C₆ carbocyclyl group. In one embodiment, the A4⁷ moiety represents a non- fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C₃-C₆ cycloalkyl group. In one embodiment, the A4⁷ moiety is a morpholinyl, piperazinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo- piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group. In another embodiment, the A₄ ⁷ moiety is a morpholinyl, isoxazolyl, pyrrolidinyl, S, S- dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group. In another embodiment, the A₄ ⁷ moiety is a morpholinyl group. In one embodiment, the A4⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-(C 1-C4 alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C₁- C₄ hydroxyalkyl, hydroxy and -NR⁷R⁷⁷, wherein each R⁷ and R⁷⁷ are the same or different and are selected from hydrogen and C₁-C₄ alkyl. In one embodiment, the A₄ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, Ci-C₂ alkyl and Ci-C₂ haloalkyl. In another embodiment, the A₄ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted Ci-C₂ alkyl groups. In a further embodiment of the invention, the A₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci -C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy and -NR⁷R⁷⁷, wherein each R⁷ and R⁷⁷ are the same or different and are selected from hydrogen and Ci-C₄ alkyl. In another embodiment, the A₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, Ci-C₂ alkyl and Ci-C₂ haloalkyl. In another embodiment, the A₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C₂ alkyl groups.

In one embodiment, Li is a Ci -C₃ alkylene group or a Ci-C₃ hydroxyalkylene group. In another embodiment, Li is a Ci-C₂ alkylene group. In another embodiment, Li is a methylene group.

In one embodiment, L₄ is a Ci-C₃ alkylene group or a Ci-C₃ hydroxyalkylene group. In another embodiment, L₄ is a Ci-C₂ alkylene group. In another embodiment, L₄ is a methylene group. In one embodiment when Ri is -A₁-A/, Ai is a non- fused unsubstituted phenyl or piperazinyl group and A/ is a non-fused morpholinyl, pyrazolyl, isoxazolyl, triazolyl, piperidin-2-onyl or phenyl group, which is unsubstituted or substituted with 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C₂ alkyl and Ci-C₂ haloalkyl groups. In another embodiment when Ri is -A₁-A/, it is an unsubstituted non- fused - phenyl-morpholino group.

In one embodiment of the invention, R¹ is -Ai-Li-A/.

When Ri is -Ai-Li-A/, Ai is typically a non-fused unsubstituted phenyl group. Li is typically -CH₂- or -CH₂-CH₂-, more typically -CH₂-. A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₄ alkyl) or -SO₂-NR⁷R⁷⁷ group, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C₂ alkyl and Ci-C₂ alkoxy groups. In one embodiment, A/ is a non- fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₄ alkyl) or -SO₂-NR⁷R⁷⁷ substituent, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci- C₄ alkyl, and/or (b) 1 or 2 unsubstituted Ci-C₂ alkyl groups. In another embodiment, A⁷ is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SC>2-(Ci-C4 alkyl) or -SO₂-NR⁷R⁷⁷ substituent, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C1-C4 alkyl, and/or (b) 1 or 2 unsubstituted Ci-C₂ alkyl groups. In a further embodiment of the invention, when Ri is -Ai-Li-A/, Ai is typically a non-fused unsubstituted phenyl group. Li is typically -CH₂-. A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO₂-(Ci-C₄ alkyl) group and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C₂ alkyl and Ci-C₂ alkoxy groups. In another embodiment, A/ is a non-fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which carries a single unsubstituted -S(O)₂-(Ci-C₄ alkyl) substituent.

When Ri is -Li-Ai-A/, Li is typically -CH₂-. Ai is typically a non-fused unsubstituted phenyl group. A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C₂ alkyl groups. Preferably, A/ is a morpholinyl or piperazinyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C₂ alkyl groups.

Typically, A represents a -(C_rC₂ alkylene)-NR⁷-, -CO-NR⁷- or -NR⁷-CO- group, in which R⁷ is hydrogen or Ci-C₂ alkyl, preferably hydrogen. In one embodiment, A represents a -CO-NH- group. For the avoidance of doubt, the right hand side of these groups is bonded to Ri and the left hand side is bonded to W.

Typically, B represents a -CO-NR⁷-, -NR⁷-C0-, -(Ci-C₂ alkylene)-NR⁷-, -NR⁷- or - NR⁷-CO-NR⁷⁷- group, wherein R⁷ and R⁷⁷ are the same or different and represent hydrogen or Ci-C₂ alkyl. For the avoidance of doubt, the left hand side is of these groups is bonded to R₄.

In one embodiment, B represents a -CO-NH-, -NH-CO-, -(Ci-C₂ alkylene)-NH-, - NH- or -NH-CO-NH- group.

Typically, R₂ represents H, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy or halogen. In one embodiment, R₂ is present on a carbon atom ortho to the group W. In one embodiment, R₂ is chlorine, trifluoromethoxy or C₁-C₄ alkyl, typically Ci-C₂ alkyl such as methyl.

In one embodiment, W represents a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety. In another embodiment, W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety. In another embodiment, W represents a 5- or 6- membered heterocyclyl moiety. In another embodiment, W represents a piperazinyl moiety.

When the group W represents a cyclic moiety it is typically unsubstituted or substituted by C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy or halogen. In one embodiment, it is unsubstituted or substituted by chlorine, trifluoromethoxy or C1-C4 alkyl, typically Ci-C₂ alkyl such as methyl. In another embodiment, it is unsubstituted.

In one embodiment, Y₁, Y₂ and Y₃ each represent CH; provided that at the same time, W is not phenyl.

In one embodiment, Yi and Y₂ represent N and Y₃ represents CH. In one embodiment, Y₂ and Y₃ represent N and Yi represents CH.

The skilled man will readily appreciate that when any of Yi, Y₂ and Y₃ represent CH, the substituent R₂ may also be bonded to such a Y group.

Typically, R₄ is a moiety -A₄, -A₄-A₄ ⁷, -L₄-A₄ or -A₄-L₄-A₄ ⁷ wherein A₄, A₄ ⁷, L₄ and

L _^44 are as defined above. In one embodiment of the inventon, R₄ is -A₄ or -A₄-A₄ ⁷.

When R₄ is -A₄-A₄ ⁷, A₄ is typically a non-fused phenyl or 5- to 6- membered heteroaryl moiety which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C₂ alkyl, halogen and Ci-C₂ haloalkyl substituents. In one embodiment, A₄ is a non-fused phenyl, pyridyl or oxadiazolyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from Ci-C₂ alkyl, halogen and C₁- C₂ haloalkyl substituents. A₄ ⁷ is typically a non-fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C₃-C₆ cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C₂ alkyl groups. In one embodiment, A₄ ⁷ is a non- fused morpholinyl, piperazinyl, isoxazolyl, triazolyl, piperidin-2,2-dionyl, cyclopropyl or cyclohexyl group, which is unsubstituted or substituted by an unsubstituted Ci-C₂ alkyl group. In a further embodiment of the invention, when R₄ is -A₄-A₄ ⁷, A₄ is typically a non- fused unsubstituted phenyl or 5- to 6- membered heteroaryl moiety. Preferably, A₄ is a non- fused unsubstituted phenyl, pyridyl or oxadiazolyl group. A₄ ⁷ is typically a non- fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C₃-C₆ cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C₂ alkyl groups. In one embodiment, A₄ ⁷ is a non-fused morpholinyl, isoxazolyl, triazolyl, piperidin-2,2- dionyl, cyclopropyl or cyclohexyl group, which is unsubstituted or substituted by an unsubstituted Ci-C₂ alkyl group.

In one embodiment, when R₄ is -A₄-A₄ ⁷, it is a non- fused unsubstituted -phenyl- morpholino group.

When R₄ is -A₄-L₄-A₄ ⁷, A₄ is typically a non- fused unsubstituted phenyl group. L₄ is typically -CH₂-. A₄ ⁷ is typically a non-fused 5- to 6- membered heterocyclyl group, preferably a piperazinyl group or a S,S-dioxo-thiomorpholinyl group, which is unsubstituted or substituted by an unsubstituted -SO₂-(Ci-C₂ alkyl) substituent. More typically, A₄ ⁷ is a non-fused unsubstituted 5- to 6- membered heterocyclyl group, preferably a S,S-dioxo-thiomorpholinyl group.

In one embodiment, when R₄ is -A₄-L₄-A₄ ⁷ it is -phenyl-CH₂-(S,S- dioxothiomorpholino), wherein the cyclic moieties are non-fused and unsubstituted, or - phenyl-CH₂-piperazinyl-SO₂-(Ci-C₂ alkyl). In one embodiment of the invention:

Ri is a moiety -A₁, -Li-Ai, -A₁-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NR⁷-, -NR⁷-CO-, -NR⁷- or -(C₁- C₂ alkylene)-NR⁷- moiety, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl; R₂ represents H, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy or halogen; R₄ is a moiety -A₄, -L₄-A₄, -A₄-A₄ ⁷ or -A₄-L₄-A₄ ⁷;

W represents a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety being unsubstituted or substituted by Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy or halogen;

Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N; each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C₃-Cs carbocyclyl moiety; each Li and L₄ is the same or different and represents a Ci-C₄ alkylene or a Ci-C₄ hydroxy alky lene group; 5 the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C₄ alkyl)-Xi, -CO₂R⁷, -SO₂NRV, -S(O)₂-R⁷, -CONR⁷R⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CO-o NR⁷-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and -CO-O-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and/or (b) 1 , 2 or 3 unsubstituted substituents selected from -(Ci-C₄ alkyl)-X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano, nitro and

-NR⁷R⁷⁷, wherein Xi is -CO₂R⁷, -SO₂-R⁷, -NR⁷-CO₂-R⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷ or -SO₂-

NR⁷R⁷⁷, each X₂ is the same or different and is cyano, nitro or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is thes same or different and represents hydrogen or Ci-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents Ci-C₄ alkyl.

In one embodiment of the invention:

Ri is a moiety -A₁, -Li-Ai, -A₁-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NR⁷-, -NR⁷-C0-, -NR⁷- or -(C₁-o C₂ alkylene)-NR⁷- moiety, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or Ci-C₄ alkyl;

R₂ represents H, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy or halogen;

R₄ is a moiety -A₄, -L₄-A₄, -A₄-A₄ ⁷ or -A₄-L₄-A₄ ⁷;

W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl5 moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl,

Ci-C₂ haloalkoxy or halogen;

Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N; o each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-C₆ carbocyclyl moiety; each Li and L₄ is the same or different and represents a Ci-C₄ alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(C1-C4 5 alkyl)-Xi, -CO₂R⁷, -SO₂NRV, -S(O)₂-R⁷, -CONR⁷R⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CO-

NR⁷-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and -CO-O-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(Ci-C₄ alkyl)-X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano, nitro and

-NR⁷R⁷⁷, wherein Xi is -CO₂R⁷, -SO₂-R⁷, -NR⁷-CO₂-R⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷ or -SO₂-o NR⁷R⁷⁷, each X₂ is the same or different and is cyano, nitro or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents Ci-C₄ alkyl.

In one embodiment of the invention:

Ri is a moiety -Ai, -Li-Ai, -A₁-A/ or -Ai-Li-A/; s A and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -(C₁-

C₂ alkylene)-NH- moiety;

R₄ is a moiety -A₄, -L₄-A₄, -A₄-A₄ ⁷ or -A₄-L₄-A₄ ⁷;

W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclylo moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl,

Ci-C₂ haloalkoxy or halogen;

Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N; 5 each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-C₆ carbocyclyl moiety; each Li and L₄ is the same or different and represents a Ci-C₂ alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring;o and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH₂-

Xi, -CO₂R⁷⁷⁷, -SO₂NR⁷R⁷⁷⁷, -S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷ and -CO- NI^-(C₁-C₂ alkyl)-NR^/R^/// and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-

X₂, halogen, C1-C4 alkyl, C1-C4 alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, C1-C4 hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷⁷, wherein Xi is -CO₂R⁷⁷⁷, -NR⁷-CO₂-R⁷⁷⁷ or -SO₂-

NR⁷R⁷⁷⁷, each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or C₁-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents C1-C4 alkyl.

In one embodiment of the invention:

Ri is a moiety -A₁, -L₁-A₁, -A₁-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -CH₂- NH- moiety;

R₂ represents H, Ci-C₂ alkyl, Ci-C₂ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy or halogen;

R₄ is a moiety -A₄, -L₄-A₄, -A₄-A₄ ⁷ or -A₄-L₄-A₄ ⁷;

W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C₂ alkyl, Ci-C₂ alkoxy, Ci-C₂ haloalkyl,

Ci-C₂ haloalkoxy or halogen;

Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y3 represents N; each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-C₆ carbocyclyl moiety; each Li and L₄ is the same or different and represents a Ci-C₂ alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH₂-

Xi, -CO₂R⁷⁷⁷, -SO₂NR⁷R⁷⁷⁷, -S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷ and -CO-

NR⁷-(Ci-C₂ alkyl)-NR⁷R⁷⁷⁷ and/or (b) 1 or 2 unsubstituted substituents selected from -CH₂-

X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₂ haloalkyl, Ci-C₂ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano and -NR⁷R⁷⁷⁷, wherein Xi is -CO₂R⁷⁷⁷, -NR⁷-CO₂-R⁷⁷⁷ or -SO₂- NR⁷R⁷⁷⁷, each X₂ is the same or different and is cyano or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl and each R⁷⁷⁷ is the same or different and represents Ci-C₄ alkyl. In one embodiment of the invention:

Ri is a moiety -A₁-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -CH₂-

NH- moiety; 5 R₂ represents H, Ci-C₂ alkyl, Ci-C₂ haloalkoxy or halogen;

R₄ is a moiety -A₄ or -A₄-A₄ ⁷;

W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl or 6- membered heterocyclyl moiety being unsubstituted or substituted by Ci-C₂ alkyl, Ci-C₂ alkoxy, Ci-C₂ haloalkyl, Ci-C₂o haloalkoxy or halogen;

Y₁, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N; each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-C₆ carbocyclyl moiety; s each Li and L₄ is the same or different and represents a Ci-C₂ alkylene group; the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by -S(O)₂-R⁷⁷⁷, halogen or Ci-C₄ alkoxy, and R⁷⁷⁷ represents C₁-o C₄ alkyl.

The medicaments of the present invention are for use in treating or preventing a hepatitis C viral infection in the human or animal body. Preferably, the medicaments are for use in humans.

Compounds of formula (I) containing one or more chiral centre may be used in5 enantiomerically or diastereoisomerically pure form, or in the form of a mixture of isomers. For the avoidance of doubt, the compounds of formula (I) can, if desired, be used in the form of solvates. Further, for the avoidance of doubt, the compounds of the invention may be used in any tautomeric form.

As used herein, a pharmaceutically acceptable salt is a salt with a o pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p- toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines and heterocyclic amines. Examples of compounds of the invention include:

5-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-furan-2-carboxylic acid [4-

(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide;

N-(3-bromo-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide; N-(3-chloro-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide;

N-(4-isoxazol-5-yl-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide;

N-(3-methoxy-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide;

N-(lH-indazol-6-yl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide;

4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid phenylamide; 4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid benzylamide;

5-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid

(3-bromo-phenyl)-amide;

5-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid 3-chloro-benzylamide;

(4-isoxazol-5-yl-phenyl)-amide;

( 1 H-indazol-6-yl)-amide; 5-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid

[4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide; 4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid benzo [1,3] dioxol-5 -ylamide;

4-[3-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l -carboxylic acid 2-chloro- benzylamide; 4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid

(4-isoxazol-5-yl-phenyl)-amide;

4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid

(3-bromo-phenyl)-amide;

4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine- 1 -carboxylic acid (3-methoxy-phenyl)-amide;

[4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide;

5-[5-cyclopropanecarbonyl-amino)-2-methyl-phenyl]-thiophene-2-carboxylic acid [4-(l,l- dioxo- 1 lambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide; 5-[5-(3-methoxy-benzoylamino)-2-methyl-phenyl]-thiophene-2-carboxylic acid [4-(l,l- dioxo- 1 lambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide; lH-pyrazole-4-carboxylic acid (3-{5-[4-(l,l-dioxo-llambda-6-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-thiophen-2-yl}-4-methyl-phenyl)-amide;

5-[2-methyl-5-(4-morpholin-4-yl-benzoylamino)-phenyl]-thiophene-2-carboxylic acid [4- (l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide;

5- {2-methyl-5-[(thiophene-2-carbonyl)-amino]-phenyl} -thiophene-2-carboxylic acid [4-

(1,1 -dioxo- 1 lambda- * 6 * -thiomorpholin-4-ylmethyl)phenyl] -amide;

3-[(3-bromo-phenylcarbamoyl)-ethynyl]-4-methyl-N-(4-morpholin-4-yl-phenyl)- benzamide; 4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N- {4-[4-(propane- 1 -sulfonyl)-piperazin-

1 -ylmethyl] -phenyl} -benzamide;

4-[2[(cyclopropylmethyl-amino)-pyrimidin-4-yl]-N- {4-[4-(propane- 1 -sulfonyl)-piperazin-

1 -ylmethyl] -phenyl} -benzamide; and pharmaceutically acceptable salts of any one thereof. In general, the compounds of formula (I) may be prepared by analogy with known methods. See, for example, the processes disclosed in WO 2007/031791. The present invention further provides an analogy process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof which comprises,

(a) when the group A represents -CO-NR⁷-, coupling a carboxylic acid (or an activated derivative thereof) of formula (II)

wherein R2, R4, Yi, Y2, Y3, B and W are as defined above; with an amine of formula HNR'-RI wherein R⁷ and Ri are as defined above; or (b) when the group A represents -CO-NH-, reacting a compound of formula (III)

wherein R2, R4, Yi, Y2, Y3, B and W are as defined above and H represents an acidic hydrogen such as a hydrogen attached to nitrogen or an alkyne; with an isocyanate of formula OCN-Ri wherein Ri is as defined above; or

(c) when the group B represents -NR -CO-, coupling an amine of formula (IV)

wherein Ri, R2, Yi, Y2, Y3, A and W are as defined above; with a carboxylic acid (or an activated derivative thereof) of formula R4-COOH wherein

R4 is as defined above; and optionally after (a), (b) or (c) carrying out one or more of the following: • converting the compound obtained to a further compound of the invention • forming a pharmaceutically acceptable salt of the compound.

Specific processes for the preparation of compounds of Formula (I) are disclosed within the Examples section of the present specification. Such processes form an aspect of the present invention. The necessary starting materials are either commercially available, are known in the literature or may be prepared using known techniques. Specific processes for the preparation of certain key starting materials are disclosed within the Examples section of the present specification and such processes form an aspect of the present invention.

Compounds of formula (I) can be converted into further compounds of formula (I) using standard procedures.

Certain intermediates are novel. Such novel intermediates form another aspect of the invention.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and/or removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3^rd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1999).

The amide coupling reactions referred to above may be carried out by reaction of amines with acid chlorides, or by reaction with carboxylic acids and a suitable coupling reagent e.g. HBTU or EDAC/HOBT. As explained above, the compounds of the invention are potentially useful as pharmaceuticals since they show activity against hepatitis C virus. The present invention therefore provides a method for treating a patient suffering from or susceptible to a hepatitis C infection, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof. Also provided is a method for alleviating or reducing the incidence of a hepatitis C infection in a patient, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof. The present invention further provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the treatment of the human or animal body.

Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy. In a further aspect, the present invention provides the use of a compound of formula

(I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

Compounds of formula (I) are also believed to be novel. The present invention therefore also provides a biphenyl derivative of formula (I), or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier. The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

Said pharmaceutical composition typically contains up to 85 wt% of a compound of the invention. More typically, it contains up to 50 wt% of a compound of the invention. Preferred pharmaceutical compositions are sterile and pyrogen free.

The compounds of the invention may be administered in a variety of dosage forms.

Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

The compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

The suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride. Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

Compounds of the present invention may be used in conjunction with known antiviral agents. Preferred known anti-viral agents in this regard are interferon and ribavirin, which are known for the treatment of hepatitis C (Clinical Microbiology Reviews, Jan. 2000, 67-82). The said medicament therefore typically further comprises interferon and/or ribavirin. Further, the present invention provides a pharmaceutical composition comprising:

(a) a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof;

(b) interferon and/or ribavirin; and

(c) a pharmaceutically acceptable carrier or diluent.

Also provided is a product comprising:

(a) a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof; and

(b) interferon and/or ribavirin, for separate, simultaneous or sequential use in the treatment of the human or animal body.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical dose is from about 0.01 to 100 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated, the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 0.05 to 16 mg per kg of body weight, more preferably, from 0.05 to 1.25 mg per kg of body weight.

The following Examples illustrate the invention. They do not however, limit the invention in any way. In this regard, it is important to understand that the particular assay used in the Examples section is designed only to provide an indication of anti-hepatitis C activity. There are many assays available to determine such activity, and a negative result in any one particular assay is therefore not determinative.

Materials and Methods:

All temperatures are in ⁰C. Thin layer chromatography (TLC) was carried out on Si 6OG coated plastic 5 plates with uv254 indicator (Polygram). All NMR spectra were obtained at 250MHz in dβ-DMSO unless stated otherwise, chemical shifts expressed as ppm, apparent coupling constants (J) given for obvious multiplicities. "Concentrated" implies solvents were removed in vacuo. All solids were dried at 40 ⁰C.

LC-MS CONDITIONS

Samples were run on a MicroMass ZMD, using electrospray with simultaneous positive - negative ion detection. All retention times (rt) are in minutes. Column : Synergi Hydro-RP, 30 x 4.6mm LD, 4μm. 15 Gradient : 95:5 to 5:95 v/v H₂O/CH₃CN + 0.05% Formic Acid over 4.0 min, hold 3 min, return to 95:5 v/v H₂O/CH₃CN + 0.05% Formic Acid over 0.2 min and hold at 95:5 v/v H₂O/CH₃CN + 0.05% Formic Acid over 3 min.

Detection : PDA 250 - 340 nm. Flow rate : 1.5 ml/min.

The abbreviations or terms used in the Examples have the following meanings:

THF: Tetrahydrofuran

DCM: Dichloromethane

DME: Dimethoxyethane DMF: N,N-Dimethylformamide

EtOAc: Ethyl acetate

DMSO: Dimethyl sulphoxide

TFA: Trifluoroacetic acid

BINAP: 2,2 '-Bis(diphenylphosphino)- 1 , 1 '-binaphthyl TBME: tert-Butyl methyl ether

HBTU: O-Benzotriazol- 1 -yl-N,N,N ' ,N '-tetramethyluronium hexafluorophosphate

RT: Room temperature

Intermediate 1: S-Bromo-furan-l-carboxylic acid ethyl ester A solution of 5-bromofuran-2-carboxylic acid (2 g) in ethanol (15 ml) was treated with cone, sulphuric acid (2 drops) and heated to reflux overnight. The mixture was then concentrated to dryness. The residue was partitioned between DCM (50 ml) and 2M NaHCO₃. The DCM was separated, dried, and concentrated to dryness to afford an oil (1.6 g, 69%).

Intermediate 2: 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl- [l,3,2]dioxaborolan-2-yl)-benzamine

Step 1: 3-Bromo-4-methyl-N-(4-morpholin-4-yl-phenyl)-benzamide

A solution of 3-bromo-4-methylbenzoic acid (2.15 g), thionyl chloride (5 ml) and DMF (1 drop) was heated to reflux for 2h. The mixture was concentrated, the residue was re- dissolved in DCM (25 ml) and N-(4-aminophenyl)morpholine (1.78 g) was added cautiously portionwise. Sodium carbonate (2 g) was added slowly and the mixture stirred at RT for 1 day. The resulting mixture was washed with water (30 ml), extracted with DCM (25 ml) and the layers separated. The organics were dried over MgSO₄ and passed through SiO₂ (20 g). The filtrate was concentrated to a volume of 5 ml and diluted with petrol to afford an off-white solid (1.95 g, 52%).

Step 2: 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-(4,4,5,5-tetramethyl-ri,3,21dioxaborolan-

2-yl)-benzamine

The 3-bromo-4-methyl-N-(4-morpholin-4-yl-phenyl)-benzamide from Step 1 (1.95 g), bis(pinnacolato)diborane (1.98 g), potassium carbonate (2.55 g) and PdCl₂dppf (312 mg) were heated to 80 ⁰C in DMF (30 ml) for 24h. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate (100 ml) and washed with water. The organics were dried over MgSO₄ then passed through a 20 g SiO₂ SPE column (eluting with ethyl acetate). The filtrate was reduced in volume to about 15-20 ml then diluted with petrol to afford a white solid that was isolated by filtration, washed with petrol and dried in vacuo giving the title compound (1.57 g, 71%).

Intermediate 3 : 6- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -nicotinic acid

Step 1: 6-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-nicotinic acid ethyl ester

Intermediate 2 (422 mg) was treated with ethyl-2-chloro nicotinate (278 mg) as described in Example 1 , Step 1. The partitioning used ethyl acetate rather than DCM for solubility reasons. The residue was chromatographed using DCM followed by 1% triethylamine in DCM to elute a material 85% pure (249 mg, 56%).

Step 2: 6-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamovπ-phenyll-nicotinic acid 6- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -nicotinic acid ethyl ester from Step 1 (249 mg) was treated with sodium hydroxide (22 mg) in methanol (10 ml) and heated to reflux for 1Oh. It was then cooled, concentrated to dryness and triturated with acetone (5 ml). The solid formed was collected and dried in vacuo to afford the title compound (184 mg, 75%).

Intermediate 4: 5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- thiophene-2-carboxylic acid

Step 1: 5-Bromo-thiophene-2-carboxylic acid ethyl ester

A solution of 5-bromo-2-thiophenecarboxylic acid (1 g) in ethanol (10 ml) was treated with cone, sulphuric acid (2 drops) and heated to reflux overnight. The mixture was then concentrated to dryness. The residue was partitioned between DCM (50 ml) and 2M

NaHCO₃. The DCM was separated, dried over MgSO₄ and concentrated to dryness to afford the ester as an oil (560 g, 49%).

Step 2: 5-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-thiophene-2- carboxylic acid ethyl ester Intermediate 2 (422 mg) and 5-bromo-thiophene-2-carboxylic acid ethyl ester (352 mg) were dissolved in isopropanol (10 ml) and treated with IM sodium bicarbonate (5 ml), palladium tetrakis(triphenylphosphine) (58 mg, 5 %mol) and heated to 90 ⁰C overnight.

The mixture was partitioned between DCM (50 ml) and water (50 ml) and the layers separated. The organics were dried over MgSO₄ and evaporated. The residue was chromatographed on a 20 g SiO₂ SPE column (DCM up to 2% methanol in DCM) to afford the title compound (227 mg, 50%).

Step 3 : 5-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-thiophene-2- carboxylic acid

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid ethyl ester (227 mg) was treated with sodium hydroxide (20 mg) in methanol (10 ml) at reflux for 1Oh. It was then concentrated to dryness, then triturated with acetone. The solvent was decanted and the solid dried in vacuo to afford a white solid (170 mg, 77%). Intermediate 5: [4-Methyl-3-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]- carbamic acid tert-butyl ester

(3-Bromo-4-methyl-phenyl)-carbamic acid tert-butyl ester (3.4 g) and bis(pinnacolato)diborane (4.5 g) in dry DMF (55 ml) were treated with potassium acetate (5.8 g) and PdC^dppf (650 mg) and were heated to 80 ⁰C, under nitrogen, for 16h. The mixture was evaporated and the residue purified on silica. Gradient elution with 1-20% (4:1 EtOAc:Hexane) in hexane over 40 min. gave an off-white solid (2.5 g). 1H NMR 1.020-1.040 (s, 6H), 1.165 (s, 9H), 1.330 (s, 6H), 2.370-2.377 (s, 3H), 6.90 (d, IH), 7.20 (s, IH), 7.65 (s, IH), 9.05 (s, IH).

Intermediate 6: 5-(5-Amino-2-methyl-phenyl)-thiophene-2-carboxylic acid [4-(l,l- dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Step 1: 5-Bromo-thiophene-2-carboxylic acid [4-0 J-dioxo-llambda-*6*-thiomorpholin- 4-ylmethyl)-phenyll-amide

To a solution of 5-bromo-2-thiophene carboxylic acid (241 mg) in toluene (6 ml) was added oxalyl chloride (0.9 ml) and a drop of dry DMF. The reaction mixture was stirred under nitrogen for 3h and was then evaporated and dried in vacuo. Anhydrous DCM was added followed by 4-(l,l-dioxo-l lambda* 6 *-thiomorpholin-4-ylmethyl)-phenylamine (279 mg) and triethylamine (0.16 ml). The reaction mixture was stirred under nitrogen for 16h and was then partitioned between water (50 ml) and DCM (50 ml). The organic layer was evaporated giving the title compound (450 mg, 90%). LC-MS: rt 2.73 ; m/z 431 ES+. Step 2: (3-(5-[4-(l.l-Dioxo-llambda-*6*-thiomorpholin-4-ylmethvπ-phenylcarbamoyll- thiophen-2-vU-4-methyl-phenyl-carbamic acid tert-butyl ester

To a solution of Intermediate 5 (388 mg) and 5-bromo-thiophene-2-carboxylic acid [4- (l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (450 mg) in DME (8.5 ml), were added cesium carbonate (379 mg) and water (4.25 ml). The reaction mixture was stirred for 16h to 85 ⁰C under nitrogen. The mixture was cooled to RT and partitioned between water and ethyl acetate (50 ml). The organic layer was then evaporated and the residue purified on silica gel (eluent 0% to 5% methanol in DCM) over 45 min giving the title compound (400 mg, 69%). LC-MS: rt 3.02; m/z 556 ES+.

Step 3: 5-(5-Amino-2-methyl-phenvπ-thiophene-2-carboxylic acid [4-d.l-dioxo-llambda- * 6 * -thiomorpholm-4-ylmethvO-phenyl] -amide

(3- {5-[4-(l , 1 -Dioxo- 1 lambda-*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-thiophen- 2-yl}-4-methyl-phenyl-carbamic acid tert-butyl ester was stirred under nitrogen in 1 : 1 TFA:DCM (50 ml) for 2h. The reaction mixture was reduced in vacuo to a solid residue. This residue was taken up in IM HCl (50 ml) and DCM (50 ml). The aqueous layer was then basified (pH 10) using 2N NaOH, and then extracted with DCM. The organics were combined and reduced in vacuo to afford the title compound as an oil (296 mg). LC-MS: rt 2.62; m/z 456 ES+.

Intermediate 7: 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-piperazin-l-yl-benzamide

Step 1 : 4-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l- carboxylic acid tert-butyl ester A solution of 3-bromo-4-methyl-N-(4-morpholin-4-yl-phenyl)-benzamide (Intermediate 2,

Step 1) (918 mg), and Boc piperazine (500 mg) in dry dioxane (50 ml) was treated with sodium tert-butoxide (492 mg), tris(dibenzylideneacetone)dipalladium(0) (67 mg) and

BINAP (136 mg) and was heated, under nitrogen to 115 ⁰C for 48h. The mixture was then cooled, diluted with ethyl acetate and filtered through celite. The organics were evaporated and the residue purified via column chromatography (2: 1 Petrol/Ethyl acetate) giving the product as a yellow solid (650 mg, 56%).

LC-MS: rt 3.02 ; m/z 481 ES+.

Step 2: 4-Methyl-N-(4-morpholin-4-yl-phenyl)-3-piperazin- 1 -yl-benzamide

A solution of 4-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l- carboxylic acid tert-butyl ester (300 mg) and TFA (1 ml) in THF (10 ml) was stirred overnight at RT. The solution was evaporated giving a red oil which was taken through the next stage without further purification (258 mg).

LC-MS: rt 2.16 ; m/z 381 ES+.

Intermediate 8: 4-[4-(Propane-l-sulfonyl)-piperazin-l-ylmethyl]-phenylamine

Step 1: 4-(Propane-l-sulfonyl)-piperazine-l-carboxylic acid ethyl ester Piperazine-1-carboxylic acid ethyl ester (18 g) was dissolved in TBME (50 ml) and triethylamine (15.9 ml) added. The stirred TBME solution was cooled to 0 ⁰C prior to dropwise addition of n-propylsulfonyl chloride (12.8 ml). The stirred reaction mixture was allowed to warm to RT over 2h before being partitioned between IM HCl and DCM. The DCM was dried and the solvent was removed under vacuum to give the expected product as a solid (22.73 g, 76%). Step 2: 1 -(Propane- 1-sulfonvD-piperazine

The ester from Step 1 (7 g) was dissolved in ethanol (70 ml) and 4M NaOH (100 ml). The mixture was stirred at 100 ⁰C for 2Oh after which time the ethanol was removed under vacuum. The aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organics layers were dried and evaporated giving a straw coloured oil (4.9 g, 94%). Step 3: l-(4-Nitro-benzyl)-4-(propane-l-sulfonyl)-piperazine

1 -(Propane- l-sulfonyl)-piperazine (4.9 g) was dissolved in DMF (35 ml) and K2CO3 (7.14 g) added. The reaction mixture was then cooled to 0 ⁰C and 4-nitrobenzyl bromide (5.6 g) in DMF (10 ml) added dropwise. Stirring was continued for 10 min prior to allowing the reaction mixture to warm to RT over Ih. Water (800 ml) was chilled to 0 ⁰C and the reaction mixture added slowly to induce precipitation of the product as a white solid over 15 min. The solid was filtered off, washed with water and petroleum ether prior to drying under vacuum for 16h to give the title compound (7.95 g, 94%). Step 4: 4-[4-(Propane- 1 -sulfonvD-piperazin- 1 -ylmethyll-phenylamine l-(4-Nitro-benzyl)-4-(propane-l-sulfonyl)-piperazine (5.5 g) in methanol (250 ml) was hydrogenated at atmospheric pressure over 5% Pt/C (550 mg). The catalyst was filtered off and the bulk of the methanol removed under vacuum, a further filtration through celite removed any remaining catalyst. The methanol was removed under vacuum to give the title compound as a yellow powder (5.11 g, 100%).

¹R NMR 0.99 (3H, t, J7.4 Hz), 1.69 (2H, m), 2.37 (4H, m), 2.99 (2H, m), 3.13 (4H, m), 3.31 (2H, s), 4.97 (2H, s), 6.51 (2H, J8.5 Hz), 6.93 (2H, d, J8.5 Hz). LC-MS: rt 0.87 ; m/z 298 ES+. Example 1

5- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -furan-2-carboxylic acid [4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Step 1 : 5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-furan-2-carboxylic acid ethyl ester

A mixture of Intermediate 1 (329 mg) and Intermediate 2 (422 mg) in isopropanol (10 ml) was heated with IM sodium bicarbonate (5 ml) and palladium tetrakis(triphenylphosphine) (58 mg) to 90 ⁰C. After 16h, the mixture was partitioned between DCM (50 ml) and water (50 ml). The dried extract was evaporated and the residue was chromatographed on silica gel. Gradient elution with petrol-DCM (50:50 up to 0:100) gave the title compound (360 mg, 83%). Step 2: 5-r2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-furan-2-carboxylic acid

The ester from Step 1 (360 mg) was treated with sodium hydroxide (53 mg) in methanol

(10 ml) and heated to reflux for 4h. It was then cooled and concentrated to dryness. The residue was acidified until the solid precipitated. The mixture was passed through a C 18 SPE column. The fractions isolated were concentrated to dryness, triturated with EtOH and the supernatant concentrated to give the expected compound as a solid (320 mg, 87%). Step 3 : 5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyll-furan-2-carboxylic acid [4-(l.l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyll-amide A mixture of the acid from Step 2 (30 mg), 4-( 1,1 -dioxo-1 lambda* 6* -thiomorpholin-4- ylmethyl)-phenylamine (12.4 mg) and HBTU (56 mg) in anhydrous DMF (1 ml) containing triethylamine (0.25 ml) was stirred at RT for 16h. The mixture was poured into water (4 ml) and filtered. The residue was collected and purified by preparative HPLC giving the title compound as a colourless solid (6 mg, 14%). 1R NMR 2.51 (s, 3H), 2.90 (m, 4H), 3.36 (m, 8H), 3.65 (m, 2H), 3.76 (m, 4H), 6.95 (d, 2H), 7.06 (d, IH), 7.32 (d, 2H), 7.52 (m, 2H), 7.74 (dd, 4H), 7.90 (d, IH), 8.43 (s, IH), 10.21 (s, IH), 10.30 (s, IH). LC-MS: m/z 629 ES+.

Example 2

N-(3-Bromo-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide

Intermediate 3 (30 mg), 3-bromoaniline (11.8 mg) and HBTU (52 mg) in anhydrous DMF (1 ml) containing triethylamine (0.25 ml) were stirred at RT for 16h. The mixture was then concentrated to dryness and purified by preparative HPLC giving the title compound as a colourless solid (15 mg, 39%).

¹R NMR 2.60 (s, 3H), 3.22 (m, 4H), 3.89 (m, 4H), 7.07 (d, 2H), 7.49 (m, 2H), 7.64 (d, IH), 7.77 (d, 2H), 7.98 (m, 2H), 8.10 (d, IH), 8.21 (s, IH), 8.29 (s, IH), 8.60 (dd, IH), 9.38 (s, IH), 10.28 (s, IH), 10.83 (s, IH). LC-MS: m/z 571/573 ES+. Example 3

N-(3-Chloro-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide This material was prepared as for Example 2 except that 3-chlorobenzylamine (9.6 mg) was used. Yield (14 mg, 38%).

¹R NMR 2.36 (s, 3H), 3.01 (m, 4H), 3.68 (m, 4H), 4.48 (d, 2H), 6.88 (d, 2H), 7.26 (m, 3H), 7.36 (s, IH), 7.42 (d, IH), 7.56 (d, 2H), 7.72 (d, IH), 7.88 (dd, IH), 7.98 (s, IH), 8.32 (dd, IH), 9.12 (s, IH), 9.33 (t, IH), 10.06 (s, IH). LC-MS: m/z 541 ES+.

Example 4

N-(4-Isoxazol-5-yl-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)- phenyl] -nicotinamide This material was prepared as for Example 2 except that 4-isoxazol-5-yl-phenylamine (10.9 mg) was used. Yield (15 mg, 39%).

¹R NMR 2.47 (s, 3H), 3.08 (m, 4H), 3.75 (m, 4H), 6.99 (m, 3H), 7.50 (d, IH), 7.65 (d, 2H), 7.95 (m, 7H), 8.47 (dd, IH), 8.66 (d, IH), 9.27 (d, IH), 10.15 (s, IH), 10.80 (s, IH). LC-MS: m/z 560 ES+.

Example 5

N-(3-Methoxy-phenyl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide

This material was prepared as for Example 2 except that p-anisidine (8.4 mg) was used. Yield (10 mg, 28%).

¹R NMR 2.51 (s, 3H), 3.08 (m, 4H), 3.73 (m, 4H), 3.79 (s, 3H), 6.73 (d, IH), 6.94 (d, 2H), 7.30 (t, IH), 7.40 (d, IH), 7.53 (m, 2H), 7.63 (d, 2H), 7.83 (d, IH), 7.96 (dd, IH), 8.07 (s, IH), 8.46 (dd, IH), 9.24 (d, IH), 10.14 (s, IH), 10.51 (s, IH). LC-MS: m/z 523 ES+. Example 6

N-(lH-Indazol-6-yl)-6-[2-methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]- nicotinamide

This material was prepared as for Example 2 except that 6-aminoindazole (9 mg) was used.

Yield (10 mg, 28%).

¹R NMR 2.51 (s, 3H), 3.08 (m, 4H), 3.75 (m, 4H), 6.95 (d, 2H), 7.41 (d, IH), 7.50 (d, IH),

7.65 (d, 3H), 7.78 (d, IH), 7.88 (d, IH), 8.00 (m, 3H), 8.08 (s, IH), 8.33 (s, IH), 8.47 (dd,

IH), 9.27 (d, IH), 10.15 (s, IH), 10.66 (s, IH).

LC-MS: m/z 533 ES+.

Example 7

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid phenylamide To a solution of Intermediate 7 (25 mg) in THF (2 ml) and triethylamine (0.14 ml) was added phenylisocyanate (0.01 ml) and the resulting solution was stirred for 2h at RT. The reaction mixture was evaporated in vacuo and purified via column chromatography eluting with (2:1 petrol/ethyl acetate) to (3:1 ethyl acetate/petrol) to give the title compound as a yellow solid (26 mg, 79%). ¹H NMR 2.37 (3H, s), 2.87-3.02 (4H, m), 3.03-3.16 (4H, m), 3.60-3.82 (8H, m), 6.89-7.01 (3H, m), 7.19-7.38 (3H, m), 7.49 (2H, d, J 7.6 Hz), 7.56-7.67 (4H, m), 8.64 (IH, s), 9.97 (IH, s). LC-MS: rt 2.84 ; m/z 500 ES+.

Example 8

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid benzylamide

To a solution of Intermediate 7 (25 mg) in THF (2 ml) and triethylamine (0.14 ml) was added benzylisocyanate (0.01 ml) and the resulting solution was stirred for 2h at RT. The reaction mixture was evaporated in vacuo and purified via column chromatography eluting with (2:1 petrol/ethyl acetate) to (3:1 ethyl acetate/petrol) to give the title compound as a white solid (9 mg, 34%).

¹R NMR 2.34 (3H, s), 2.78-2.97 (4H, m), 3.01-3.16 (4H, m), 3.36-3.61 (4H, m), 3.68-3.85 (4H, m), 4.29 (2H, d, J 5.7 Hz), 6.95 (2H, d, J 9.5 Hz), 7.18-7.38 (6H, m), 7.55-7.65 (5H, m), 9.96 (IH, s).

LC-MS: rt 2.82 ; m/z 514 ES+.

Example 9

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid (3-bromo-phenyl)-amide

Intermediate 4 (30 mg), 3-bromoaniline (11.6 mg) and HBTU (51 mg) in anhydrous DMF

(1 ml) containing triethylamine (0.25 ml) were stirred at RT for 16h. The mixture was then concentrated to dryness and purified by HPLC to give a solid (20 mg, 51%).

¹U NMR 3.06 (m, 4H), 3.33 (s, 3H), 3.72 (m, 4H), 6.92 (d, 2H), 7.34 (m, 2H), 7.38 (d,

IH), 7.51 (d, IH), 7.60 (d, 2H), 7.73 (d, IH), 7.91 (d, IH), 8.06 (m, 3H), 10.12 (s, IH),

10.43 (s, IH).

LC-MS: m/z 578/579 ES+. Example 10

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid 3-chloro-benzylamide

The title compound was prepared according to the procedure described for Example 9 except that 3-chlorobenzylamine (9.5 mg) was used. Yield (14 mg, 38%).

¹H NMR 3.06 (m, 4H), 3.33 (s, 3H), 3.73 (m, 4H), 4.47 (d, 2H), 6.92 (d, 2H), 7.34 (m, 5H), 7.47 (d, IH), 7.61 (d, 2H), 7.87 (m, 2H), 8.00 (s, IH), 9.18 (t, IH), 10.10 (s, IH). LC-MS: m/z 546 ES+.

Example 11

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid (4-isoxazol-5-yl-phenyl)-amide

The title compound was prepared according to the procedure described for Example 9 except that 4-isoxazol-5-yl-phenylamine (10.8 mg) was used.

Yield (21 mg, 53%).

¹H NMR 3.05 (m, 4H), 3.33 (s, 3H), 3.73 (m, 4H), 6.93 (d, 2H), 7.42 (m, 2H), 7.49 (m,

IH), 7.61 (m, 2H), 7.71 (d, IH), 7.89 (m, 2H), 8.00 (m, IH), 8.05 (m, IH), 8.12 (d, IH),

8.20 (s, IH), 10.11 (s, IH), 10.41 (s, IH). LC-MS: m/z 578/579 ES+.

Example 12

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid (lH-indazol-6-yl)-amide The title compound was prepared according to the procedure described for Example 9 except that 6-aminoindazole (9 mg) was used.

Yield (15 mg, 41%).

¹H NMR 2.88 (m, 4H), 3.08 (m, 8H), 3.37 (s, 3H), 3.63 (m, 2H), 3.73 (m, 4H), 6.92 (d,

2H), 7.31 (d, 2H), 7.41 (d, IH), 7.51 (d, IH), 7.61 (d, 2H), 7.73 (d, 2H), 7.89 (dd, IH), 8.05 (m, 2H), 10.12 (s, IH), 10.32 (s, IH).

LC-MS: m/z 538 ES+. Example 13

5-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-thiophene-2-carboxylic acid [4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide

The title compound was prepared according to the procedure described for Example 9 except that 4-(l,l-dioxo-l lambda* 6 *-thiomorpholin-4-ylmethyl)-phenylamine (16.2 mg) was used.

Yield (10 mg, 23%).

¹U NMR 2.42 (s, 3H), 3.01 (m, 4H), 3.56 (m, 2H), 3.65 (m, 4H), 6.85 (d, 2H), 7.25 (d, 2H), 7.33 (d, IH), 7.44 (d, IH), 7.53 (d, 2H), 7.63 (d, 2H), 7.84 (d, IH), 7.99 (m, 2H), 10.04 (s, IH), 10.22 (s, IH). LC-MS: m/z 645 ES+.

Example 14

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid benzo[l,3]dioxol-5-ylamide

To a solution of Intermediate 7 (43 mg) in THF (2.5 ml) and triethylamine (0.25 ml) was added 3,4-(methylenedioxy)phenylisocyanate (23 mg) and the resulting solution was stirred for 2h at RT, then was evaporated in vacuo and purified via column chromatography eluting with (2:1 ethyl acetate/petrol) to give the title compound as a white powder (5.5 mg, 11%).

¹H NMR 2.33 (3H, s), 2.83-2.97 (4H, m), 3.01-3.11 (4H, m), 3.52-3.65 (4H, m), 3.66-3.80 (4H, m), 5.93 (2H, s), 6.73-6.97 (5H, m), 7.17 (2H, m), 7.30 (IH, d, J8.2 Hz), 7.53-7.64 (2H, m), 8.50 (IH, s), 9.94 (IH, s). LC-MS: rt 2.81; m/z 544 ES+.

Example 15

4-[3-(4-Morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid 2- chloro-benzylamide

Step 1: 3-Bromo-N-(4-morpholin-4-yl-phenyl)-benzamide

To a solution of 3-bromo-benzoic acid (2 g) and N-(4-aminophenyl)morpholine (1.77 g) in DMF (150 ml) was added HBTU (5.65 g) and triethylamine (3.46 ml). The reaction mixture was stirred overnight at RT. The solution was reduced to half its volume and water was added. The precipitate formed was filtered off, washed with more water and dried overnight to give the title compound as an off- white solid (3.01 g, 83%). Step 2: 4-r3-(4-Morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l-carboxylic acid tert-butyl ester A solution of the above intermediate (1 g), and N-Boc piperazine (565 mg) in dry dioxane (35 ml) was treated with sodium tert-butoxide (830 mg), tris(dibenzylideneacetone)dipalladium(0) (210 mg) and BINAP (277 mg) and was heated to 110 ⁰C, under nitrogen, for 5 days. The mixture was cooled, diluted with acetone and filtered through celite. The solution was evaporated and the residue purified via column chromatography. Elution with (2:1 petrol/ethyl acetate up to 1:1 petrol/ethyl acetate) gave the title compound (365 mg, 27%).

Step 3: N-(4-Morpholin-4-yl-phenyl)-3-piperazin-l-yl-benzamide The product from Step 2 (200 mg) and TFA (7 ml) in THF (10 ml) was stirred overnight at RT. The dark solution was evaporated to dryness and used without further purification in the subsequent step (165 mg).

Step 4: 4-r3-(4-Morpholin-4-yl-phenylcarbamoyl)-phenyll-piperazine-l-carboxylic acid 2- chloro-benzylamide

The product from Step 3 (40 mg) in THF (1.5 ml) and triethylamine (0.09 ml) was treated with 2-chloro-benzylisocyanate (0.029 ml) and the resulting solution was stirred overnight at RT. The reaction mixture was evaporated in vacuo and purified via preparative HPLC giving the title compound as a white powder (15 mg, 26%). 1U NMR 3.03-3.16 (4H, m), 3.18-3.31 (4H, m) 3.50-3.64 (4H, m), 3.70-3.84 (4H, m), 4.34 (2H, app. d, J5.7 Hz), 6.95 (2H, d, J 8.9 Hz) 7.14-7.55 (9H, m), 7.63 (2H, d, J8.8 Hz), 10.10 (IH, s). LC-MS: rt 2.80 ; m/z 534 ES+.

Example 16

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid (4-isoxazol-5-yl-phenyl)-amide

4-Isoxazol-5-yl-phenylamine hydrochloride (19.6 mg) in toluene (2 ml) was treated with oxalyl chloride (0.013 ml). The reaction mixture was stirred at 10 ⁰C for 45 min and was then heated to 130 ⁰C for 3h under nitrogen before the addition of triethylamine (0.13 ml) at 25 ⁰C. After stirring for a further 25 min, Intermediate 7 (46 mg) was added and the resulting solution was stirred for 18h. The mixture was evaporated to dryness and the residue purified via preparative HPLC to give the title compound as a colourless product (14 mg, 68%). 1R NMR 2.37 (3H, s), 2.84-3.19 (8H, m), 3.59-3.86 (8H, m), 6.85-6.99 (3H, m), 7.34 (IH, d, J 8.2 Hz), 7.56-7.82 (8H, m), 8.61 (IH, d, J 1.9 Hz), 8.96 (IH, s), 9.98 (IH, s). LC-MS: rt 2.85 ; m/z 567 ES+.

Example 17 4- [2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl] -piperazine-1-carboxylic acid (3-bromo-phenyl)-amide To Intermediate 7 (44 mg) in THF (2.5 ml) and triethylamine (0.042 ml) was added 3- bromophenylisocyanate (0.024 ml) and the resulting solution was stirred for 2h at RT. The mixture was evaporated in vacuo and the residue purified via preparative HPLC to give the title compound as a light brown solid (26 mg, 37%). 1R NMR 2.37 (3H, s), 2.86-3.00 (4H, m), 3.04-3.13 (4H, m), 3.56-3.82 (8H, m), 6.95 (2H, d, J 8.8 Hz), 7.09-7.54 (5H, m), 7.52-7.71 (3H, m), 7.82-7.86 (IH, app.t, J 1.9 Hz), 8.82 (IH, s), 9.97 (IH, s). LC-MS: rt 2.97 ; m/z 580 ES+.

Example 18

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid (3-methoxy-phenyl)-amide

The title compound was prepared according to the procedure described for Example 17 except that 3-methoxyphenylisocyanate (0.025 ml) was used. Yield of a yellow solid (5 mg, 8%).

¹R NMR 2.37 (3H, s), 2.84-3.14 (8H, m), 3.54-3.81 (1 IH, m), 6.53 (IH, d, J 8.0 Hz), 6.95 (2H, d, J 8.8 Hz), 7.05-7.25 (3H, m), 7.33 (IH, d, J 8.2 Hz), 7.56-7.69 (4H, m), 8.62 (IH, s), 9.97 (IH, s). LC-MS: rt 2.81; m/z 530 ES+.

Example 19

4-[2-Methyl-5-(4-morpholin-4-yl-phenylcarbamoyl)-phenyl]-piperazine-l-carboxylic acid [4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

To a solution of 4-nitrophenylchloro formate (45 mg) in DCM (4 ml) and triethylamine (0.051 ml) was added 4-(l , 1 -dioxo- 1 lambda* 6 *-thiomorpholin-4-ylmethyl)-phenylamine (62 mg, 1.1 eq) and the mixture was stirred at RT for Ih. Intermediate 7 (46 mg) was added in a solution of DCM:triethylamine (3.25:0.75, 4 ml) and the mixture then stirred overnight at RT. The mixture was evaporated to dryness in vacuo and the residue purified via preparative HPLC to give the title compound as a yellow solid (23 mg, 15%). 1R NMR 2.37 (3H, s), 2.76-3.21 (16H, m), 3.52-3.84 (1OH, m), 6.94 (2H, d, J 8.8 Hz), 7.21 (2H, d, J 8.2 Hz), 7.34 (IH, d, J 8.2 Hz), 7.46 (2H, d, J 8.2 Hz), 7.56-7.69 (4H, m), 8.65 (IH, s), 9.94 (IH, s). LC-MS: rt 2.69 ; m/z 647 ES+.

5- [S-Cyclopropanecarbonyl-aminoJ-l-methyl-phenyl] -thiophene-2-carboxylic acid [4- (l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide

Intermediate 6 (84 mg) in DMF (1 ml) containing triethylamine (0.052 ml) was treated with cyclopropane carbonyl chloride (0.020 ml) and the mixture stirred for 16h at RT. The reaction mixture was poured into water (6 ml) and the solid formed filtered off and then dried in vacuo. Yield (40 mg, 41%). ¹H NMR 0.81 (m, 4H), 1.77 (m, IH), 2.38 (s, 3H), 2.90 (m, 4H), 3.12 (m, 4H), 3.65 (s, 2H), 3.73 (m, 4H), 7.31 (m, 4H), 7.52 (dd, IH), 7.71 (m, 2H), 7.81 (s, IH), 8.03 (d, IH), 10.28 (s, 2H). LC-MS: m/z 510 ES+.

Example 21

5- [5-(3-Methoxy-benzoylamino)-2-methyl-phenyl] -thiophene-2-carboxylic acid [4- (l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide

The title compound was prepared according to the procedure described in Example 20 except that m-anisoyl chloride (75 mg) was used.

Yield (30 mg, 28%).

¹H NMR 1.77 (s, 3H), 2.42 (s, 3H), 2.90 (m, 4H), 3.13 (m, 4H), 3.66 (s, 2H), 7.18 (m,

IH), 7.34 (m, 3H), 7.47 (m, IH), 7.57 (m, 3H), 7.75 (m, 3H), 7.98 (s, IH), 8.06 (d, IH),

10.30 (s, 2H). LC-MS: m/z 590 ES+.

Example 22 lH-Pyrazole-4-carboxylic acid (3-{5-[4-(l,l-dioxo-llambda-6-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-thiophen-2-yl}-4-methyl-phenyl)-amide The title compound was prepared according to the procedure described as in Example 1 , Step 3 except that 4-pyrazole carboxylic acid (49 mg) and Intermediate 6 were used. Yield (35 mg, 34%).

¹U NMR 2.41 (s, 3H), 2.88 (m, 4H), 3.12 (m, 4H), 3.66 (s, 2H), 7.34 (m, 5H), 7.72 (m, 3H), 7.90 (m, IH), 8.05 (d, 2H), 8.38 (d, 2H), 9.88 (s, IH), 10.30 (s, 2H). LC-MS: m/z 550 ES+.

Example 23

5- [2-Methyl-5-(4-morpholin-4-yl-benzoylamino)-phenyl] -thiophene-2-carboxylic acid [4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide The title compound was prepared according to the procedure described as in Example 1 , Step 3 except that 4-morpholin-4-yl benzoic acid (91 mg) and Intermediate 6 were used. Yield (23 mg, 8%). ¹R NMR 2.41 (s, 3H), 2.89 (m, 4H), 3.13 (m, 4H), 3.27 (m, 4H), 3.65 (s, 2H), 3.76 (m, 4H), 7.04 (d, 2H), 7.33 (m, 4H), 7.75 (m, 3H), 7.98 (m, 4H), 10.04 (s, IH), 10.30 (s, IH). LC-MS: m/z 645 ES+.

Example 24

S-^-Methyl-S-Kthiophene^-carbonylJ-aminol-phenylJ-thiophene-Σ-carboxylic acid [4-(l,l-dioxo-llambda-*6*-thiomorpholin-4-ylmethyl)phenyl]-amide

The title compound was prepared according to the procedure described as in Example 1 ,

Step 3 except that thiophene-2-carboxylic acid (56 mg) and Intermediate 6 were used.

Yield (14 mg, 6%).

¹U NMR 2.42 (s, 3H), 2.89 (m, 4H), 3.13 (m, 4H), 3.66 (s, 2H), 7.25 (t, IH), 7.34 (m, 4H),

7.75 (m, 3H), 7.89 (m, 2H), 8.05 (m, 2H), 10.30 (s, 2H).

LC-MS: m/z 566 ES+.

Example 25

3-[(3-Bromo-phenylcarbamoyl)-ethynyl]-4-methyl-N-(4-morpholin-4-yl-phenyl)- benzamide

Step 1:

To a solution of 3-iodo-4-methyl-benzoic acid (1 g) and N-(4-aminophenyl)morpholine (679 mg) in DMF (80 ml) was added HBTU (2.17 g) and triethylamine (1.32 ml). The mixture was stirred overnight at RT. The solution was reduced to half its volume and water was added. The precipitate was filtered off, washed with more water and dried overnight to give the required intermediate used in Step 2 (1.21 g, 75%).

Step 2: A mixture of the above intermediate (827 mg) and trimethylsilylacetylene (0.3 ml) in DMF

(40 ml) was stirred under nitrogen with copper iodide (11 mg), triethylamine (0.576 ml), bis(triphenylphosphine) palladium II chloride (84 mg) and was heated to 40 ⁰C. After 48h, the solution was evaporated to dryness, re-dissolved in acetone and filtered through a thick pad of celite. The filtrate was evaporated to dryness and purified via column chromatography (4:1 petrol/ethyl acetate) to give the product as an off- white solid (240 mg, 31%).

Step 3:

A solution of the alkyne from Step 2 (393 mg) and tetrabutyl ammonium fluoride (1.5 ml) in THF (20 ml) was stirred overnight at RT. The THF was evaporated off and the residue partitioned between ethyl acetate and water. The dried extract was then evaporated to give a white solid (258 mg, 81%).

Step 4:

To a solution of the alkyne from Step 3 (65 mg) in THF (2.5 ml) at -78 ⁰C, was added drop wise butyllithium (1.6M solution, 0.33 ml). The resulting mixture was allowed to warm to RT and was then treated with 3-bromophenyl isocyanate (0.031 ml). The resulting solution was allowed to stir for a further 8h. The solvent was evaporated to dryness and the resulting residue was purified via preparative HPLC to give the title compound as a yellow powder (6.2 mg, 6%).

¹U NMR 2.58 (3H, s), 2.99-3.18 (4H, m), 3.69-3.82 (4H, m), 6.96 (2H, d, J 8.8 Hz), 7.25- 7.43 (3H, m), 7.53-7.72 (3H, m), 7.97-8.10 (3H, m), 10.18 (IH, s), 11.07 (IH, s).

LC-MS: rt 3.03 ; m/z 518 ES+. Example 26

4-[6-(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-{4-[4-(propane-l-sulfonyl)- piperazin-l-ylmethyl]-phenyl}-benzamide

Step 1 : 4-(6-Chloro-pyrimidin-4-vD-benzoic acid methyl ester

A mixture of 4,6-dichloropyrimidine (0.1 g), 4-carbomethoxyphenyl boronic acid (0.135 g), palladium (II) bis triphenylphosphine dichloride (0.01 g) and sodium carbonate (0.2 g) in DME (3 ml), ethanol (0.4 ml) and water (0.6 ml) was heated at 130 ⁰C in a CEM microwave for 15 minutes. This procedure was repeated a further five times at this scale in the same apparatus. Water and ethyl acetate were added to the combined reaction mixtures and the organic phase was washed with portions of saturated ammonium chloride, dried over sodium sulphate and concentrated in vacuo. Chromatography on silica (15-20% ethyl acetate in 40-60° petroleum ether) gave the title compound as a colourless solid (0.3 g) ¹R NMR (CDCl₃) 3.90 (3H, s), 7.74 (IH, s), 8.09 (4H, dd), 9.01 (IH, s). LC-MS: rt 2.31 ; m/z 249 ES+.

Step 2: 446-(Cvclopropylmethyl-amino)-pyrimidin-4-yl^"|-benzoic acid methyl ester A mixture of 4-(6-chloro-pyrimidin-4-yl)-benzoic acid methyl ester (0.1 g), diisopropylethylamine (0.14 ml) and cyclopropylmethylamine (313 mg) in isopropyl alcohol (1.6 ml) were heated in a microwave oven at 120 ⁰C for 15 minutes. Further cyclopropyl methylamine (16 mg), then two further batches of cyclopropyl methylamine (8 mg) were added, the mixture heated at 120 ⁰C in the microwave for 15 minutes after each addition. The mixture was concentrated in vacuo, then taken up in ethyl acetate and washed with water and brine, dried over sodium sulphate and finally concentrated in vacuo to give the title compound as a colourless solid (0.116 g).

1H NMR0.02 (2H, m), 0.25 (2H, m), 0.84 (IH, m), 3.00 (IH, m), 3.65 (3H, s), 6.81 (IH, s), 7.38 (IH, bs), 7.85 (4H, dd), 8.28 (IH, s). LC-MS: rt 1.94; m/z 284 ES+ 282 ES-.

Step 3 : 446-(Cvclopropylmethyl-amino)-pyrimidin-4-yl^"|-N- (4-[4-(propane- 1 -sulfonyl)- piperazin- 1 -ylmethyll -phenyl} -benzamide

A solution of 4-[6-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzoic acid methyl ester

(0.116 g) in methanol (2 ml) was treated with 2.5M aqueous sodium hydroxide (0.32 ml). After 18 h at 40 ⁰C, 2M aqueous hydrochloric acid (0.4 ml) was added and the mixture concentrated in vacuo. The resulting white solid (ES+ 270, ES- 268, r.t. 1.63 min) was used directly in the next step.

The aforementioned white solid was dissolved in DMF (1.6 ml) and successively treated with 1-hydroxybenzotriazole hydrate (0.303 g), N-methylmorpholine (0.175 ml) and Intermediate 8 (0.28 g). The resulting mixture was stirred at RT for 1.25 h. The mixture was concentrated in vacuo, then partitioned between ethyl acetate and water. The organic phase was washed with saturated brine, dried over sodium sulphate and concentrated in vacuo. Chromatography on silica (DCM/ ethanol/ ammonia, 100/8/1) and subsequent trituration with methanol afforded the title compound as a white solid (0.095 g). 1H NMR0.27 (2H, m), 0.48 (2H, m), 1.03 (3H, t), 1.09 (IH, m), 1.71 (2H, dq), 2.45

(4H,m), 3.02 (2H, dd), 3.18 (4H, m), 3.26 (IH, dd), 3.51 (2H, s), 7.06 (IH, s), 7.31 (2H, d),

7.61 (IH, m), 7.77 (2H, d), 8.09 (4H, m), 8.53 (IH, s), 1O.34(1H, s).

LC-MS: m/z 549 ES+ 547 ES-.

Example 27

4-[2[(Cyclopropylmethyl-amino)-pyrimidin-4-yl]-N-{4-[4-(propane-l-sulfonyl)- piperazin-l-ylmethyl]-phenyl}-benzamide

Step 1 : 4-(2-Chloro-pyrimidin-4-yl)-benzoic acid tert-butyl ester A mixture of 2,4-dichloropyrimidine (0.745 g), 4-tert butoxycarbonylphenyl boronic acid (0.83 g), palladium tetrakis triphenylphosphine (0.29 g) and caesium carbonate (1.625 g) in DME (60 ml) and water (60 ml) was heated at 70 ⁰C for 18 h. Water and ethyl acetate were added and the organic phase was washed with 2M hydrochloric acid, saturated sodium carbonate, dried over sodium sulphate and concentrated in vacuo. Chromatography on silica (DCM, acetone, acetonitrile, ethanol, methanol gradient) gave 4-(2-chloro-pyrimidin- 4-yl)-benzoic acid tert-butyl ester (0.797 g) as a colourless solid after crystallisation from ether/hexane.

¹U NMR (CDCl₃) 1.56 (9H, s), 8.05 (2H, d), 8.22 (IH, d), 8.29 (2H, d), 8.89 (IH, s). LC-MS: m/z (M+l-tBu)⁺ 235/237 (2.73 min). Step 2: 4-r2-(Cvclopropylmethyl-amino)-pyrimidin-4-vH-benzoic acid tert-butyl ester A mixture of 4-(2-chloro-pyrimidin-4-yl)-benzoic acid tert-butyl ester (0.1 g) and cyclopropylmethylamine (0.048 g) in ethanol (1.7 ml) were heated in a microwave at 130 ⁰C for 75 min. The mixture was concentrated in vacuo, then taken up in ethyl acetate and washed with water and brine, dried over sodium sulphate and finally concentrated in vacuo to give 4- [2-(cyclopropylmethyl-amino)-pyrimidin-4-yl] -benzoic acid tert-butyl ester as a colourless solid (0.105 g).

¹R NMR 0.10 (2H, m), 0.20 (2H, m), 0.92 (IH, m), 1.336 (9H, s), 3.01 (2H, bt), 6.94 (IH, d), 7.15 (IH, bt), 7.77 ( 2H, d), 7.96 (2H, d), 8.16 (IH, d). LC-MS: m/z M⁺ 326 (2.85min).

Step 3 : 4-[2[(Cvclopropylmethyl-amino)-pyrimidin-4-yll-N- (4-[4-(propane- 1 -sulfonvO- piperazin- 1 -ylmethyl] -phenyl I -benzamide

A solution of 4-[2-(cyclopropylmethyl-amino)-pyrimidin-4-yl]-benzoic acid tert-butyl ester (0.1 g) in DCM (1 ml) was treated with trifluoroacetic acid (0.5 ml). After 18 h at RT, the mixture was concentrated in vacuo. The resulting white solid (m/z ES+ 270, ES- 268, r.t.

2.0 min) was used directly in the next step.

The aforementioned white solid was dissolved in DMF (1.6 ml) and successively treated with HBTU (0.212 g), N-methylmorpholine (0.122 ml) and Intermediate 8 (0.166 g). The resulting mixture was stirred at RT for 2.5 h. The mixture was treated with water and the resulting solid was filtered at the pump. Chromatography on silica (DCM/ ethanol/ ammonia, 100/8/1) and subsequent trituration with methanol gave the title compound as a white solid (0.1 g).

¹R NMR 0.35 (2H, m), 0.51 (2H, m), 0.99 (3H, t), 1.19 (IH, m), 1.69 (2H, m), 2.51 (2H,m), 3.04 (2H, m), 3.18 (4H, m), 3.27 (2H, m), 3.69 (2H, s), 7.25 (2H, d), 7.35 (IH, m),

7.37 (IH, d), 7.73 (2H, d), 8.07 (2H, d), 8.25 (2H, d), 8.40 (IH, d), 10.36 (IH, s).

LC-MS: m/z M⁺ 549, ES- 547 (1.99 min).

Pharmacological Example

Cells used:

HCV replicon cells Huh 9B (ReBlikon), containing the firefly luciferase - ubiquitin - neomycin phosphotransferase fusion protein and EMCV-IRES driven HCV polyprotein with cell culture adaptive mutations.

Cell culture conditions:

Cells were cultured at 37 ⁰C in a 5% CO₂ environment and split twice a week on seeding at 2 x 10⁶ cells/flask on day 1 and 1 x 10⁶ 3 days later. G418 at 0.5mg/ml was added to the culture medium but not the assay medium. The culture medium consisted of DMEM with 4500g/l glucose and glutamax (Gibco

61965-026) supplemented with 1 x non-essential amino acids (Invitrogen 11140-035), penicillin (100 IU/ml) / streptomycin (100 μg/ml) (Invitrogen 15140-122), FCS (10%, 50ml) and 1 mg/ml G418 (Invitrogen 10131-027) & 10 % Australian foetal calf serum (Invitrogen 10099-141).

Assay procedure: A flask of cells was trypsinised and a cell count carried out. Cells were diluted to

100,000 cells/ml and 100 μl of this used to seed one opaque white 96-well plate (for the replicon assay) and one flat-bottomed clear plate (for the tox assay) for every seven compounds to be tested for IC50. Wells G12 and Hl 2 were left empty in the clear plate as the blank. Plates were then incubated at 37⁰C in a 5% CO₂ environment for 24 h. On the following day compound dilutions are made up in medium at twice their desired final concentration in a clear round bottomed plate. All dilutions have a final DMSO concentration of 1%.

Once the dilution plate had been made up, controls and compounds were transferred to the assay plate (containing the cells) at 100 μl /well in duplicate plates. Exception: no compound was added to wells Al and A2 of either plate and 100 μl of 1% DMSO was added to these instead. Plates were then incubated at 37⁰C with 5% CO₂ for 72h.

At the end of the incubation time, the cells in the white plate were harvested by washing 23.5mM beetle luciferin (Promega E 1603), 26mM ATP (Sigma O-2060) in 10OnM Tris buffer pH 7.8 aliquoted and stored at -80 ⁰C was thawed and diluted 1 :50 in luciferase assay buffer (2OmM Tricine (Sigma T-0377), 1.07mM magnesium carbonate hydroxide (Sigma M-5671), O.lmM EDTA (Sigma E-5134), 2.67mM MgSO₄ (BDH 101514Y), 33.3mM dithiothreitol (Sigma 150460) pH 7.8).

The M injector of the microplate luminometer (Lmax, Molecular Devices) was primed with 5 x 300 μl injections of the diluted substrate. After 5-60 min incubation in lysis buffer at room temperature, a plate was inserted into the luminometer and 100 μl luciferase assay reagent was added by the injector on the luminometer. The signal was measured using a 1 second delay followed by a 4 second measurement programme. The IC₅₀, the concentration of the drug required for reducing the replicon level by 50% in relation to the untreated cell control value, can be calculated from the plot of the percentage reduction of the luciferase activity vs. drug concentration. The clear plate was stained with 100 μl 0.5% methylene blue in 50% ethanol at room temperature for Ih, followed by solvation of the absorbed methylene blue in lOOμl per well of 1% lauroylsarcosine. Absorbance of the plate was measured on a microplate spectrophotometer (Molecular Devices) and the absorbance for each concentration of compound expressed as a proportion of the relative DMSO control. The TD50, the concentration of drug required to reduce the total cell area by 50% relative to the DMSO controls, can be calculated by plotting the absorbance at 620 nm minus background against drug concentration.

When tested in the above screen, the compounds of the Examples gave IC50 values for inhibition of human neutrophil elastase activity of less than 30 μM (micromolar), indicating that the compounds of the invention are expected to possess useful therapeutic properties. Specimen results are shown in the following Table:

Table

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

- Ri is a moiety -Ai, -Li-Ai, -A₁-A/, -Li-Ai-A/ or -Ai-Li-A/;

A and B are the same or different and each represent a -CO-NR⁷-, -NR -CO-, -NR⁷- CO-NR⁷⁷-, -NR⁷- or -(C_rC₂ alkylene)-NR⁷- moiety, wherein R⁷ and R⁷⁷ are the same or different and each represent hydrogen or C₁-C₄ alkyl;

W represents ethynyl or a phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl, 5- or 6- membered heterocyclyl or C₃-Cs carbocyclyl moiety being unsubstituted or substituted by Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy or halogen;

Yi, Y₂ and Y₃ each independently represent CH or N; provided that when W is phenyl, at least one of Yi, Y₂ and Y₃ represents N; each A₁, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C₃-Cs carbocyclyl moiety;

each Li and L₄ is the same or different and represents a Ci-C₄ alkylene or a Ci-C₄ 5 hydroxy alkylene group;

the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being optionally fused to a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl ring; and 0 the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(Ci-C₄ alkyl)-Xi, -CO₂R⁷, -SO₂NRV, -S(O)₂-R⁷, -CONR⁷R⁷⁷, -NR⁷-CO-R⁷⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CO- NR⁷-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and -CO-O-(Ci-C₄ alkyl)-NR⁷R⁷⁷ and/or (b) 1, 2 or 3 s unsubstituted substituents selected from -(Ci-C₄ alkyl)-X₂, halogen, Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy, Ci-C₄ hydroxyalkyl, hydroxy, cyano, nitro and -NR⁷R⁷⁷, wherein Xi is -CO₂R⁷, -SO₂-R⁷, -NR⁷-CO₂-R⁷⁷, -NR⁷-S(O)₂-R⁷⁷⁷, -CONR⁷R⁷⁷ or -SO₂- NR⁷R⁷⁷, each X₂ is the same or different and is cyano, nitro or -NR⁷R⁷⁷, each R⁷ and R⁷⁷ is the same or different and represents hydrogen or Ci-C₄ alkyl and each R⁷⁷⁷ is the same or0 different and represents Ci-C₄ alkyl.

2. A compound according to claim 1, wherein W represents a phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety; said phenyl, 5- or 6- membered heteroaryl or 5- or 6- membered heterocyclyl moiety being unsubstituted or substituted by5 Ci-C₄ alkyl, Ci-C₄ alkoxy, Ci-C₄ haloalkyl, Ci-C₄ haloalkoxy or halogen.

3. A compound according to claim 1 or 2, wherein each Ai, A₄, A/ and A₄ ⁷ are the same or different and represent a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C₃-C₆ carbocyclyl moiety. o

4. A compound according to any one of the preceding claims, wherein A and B are the same or different and each represent a -CO-NH-, -NH-CO-, -NH- or -(Ci-C₂ alkylene)- NH- moiety.

5 5. A compound according to any one of the preceding claims, wherein each Li and L₄ is the same or different and represents a C1-C2 alkylene group.

6. A compound according to any one of the preceding claims, wherein R₂ represents H, Ci-C₂ alkyl, Ci-C₂ haloalkoxy or halogen. 0

7. A compound according to any one of the preceding claims, wherein and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R₄ are unsubstituted or are substituted by -S(O)₂-R^/tf, halogen or C₁-C₄ alkoxy, and R^/tf represents C₁-C₄ alkyl. 5

8. A compound of formula (I), as defined in any preceding claim, or a pharmaceutically acceptable salt thereof, for use in therapy.

9. Use of a compound of formula (I), as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use ino treating or alleviating HCV.

10. A pharmaceutical composition comprising a compound of formula (I), as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable diluent or carrier. 5

11. A pharmaceutical composition according to claim 10, which further comprises interferon and/or ribavirin.

12. A product containing: 0 a. a compound of formula (I), as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof; b. interferon and/or ribavirin; and c. a pharmaceutical acceptable carrier or diluent; for simultaneous separate or sequential use in the treatment of the human or animal body.

13. A method of alleviating an HCV infection in a patient, which method comprises administering to said patient an effective amount of a compound of formula (I), as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.