BIPHENYL DERIVATIVES AND THEIR USE IN TREATING HEPATITIS C

The present invention relates to a series of biphenyl derivatives 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 which is a biphenyl derivative of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or alleviating HCV

wherein:

R ₁ is a C ₁ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, -A ₁ -L ₁ - A/, -A ₁ -Y ₁ -A/, -A ₁ -HCt _I -A/, -L ₁ -A ₁ -Y ₁ -A/, -L ₁ -A ₁ -HBt ₁ -A/, -L ₁ -He^-A ₁ , -L ₁ -Yi-A ₁ , -L ₁ -Y ₁ -HCt ₁ -Ai, -L ₁ -HCt ₁ -Y ₁ -A ₁ , -L ₁ -Y ₁ -HCt ₁ -L/, -A ₁ -Y ₁ -HCt ₁ -A ₁ ⁷ , -A ₁ -HCt ₁ -Y ₁ -A/, -Ai-Heti-Li-A/, -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L ₁ ⁷ ;

A and B are the same or different and each represent a direct bond or a -CO- NR ⁷ -, -NR ⁷ -CO-, -NR ⁷ -CO ₂ -, -CO-, -NR ⁷ -CO-NR ⁷⁷ -, -NR ⁷ -S(O) ₂ -, -S(O) ₂ -NR ⁷ -, -SO ₂ -, -NR ⁷ -, -NR ⁷ -CO-CO-, -CO-O-, -0-C0-, -(C ₁ -C ₂ alkylene)-NR ⁷ - or -(C ₁ -C ₂ hydroxyalkylene)-NR ⁷ - moiety, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or C ₁ -C ₄ alkyl;

R ₂ and R ₃ are the same or different and each represent Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ; R ₄ is a Ci-C ₆ alkyl group or a moiety -A ₄ , -L ₄ -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ -A ₄ ⁷ , -A ₄ -L ₄ - A ₄ ⁷ , -A ₄ -Y ₄ -A ₄ ⁷ , -A ₄ -HeU-A ₄ ⁷ , -L ₄ -A ₄ -Y ₄ -A ₄ ⁷ , -L ₄ -A ₄ -HeU-A ₄ ⁷ , -L ₄ -HeU-A ₄ , -L ₄ -Y ₄ -A ₄ ,

-L ₄ -Y ₄ -HCt ₄ -A ₄ , -L ₄ -HCt ₄ -Y ₄ -A ₄ , -L ₄ -Y ₄ -HCt ₄ -L/, -A ₄ -Y ₄ -HCt ₄ -A ₄ ⁷ , -A ₄ -HCt ₄ -Y ₄ -V, -A ₄ -HCt ₄ -L ₄ - A ₄ ⁷ , -A ₄ -L ₄ -HCt ₄ - A ₄ ⁷ or -L ₄ -HCt ₄ -L/, each A ₁ , A ₄ , A ₁ and A/ are the same or different and represent a phenyl, 5- to 10- membered heteroaryl, 5- to 10- membered heterocyclyl or C ₃ -C ₈ carbocyclyl moiety; each L ₁ and L ₄ is the same or different and represents a C ₁ -C ₄ alkylene or a C ₁ - C ₄ hydroxyalkylene group; each Y ₁ and Y ₄ is the same or different and represents -CO-, -SO- or -S(O) ₂ -; each L/ and L ₄ ⁷ is the same or different and represents hydrogen or a C ₁ -C ₄ alkyl group; and each Hefy and Het ₄ is the same or different and represents -O-, -S- or -NR ⁷ -, wherein R ^; is hydrogen or a C ₁ -C ₄ alkyl group, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ₁ and R ₄ being optionally fused to a phenyl, 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ₁ and R ₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(C ₁ - C ₄ alkyl)-Xi, -CO ₂ R ⁷ , -SO ₂ NR ⁷ R ⁷⁷ , -S(O) ₂ -R ⁷ , -CONR ⁷ R ⁷⁷ , -NR ⁷ -CO-R ⁷⁷⁷ , -NR ⁷ -S (O) ₂ -R ⁷⁷⁷ , -CO-NR^(C ₁ -C ₄ alkyl)-NR ⁷ R ⁷⁷ and -CO-O-(C ₁ -C ₄ alkyl)-NR ⁷ R ⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(C ₁ -C ₄ alkyl)-X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano, nitro and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷ , -SO ₂ -R ⁷ , -NR ⁷ -CO ₂ -R ⁷⁷ , -NR ⁷ -S(O) ₂ -R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷ or -SO ₂ -NR ⁷ R ⁷⁷ , each X ₂ is the same or different and is cyano, nitro or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen or C ₁ -C ₄ alkyl and each R ⁷⁷⁷ is the same or different and represents C ₁ -C ₄ alkyl.

As used herein, a C ₁ -C ₆ alkyl moiety is a linear or branched alkyl moiety containing from 1 to 6 carbon atoms, such as a C ₁ -C ₅ or C ₁ -C ₄ alkyl moiety. Examples OfC ₁ -C ₆ alkyl moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, -CH(Et) ₂ and -CH ₂ -CH ₂ -CH(CH ₃ ) ₂ . For the avoidance of doubt, where two alkyl moieties are present in a substituent, the alkyl moieties may be the same or different.

As used herein, a C ₁ -C ₄ alkylene or C ₁ -C ₂ alkylene group is any divalent linear or branched C ₁ -C ₄ or C ₁ -C ₂ alkyl moiety. Linear C ₁ -C ₄ alkylene groups are methylene, ethylene, n-propylene and n-butylene groups. Methylene, ethylene and n-propylene

groups are preferred. Branched C ₁ -C ₄ alkylene groups include -CH(CH ₃ )-, -CH(CH ₃ )- CH ₂ - and -CH ₂ -CH(CH ₃ )-.

As used herein, a C ₁ -C ₄ hydroxyalkylene or C ₁ -C ₂ hydroxyalkylene group is a said Ci-C ₄ alkylene or Ci-C ₂ alkylene group which is substituted by a single hydroxy group. Particularly preferred C ₁ -C ₄ hydroxyalkylene groups are branched Ci-C ₄ 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 C ₁ -C ₄ alkoxy moiety is a said C ₁ -C ₄ alkyl moiety attached to an oxygen atom. A preferred C ₁ -C ₄ alkoxy moiety is methoxy. A C ₁ -C ₄ hydroxyalkyl moiety is a said C ₁ -C ₄ alkyl moiety substituted by a single hydroxyl moiety. Preferred hydroxyalkyl moieties are Ci-C ₂ hydroxyalkyl moieties, for example -C(OH)-CH ₃ and -CH ₂ OH. A C ₁ -C ₄ haloalkyl or C ₁ -C ₄ haloalkoxy moiety is typically a said C ₁ -C ₄ alkyl or

C ₁ -C ₄ 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 -CX ₃ and -OCX ₃ wherein X is a said halogen atom, for example chlorine and fluorine. A particularly preferred haloalkyl moiety is -CF ₃ . A particularly preferred haloalkoxy moiety is -OCF ₃ .

Preferably, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ₁ and R ₄ are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -(C ₁ -C ₂ alkyl)-Xi, -CO ₂ R ^/7/ , -SO ₂ R" ⁷ , -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ^77/ , -NR ⁷ - SO ₂ -R ⁷⁷⁷ and -CO-NR^(C ₁ -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from -(C ₁ -C ₂ alkyl)-X ₂ , halogen, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₄ haloalkyl, Ci-C ₄ haloalkoxy, Ci-C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein Xi is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ⁷⁷⁷ , -NR ⁷ -S (O) ₂ -R ⁷⁷⁷ or -SO ₂ NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R ^7// is the same or different and represents C ₁ -C ₄ alkyl. More preferably the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in

R ₁ and R ₄ are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -X ₁ , -CO ₂ -R ⁷⁷⁷ , -SO ₂ R ⁷⁷⁷ , -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ⁷⁷⁷ , -NR ⁷ -SO ₂ -R ^7// and -CO-NR ⁷ -(C _! -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ and/or (b) 1 or 2 unsubstituted

substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein Xi is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ⁷⁷⁷ or -SO ₂ NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ - C ₄ alkyl and each R ⁷⁷⁷ is the same or different and represents C ₁ -C ₄ alkyl.

More typically, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in Ri and R ₄ are unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -Xi, -CO ₂ -R ⁷⁷⁷ , -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷ ', -NR ⁷ -CO-R ^7// , -NR ^/ -S0 ₂ -R ^/// and alkyl)-NR ⁷ R ⁷⁷⁷ and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ⁷⁷⁷ or -SO ₂ NR ⁷ R ⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ^7/ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or Ci-C ₄ alkyl and each R ⁷⁷⁷ is the same or different and represents C ₁ -C ₄ 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, knidazolyl, isoxazolyl, pyrrolyl, thienyl, thiazolyl, furanyl, pyridyl, pyrazinyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and triazolyl moieties are preferred.

A 5- to 10- membered heteroaryl moiety is optionally fused to a phenyl, 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl ring. Preferably, it is non- fused or fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is non-fused or fused to a phenyl ring. Most preferably, it is a non-fused 5- to 6- membered ring as defined above, or is a quinoxalinyl moiety. A said fused or non-fused heteroaryl moiety is unsubstituted or substituted as set out above. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, Ci-C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein

each X ₂ is the same or different and is cyano or -NRR^, and each R ^; and R ^;/ is the same or different and represents hydrogen or C ₁ -C ₄ alkyl. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy. As used herein, a 5- to 10-membered heterocyclyl moiety is a monocyclic non- aromatic, saturated or unsaturated Cs-C ₁₀ 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, SO ₂ , CO and N. Typically, it is a saturated C ₅ -C ₁₀ ring (preferably a C ₅ -C ₆ ring) in which 1, 2 or 3 of the carbon atoms in the ring are replaced with a moiety selected from O, S, SO ₂ , CO and NH. Preferably, a heterocyclyl moiety contains up to two CO moieties.

Preferably, 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 pyrazolidinyl, piperidyl, piperidin-2,6-dionyl, piperidin-2- onyl, piperazinyl, morpholinyl, thiomorpholinyl, S-oxothiomorpholinyl, S ₃ 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

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 moieties are preferred heterocyclyl moieties. Typically, these preferred moieties are selected from piperidyl, piperidin-2,6-dionyl, piperidin-2-onyl, piperazinyl, morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, 1,3-dioxolanyl, pyrrolidinyl, imidazol-2- onyl, pyrrolidin-2-onyl, tetrahydrofuranyl and tetrahydropyranyl moieties. A 5- to 10- membered heterocyclyl moiety is optionally fused to a phenyl, 5- to

10- membered heteroaryl or 5- to 10- membered heterocyclyl ring. Preferably, it is non- fused or fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered

heterocyclyl ring. More preferably, it is non-fused or fused to a phenyl ring. Most preferably, 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. Typically, it is unsubstituted or substituted by (a) an unsubstituted -SO ₂ R ⁷⁷⁷ or -SO ₂ -NR ⁷ R." substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ IIaIOaIkOXy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen or C ₁ -C ₄ alkyl and each R ⁷⁷⁷ is C ₁ -C ₄ alkyl. More typically, it is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) or -SO ₂ -NR ⁷ R ⁷⁷ substituent, wherein R and R are the same or different and each represent hydrogen or C ₁ -C ₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy. Most typically, it is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) or -SO ₂ -N(C ₁ -C ₄ alkyl) ₂ substituent and/or (b) 1 or 2 unsubstituted substituents selected from C ₁ -C ₄ 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 -SO ₂ R ⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen or Ci-C ₄ alkyl and each R ⁷⁷⁷ is Ci-C ₄ alkyl. More typically, it is unsubstituted or substituted by (a) an unsubstituted -SO ₂ - (C ₁ -C ₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy. Most typically, it is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from C ₁ -C ₄ 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 -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , and each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen

or C ₁ -C ₄ alkyl. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ IIaIOaUCyI, C ₁ -C ₂ haloalkoxy and hydroxy. Most preferably, said preferred substituents are selected from C ₁ -C ₄ 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 10- membered heteroaryl or 5- to 10- membered heterocyclyl ring. Preferably, it is non-fused or fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is non-fused or fused to a 5- to 6- membered heteroaryl or heterocyclyl ring. Most preferably, it is non-fused or is a fused ring system which is an indazolyl, indolyl, benzimidazolyl, benzo[l,3]dioxolanyl, benzothiazolyl or lH-benzo[d]imidazol- 2(3H)-onyl moiety.

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, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ alkyl and hydroxy groups. Most preferably, the fused moiety is unsubstituted or substituted by a halogen or C ₁ -C ₂ haloalkyl substituent.

As used herein, a C ₃ -C ₈ carbocyclic moiety is a monocyclic non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 8 carbon atoms. Preferably 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.

A C ₃ -C ₈ carbocyclyl group is optionally fused to a phenyl, 5- to 10- membered heteroaryl or 5- to 10- membered heterocyclyl group. Preferably, it is non-fused or fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring. More preferably, it is non-fused.

A said fused or non-fused carbocyclyl moiety is unsubstituted or substituted as set out above. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, Ci-C ₂

haloalkyl, C ₁ -C ₂ IIaIOaIkOXy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , and each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen or C ₁ -C ₄ alkyl. More preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C ₁ -C ₄ alkyl, cyano and C ₁ -C ₂ haloalkyl substituents.

Typically, each A ₁ moiety is the same or different and represents a non-fused 5- to 6- membered heterocyclyl or C ₃ -C ₈ 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. More preferably, it is a non-fused group or an indazolyl, indolyl, benzimidazolyl, benzo[ 1 ,3]dioxolanyl, lH-benzo[d]imidazol-2(3H)-onyl, benzothiazolyl or quinoxalinyl group. Most preferably, 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.

A ₁ is substituted or unsubstituted as set out above. However, when A ₁ is other than a non-fused phenyl ring, it is typically unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NRR ⁷⁷ , wherein each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , and each R ⁷ and R ⁷⁷ is the same or different and represents hydrogen or Ci-C ₄ alkyl. Preferably, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy.

Typically, each A ₁ ⁷ moiety is the same or different and represents a non-fused phenyl, C ₃ -C ₈ carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group. More preferably, each A/ moiety is the same or different and represents a phenyl, oxazolyl, piperazinyl, triazolyl, piperidinyl, piperidin-2-onyl, piperidin-2,6-dionyl, morpholinyl, pyrrolidinyl, pyrazolyl, isoxazolyl, cyclohexyl, thiomoφholinyl or S,S-dioxothiomorpholinyl group. More preferably, each A/ moiety is the same or different and represents a morpholino, piperazinyl or S ₅ S- dioxothiomorpholinyl group. Most preferably, each Ai is a piperazinyl moiety.

Preferably, each A ₁ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -R ⁷⁷⁷ or -SO ₂ NR ⁷ R ⁷⁷ substitutent and/or (b) 1 or 2 unsubstituted

substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy and -NR ⁷ R ⁷⁷ , wherein each R ⁷ and R ⁷⁷ are the same or different and are selected from hydrogen and Ci-C ₄ alkyl and R ⁷⁷⁷ represents Ci- C ₄ alkyl. More preferably, each A/ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(Ci-C ₄ alkyl) or -SO ₂ -NRR ⁷⁷ substituent, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or C ₁ -C ₄ alkyl, and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and Ci-C ₂ hydroxyalkyl.

In a further embodiment of the invention, each A ₁ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -R ⁷⁷⁷ substitutent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, CpC ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy and -NRR ^7/ , wherein each R ⁷ and R ^7/ are the same or different and are selected from hydrogen and C ₁ -C ₄ alkyl and each R ⁷⁷⁷ represents C ₁ -C ₄ alkyl. More preferably, each A ₁ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ hydroxyalkyl.

In a further embodiment of the invention each A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C ₄ alkyl, Ci- C ₄ alkoxy, Ci-C ₂ haloalkyl, Ci-C ₂ haloalkoxy, Ci-C ₄ hydroxyalkyl, hydroxy and -

NR ⁷ R ⁷⁷ , wherein each R ⁷ and R ⁷⁷ are the same or different and are selected from hydrogen and Ci-C ₄ alkyl. More preferably, each Ai moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ - C ₂ alkyl, Ci-C ₂ haloalkyl and Ci-C ₂ hydroxyalkyl. It is particularly preferred that each Ai moiety is the same or different and represents a group

wherein R is Ci-C ₄ alkyl, -S(O) ₂ -R ⁷ or -S(O) ₂ -NR ⁷ R ⁷⁷ wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or C ₁ -C ₄ alkyl. Preferably, R is C ₁ -C ₄ alkyl or -SO ₂ -(Ci-C ₄ alkyl).

Typically, each A ₄ moiety is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C ₃ -C ₈ 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. Preferably, each A ₄ moiety is the same or different and represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₈ carbocyclyl group, or a phenyl group which is optionally fused to a 5- to 6- membered heteroaryl group. More preferably, each A ₄ moiety is the same or different and represents phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, pyrrolidinyl, azetidinyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C ₃ -C ₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S, S- dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl. Most preferably, each A ₄ moiety is the same or different and represents phenyl, furanyl, imidazolyl, pyrazolyl, tetraliydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C ₃ -C ₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S- dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl.

Preferably, each A ₄ moiety is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CO ₂ R ⁷⁷⁷ and -CONR ⁷ R ⁷⁷⁷ and/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, -NR ⁷ R ⁷⁷⁷ , C ₁ -C ₄ haloalkyl, C ₁ -C ₄ haloalkoxy and cyano, wherein R ⁷ represents hydrogen or C ₁ -C ₄ alkyl and R ⁷⁷⁷ represents C ₁ -C ₄ alkyl. More preferably, each A ₄ moiety is unsubstituted or substituted by (a) a single unsubstituted -CONR ⁷ R ⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR ⁷ R ⁷⁷⁷ , C ₁ -C ₄ alkyl, C ₁ -C ₂ alkoxy, Ci-C ₂ haloalkyl and cyano, wherein R ⁷ is hydrogen or C ₁ -C ₄ alkyl and R ⁷⁷⁷ represents C ₁ -C ₄ alkyl.

Typically, each A ₄ ⁷ moiety is the same or different and represents a non-fused phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₆ carbocyclyl group. Preferably, each A ₄ ⁷ moiety is the same or different and represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₆ cycloalkyl group. More preferably, each A ₄ ⁷ moiety is the same or different and is a morpholinyl, piperazinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6- dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group. Most preferably, each A ₄ ⁷ moiety is the same or different and is a morpholinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group.

Preferably, each A ₄ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, CpC ₄ alkoxy, C ₁ -C ₂ haloalkyl, Ci-C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy and -NR ⁷ R ⁷⁷ , wherein each R ⁷ and R ⁷⁷ are the same or different and are selected from hydrogen and C ₁ -C ₄ alkyl. More preferably, each A ₄ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, Ci-C ₂ alkyl and C ₁ -C ₂ haloalkyl. Most preferably, each A ₄ ⁷ moiety is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted C ₁ -C ₂ alkyl groups.

In a further embodiment of the invention, each A ₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ - C ₄ alkoxy, Ci-C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, Ci-C ₄ hydroxyalkyl, hydroxy and -NR ⁷ R ⁷⁷ , wherein each R ⁷ and R ⁷⁷ are the same or different and are selected from hydrogen and C ₁ -C ₄ alkyl. More preferably, each A ₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C ₁ -C ₂ alkyl and CpC ₂ haloalkyl. Most preferably, each A ₄ ⁷ moiety is unsubstituted or substituted by 1 or 2 unsubstituted Ci-C ₂ alkyl groups.

Preferably, L ₁ is a Ci-C ₃ alkylene group or a C ₁ -C ₃ hydroxyalkylene group. Preferably, L ₄ is a C ₁ -C ₃ alkylene group or a C ₁ -C ₃ hydroxyalkylene group. Preferably, Y ₁ and Y ₄ are each -CO-.

Preferably, each L ₁ ⁷ and L ₄ ⁷ are the same or different and represent hydrogen or a C ₁ -C ₂ alkyl group. Preferably L ₁ ⁷ is as defined above and L ₄ ⁷ represents a C ₁ -C ₂ alkyl group. Preferably, each Heti and Het ₄ are the same or different and represent -0-,

-NR ⁷ - or -S-, wherein R ⁷ is hydrogen or Ci-C ₂ alkyl. More preferably, η&U is as defined above and Het ₄ represents -O- or -NH-. Most preferably, Het] is as defined above and Het ₄ represents -0-.

Typically, R ₁ is a C ₁ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A ₁ ⁷ , -L ₁ -Ai-A ₁ ⁷ , -Ai-L ₁ -A/, -Ai-Yi-A ₁ ⁷ , -A ₁ -HCt ₁ -A/, -L ₁ -A ₁ -HeVA ₁ ⁷ , -L ₁ -Y ₁ -HCt ₁ -A ₁ ⁷ , -Li-Heti-Y _r A ₁ ⁷ , -L ₁ -Y ₁ -HCt ₁ -L/, -Ai-Heti-Li-A/, -A ₁ -L ₁ -HCt ₁ -A ₁ ⁷ or -L ₁ -HCt ₁ -L/, wherein A ₁ , Het _b L ₁ , Y ₁ , A ₁ ⁷ and L ₁ ⁷ are as defined above. Preferably, R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A ₁ ⁷ , -L ₁ -A ₁ -A ₁ ⁷ , -A ₁ -L ₁ -A ₁ ⁷ , -A ₁ -Y ₁ -A ₁ ⁷ , -L ₁ -A ₁ -HCt ₁ -A ₁ ⁷ , -L ₁ -

Heti-Yi-A/, -L ₁ -Y ₁ -HCt ₁ -L/, -A ₁ -HeI ₁ -L ₁ -A/, -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L/, wherein Ai, Hetϊ, L ₁ , Y ₁ , A/ and L/ are as defined above.

When R ₁ is -A ₁ -A/, A ₁ is preferably a non-fused unsubstituted phenyl or piperazinyl group and A/ is preferably a non-fused morpholinyl, S,S- dioxothiomorpholinyl, 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-C ₂ alkyl and Ci-C ₂ haloalkyl groups. More preferably, 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, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl groups. Most preferably, when R ₁ is -A ₁ -A/ it is an unsubstituted non-fused -phenyl- niorpholino group.

In a preferred embodiment of the invention, R ¹ is -A ₁ -Li-A/.

When Ri is -Ai-L ₁ -A/, A ₁ is typically a non-fused unsubstituted phenyl group. L ₁ is typically -CH ₂ - or -CH ₂ -CH ₂ -, more typically -CH ₂ -. A/ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(Ci-C ₄ alkyl) or -SO ₂ -NR ⁷ R ⁷⁷ group, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or Ci-C ₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, Ci-C ₂ alkyl and Ci-C ₂ alkoxy groups. More preferably, Ai is a non-fused unsubstituted morpholinyl, thiomorpholinyl, S ₅ S- dioxo-thioniorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SO ₂ - (Ci-C ₄ alkyl) or -SO ₂ -NR ⁷ R ⁷⁷ substituent, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or Ci-C ₄ alkyl, and/or (b) 1 or 2 unsubstituted C ₁ -C ₂ alkyl groups. More preferably still, A ⁷ is a piperazinyl group which is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(Ci-C ₄ alkyl) or -SO ₂ -NR ⁷ R ⁷⁷ substituent, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or Ci-C ₄ alkyl, and/or (b) 1 or 2 unsubstituted Ci-C ₂ alkyl groups.

In a further embodiment of the invention, when Ri is -Ai-Li-A/, Ai is typically a non-fused unsubstituted phenyl group. L ₁ is typically -CH ₂ -. Ai is typically a non- fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) group and/or (b) 1 or 2 unsubstituted substituents selected from halogen, hydroxy, C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy groups. More

preferably, A/ is a non-fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo- thiomoφholinyl, piperidinyl, pyrrolidinyl or piperazinyl group or A/ is a piperazinyl group which carries a single unsubstituted -S(O) ₂ -(C ₁ -C ₄ alkyl) substituent.

In a further embodiment of the invention, when R ₁ is -A ₁ -L ₁ -A/, A ₁ is typically a non-fused unsubstituted phenyl group. L ₁ is typically -CH ₂ -. 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 halogen, hydroxy, C ₁ -C ₂ alkyl and C ₁ -C ₂ alkoxy groups. More preferably, A ₁ is a non-fused unsubstituted morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, piperidinyl, pyrrolidinyl or piperazinyl group.

When R ₁ is -L ₁ -A ₁ -HCt ₁ -A/, L ₁ is typically -CH ₂ -. A ₁ is typically a non-fused unsubstituted phenyl group. Het _! is typically -O- or -S-, more typically -S-. A/ is typically a non- fused phenyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C ₁ -C ₂ alkyl and C ₁ -C ₂ hydroxyalkyl groups. Preferably, when R ₁ is -L ₁ -A ₁ -He^ -A/, it is -CH ₂ -(phenyl)-S-(4-hydroxymethylphenyl).

When R ₁ is -L ₁ -A ₁ -A/, L ₁ is typically -CH ₂ -. A ₁ 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 C ₁ -C ₂ alkyl groups. Preferably, A ₁ ⁷ is a morpholinyl or piperazinyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C ₁ -C ₂ alkyl groups.

When R ₁ is -A ₁ -HCt ₁ -L ₁ -A/ or -A ₁ -L ₁ -HBt ₁ -A/, L ₁ is typically -CH ₂ -. A ₁ is typically a non-fused unsubstituted phenyl group. Het _! is typically -O- or -NR ⁷ -, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl. A/ is typically a non-fused phenyl or cyclohexyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C ₁ -C ₂ alkyl groups.

When R ₁ is -A ₁ -Y ₁ -A/, A ₁ is typically a non-fused unsubstituted phenyl group. Y ₁ is typically -CO-. A/ is typically a non-fused phenyl or 5- to 6- membered heteroaryl group which is unsubstituted or substituted with 1 or 2 C ₁ -C ₂ alkyl groups. Preferably, A/ is an unsubstituted phenyl or pyridyl group.

When R ₁ is -L ₁ -Y ₁ -HCt ₁ -L/, it is typically a moiety -L ₁ -Y ₁ -HCt ₁ -H, wherein L ₁ , Y ₁ and Heti are as defined above. Preferably, it is a moiety -CH(CH ₂ OH)-CO ₂ H.

When R ₁ is -L ₁ -HeI ₁ -Y ₁ -A ₁ , it is typically -CH ₂ -NH-CO-A/, wherein A/ is as defined above. Preferably, A/ is a non-fused unsubstituted phenyl group.

When Ri is -L ₁ -HBt ₁ -L ₁ ⁷ , L ₁ ⁷ is typically C ₁ -C ₄ alkyl. Preferably, when R ₁ is is a moiety -(C ₁ -C ₄ alkyl)-NR ^/ -(C ₁ -C ₄ alkyl), wherein R ⁷ is hydrogen or Ci-C ₂ alkyl.

For the avoidance of doubt, the left hand side of the A and B moieties depicted above are attached to the central biphenyl core. Thus, the right hand side of the depicted moieties are attached to R ₁ or R ₄ .

Typically, A represents a -(Ci-C ₂ alkylene)-NR ⁷ -, -CO-NR ⁷ -, -NR ⁷ -C0-, -CO-, -CO-O- or -0-C0- group, in which R ⁷ is hydrogen or C ₁ -C ₂ alkyl, preferably hydrogen.

Typically, B represents a direct bond, -CO-NR ⁷ -, -NR ⁷ -C0-, -NR ⁷ -CO ₂ -, -NR ⁷ -S(O) ₂ -, -S(O) ₂ -NR'-, -CO-, -NR ⁷ -, -(C ₁ -C ₂ alkyleneVNR ⁷ -, -NR'-CO-NR' ⁷ - or -NR ⁷ - CO-CO-, wherein R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₂ alkyl, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ , wherein A ₄ and A ₄ Ve as defined above. More typically, B represents a direct bond, -CO-NR ⁷ -, -NR ⁷ -C0-, -NR ⁷ -CO ₂ -, -NR ^; -S(0) ₂ -, -CO-, -NR ⁷ -, -(C ₁ -C ₂ alkylene)-NR ⁷ -, -NR ⁷ -C0- NR ⁷⁷ - or -NR ⁷ -C0-C0-, wherein R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₂ alkyl, provided that when B represents a direct bond, R ₄ is -A ₄ or - A ₄ -A ₄ ⁷ , wherein A ₄ and A/are as defined above. Preferably, B represents -CO-NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-,

-NH-S(O) ₂ -, -S(O) ₂ -NH-, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO-NH-, -N(CH ₃ )-C0-, -NH- CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ , wherein A ₄ and A ₄ ⁷ are as defined above. More preferably, B represents -CO- NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-, -NH-S(O) ₂ -, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO- NH-, -N(CH ₃ )-C0-, -NH-CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ , wherein A ₄ and A ₄ ⁷ are as defined above. Most preferably, B represents -NH-CO-NH- or -(C ₁ -C ₂ alkylene)-NH-.

Typically, R ₂ and R ₃ are the same or different and represent halogen, C ₁ -C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen. Preferably, R ₂ is present on a carbon atom ortho to the phenyl ring of the central biphenyl moiety.

Preferably, R ₃ is as defined above and R ₂ is chlorine, trifluoromethoxy or Ci-C ₄ alkyl, more preferably Ci-C ₄ alkyl, most preferably methyl. Typically, R ₃ is present on

a carbon atom ortho to the phenyl ring of the central biphenyl moiety (i.e is present at the 2- position).

In a further embodiment of the invention, R ₂ is halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen and R ₃ is chlorine, trifluoromethoxy or C ₁ -C ₄ alkyl, more preferably C ₁ -C ₄ alkyl, most preferably methyl.

Typically, R ₄ is a C ₁ -C ₆ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , - A ₄ -L ₄ - A/, -A ₄ -Y ₄ -A ₄ ⁷ , -A ₄ -HCt ₄ -A ₄ ⁷ , -L ₄ -A ₄ -A ₄ ⁷ , -L ₄ -He^-A ₄ ⁷ or -L ₄ -Het ₄ -L ₄ ⁷ , wherein A ₄ , A ₄ ⁷ , L ₄ , Y ₄ , Het ₄ and L ₄ ⁷ are as defined above.

Preferably, R ₄ is a C ₁ -C ₅ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ - A ₄ ⁷ , -A ₄ -Y ₄ -A ₄ ⁷ or -L ₄ -Het ₄ -L ₄ ⁷ wherein A ₄ , A ₄ ⁷ , L ₄ , Y ₄ and L ₄ ⁷ are as defined above.

In a preferred embodiment of the inventon, R ₄ is -A ₄ or -A ₄ -L ₄ -A ₄ ⁷ .

When R ₄ is -A ₄ -A ₄ ⁷ , A ₄ 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 C ₁ -C ₂ alkyl, halogen and C ₁ -C ₂ haloalkyl substituents. Preferably, A ₄ is a non-fused phenyl, pyridyl or oxadiazolyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from C ₁ -C ₂ alkyl, halogen and C ₁ -C ₂ haloalkyl substituents. A ₄ ⁷ is typically a non-fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C ₃ -C ₆ cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted C ₁ -C ₂ alkyl groups. Preferably, A ₄ 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 C ₁ -C ₂ alkyl group.

In a further embodiment of the invention, when R ₄ is -A ₄ -A ₄ , A ₄ is typically a non-fused unsubstituted phenyl or 5- to 6- membered heteroaryl moiety. Preferably, A ₄ is a non-fused unsubstituted phenyl, pyridyl or oxadiazolyl group. Aj is typically a non-fused 5- to 6- membered heteroaryl or heterocyclyl group, or a non-fused C ₃ -C ₆ cycloalkyl group, and is unsubstituted or substituted by 1 or 2 unsubstituted C ₁ -C ₂ alkyl groups. Preferably, A ₄ ⁷ is a non-fused morpholinyl, isoxazolyl, triazolyl, piperidin-2,2- dionyl, cyclopropyl or cyclohexyl group, which is unsubstituted or substituted by an unsubstituted C ₁ -C ₂ alkyl group.

Most preferably, when R ₄ is -A ₄ -A ₄ , it is a non-fused unsubstituted -phenyl- morpholino group.

When R ₄ is -A ₄ -L ₄ -A/, A ₄ is typically a non-fused unsubstituted phenyl group. L ₄ is typically -CH ₂ -. A ₄ ^/ 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 -SO ₂ -(C ₁ -C ₂ alkyl) substituent. More typically, A ₄ ^/ is a non-fused unsubstituted 5- to 6- membered heterocyclyl group, preferably a S,S-dioxo-thiomorpholinyl group.

Preferably, when R ₄ is -A ₄ -L ₄ - A ₄ ⁷ it is -phenyl-CH ₂ -(S,S-dioxothiomorpholino), wherein the cyclic moieties are non-fused and unsubstituted, or -phenyl-CH ₂ - piperazinyl-S O ₂ -(C ^C ₂ alkyl). When R ₄ is -A ₄ -Y ₄ -A ₄ ⁷ , A ₄ is typically a non-fused unsubstituted phenyl group.

Y ₄ is typically -CO-. A ₄ ⁷ is typically a non-fused 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by 1 or 2 unsubstituted C ₁ -C ₂ alkyl groups. Preferably, A ₄ ⁷ is a non-fused unsubstituted morpholinyl or piperidinyl group.

When R ₄ is -L ₄ -Het ₄ -L ₄ ⁷ , L ₄ is typically C ₁ -C ₂ alkylene. Het ₄ is typically -O- or -NR ⁷ -, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl. L ₄ ⁷ is typically C ₁ -C ₂ alkyl, more preferably methyl. Preferably, when R ₄ is -L ₄ -Het ₄ -L ₄ ⁷ , it is a -(CHz) ₂ -O-CH ₃ or -(C ₁ -C ₂ alkylene)-NR ⁷ R ⁷⁷ , wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or C ₁ -C ₄ alkyl.

In one embodiment of the invention, either: (a) R ₁ is a C ₁ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A ₁ ⁷ , -L ₁ -A ₁ -A ₁ ⁷ ,

-A ₁ -Y ₁ -A ₁ ⁷ , -Ai-Heti-A/, -L ₁ -A ₁ -Y ₁ -A ₁ ⁷ , -L ₁ -A ₁ -HBt ₁ -A ₁ ⁷ , -L ₁ -HCt ₁ -A ₁ , -L ₁ -Y ₁ -A ₁ , -L ₁ - Yi-Heti-Ai, -L ₁ -HCt ₁ -Y ₁ -A ₁ , -L ₁ -Yi-HCt ₁ -L ₁ ⁷ , -Ai-Yi-HeI ₁ -A ₁ ⁷ , -Ai-HCt ₁ -Y ₁ -A/, -A _r HeI ₁ -L ₁ -A ₁ ⁷ , -A ₁ -L ₁ -HCt ₁ -A ₁ ⁷ or -L ₁ -HCt ₁ -L ₁ ⁷ , wherein A ₁ , L ₁ , A ₁ ⁷ , Y ₁ , Heti and L ₁ ⁷ are as defined above; or (b) A represents -NR ⁷ -CO ₂ -, -CO-, -SO ₂ -, -NR ⁷ -C0-C0-, -CO-O-, -O-CO-,

-(Ci-C ₂ alkylene)-NR ⁷ - or -(Ci-C ₂ hydroxyalkylene)-NR ⁷ -, wherein R ⁷ represents hydrogen or C ₁ -C ₄ alkyl; or

(c) B represents -NR ⁷ -CO ₂ -, -CO-, -SO ₂ -, -NR ⁷ -C0-C0-, -CO-O-, -O-CO-, -(Ci-C ₂ alkylene)-NR ⁷ - or -(C ₁ -C ₂ hydroxyalkylene)-NR ⁷ -, wherein R ⁷ represents hydrogen or C ₁ -C ₄ alkyl; or

(d) R ₄ represents -L ₄ -A ₄ , -L ₄ -A ₄ -A ₄ ⁷ , -A ₄ -Y ₄ -A ₄ ⁷ , -A ₄ -HeU-A ₄ ⁷ , -L ₄ - A ₄ - Y ₄ - A ₄ ⁷ , -L ₄ -A ₄ -HeVA ₄ ⁷ , -L ₄ -HCt ₄ -A ₄ , -L ₄ -Y ₄ -A ₄ , -L ₄ -Y ₄ -HCt ₄ -A ₄ , -L ₄ -He^-Y ₄ -A ₄ , -L ₄ -Y ₄ -

HeU-L ₄ ⁷ , -A ₄ -Y ₄ -HeU-A ₄ ⁷ , -A ₄ -HeI ₄ - Y ₄ -A ₄ ⁷ , -A ₄ -HeU-L ₄ -A ₄ ⁷ or -A ₄ -L ₄ -HeU-A ₄ ⁷ , wherein L ₄ , A ₄ , A ₄ ⁷ , Y ₄ , HeU and L ₄ ⁷ are as defined above. In option (a), R ₁ is other than -A ₁ -L ₁ -A ₁ ⁷ .

In option (c), B typically represents -NR ⁷ -CO-CO- or -(C ₁ -C ₂ alkylene)-NR ⁷ -, wherein R ₁ is hydrogen or C ₁ -C ₄ alkyl. More preferably, B represents -(C ₁ -C ₂ alkylene)-NR ⁷ -.

In option (c), R ₄ typically represents -L ₄ -A ₄ or -A ₄ -Y ₄ -A ₄ ⁷ . Preferably, in this embodiment, either:

R ₁ is other than -A ₁ -L ₁ -Ai ■ _> wherein A ₁ , Li and Ai are as defined above; or

B represents -NR ⁷ -CO-CO- or -(C ₁ -C ₂ alkylene)-NR ⁷ -; or R ₄ represents -L ₄ -A ₄ or -A ₄ -Y ₄ -A ₄ ⁷ , wherein L ₄ , A ₄ , Y ₄ and A ₄ ⁷ are as defined above.

More preferably, in this embodiment, R ₁ is other than -A ₁ -L ₁ -A ₁ ⁷ . Preferred compounds of formula (I) are those wherein:

R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -Ai, -A ₁ -A ₁ ⁷ , -L ₁ -A ₁ -A ₁ ⁷ , -A ₁ -Li- A ₁ ⁷ , -A ₁ -Yi-A ₁ ⁷ , -L-ArHeti-A/, -L ₁ -HCt ₁ -Y ₁ -A ₁ ⁷ , -L ₁ -Y ₁ -HeVL/, -A ₁ -He^ -Li -A ₁ ⁷ , -A ₁ - Li-HetrA/ or -L ₁ -HCt ₁ -L ₁ ⁷ ;

A represents a -(C ₁ -C ₂ alkylene)-NR ⁷ -, -CO-NR ⁷ -, -NR ⁷ -CO-, -CO-, -CO-O- or -0-C0- group, in which R ⁷ is hydrogen or C ₁ -C ₂ alkyl;

B represents a direct bond, -CO-NR ⁷ -, -NR ⁷ -CO-, -NR ⁷ -CO ₂ -, -NR ⁷ -S(O) ₂ , -S(O) ₂ -NR ⁷ -, -CO-, -NR ⁷ -, -(C ₁ -C ₂ alkylene)-NR ⁷ -, -NR ⁷ -CO-NR ⁷⁷ - or -NR ⁷ -CO-CO-, wherein R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₂ alkyl, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ ; - R ₂ and R ₃ are the same or different and each represents C ₁ -C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, Ci-C ₂ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ; R ₄ is a Ci-C ₅ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ -A ₄ ⁷ , -A ₄ -Y ₄ - A ₄ ' or -L ₄ -HeU-L ₄ ⁷ ; - each Ai, A ₄ , A/ and A ₄ ⁷ are the same or different and represent a phenyl, 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₈ carbocyclyl moiety; each Li and L ₄ is the same or different and represents a C ₁ -C ₄ alkylene or a C ₁ - C ₄ hydroxyalkylene group;

each Y ₁ and Y ₄ is the same or different and represents -CO-; each L ₁ ⁷ and L ₄ ⁷ is the same or different and represents hydrogen or a C ₁ -C ₂ alkyl group; and each Heti and Het ₄ is the same or different and represents -O-, -NR ^/ - or -S-, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ¹ and R ⁴ being optionally fused to a phenyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl ring; and the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ¹ and R ⁴ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ - X ₁ , -CO ₂ -R ^7// , -SO ₂ R ⁷⁷⁷ , -SO ₂ NR ⁷ R" ⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ^77/ , -NR ⁷ -SO ₂ -R ^77/ and -CO- NR^(C ₁ -C ₂ alkyO-NR'R.'", and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ⁷⁷⁷ or -SO ₂ NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R is the same or different and represents C ₁ -C ₄ alkyl.

Typically, in these preferred compounds of formula (I), B represents a direct bond, -CO-NR ⁷ -, -NR ⁷ -CO-, -NR ⁷ -CO ₂ -, -NR ⁷ -S(O) ₂ -, -CO-, -NR ⁷ -, -(C ₁ -C ₂ alkylene)- NR ⁷ -, -NR ⁷ -CO-NR ⁷⁷ - or -NR ⁷ -CO-CO-, wherein R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₂ alkyl, provided that when B represents a direct bond, R ₄ is - A ₄ or -A ₄ -A ₄ ⁷ ;

Typically, in these preferred compounds of formula (I), the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R ¹ and R ⁴ are unsubstituted or substituted by (a) an unsubstituted substituent selected from -CH ₂ -X ₁ , -CO ₂ -R ^/7/ , -SO ₂ NR ^/ R ^/// ,

-CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ⁷⁷⁷ ₅ -NR ⁷ -SO ₂ -R ⁷⁷⁷ and -CO-NR ⁷ -(C _! -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ , and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ^/7/ or -SO ₂ NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R ⁷⁷⁷ is the same or different and represents C ₁ -C ₄ alkyl.

Typically, in these preferred compounds of the invention, either:

(a) R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, -A ₁ -Y ₁ -A/, -L-Ai-Heti-A/, -L ₁ -HCt ₁ -Y ₁ -A/, -L ₁ -Y ₁ -HCt ₁ -L ₁ ⁷ , -A ₁ -HCt ₁ -L ₁ -A/, -A ₁ -L ₁ - Heti-A/ or -L ₁ -HCt ₁ -L/, wherein A ₁ , L ₁ , A/, Y ₁ , Het _! and L/ are as defined above; or

(b) A is -CO-, -CO-O, -0-C0- or -(C ₁ -C ₂ alkylene)-NR ⁷ -, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl; or

(c) B is -NR ⁷ -CO ₂ -, -CO-, -NR ⁷ -C0-C0- or -(C ₁ -C ₂ alkylene)-NR ⁷ -, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl; or

(d) R ₄ is -L ₄ -A ₄ or -A ₄ -Y ₄ -A ₄ ⁷ , wherein L ₄ , A ₄ , Y ₄ and A ₄ ⁷ are as defined above. Further preferred compounds of formula (I) are those wherein:

R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A ₁ ⁷ , -L ₁ -A ₁ -A ₁ ⁷ , -A ₁ -L ₁ - A/, -A ₁ -CO-A/, -L ₁ -A ₁ -HCt ₁ -A/, -L ₁ -HCt ₁ -CO-A/, -L ₁ -CO-HCt ₁ -L/, -A ₁ -HCt ₁ -L ₁ -A ₁ ⁷ , -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L ₁ ⁷ ;

A represents a -(C ₁ -C ₂ alkylene)-NH-, -CO-NH-, -NH-CO-, -CO-, -CO-O- or -0-CO group;

B represents -CO-NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-, -NH-S(O) ₂ -, -S(O) ₂ - NH-, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO-NH-, -N(CHs)-CO-, -NH-CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ ;

R ₂ is C ₁ -C ₄ alkyl; - R ₃ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ; R ₄ is a C ₁ -C ₅ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ -A ₄ ⁷ , -A ₄ -CO-A ₄ ⁷ or -L ₄ -Het ₄ -L ₄ ⁷ ; each A ₁ moiety is the same or different and represents a non-fused 5- to 6- membered hetercyclyl or C ₃ -C ₈ 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, wherein (i) when A ₁ is a non-fused phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -X ₁ , -CO ₂ -R ⁷⁷⁷ , -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ^//7 , -NR^SO ₂ -R ⁷⁷⁷ and -CO-NR ⁷ -(C ₁ -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ , and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, Ci-C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ^77/ or -SO ₂ -NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷

are the same or different and represent hydrogen or Ci-C ₄ alkyl and each R ^7// is the same or different and represents C ₁ -C ₄ alkyl and (ii) when Ai is other than a non-fused phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, Ci-C ₂ haloalkoxy and hydroxy; - each A/ moiety is the same or different and represents a non-fused phenyl, C ₃ -

C ₈ carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) an unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) or -SO ₂ - NR ⁷ R^ substituent, wherein R ^; and R ^/; are the same or different and each represent hydrogen or Ci-C ₄ alkyl, and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ hydroxyalkyl; each A ₄ moiety is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C ₃ -C ₈ 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, each A ₄ moiety being unsubstituted or substituted by (a) a single unsubstitued -CONR ⁷ R^ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR ⁷ R^, Ci-C ₄ alkyl, Ci-C ₂ alkoxy, C ₁ -C ₂ haloalkyl and cyano, wherein R ^; is hydrogen or C ₁ -C ₄ alkyl and R ^/7/ represents C ₁ -C ₄ alkyl; - each A/ moiety is the same or different and represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by (a) an unsubstiuted -SO ₂ -(C ₁ -C ₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl; - each L ₁ and L ₄ are the same or different and represent a C ₁ -C ₃ alkylene group or a Ci-C ₃ hydroxyalkylene group

L/ represents hydrogen or a C ₁ -C ₂ alkyl group;

L/ represents a C ₁ -C ₂ alkyl group;

Hett represents -O-, -NR ^; - or -S-, wherein R ^; is hydrogen or Ci-C ₂ alkyl; and - Het ₄ represents -O- or -NH-.

Additional preferred compounds of the formula (I) are those wherein:

R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, -A ₁ -Li- A/, -A ₁ -CO-A/, -Li-Ai-Heti-A/, -L ₁ -HCt ₁ -CO-A/, -L ₁ -CO-HCt ₁ -L/, -A ₁ -HCt ₁ -L ₁ -A/, -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L/;

A represents a -(C ₁ -C ₂ alkylene)-NH-, -CO-NH-, -NH-CO-, -CO-, -CO-O- or -0-CO group;

B represents -CO-NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-, -NH-S(O) ₂ -, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO-NH-, -N(CH ₃ )-C0-, -NH-CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ - A ₄ ⁷ ;

R ₂ is C ₁ -C ₄ alkyl; - R ₃ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ; R ₄ is a C ₁ -C ₅ alkyl group or a moiety -A ₄ , -A ₄ - A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ -AV, -A ₄ -CO-A ₄ ⁷ or -L ₄ -O-L ₄ ⁷ ; each A ₁ moiety is the same or different and represents a non-fused 5- to 6- membered hetercyclyl or C ₃ -C ₈ 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, wherein (i) when A ₁ is a non-fused phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -Xi, -CO ₂ -R ⁷ ", -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ⁷⁷⁷ , -NR ⁷ -SO ₂ -R ⁷⁷⁷ and -CO-NR^(C ₁ -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ , and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ^7/7 or -SO ₂ -NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R is the same or different and represents C ₁ -C ₄ alkyl and (ii) when A ₁ is other than a non-fused phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy; each A ₁ ⁷ moiety is the same or different and represents a non-fused phenyl, C ₃ - C ₈ carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by (a) a single unsubstituted -SO ₂ -R ⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and CpC ₂ hydroxyalkyl;

each A ₄ moiety is the same or different and is a non-fused 5- to 6- membered heterocyclyl or C ₃ -C ₈ 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, each A ₄ moiety being unsubstituted or substituted by (a) a single unsubstitued -CONR!R ^U/ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR/R^ ⁷ , C ₁ -C ₄ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl and cyano, wherein R ⁷ is hydrogen or C ₁ -C ₄ alkyl and R ^//V represents C ₁ -C ₄ alkyl; each A ₄ ⁷ moiety is the same or different and represents a non-fused 5- to 6- membered heteroaryl, 5- to 6- membered heterocyclyl or C ₃ -C ₆ cycloalkyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl; each L ₁ and L ₄ are the same or different and represent a C ₁ -C ₃ alkylene group or a C ₁ -C ₃ hydroxyalkylene group - L/ represents hydrogen or a C ₁ -C ₂ alkyl group;

L ₄ ^; represents a C ₁ -C ₂ alkyl group; and

Heti represents -O-, -NR ⁷ - or -S-, wherein R ^; is hydrogen or C ₁ -C ₂ alkyl.

Typically, in these additional preferred compounds of formula (T), each A ₁ moiety is the same or different and represents a non-fused phenyl, C ₃ -C ₈ carbocyclyl, 5- to 6- membered heteroaryl or 5- to 6- membered heterocyclyl group which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ -C ₂ hydroxyalkyl.

Typically, in these additional preferred compounds of the invention, either:

(a) R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, - A ₁ -CO-A/, -Lj-ArHeti-A/, -L ₁ -HCt ₁ -CO-A/, -L ₁ -CO-HCt ₁ -L/, -A ₁ -HeI ₁ -L ₁ -A/, -A ₁ -

L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L/, wherein A ₁ , L ₁ , A/, HCt ₁ and L/ are as defined above; or

(b) A is -(C ₁ -C ₂ alkylene)-NH-, -CO-, -CO-O- or -0-C0-; or

(c) B is -NH-CO ₂ -, -CO-, -NH-CO-CO- or -(C ₁ -C ₂ alkylene)-NH-; or

(d) R ₄ is -L ₄ -A ₄ or -A ₄ -CO-A ₄ , wherein L ₄ , A ₄ and A ₄ are as defined above. Particularly preferred compounds of formula (I) are those wherein:

R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, -A ₁ -L ₁ - A/, -A ₁ -CO-A/, -L ₁ -A ₁ -HCt ₁ -A/, -L ₁ -Heti -CO- A/, -A ₁ -HCt ₁ -L ₁ -A/, -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HeI ₁ -L/;

A represents a -(C ₁ -C ₂ alkylene)-NH-, -CO-NH-, -NH-CO-, -CO-, -CO-O- or -0-CO group;

B represents -CO-NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-, -NH-S(O) ₂ -, -S(O) ₂ - NH-, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO-NH-, -N(CH ₃ )-C0-, -NH-CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A/;

R ₂ is C ₁ -C ₄ alkyl;

R ₃ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ;

R ₄ is a C ₁ -C ₅ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ -A ₄ ⁷ , -A ₄ -CO-A ₄ ⁷ or -L ₄ -Het ₄ -L ₄ ⁷ ; each A ₁ moiety is the same or different and represents a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[l,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, IH- benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group, wherein (i) when Ai is a phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -Xi, -CO ₂ -R ⁷⁷⁷ , -SO ₂ NR ⁷ R ⁷⁷⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ^7// , -NR ⁷ -SO ₂ -R ⁷⁷⁷ and -CO-NR ⁷ -(C ₁ -C ₂ alkyl)-NR ⁷ R ⁷⁷⁷ , and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, Ci-C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ^77/ or -SO ₂ -NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R is the same or different and represents Ci-C ₄ alkyl and (ii) when A ₁ is other than a phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, Ci-C ₄ alkyl, Ci-C ₄ alkoxy, Ci-C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy; - each A ₁ ⁷ moiety is the same or different and 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 which is unsubstituted or substituted by (a) a single unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) or -SO ₂ -NR ⁷ R ⁷⁷ substituent, wherein R ⁷ and R ⁷⁷ are the same or different and each represent hydrogen or Ci-C ₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, Ci-C ₂ haloalkyl and C ₁ -C ₂ hydroxyalkyl;

each A ₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C ₃ -C ₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A ₄ moiety being unsubstituted or substituted by (a) a single unsubstitued -CONR ⁷ R ⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR ⁷ R ⁷⁷⁷ , C ₁ -C ₄ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl and cyano, wherein R ⁷ is hydrogen or C ₁ -C ₄ alkyl and R ^/7/ represents C ₁ -C ₄ alkyl; each A ₄ moiety is the same or different and represents a morpholinyl, piperazinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group which is unsubstituted or substituted by (a) an unsubstituted -S(O) ₂ -(C ₁ -C ₂ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C ₁ -C ₂ alkyl and C ₁ - C ₂ haloalkyl; - each L ₁ and L ₄ are the same or different and represent a C ₁ -C ₃ alkylene group or a C ₁ -C ₃ hydroxyalkylene group

L ₁ ⁷ represents hydrogen or a C ₁ -C ₂ alkyl group;

L ₄ ⁷ represents a C ₁ -C ₂ alkyl group;

Het _ϊ represents -O-, -NR!- or -S-, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl; and - Het ₄ represents -O- or -NH-

Additional particularly preferred compounds of formula (I) are those wherein

R ₁ is a C ₂ -C ₆ alkyl group or a moiety -A ₁ , -L ₁ -A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A/, -A ₁ -L ₁ - A/, -A ₁ -CO-A/, -L ₁ -A ₁ -HCt ₁ -A/, -L ₁ -HCt ₁ -CO-A ₁ ⁷ , -Li-CO-Heti-L/, -A ₁ -HCt ₁ -L ₁ -A/, -A ₁ -L ₁ -HCt ₁ -A/ or -L ₁ -HCt ₁ -L ₁ ⁷ ; - A represents a -(C ₁ -C ₂ alkylene)-NH-, -CO-NH-, -NH-CO-, -CO-, -CO-O- or -0-CO group;

B represents -CO-NH-, -NH-CO-, -NH-CO ₂ -, -NH-, -CO-, -NH-S(O) ₂ -, -(C ₁ -C ₂ alkylene)-NH-, -NH-CO-NH-, -N(CH ₃ )-C0-, -NH-CO-CO- or a direct bond, provided that when B represents a direct bond, R ₄ is -A ₄ or -A ₄ -A ₄ ⁷ ; - R ₂ is C ₁ -C ₄ alkyl;

R ₃ is C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy or halogen; n and m are the same or different and each represent O or 1 ;

R ₄ is a C ₁ -C ₅ alkyl group or a moiety -A ₄ , -A ₄ -A ₄ ⁷ , -L ₄ -A ₄ , -A ₄ -L ₄ -A ₄ ⁷ ,

-A ₄ -CO-A ₄ ⁷ Or -L ₄ -O-L/; each A ₁ moiety is the same or different and represents a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[l,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomoφholinyl, IH- benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group, wherein (i) when A ₁ is a phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from -CH ₂ -X ₁ , -CO ₂ -R ⁷⁷⁷ , -SO ₂ NRV ⁷ , -CONR ⁷ R ⁷⁷⁷ , -NR ⁷ -CO-R ⁷⁷⁷ , -NR ⁷ -SO ₂ -R ⁷⁷⁷ and -CO-NR ⁷ -(C ₁ -C ₂ alkyl)-NR ⁷ R ^/7/ , and/or (b) 1 or 2 unsubstituted substituents selected from -CH ₂ -X ₂ , halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy, C ₁ -C ₄ hydroxyalkyl, hydroxy, cyano and -NR ⁷ R ⁷⁷ , wherein X ₁ is -CO ₂ R ⁷⁷⁷ , -NR ⁷ -CO ₂ -R ⁷⁷⁷ or -SO ₂ -NR ⁷ R ⁷⁷⁷ , each X ₂ is the same or different and is cyano or -NR ⁷ R ⁷⁷ , each R ⁷ and R ⁷⁷ are the same or different and represent hydrogen or C ₁ -C ₄ alkyl and each R ^7// is the same or different and represents C ₁ -C ₄ alkyl and (ii) when A ₁ is other than a phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₂ haloalkyl, C ₁ -C ₂ haloalkoxy and hydroxy; each A ₁ ⁷ moiety is the same or different and 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 which is unsubstituted or substituted by (a) a single unsubstituted -SO ₂ -(C ₁ -C ₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ - C ₂ hydroxyalkyl; each A ₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C ₃ -C ₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo- thiomopholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A ₄ moiety being unsubstituted or substituted by (a) a single unsubstitued -CONR ⁷ R ⁷⁷⁷ substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, -NR ^/ R ^/// , C ₁ -C ₄ alkyl, C ₁ -C ₂ alkoxy, C ₁ -C ₂ haloalkyl and cyano, wherein R ⁷ is hydrogen or C ₁ -C ₄ alkyl and R ⁷⁷⁷ represents C ₁ -C ₄ alkyl; each A ₄ ⁷ moiety is the same or different and represents a morpholinyl, isoxazolyl, pyrrolidinyl, S,S-dioxothiomorpholinyl, 2,6-dioxo-piperidinyl, triazolyl, piperidinyl, cyclopropyl or cyclohexyl group group which is unsubstituted or substituted

by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C ₁ -C ₂ alkyl and C ₁ -C ₂ haloalkyl; each L ₁ and L ₄ are the same or different and represent a C ₁ -C ₃ alkylene group or a C ₁ -C ₃ hydroxy alkylene group - L/ represents hydrogen or a C ₁ -C ₂ alkyl group;

L ₄ ⁷ represents a C ₁ -C ₂ alkyl group; and

Heti represents -O-, -NR ⁷ - or -S-, wherein R ⁷ is hydrogen or C ₁ -C ₂ alkyl.

Typically, in these additional particularly preferred compounds of formula (I), each A/ moiety is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl and C ₁ - C ₂ hydroxyalkyl.

Typically, in these additional particularly preferred compounds of the invention, either:

(a) R ₁ is a C ₂ -C ₆ alkyl group or a moiety -Ai, -Li-A ₁ , -A ₁ -A/, -L ₁ -A ₁ -A ₁ ⁷ , -A ₁ -CO-A ₁ ⁷ , -Li-Ai-Heti-A/, -L ₁ -HeVCO-A ₁ ⁷ , -Li-CO-Heti-L/, -A ₁ -HCt ₁ -L ₁ -A ₁ ⁷ , -A ₁ -

Li-Heti-A/ or -Li-Heti-L/, wherein A ₁ , L ₁ , A ₁ ⁷ , Heti and L ₁ ⁷ are as defined above; or

(b) A is -(C ₁ -C ₂ alkylene)-NH-, -CO-, -CO-O- or -O-CO-; or

(c) B is -NH-CO ₂ -, -CO-, -NH-CO-CO- or -(C ₁ -C ₂ alkylene)-NH-; or

(d) R ₄ is -L ₄ -A ₄ or -A ₄ -CO-A ₄ ⁷ , wherein L ₄ , A ₄ and A ₄ ⁷ are as defined above. The medicaments of the present invention are for use in treating or preventing a 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 in 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 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/?-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.

Especially preferred compounds of the invention include: 1 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-bromo-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

2 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(6-methoxy-pyridin-3-yl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

3 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-methyl-benzylamide) 3-[(4- moφholin-4-yl-phenyl)-amide]

4 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-methyl-butyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

5 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-fluoro-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide] 6 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(2-piperidin- 1 -yl-ethyl)-amide]

7 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-bromo-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

8 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-benzyloxy-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

9 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-{[3-(4-methyl-piperazin-l-yl)- propyl] -amide} 4'-[(4-morpholin-4-yl-phenyl)-amide]

10 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- (3 -trifluoromethyl-benzylamide) 11 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(2-thiophen-2-yl-ethyl)-amide]

12 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(lH-indazol-6-yl)-amide] 3-[(4- moφholin-4-yl-phenyl)-amide]

13 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[2-(3H-imidazol-4-yl)-ethyl]-amide} 3 - [(4-moφholin-4-yl-phenyl)-amide]

14 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(5-methyl-furan-2-yhnethyl)-amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

15 6-Methyl-4'-(pyrrolidine- 1 -carbonyty-biphenyl-S-carboxylic acid (4-morpholin-4- yl-phenyl)-amide

16 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-benzo[l,3]dioxol-5-ylamide 3-[(4- morpholin-4-yl-phenyl)-amide] 17 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-cyclopropylamide 4'-[(4-morpholin-4- yl-phenyl)-amide]

18 Furan-2-carboxylic acid [6-methyl-4'-(4-moφholin-4-yl-phenylcaxbamoyl)- biphenyl-3 -yl] -amide

19 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3-benzoyl-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

20 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-(4-morpholin-4-yl-benzylamide) 3- [(4-moφholin-4-yl-phenyl)-amide]

21 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-butylsulfamoyl-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide] 22 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3,4-dichloro-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

23 6-Methyl-biplienyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(3-trifluoromethyl-phenyl)-amide]

24 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-cyano-phenyl)-amide] 3-[(4- moφholin-4-yl-phenyl)-amide]

25 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-moφholin-4-yl-phenyl)-amide] 4'- [(3-trifluoromethoxy-phenyl)-amide]

26 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'- {[3-(l -methyl- lH-pyrazol-3-yl)- phenyl]-amide} 3-[(4-moφholin-4-yl-phenyl)-amide] 27 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3-fluoro-phenyl)-amide] 3-[(4- moφholin-4-yl-phenyl)-amide]

28 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-isoxazol-5-yl-phenyl)-amide] 3- [(4-moφholin-4-yl-phenyl)-amide]

29 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-methylsulfamoyl-phenyl)-amide] 3 - [(4-moφholin-4-yl-phenyl)-amide]

30 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-bromo-3-chloro-phenyl)-amide] 3 - [(4-moφholin-4-yl-phenyl)-amide]

31 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'- {[3-(l ~hydroxy-ethyl)-phenyl]- amide} 3 - [(4-morpholin-4-yl-phenyl)-amide]

32 3-{[2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl -4-carbonyl]- amino} -benzoic acid ethyl ester 33 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-methoxy-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

34 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3,4-dimethoxy-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

35 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-({2-[(cyclohexyl-methyl-amino)- methyl] -phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

36 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- pyridin-3 -ylamide

37 4'- [4-(2,3 -Dichloro-phenyty-piperazine- 1 -carbonyl] -6-methyl-biphenyl-3 - carboxylic acid (4-morpholin-4-yl-phenyl)-amide 38 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(2-trifluoromethyl-lH-benzoimidazol-5-yl)-amide]

39 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-cyanomethyl-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

40 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-moφholin-4-yl-phenyl)-amide] 4'- [(thiophen-3-ylmethyl)-amide]

41 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-moφholin-4-yl-phenyl)-amide] 4'- (3-trifluoromethoxy-benzylamide)

42 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(4-chloro-3-trifluoromethyl- benzylamide) 3-[(4-morpholin-4-yl-phenyl)-amide] 43 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-chloro-4-methyl-benzylamide) 3- [(4-morpholin-4-yl-phenyl)-amide]

44 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-6-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

45 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(lH-indol-5-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

46 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-benzothiazol-6-ylamide 3-[(4- moφholin-4-yl-phenyl)-amide]

47 [3-({[2'-Methyl-5 ^l -(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carbonyl]- amino} -methyl)-benzyl]-carbamic acid tert-butyl ester

48 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-7-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide] 49 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[2-(2-hydroxymetliyl- phenylsulfanyl)-benzylamide] 3-[(4-morpholin-4-yl-phenyl)-aniide]

50 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylniethyl)-phenyl]-amide} 3-[(4-moφholin-4-yl-phenyl)-amide]

51 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[(S)-l-hydroxymethyl-2-(lH-indol- 3-yl)-ethyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

52 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-(3-bromo-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide]

53 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-amino-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide] 54 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-methylsulfamoylmethyl-phenyl)- amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

55 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(5-bromo-lH-indol-7-yl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

56 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- {[4-(lH-ρyrazol-3-yl)-ρhenyl]-amide}

57 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-chloro-2-fluoro-benzylamide) 3- [(4-moφholin-4-yl-phenyl)-amide]

58 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- {[4-(piperidine-l-carbonyl)-phenyl]-amide} 59 Biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-5-yl)-amide] 3-[(4-morpholin-4-yl- phenyl)-amide]

60 Biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-6-yl)-amide] 3-[(4-morpholin-4-yl- phenyl)-amide]

61 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

62 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(3-methoxy-phenyl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

63 2 ^! -Methyl-biphenyl-3 _! 4'-dicarboxylic acid 3-[(lH-indazol-6-yl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

64 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(3-bromo-phenyl)-aniide] 4'-[(4- moφholin-4-yl-phenyl)-amide] 65 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-isoxazol-5-yl-phenyl)-amide] 4'- [(4-morpholin-4-yl-phenyl)-amide]

66 2'-Methyl-biphenyl-3,4 ^l -dicarboxylic acid 3-(3-chloro-benzylamide) 4'-[(4- morpholin-4-yl-phenyl)-amide]

67 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indazol-6-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

68 2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid (3- trifluoromethoxy-phenyl)-amide

69 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-moφholin-4-yl-phenyl)-amide] 4'- [(3-thiomorpholin-4-ylmethyl-phenyl)-amide] 70 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-dimethylcarbamoyl-phenyl)- amide] 3 - [(4-morpholin-4-yl-phenyl)-aniide]

71 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(3-ethyl-6-hydroxy-2-oxo- piperidin-3-yl)-phenyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

72 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

73 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(4-piperidin- 1 -ylmethyl-phenyl)-amide]

74 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-morpholm-4-ylmethyl-phenyl)- amide] 3-[(4-morpholin-4-yl-phenyl)-amide] 75 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(4-pyrrolidin- 1 -ylmethyl-phenyl)-amide]

76 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-({4-[(methyl-propyl-amino)-methyl]- phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

77 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-4-methyl-phenyl)- amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

78 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3-methanesulfonylamino-phenyl)- amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

79 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(2-oxo-2,3-dihydro-lH-benzoimidazol-5-yl)-amide]

80 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(2-piperidin- 1 -ylmethyl-phenyl)-amide] 81 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-hydroxymethyl-phenyl)-amide] 3- [(4-moφholin-4-yl-phenyl)-amide]

82 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(4-piperazin-l-ylmethyl-phenyl)-amide]

83 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-chloro-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide]

84 2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-c arboxylic acid ethyl ester

85 2'-Methyl-5'-(4-morpholin-4-yl-benzoylainino)-biphenyl-4-car boxylic acid (2- trifluoroniethyl-lH-benzoimidazol-5-yl)-amide 86 2'-Methyl-5'-(4-moφholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid (4- acetylamino-phenyl)-amide

87 2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid [4- (1,1 -dioxo-1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

88 2'-Methyl-5'-(4-morpholin-4-yl-benzoylaniino)-biphenyl-4-car boxylic acid 3- bromo-benzylamide

89 2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid 3- methyl-benzylamide

90 2'-Methyl-5'-(4-morpholm-4-yl-benzoylamino)-biphenyl-4-carbo xylic acid (4- bromo-3-chloro-phenyl)-amide 91 2'-Methyl-5 ^l -(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid (3- methoxy-phenyl)-amide

92 2 ^l -Methyl-5 ^l -(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid 3- trifluoromethoxy-benzylamide

93 2'-Methyl-5'-(4-morpholin-4-yl-benzoylainino)-biphenyl-4-car boxylic acid (IH- indol-6-yl)-amide

94 2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid 3- chloro-benzylamide

95 5'-{[l-Hydroxymethyl-2-(3H-imidazol-4-yl)-ethylamino]-methyl }-2 ^l -methyl- biphenyl-4-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

96 4'-[(3-Chloro-benzylamino)-methyl]-6-methyl-biphenyl-3-carbo xylic acid (4- morpholin-4-yl-phenyl)-amide 97 4'-[(lH-Indazol-6-ylamino)-methyl]-6-methyl-biphenyl-3-carbo xylic acid (4- morpholin-4-yl-phenyl)-amide

98 4'-Cyclopropylaminomethyl-6-metliyl-biphenyl-3-carboxylic acid (4-morpholin- 4-yl-phenyl)-amide

99 (S)-3-Hydroxy-2-{[2'-methyl-5'-(4-morpholin-4-yl-phenylcarba moyl)-biphenyl-4- ylmethyl]-amino}-propionic acid

100 4'-{[2-(3H-IJtnidazol-4-yl)-etliylaniino]-methyl}-6-methyl-b iphenyl-3-carboxylic acid (4-moφholin-4-yl-phenyl)-amide

101 4'- { [ 1 -Hydroxymethyl-2-(3H-imidazol-4-yl)-ethylaniino]-methyl} -6-methyl- biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide 102 4'-[(2-Dimetliylamino-etliylamino)-methyl]-6-methyl-biphenyl -3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

103 4'-(3-Bromo-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (4-morpholin- 4-yl-phenyl)-amide

104 3-Hydroxy-quinoxaline-2-carboxylic acid [2'-methyl-5'-(4-morpholin-4-yl- phenylcarbamoyl)-biphenyl-4-yl]-amide

105 4'-(2-Benzoylamino-acetylamino)-6-methyl-biplienyl-3-carboxy lic acid (4- morpholin-4-yl-phenyl)-amide

106 4'-[2-(3-Chloro-phenyl)-acetylamino]-6-methyl-biphenyl-3-car boxylic acid (4- morpholin-4-yl-phenyl)-amide 107 4'-(3-Methoxy-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (4- moφholin-4-yl-phenyl)-amide

108 lH-Pyrazole-4-carboxylic acid [6-methyl-4'-(4-morpholin-4-yl- phenylcarbamoyl)-biphenyl-3-yl]-amide

109 4'-(2-Hydroxy-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (4-morpholin- 4-yl-phenyl)-amide

110 4'-(3,4-Dimethoxy-benzoylamino)-6-methyl-biphenyl-3-carboxyl ic acid (4- morpholin-4-yl-phenyl)-amide

111 N-[2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl- 4-yl]-4- trifluoromethyl-nicotinamide

112 4'-(3-Methoxy-benzoylamino)-6-nietliyl-biρlienyl-3-carboxyl ic acid (4- morpholin-4-yl-phenyl)-amide 113 4'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-3-carboxy lic acid (4- morpholin-4-yl-phenyl)-amide

114 Furan-2-carboxylic acid [2-methyl-3'-(4-moφholin-4-yl-pb.enylcarbamoyl)- biphenyl-4-yl] -amide

115 4'-(2-Methoxy-benzoylamino)-2'-methyl-biphenyl-3 -carboxylic acid (4- morpholin-4-yl-phenyl)-amide

116 4'-(3 -Methoxy-benzoylamino)-2'-methyl-biphenyl-3 -carboxylic acid (4- moφholin-4-yl-phenyl)-amide

117 4'-(4-Dimethylaminomethyl-benzoylamino)-6-methyl-biphenyl-3- carboxylic acid (4-morpholin-4-yl-phenyl)-amide 118 6-Methyl-4'-(4-moφholin-4-ylmethyl-benzoylaniino)-biphenyl- 3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

119 6-Methyl-4'-(4-moφholin-4-yl-benzoylamino)-biphenyl-3 -carboxylic acid (4- moφholin-4-yl-phenyl)-amide

120 Biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*-thiomoφholin-4- ylmethyl)-phenyl] -amide} 3-[(4-moφholin-4-yl-phenyl)-amide]

121 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-cyclopropylamide 4'-{[4-(l,l-dioxo- llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide}

122 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenyl]-amide} 3-[(3-methyl-butyl)-amide] 123 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenyl]-amide} 3-(3-fluoro-benzylamide) 124 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenyl]-amide} 3-[(tetrahydro-furan-2-ylmethyl)- amide] 125 6-Methyl-biρhenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenyl]-amide} 3-[(2-piperidin-l-yl-ethyl)-amide] 126 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda ^:1: 6*- thiomoφholin-4-ylmemyl)-phenyl]-amide} 3-[(2-methoxy-ethyl)-amide]

127 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-{[2-(3H-imidazol-4-yl)-ethyl]- amide}

128 2'-Methyl-5 '-(4-pyrrolidin- 1 -yl-piperidine- 1 -carbonyl)-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylnietb.yl)-plienyl ]-aniide

129 6-Methyl-biphenyl-S^'-dicarboxylic acid bis-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide}

130 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-dimethylamino-phenyl)-amide] 4'- { [4-( 1 , 1 -dioxo- 1 lambda* 6* -thiomoφholin-4-ylniethyl)-phenyl] -amide} 131 4'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-3-carboxy lic acid [4-(l,l- dioxo-llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

132 5 ^l -(Cyclopropanecarbonyl-amino)-2'-metliyl-biphenyl-4-carboxyl ic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

133 Furan-2-carboxylic acid {3'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-2-methyl-biphenyl-4-yl} -amide

134 4'-(2-Methoxy-benzoylamino)-2'-methyl-biphenyl-3-carboxylic acid [4-(l,l- dioxo-llambda ^:|: 6*-thiomorpholin-4-ylmetb.yl)-phenyl]-amide

135 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 4'-[(4-morpholin-4-yl-phenyl)-amide] 136 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[3-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-[(4-moφholin-4-yl-phenyl)-amide] 137 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3- {[3-(2-oxo-pyrrolidin- 1 -yl)-propyl]- amide} 138 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'- {[4-(l,l -dioxo- llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-{[4-(3-ethyl-2,6-dioxo-piperidin-3- yl)-phenyl]-amide}

139 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-[(4-[l,2,4]triazol-l-yl-phenyl)- amide]

140 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3- {[4-(morpholine-4-carbonyl)- phenyl] -amide}

141 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-[(4-methylcarbamoyl-phenyl)- amide]

142 6-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-dimethylcarbamoyl-phenyl)- amide] 4'- {[4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide}

143 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'- {[4-(l ,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-[(5-ethyl-[l,3,4]thiadiazol-2-yl)- amide]

144 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-{[4-(piperidine-l-carbonyl)- phenyl] -amide}

145 6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 3-[(3-methyl-isothiazol-5-yl)-amide]

146 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-cyclohexylmethyl-amide 4'-{[4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide}

147 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-cycloheptylamide 4'-{[4-(l,l-dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide}

148 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-cyclopentylamide 4'-{[4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide} 149 N-[5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-yl]- 4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-benzamide

150 N-[5 ^l -(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-yl]-4-(l,l -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-benzamide

151 4'-[4-(1 , 1 -Dioxo-1 lambda*6*-thiomorpholin-4-ylmethyl)-benzoylamino]-6- methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

152 Morpholine-4-carboxylic acid {4'-[4-(l,l -dioxo- llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

153 Furan-2-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl] -6-methyl-biphenyl-3 -yl} -amide 154 5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

155 Thiophene-2-carboxylic acid {4 ^l -[4-(l,l-dioxo-llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

156 N-{4 ^l -[4-(l,l-Dioxo-llambda ^:i: 6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]- 6-methyl-biphenyl-3-yl}-nicotinamide

157 l-Methyl-lH-pyrrole^-carboxylic acid {4'-[4-(l,l~dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl -3-yl}-amide 158 5'-(Cyclohexanecarbonyl-amino)-2'-nietliyl-biphenyl-4-carbox ylic acid [4-(I ₅ I- dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

159 7,7'-Dimethyl-N*4*-(4-morpholin-4-yl-phenyl)-N*4 ^l!(! -(4-[l,2 ₅ 4]triazol-l-yl- phenyl)-[6,6 ^l ]biquinazolinyl-4,4'-diamine

160 2'-Methyl-5'-(4-methyl-benzoylamino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- 1 lambda* 6 * -thiomorpholin-4-ylmethyl)-phenyl] -amide

161 5'-[4-(1 ,1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-benzoylamino]-2'- methyl-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda* 6 * -thiomorpholin-4- ylmethyl)-phenyl] -amide

162 5'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmetliyl)-benzo ylamino]-2 ^l - methyl-biphenyl-4-carboxylic acid 3-chloro-benzylamide

163 5'-(3-Cyclohexyl-propionylamino)-2'-methyl-biplienyl-4-carbo xylic acid [4-(l , 1 - dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

164 5'-(Cycloheptanecarbonyl-amino)-2'-metliyl-biphenyl-4-carbox ylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide 165 5'-(2-Cyclohexyl-acetylamino)-2'-methyl-biphenyl-4-carboxyli c acid [4-(l,l- dioxo- 1 lambda* 6 * -thiomoipholin-4-ylmethyl)-phenyl] -amide

166 5'-(2-Cyclopentyl-acetylamino)-2'-methyl-biplienyl-4-carboxy lic acid [4-(l,l- dioxo- 1 lambda* 6 * -thiomoφholin-4-ylmethyl)-phenyl] -amide

167 5'-(Cyclopentanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

168 3'-(Cyclopropatiecarbonyl-amino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

169 3'-(Cyclobutanecarbonyl-amino)-biplienyl-4-carboxylic acid [4-(l,l-dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide 170 Tetrahydro-pyran-4-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmeth.yl)-phenylcarbamoyl]-6-methyl-bipheny l-3-yl}-amide 171 2'-Methyl-5'-(2-tetrahydro-pyran-4-yl-acetylamino)-biplienyl -4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda* 6* -tbiomoφholin-4-ylmethyl)-phenyl] -amide

172 3'-(Cyclopropanecarbonyl-amino)-2,4'-dimethyl-biphenyl-4-car boxylic acid [4- (l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amid e

173 2'-Methyl-5 '- [( 1 -trifluoromethyl-cyclopropanecarbonyty-amino] -biphenyl-4- carboxylic acid [4-(l,l-dioxo-llainbda*6*-thiomorpholin-4-ylmethyl)-phenyl]- amide

174 5'-[(I -Cyano-cyclopropanecarbonyl)-amino]-2'-methyl-biphenyl-4-car boxylic acid [4-( 1 , 1 -dioxo- 1 lambda*6*-ttøomoφholin-4-ylmethyl)-phenyl] -amide

175 2'-Methyl-5'-[(l-methyl-cyclopropanecarbonyl)-amino]-bipheny l-4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda* 6 * -thiomorpholin-4-ylmethyl)-phenyl] -amide 176 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biplienyl-4-carbox ylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

177 Thiazole-4-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

178 5'-(2-Cyclopropyl-acetylamino)-2'-methyl-biphenyl-4-carboxyl ic acid [4-( 1,1- dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

179 Thiazole-5-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

180 5'-Acetylamino-2'-methyl-biphenyl-4-carboxylic acid [4-( 1,1 -dioxo- 1 lambda* 6*- thiomorpholin-4-ylmethyl)-phenyl]-amide 181 5'-(2-Ethyl-butyrylamino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

182 5 ^l -Butyrylamino-2 ^l -methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

183 5'-Isobutyrylamino-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- llambda*6*-thiomorpholm-4-ylmethyl)-phenyl]-amide

184 5'-(2,2-Dimethyl-propionylamino)-2'-methyl-bipb.enyl-4-carbo xylic acid [4-(l , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

185 5'-(Cyclopropanecarbonyl-amino)-2'-trifluoromethoxy-biphenyl -4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide 186 5'-(Cyclopropanecarbonyl-amino)-2'-methoxy-biphenyl-4-carbox ylic acid [4-(l,l- dioxo- 1 lambda* 6* -thiomorpb.olin-4-ylmeth.yl)-phenyl] -amide

187 5'-(Cyclohexanecarbonyl-amino)-2'-methoxy-biplienyl-4-carbox ylic acid [4-(l , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

188 5'-(3-Ethyl-ureido)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6 ^!|! -thiomorpholin-4-ylmethyl)-phenyl]-amide

189 5'-(3-Cyclohexyl-ureido)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide 190 2 ^l -Methyl-5'-(2-oxo-propionylamino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpliolin-4-ylmethyl)-phenyl]-amide

191 5'-(Cyclohexanecarbonyl-amino)-2'-fl.iioro-biphenyl-4-caτbo xylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

192 5 ^l -(Cyclohexanecarbonyl-amino)-2'-trifluoromethoxy-biphenyl-4- carboxylic acid [4-(l , 1 -dioxo-1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

193 2'-Chloro-5 '-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-( 1,1- dioxo- 1 lambda*6* -thiomorpholm-4-ylmethyl)-phenyl] -amide

194 2'-Chloro-5'-(cyclopropanecarbonyl-aniino)-biphenyl-4-carbox ylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-aniide 195 5'-(Cyclobutanecarbonyl-aniino)-2'-methyl-biphenyl-4-carboxy lic acid [4-( 1,1- dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

196 3'-(Cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

197 5'-[(lH-Indazol-6-ylamino)-methyl]-2'-methyl-biphenyl-4-carb oxylic acid [4-(l,l- dioxo- 1 lambda*6 ^:1: -thiomorpholin-4-ylmethyl)-phenyl] -amide

198 5'-[(3-Bromo-phenylamino)-methyl]-2'-methyl-biplienyl-4-carb oxylic acid [4- (1,1 -dioxo- 1 lambda*6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

199 5'-[(3-Chloro-benzylamino)-methyl]-2'-methyl-biphenyl-4-carb oxylic acid [4- (1,1 -dioxo- 1 lambda* 6 *-thiomorpholin-4-ylmethyl)-phenyl] -amide 200 5 ¹ - {[l-Hydroxymethyl-2-(3H-imidazol-4-yl)-ethylamino]-methyl}-2 ^t -methyl- biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4- ylmethyl)-phenyl] -amide 201 5'-[(lH-Indazol-6-ylamino)-methyl]-2'-methyl-biphenyl-4-carb oxylic acid [4-(l,l- dioxo-llambda*6 ^:|: -thiomorpholin-4-ylmethyl)-plienyl]-amide 202 5'-(4-Chloro-benzenesulfonylamino)-2'-methyl-biphenyl-4-carb oxylic acid [4-

(1,1 -dioxo- 1 lambda*6 ^!|: -thiomorpholin-4-ylmethyl)-phenyl]-amide 203 2'-Methyl-5'-(6-morpholin-4-yl-pyridine-3-sulfonylamino)-bip henyl-4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda* 6 * -thiomorpholin-4-ylmethyl)-phenyl] -amide

204 5'-(5-Chloro-thiophene-2-sulfonylamino)-2'-methyl-biphenyl-4 -carboxylic acid [4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-a mide

205 5'-(5-Cyclopropyl-[l,2,4]oxadiazol-3-yl)-2'-methyl-biphenyl- 4-carboxylic acid [4- (1,1 -dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide 206 5 ^I -(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2'-methyl-biphenyl-4-c arboxylic acid [4- (1,1 -dioxo-1 lambda*6*~thiomorpholm-4-ylmethyl)-phenyl]-amide

207 5'-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)-2'-methyl-biphenyl-4- carboxylic acid [4- (1,1 -dioxo-1 lambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

208 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-cyclopropylamide 4'- {[4-(2- diethylamino-ethylcarbamoyl)-phenyl]-amide}

209 Furan-2-carboxylic acid [4'-(3-chloro-benzylcarbamoyl)-6-methyl-biphenyl-3-yl]- amide

210 5'-tert-Butoxycarbonylamino-2'-methyl-biρhenyl-4-carboxylic acid ethyl ester

211 5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid (lH-indazol-6- yl)-amide

212 5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid (4-oxazol-5-yl- phenyl)-amide

213 Thiophene-2-carboxylic acid [4'-(lH-indazol-6-ylcarbamoyl)-6-methyl-biphenyl- 3 -yl] -amide 214 lH-Pyrazole-4-carboxylic acid [6-methyl-4'-(3-methyl-benzylcarbamoyl)- biphenyl-3-yl]-amide

215 N-[6-Meth.yl-4'-(3-methyl-benzylcarbanioyl)-biphenyl-3-yl]-i sonicotiiiamide

216 5 ^l -(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyli c acid 3-chloro- benzylamide 217 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid 4-(4- methyl-piperazin- 1 -yl)-benzylamide

218 5'-(Cycloproρanecarbonyl-ammo)-2'-methyl-biphenyl-4-carboxy lic acid (4- [ 1 ,2,4]triazol- 1 -yl-phenyl)-amide

219 5'-(Cyclohexanecarbonyl-amino)-2 ^l -methyl-biphenyl-4-carboxylic acid (4- [1 ,2,4]triazol- 1 -yl-phenyl)-amide

220 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid [4-(3- ethyl-2,6-dioxo-piperidin-3-yl)-phenyl]-amide

221 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid [4-(3- ethyl-2,6-dioxo-piperidin-3-yl)-phenyl]-amide

222 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid (4- dimethylaminomethyl-phenyl)-amide 223 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (4- dimethylaminomethyl-phenyl)-amide

224 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (2- piperidin- 1 -ylmethyl-phenyl)-amide

225 5'-(Cycloproρanecarbonyl-amino)-2'-methyl-biphenyl-4-carbox ylic acid (3- dimethylaminomethyl-phenyl)-amide

226 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid (4- morpholin-4-ylmethyl-phenyl)-amide

227 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-bipb.enyl-4-carboxy lic acid (4- pyrrolidin- 1 -ylmethyl-phenyl)-amide 228 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (4- piperidin- 1 -ylmethyl-phenyl)-aniide

229 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (4- piperidin- 1 -ylmethyl-phenyl)-amide

230 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (4- pyrrolidin- 1 -ylmethyl-phenyl)-amide

231 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid (4- isoxazol-5-yl-phenyl)-amide

232 5'-(Cyclohexanecarbonyl-amino)-2 ^l -methyl-biphenyl-4-carboxylic acid (4- hydroxyniethyl-phenyl)-amide 233 Furan-2-carboxylic acid [4'-(lH-indol-6-ylcarbamoyl)-6-metliyl-biplienyl-3-yl]- amide,

234 (R)-Piperidine-2-carboxylic acid (4' - {4-[4-(propane-l -sulfonyl)-piperazin-l - ylmethyl]-phenylcarbamoyl}-6-trifluoroniethoxy-biphenyl-3-yl )-amide,

235 5'-(3-Cyclohexyl-ureido)-2'-trifluoromethoxy-biphenyl-4-carb oxylic acid [4-(4- methanesulfonyl-piperazin- 1 -ylmethyl)-phenyl] -amide

236 (S)-Pyrrolidine-2-carboxylic acid (4'-{4-[4-(propane-l-sulfonyl)-piperazin-l- ylmethyl]-ρhenylcarbamoyl} -ό-trifluoromethoxy-biphenyl-S -yl)-amide

237 5'-(Cyclopropanecarbonyl-amino)-2'-trifluoromethoxy-biphenyl -4-carboxylic acid {4-[4-(propane-l-sulfonyl)-piρerazin-l-ylmethyl]-phenyl}-am ide.

238 (S)-Piperidine-2-carboxylic acid (4'-{4-[4-(propane-l-sulfonyl)-piperazin-l- ylmethyl]-phenylcarbamoyl} -6-trifluoromethoxy-biphenyl-3 -yl)-amide. 239 4-Methyl-piperazine-l-carboxylic acid {4'-[4-(4-methanesulfonyl-piperazin-l- ylmethyl)-phenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-yl} -amide

240 5 ' -(2-Methylamino-acetylamino)-2' -trifl.uoromethoxy-biphenyl-4-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 -ylmethyl)-phenyl] -amide

241 (S)-2- {4 ' - [4-(4-Methanesulfonyl-piperazin- 1 -ylmethyl)-phenylcarbamoyl] -6- trifluoromethoxy-biphenyl-S-ylcarbamoylJ-azetidine-l-carboxy lic acid

242 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid {4-[2- (1,1 -dioxo- 1 lambda* 6* -thiomorpholin-4-yl)-ethyl] -phenyl} -amide

243 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid [4-(4- propane- 1 -sulfonyl-piperazin- 1 -ylmethyl)-phenyl] -amide 244 2'-Methoxy-5'-(4-morpholin-4-yl-ρhenylsulfamoyl)-biphenyl-4 -carboxylic acid [4-(l , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

245 2' -Methoxy-5 ' -(4-morpholin-4-yl-ρhenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4-methanesulfbnyl-piperazin- 1 -ylmethyl)-phenyl] -amide

246 2 '-Methoxy-5 '-(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4-propane-2-sulfonyl-piperazin-l-ylmethyl)-phenyl] -amide

247 2'-Methoxy-5'-(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4- carboxylic acid [4-(4-dimethylsulfamoyl-piρerazin- 1 -ylmethyl)-phenyl] -amide

248 2 ' -Methoxy-5 ' -(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4-propane- 1 -sulfonyl-piperazin- 1 -ylmethyl)-phenyl] -amide 249 2'-Chloro-5'-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxyl ic acid [4-(4- methyl-piperazin- 1 -ylmethyl)-phenyl] -amide

250 (R)-Pyrrolidine-2-carboxylic acid (6-cmoro-4'-[4-(4-methanesulfonyl-piperazin- 1 -ylmethyl)-phenylcarbamoyl] -biphenyl-3 -yl} -amide

251 (R)-Piperidine-2-carboxylic acid {6-chloro-4'-[4-(4-(propane-l-sulfonyl)- piperazin-l-ylmethyl)-phenylcarbamoyl]-biphenyl-3-yl} -amide

252 2'-Chloro-5'-(2-methylamino-acetylamino)-biphenyl-4-carboxyl ic acid [4-(4- methanesulfonyl-piperazin-l-yhnethyl)-phenyl]-amide

253 2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid {4-[4-(propane-l- sulfonyl)-piperazin- 1 -ylmethylj-phenyl} -amide

254 2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid {4-[4-(propane-2- sulfonyl)-piperazin- 1 -ylmethyl] -phenyl} -amide 255 2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid [4- (4dimethylsulfamoyl-piperazin-l-ylmethyl]-phenyl}-amide

256 6-Trifluoromethoxy-biphenyl-3,4' -dicarboxylic acid 4' - {[4-(4-methanesulfonyl- piperazin-l-ylmethyl)-phenyl] -amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

257 6-Methoxy-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-( {4-[4-(propane-l -sulfonyl)-piperazin- 1 -ylmethylj-phenyl} -amide)

258 6-Methoxy-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4' -( {4-[4-(propane-2-sulfonyl)-piperazin- 1 -ylmethyl] -phenyl} -amide)

259 6-Methoxy-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(4-dimethylsulfamoyl- piperazin-l- ylmethyl)-phenyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide] 260 6-Methoxy-biphenyl-3,4'-dicarboxylic acid 3-[(2-methyl-4-morpholin-4-yl- phenyl)-amide] 4'-({4-[4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethyl] -phenyl} - amide)

261 6-Methoxy-biphenyl-3, 4 '-dicarboxylic acid 3-{[4-(4-(l,l-dioxo-llambda*6*- thiomorpholin-4-yl)-phenyl]-amide} 4'-{[4-(4-methyl-piperazin-l-yi)-phenyi]- amide}

262 6-Methoxy-biphenyl-3, 4 '-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 4' {[4-(4-methanesulfonyl-piperazin- 1 -ylmethyl)-phenyl]-amide}

263 6-Chloro-biphenyl-3, 4 '-dicarboxylic acid 4'-({4-[4-(butane-l-sulfonyl)piperazin- l-ylmethyl]-phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

264 6-Chloro-biphenyl-3,4'-dicarboxylic acid 3-[(3-fluoro-4-morpholin-4-yl-phenyl)- amide] 4' -( {4-[4-(propane-l -sulfonyl)-piperazin-l -ylmethyl] -phenyl} -amide)

265 6-Chloro-biphenyl-3, 4 '-dicarboxylic acid 3-{[4-(4-methanesulfonyl-piperazin-l- ylmethyl)-phenyl]-amide} 4'-[(4-morpholin-4-yl-phenyl)-amide] and pharmaceutically acceptable salts thereof.

The compounds of formula (I) may be prepared by analogy with known methods. For example, they can be prepared by the following reactions:

scheme (1)

scheme (2)

wherein R ₂ , R ₃ , n and m are as defined above, and either X and Y are, respectively, -A-Ri or -B-R ₄ , wherein A, B, Ri and R ₄ are as defined above, or X and Y represent groups which can be further reacted by standard techniques to yield the moieties -A-Ri or -B-R ₄ , for example amino groups or carbocyclic acid groups.

The coupling reactions shown in schemes (1) and (2) can be effected by known methods, for example cesium carbonate and palladium catalyst in aqueous DMF at reflux. The starting materials used in schemes (1) and (2) are known compounds or can be prepared by analogy with known methods.

Methods for converting the moieties X and Y into moieties -A-R ₁ and -B-R ₄ , and for converting moieties -A-Ri and -B-R ₄ into other moieties set out in the definitions Of-A-R ₁ and -B-R ₄ , are known to those of skill in the art. By way of example, some representative techniques are set out below.

Examples of Suzuki Coupling reaction.

(A) (B) (C) (D) (E)

(D (2) (3) (4)

The above aryl bromides and boronic acids/esters can be coupled under standard conditions (cesium carbonate and palladium catalyst in aqueous DME at reflux) to provide a number of diverse biphenyl cores. These may have two carbonyl functionalities, two amino functionalities or one of both types. Some products from these reactions are shown below (for the sake of brevity, a substituent on the aromatic ring is either shown as "C" or "N" and the R ₂ and R ₃ substituents are simply shown as 'R').

Product of: A/B1

Product of: C/D1

Product of: E4

By careful usage of monomers i.e. esters vs. acids and nitro groups vs. protected amines it can be seen that amide and reverse amide groups may be placed selectively at either end of the biphenyl core. The initial amide coupling reactions 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. Subsequent to this and dependent on the second functionality to be converted to the second amide, a hydrolysis of an ester, a deprotection of a protected amine, or a hydrogenation of a nitro-group will then furnish intermediates which are readily coupled as described above to give the final compounds shown below.

Analogues in which one of the amides has been replaced by a ring structure may be prepared, for example, via dehydration of a primary amide into a nitrile. Suitable adaptation of the nitrile furnishes compounds with heteroaromatic rings, e.g. 1,2,4- oxadiazoles or 1,2,4-triazoles. Replacement of the amide with aryl, carbocyclyl and heterocyclyl groups may be performed by analogy.

In some analogues one of the amide groups is reduced to the amine. These compounds can be prepared via reduction of an acid, usually with an organometallic reagent such as lithium borohydride, followed by oxidation to the aldehyde with manganese dioxide and then subsequent reductive animation. This final step is routinely carried out in the presence of a mild reducing agent such as sodium tri(acetoxy) borohydride:

As explained above, the compounds of the invention are active 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 biphenyl derivative 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 biphenyl derivative of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for the treatment of the human or animal body. 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.

Yet further the present invention provides a pharmaceutical composition comprising a biphenyl derivative of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable 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. Further, the pharmaceutical compositions of the invention typically contain a compound of the invention which is a substantially pure optical isomer. 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 anti-viral 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 biphenyl derivative of the 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 biphenyl derivative of the 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.

EXAMPLES Core l

Intermediate 1

6-Methyl-biphenyl-3, 4'-dicarboxylic acid 4'-ethyl ester

A mixture of 3-bromo-4-methyl benzoic acid (7.5Og), 4-(ethoxycarbonylphenyl) boronic acid (6.82g), cesium carbonate (11.34g) and tetrakis(triphenylphosphine) palladium (0), 5 mol% (2.0Ig) was heated to reflux under nitrogen in DME (150 ml) for

18 h. The reaction mixture was then cooled to room temperature and filtered. The resulting filtrate was then evaporated and purified on silica gel, eluting with 0-30%

20:8: 1 CH ₂ Cl ₂ / EtOH / NH ₃ in CH ₂ Cl ₂ gave the title compound as a white solid 2.5g.

Intermediate 2 2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-c arboxylic acid ethyl ester

6-Methyl-biphenyl-3, 4'-dicarboxylic acid 4'-ethyl ester (3.54g) in toluene (70ml) was treated with oxalyl chloride (4ml) followed by DMF (3 drops). The reaction was stirred

at room temperature for 2 hours and then evaporated to dryness. The resulting residue was redissolved in toluene (30ml) and evaporated to dryness twice to yield the acid chloride.

A solution of triethylamine (0.25g) in dichloromethane (5ml) was added to A- morpholin-4-yl-phenylamine (0.44g). Then a solution of the above acid chloride (0.75g) in dichloromethane (7ml) was added and the reaction mixture stirred for 18 h. The mixture was then partitioned between IM HCl and dichloromethane. The dried extracts were evaporated giving a colourless solid, used without further purification in the next synthetic step

Intermediate 3

2'-Methyl-5 ^l -(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid

2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-c arboxylic acid ethyl ester (0.89g) in THF (10ml) and 0.5M NaOH (15m) was heated to 100 ⁰ C for 3 hours then cooled to room temperature. THF was evaporated and the residue extracted with dichloromethane. The aqueous layer was acidified to pH 1 and a grey solid precipitated which was collected by filtration and dried (0.74g).

¹ H NMR (DMSO, δ) 2.33 (s, 3H) 3.26 (br s, 4H) 3.87 (br s, 4H) 7.26 (br d, 2H) 7.50 (d,

IH) 7.58 (d, 2H) 7.75 (d, 2H) 7.89 (s, IH) 7.94 (d, IH) 8.06 (d, 2H) 10.23 (s, IH)

Example 1

6-Methyl-biphenyl-3, 4'-dicarboxylic acid 4'-[(3-bromo-phenyl)-amide]-[(4 morpholin-

4-yl-phenyl)-amide]

2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-c arboxylic acid (Intermediate 3)(54mg), EDACHCl (25mg), HOBT.H ₂ O (17mg) and N- methylmorpholine (26mg) were stirred in DMF (ImI). The mixture was then treated with 3-bromo-phenylamine (22mg) and the whole reaction mixture was stirred at 2OC overnight. The reaction mixture was evaporated to dryness. The residue was redissolved in acetonitrile (0.5ml) and water (3mL) was added. The resulting brown solid was filtered and dried (55mg).

¹ H NMR (DMSO, δ) 2.35 (s, 3H) 3.10-3.06 (m, 4H) 3.73-3.77 (m, 4H) 6.95 (d, 2H) 7.33-7.39 (m, 2H) 7.50 (d, IH) 7.62-7.66 (m, 4H) 7.81 (dd, IH) 7.89 (s, IH) 7.93 (d, IH) 8.09 (d, 2H) 8.17 (s, IH) 10.08 (s, IH) 10.49 (s, IH) LC-MS ES+ = 570

Examples 2 to 8 were prepared in an analogous fashion to Example 1 using Intermediate 3:

Example 2 6-Methyl-biphenyl-3,4'~dicarboxylic acid 4'-[(6-methoxy-pyridin-3-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

¹ H NMR (DMSO, δ) 2.35 (s, 3H) 3.06-3.10 (m, 4H) 3.77-3.73 (m, 4H) 3.86 (s, 3H) 6.88 (d, IH) 6.95 (d, 2H) 7.50 (d, IH) 7.61-7.66 (m, 4H) 7.89 (s, IH) 7.93 (d, IH) 8.09 (d, 3H) 8.57 (d, IH) 10.09 (s, IH) 10.40 (s, IH) LC-MS ES+ = 523

Example 3

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-methyl-benzylamide) 3-[(4-morpholin- 4-yl-phenyl)-amide]

Example 4

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-methyl-butyl)-amide] 3-[(4-morpholin-

4-yl-phenyl)-amide]

¹ H NMR (DMSO, δ) 0.93 (d, 6H) 1.47 (dt, 2H) 1.66 (septet, IH) 2.32 (s, 3H) 3.08 (m,

4H) 3.34 (m ,2H) 3.75 (m, 4H) 6.94 (d, 2H) 7.46-7.51 (m, 3H) 7.63 (d, 2H) 7.86-7.97

(m, 4H) 8.51 (t, IH) 10.06 (s, IH)

LC-MS ES+ = 486

Example 5

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-fluoro-benzylamide) 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 6

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(2- piperidin- 1 -yl-ethyl)-amide]

Example 7 θ-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-bromo-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 8

6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3-benzyloxy-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 9 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3- {[3-(4-methyl-piperazin- 1 -yl)-propyl]- amide} 4'-[(4-morpholin-4-yl-phenyl)-amide] This compound was prepared in by analogous methods from Intermediate 1.

Examples 10-16 were prepared in an analogous fashion to Example 1.

Example 10

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-(3- trifluoromethyl-benzylamide)

¹ H NMR (DMSO, δ) 2.33 (s, 3H) 3.06-3.1 (m, 4H) 3.73-3.77 (m, 4H) 4.61 (d, 2H) 6.94 (d, 2H) 7.48 (d, IH) 7.60 (d, IH) 7.63-7.67 (m, 5H) 7.71 (s, IH) 7.86 (m, IH) 7.91 (dd, IH) 8.03 (d, 2H) 8.25 (m, IH) 9.27(t, IH) 10.08 (s, IH)

LC-MS ES+ = 574

Example 11

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(2- thiophen-2-yl-ethyl)-amide]

Example 12

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indazol-6-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 13 θ-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[2-(3H-imidazol-4-yl)-ethyl]-amide} 3-

[(4-morpholin-4-yl-plienyl)-amide]

Example 14

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(5-methyl-furan-2-ylmethyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 15 6-Methyl-4'-(pyrrolidine-l-carbonyl)-biphenyl-3-carboxylic acid (4-morpholin-4-yl- phenyl)-amide

Example 16

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-benzo[l,3]dioxol-5-ylamide 3-[(4- moφholin-4-yl-phenyl)-amide]

Example 17

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-cyclopropylamide 4'-[(4-morpholin-4-yl- phenyl)-amide] This compound was prepared by analogous methods using Intermediate 1.

Example 18

Furan-2-carboxylic acid [6-methyl-4'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-3- yl] -amide This compound was prepared by analogous methods using Intermediate 23

Examples 19-59 were prepared in an analogous fashion to Example 1.

Example 19

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-benzoyl-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 20

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(4-morpholin-4-yl-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 21

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-butylsulfamoyl-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 22

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3,4-dichloro-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 23

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(3- txifluoromethyl-phenyl)-amide]

Example 24

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-cyano-phenyl)-amide] 3-[(4-morpholin-

4-yl-phenyl)-amide]

Example 25

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(3- trifluoromethoxy-phenyl)-amide]

Example 26 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(3- trifluoromethoxy-phenyl)-amide]

Example 27 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(3- trifluoromethoxy-phenyl)-amide]

Example 28

6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-isoxazol-5-yl-phenyl)-amide] 3-[(4- morpliolin-4-yl-phenyl)-amide]

¹ H NMR (DMSO, δ) 2.36 (s, 3H) 3.06-3.1 (m, 4H) 3.73-3.77 (m, 4H) 6.96-6.98 (m, 3H) 7.50 (d, 2H) 7.64 (d, 4H) 7.92 (dd, 4H) 8.11 (d, 2H, d) 8.65 (d, IH, d) 10.1 (s, IH) 10.61 (s, IH) LC-MS ES+ = 559

Example 29 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-methylsulfamoyl-phenyl)-amide] 3-[(4- morρholin-4-yl-phenyl)-amide]

¹ H NMR (DMSO, δ) 2.49 (s, 3H) 2.57 (d, 3H) 3.20-3.24 (m, 4H) 3.87- 3.91 (m, 4H) 7.09 (d, 2H) 7.52 (q, IH) 7.64 (d, IH) 7.78 (d, 4H) 7.93 (d, 2H) 8.03-8.08 (m, 2H) 8.22 (dd, 4H) 10.23 (s, IH) 10.86 (s, IH)

LC-MS ES+ = 585

Example 30 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-bromo-3-chloro-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 31

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[3-(l-hydroxy-ethyl)-phenyl]-amide} 3- [(4-morpholin-4-yl-phenyl)-amide]

Example 32

3-{[2'-Methyl-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphe nyl-4-carbonyl]-amino}- benzoic acid ethyl ester

Example 33

6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3-methoxy-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 34 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(3,4-dimethoxy-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 35

6-Metb.yl-biphenyl-3,4 ^l -dicarboxylic acid 4'-({2-[(cyclohexyl-methyl-amino)-methyl]- phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 36

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- pyridin-3 -ylamide

Example 37

4'-[4-(2,3-Dichloro-phenyl)-piperazine-l-carbonyl]-6-meth yl-biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

Example 38

6-Methyl-biphenyl-3,4'-dicarboxylicacid 3-[(4-morpholin-4-yl-ρhenyl)-amide] 4'-[(2- trifluoromethyl-lH-benzoimidazol-5-yl)-amide]

¹ H NMR (DMSO, δ) 2.36 (s, 3H) 3.06-3.1 (m, 4H) 3.73-3.77 (m, 4H) 6.95 (d, 2H) 7.50

(d, IH) 7.62-7.66 (m, 4H) 7.74 (s, 2H) 7.90 (d, IH) 7.95 (d, IH) 8.12 (d, 2H) 8.39 (s, IH) 10.1 (s, IH) 10.52 (s, IH) 13.85 (br s, IH)

LC-MS ES+ = 600

Example 39

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-cyanomethyl-phenyl)-aniide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 40 θ-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- [(thiophen-3 -ylmethyl)-amide]

Example 41 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-(3- trifluoromethoxy-benzylamide)

Example 42

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(4-chloro-3-trifluoromethyl-benzylamide) 3 - [(4-morpholin-4-yl-phenyl)-amide]

Example 43

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-chloro-4-methyl-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 44

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-6-yl)-amide] 3-[(4-morpholin-4- yl-phenyl)-amide]

¹ H NMR (DMSO, δ) 2.36 (s, 3H) 3.06-3.08 (m, 4H) 3.73-3.77 (m, 4H) 6.40 (br s, IH) 6.95 (d, 2H) 7.31-7.35 (m, 2H) 7.50 (d, 2H) 7.60-7.66 (m, 4H) 7.90-7.97 (m, 2H) 8.09- 8.13 (m, 3H) 10.1 (s, IH) 10.27 (s, IH) 11.1 (s, IH)

LC-MS ES+ = 53

Example 45

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-5-yl)-amide] 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 46

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-benzothiazol-6-ylamide 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 47

[3 -( { [2'-Methyl-5 ^! -(4-moφholin-4-yl-phenylcarbamoyl)-biρhenyl-4-carbonyl]-am ino} - methyl)-benzyl]-carbamic acid tert-butyl ester

Example 48 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(lH-indol-7-yl)-amide] 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 49

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[2-(2-hydroxymethyl-phenylsulfanyl)- benzylamide] 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 50

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl] -amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 51

6-Methyl-biphenyl-3,4 ^l -dicarboxylic acid 4'-{[(S)-l-hydroxymethyl-2-(lH-indol-3-yl)- ethyl] -amide} 3 - [(4-morpholin-4-yl-phenyl)-amide]

Example 52 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-(3-bromo-benzylamide) 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 53 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-amino-phenyl)-amide] 3-[(4-morpholin- 4-yl-phenyl)-amide]

Example 54

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4 ^l -[(4-methylsulfamoylmethyl-phenyl)-amide]

3-[(4-morpholin-4-yl-phenyl)-amide]

Example 55

6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(5-bromo-lH-indol-7-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 56 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-{[4- ( 1 H-pyrazol-3 -yl)-phenyl] -amide}

Example 57

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-(3-chloro-2-fluoro-benzylamide) 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 58

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-{[4- (piperidine-l-carbonyl)-phenyl]-amide}

Example 59

Biρhenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-5-yl)-amide] 3-[(4-morpholin-4-yl- phenyl)-amide]

Core 2

Intermediate 4

Biphenyl-3,4'-dicarboxylic acid 4 '-ethyl ester

A mixture of 3-bromo-benzoic acid (4.02g) and 4-ethoxycarbonyl-phenyl boronic acid (3.88g) in DME (100ml) containing cesium carbonate (6.5g) and tetrakis(triphenylphosphine) palladium (0) (1.15g) was heated to reflux for 24h. The cooled mixture was then filtered through celite and evaporated giving the crude title compound as a white solid which was used without purification in the next synthetic step.

Intermediate s

3'-(4-Morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxyl ic acid ethyl ester Biphenyl-3, 4'-dicarboxylic acid 4'-ethyl ester (660mg) in toluene (10ml) was treated with oxalyl chloride (ImI) followed by DMF (2 drops). The reaction was stirred at room temperature for 2 hours and then evaporated to dryness. The resulting residue was redissolved in toluene (30ml) and evaporated to dryness twice to yield the acid chloride.

A solution of triethylamine (494mg) in dichloromethane (10ml) was added to 4- morpholin-4-yl-phenylamine (435mg). Then a solution of the above acid chloride in dichloromethane (7ml) was added and the reaction mixture stirred for 18 h. The mixture was then partitioned between IM HCl and dichloromethane. The dried extracts were evaporated giving a colourless solid, used without further purification in the next synthetic step

Intermediate 6

3 ' -(4-Morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid 3'-(4-Moφholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester

(850mg) in THF (12ml) and IM NaOH (25m) was heated to 100 ⁰ C for 3 hours then cooled to room temperature. THF was evaporated and the residue extracted with dichloromethane. The aqueous layer was acidified to pH 1 and a grey solid precipitated which was collected by filtration and dried (793mg)

Example 60

Biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indol-6-yl)-arnide] 3-[(4-morpholin-4-yl- phenyl)-amide]

3'-(4-Morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxyl ic acid (30mg)

(Intermediate 6), EDACHCl (14mg), HOBT.H ₂ O (lOmg) and N-methylmorpholine (15mg) were stirred in DMF (0.5ml). The mixture was then treated with lH-indol-6- ylamine (lOmg) and the whole reaction mixture was stirred at 2OC overnight. The reaction mixture was diluted with water and the solid collected by filtration. This was then recrystallised from 3:1 EtOH:H ₂ 0 at 140C (in microwave) giving the title compound as an off-white solid (5mg).

¹ H NMR (DMSO, δ) 3.10 (t, 4H) 3.76 (t, 4H) 6.41 (s, IH) 6.98 (d, 2H) 7.31-7.35 (m, 2H) 7.51 (m, IH) 7.63-7.72 (m, 3H) 7.95-8.00 (m, 4H) 8.13-8.17 (m, 3H) 8.32-8.35 (m, IH) 10.24 (s, IH) 10.26 (s, IH) 11.10 (s, IH) LC-MS ES+ = 517.

Example 61

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

This compound was prepared in an analogous fashion to Example 1.

Examples 62 to 66 were prepared from Intermediates generated from the coupling reaction F4 and are prepared in an analogous fashion to Example 1.

Example 62 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(3-methoxy-phenyl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

Example 63

2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(lH-indazol-6-yl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

Example 64

2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(3-bromo-phenyl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

Example 65

2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-isoxazol-5-yl-phenyl)-amide] 4'-[(4- morpholin-4-yl-phenyl)-amide]

Example 66

2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-(3-chloro-benzylamide) 4'-[(4-morpholin-4- yl-phenyl)-amide]

Examples 67 to 84 were prepared in an analogous fashion to Example 1.

Example 61

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(lH-indazol-6-yl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 68

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid (3- trifluoromethoxy-phenyl)-amide

Example 69

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(3- thiomorpholin-4-ylmethyl-phenyl)-amide]

Example 70 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-[(4-dimethylcarbamoyl-phenyl)-amide] 3- [(4-morpholin-4-yl-phenyl)-amide]

Example 71

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'- {[4-(3-ethyl-6-hydroxy-2-oxo-piperidin-3- yl)-phenyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 72

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 73 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(4- piperidin- 1 -ylmethyl-ρhenyl)-amide]

Example 74

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-morpholin-4-ylmethyl-phenyl)-amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 75 6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(4- pyrrolidin- 1 -ylmethyl-ρhenyl)-amide]

Example 76

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-( {4-[(methyl-propyl-amino)-methyl]- phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 77

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-acetylamino-4-methyl-phenyl)-amide] 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 78 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(3-methanesulfonylamino-phenyl)-amide] 3 - [(4-morpholin-4-yl-phenyl)-amide]

Example 79

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(2- oxo-2,3-dihydro- lH-benzoimidazol-5-yl)-amide]

Example 80

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(2- piperidin-l-ylmethyl-phenyl)-amide]

Example 81

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-[(4-hydroxymethyl-phenyl)-amide] 3-[(4- morpholin-4-yl-phenyl)-amide]

Example 82

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-[(4- piperazin- 1 -ylmethyl-phenyl)-amide]

Example 83 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4'-(3-chloro-benzylamide) 3-[(4-morpholin-4- yl-phenyl)-amide]

Example 84

2'-Methyl-5 ^l -(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester

Core 3

Intermediate 7 2'-Methyl-5'-(4-morpholm-4-yl-benzoylamino)-biphenyl-4-carbo xylic acid ethyl ester

5'-Amino-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (2.15g), 4-morpholin-4-yl benzoic acid (1.27g), N-methylmorpholine (2.05ml), 1-hydroxybenzotriazole (826mg) and l-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride (1.17g) in dry DMF (30ml) was stirred at 2OC for 18h. Then the DMF was evaporated and the residue partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with 1-2% methanol in dichloromethane gave a colourless solid (2.4g)

Intermediate 8 2'-Methyl-5 '-(4-morpholin-4-yl-benzoylamino)-biρhenyl-4-carboxylic acid

2'-Methyl-5'-(4-morpholin-4-yl-benzoylaniino)-biphenyl-4- carboxylic acid ethyl ester (2.4g) was stirred in a mixture of THF (25ml) and IM sodium hydroxide (50ml) at IOOC for 4h. The mixture was allowed to cool and the THF was evaporated. The residue was acidified and the resultant colourless precipitate collected by filtration and dried (1.98g).

Examples 85 and 86 were prepared in an analogous fashion to Example 87

Example 85 2'-Methyl-5 ^l -(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid (2- trifluoromethyl- 1 H-benzoimidazol-5-yl)-amide

Example 86

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid (4- acetylamino-phenyl)-amide

Example 87

2' -Methyl-5 ' -(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid [4-(l , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid (60mg) 4- (1,1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (35mg), N- methylmorpholine (0.035ml), 1-hydroxybenzotriazole (20mg) and l-ethyl-3-(3- (dimethylaminopropyl)carbodiimide hydrochloride (29mg) in dry DMF (2ml) was stirred at 2OC for 18h. Water was then added and the resultant precipitate collected by filtration and dried (44mg).

¹ H NMR (DMSO,δ) 2.24 (s, 3H) 2.88 (m, 4H) 3.12 (m, 4H) 3.27 (m, 4H) 3.66 (s, 2H) 3.76 (m, 4H) 6.95 (d, 2H) 7.28-7.7.42 (m, 3H) 7.52 (d, 2H) 7.74-7.78 (m, 4H) 7.91 (d, 2H) 8.05 (d, 2H) 10.05 (s, IH) 10.39 (s, IH). LC-MS ES+ = 639.

Example 88

2'-Methyl-5 ^l -(4-morpholin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid 3-bromo- benzylamide

Example 89

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid 3-methyl- benzylamide

Example 90 2'-Methyl-5'-(4-moφholin-4-yl-benzoylamino)-biphenyl-4-carb oxylic acid (4-bromo-3- chloro-phenyl)-amide

Example 91

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid (3-methoxy- phenyl)-amide

Example 92

2'-Methyl-5'-(4-morpholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid 3- trifluoromethoxy-benzylaniide

Example 93

2'-Methyl-5'-(4-moφholin-4-yl-benzoylamino)-biphenyl-4-c arboxylic acid (lH-indol-6- yl)-amide

Example 94

2 ^l -Methyl-5 ^l -(4-moφh.olin-4-yl-benzoylamino)-biphenyl-4-carboxylic acid 3-chloro- benzylamide

Examples 95 to 102 are prepared by a reductive amination procedure, via an aldehyde intermediate, generated in analogous procedures to Intermediate 42 and Example 197

Example 95

5'- {[ 1 -Hydroxymethyl-2-(3H-imidazol-4-yl)-ethylamino]-methyl} -2'-methyl-biphenyl-

4-carboxylic acid (4-mθrpholin-4-yl-phenyl)-amide

Example 96

4'-[(3-Chloro-benzylamino)-methyl]-6-methyl-biphenyl-3-ca rboxylic acid (4- morpholin-4-yl-phenyl)-amide

Example 97 4'-[(lH-Indazol-6-ylamino)-methyl]-6-methyl-biphenyl-3-carbo xylic acid (4- morpholin-4-yl-phenyl)-amide

Example 98

4 ^l -Cyclopropylaminomethyl-6-methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl- phenyl)-amide

Example 99

(S)-3-Hydroxy-2-{[2'-methyl-5'-(4-morpholm-4-yl-phenylcar bamoyl)-biplienyl-4- ylmethyl] -amino} -propionic acid

Example 100

4'-{[2-(3H-Imidazol-4-yl)-ethylammo]-methyl}-6-methyl-bip henyl-3-carboxylic acid

(4-morpholin-4-yl-phenyl)-amide

Example 101

4'-{[l-Hydroxymethyl-2-(3H-imidazol-4-yl)-ethylamino]-met hyl}-6-methyl-biphenyl- 3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

Example 102 4'-[(2-Dimethylamino-ethylamino)-methyl]-6-methyl-biphenyl-3 -carboxylic acid (4- morpholin-4-yl-phenyl)-amide

Core 4

Intermediate 9

(4-Bromo-3-methyl-phenyl)-carbamic acid tert-butyl ester

A solution of 4-bromo-3-methyl aniline (500mg) in methanol (20ml) was treated with triethylamine (0.75ml) and Boc anhydride (1.18g) and was stirred at 2OC for 18h. The solvent was then evaporated and the residue partitioned between water and

dichloromethane. The dried extracts were then evaporated giving the title compound as a pale brown solid (770mg).

Intermediate 10 4'-tert-Butoxycarbonylamino-2'-methyl-biphenyl-3-carboxylic acid

A mixture of (4-bromo-3-methyl-phenyl)-carbamic acid tert-butyl ester (765mg), 3- carboxyphenyl boronic acid (446mg), cesium carbonate (875mg) and tetrakis(triphenylphosphine)palladium° (catalytic quantity), in 1:2 aqueous DME (30ml) was heated to reflux for 18h. The mixture was then allowed to cool and was then partitioned between IM HCl and dichloromethane. The dried extracts were then evaporated giving the title compound as a pale brown foam (785mg).

Intermediate 11 [2-Methyl-3 '-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-yl]-carbamic acid tert- butyl ester

A mixture of 4'-tert-butoxycarbonylamino-2'-methyl-biphenyl-3-carboxylic acid (436mg), 4-morpholin-4-yl aniline (238mg), triethylamine (0.55ml) and O-benzotriazol- l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (757mg) in dry DMF (15ml) was stirred at 20C for 18h. Water (50ml) was then added and the resulting colourless precipitate was collected by filtration and dried (680mg)

Intermediate 12 4 ' - Amino-2 ' -methyl-biphenyl-3 -carboxylic acid (4-morpholin-4-yl-phenyl)-amide

[2-Methyl-3 '-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-yl]-carbamic acid tert- butyl ester (670mg) was stirred in methanol (15ml) and 5M HCl (5ml) at 2OC for 2 days. TLC indicated that the reaction was progressing slowly and so the mixture was heated to reflux for 6h. The reaction was allowed to cool and was then basified and extracted with dichloromethane. The dried extract was evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam which crystallized on standing (354mg).

Examples 103 to 112 were prepared from intermediates produced from coupling A/Bl and are synthesized in an analogous fashion to Example 114.

Example 113

4'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-3-carb oxylic acid (4-morpholin-

4-yl-phenyl)-amide

This was prepared in an analogous fashion to Example 114

Example 114

Furan-2-carboxylic acid [2-methyl-3 '-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4- yl] -amide

A solution of 4'-amino-2'-methyl-biphenyl-3-carboxylic acid (4-morpholin-4-yl- phenyl)-amide (40mg) and triethylamine(0.4ml) in dry DMF (3ml) was treated with furan-2-carbonyl chloride (0.015ml) and the mixture stirred at 2OC for 18h. The mixture was then partitioned between water and dichloromethane. The dried extract was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 400:8:1 gave a colourless foam (46mg).

¹ H NMR (DMSO,δ) 2.28 (s, 3H) 3.09 (t, 4H) 3.74 (t, 4H) 6.74 (m, IH) 6.93 (d, 2H) 7.30-7.38 (m, 2H) 7.56-7.76 (m, 6H) 7.93-7.99 (m, 3H) 10.12 (s, IH) 10.24 (s, IH).

Examples 115 and 116 were prepared in an analogous fasion to Example 114 ₍

Example 115

4'-(2-Methoxy-benzoylamino)-2'-methyl-biphenyl-3-carboxyl ic acid (4-morpholin-4-yl- phenyl)-amide

Example 116

4'-(3-Methoxy-benzoylamino)-2'-methyl-biphenyl-3-carboxyl ic acid (4-morpholin-4-yl- phenyl)-amide

Examples 117 to 119 were prepared from intermediates produced from coupling A/Bl and are synthesised in an analogous fashion to Example 114.

Core 5

Intermediate 13

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3 -methyl ester

A mixture of 3-bromo-4-methyl-benzoic acid methyl ester (3g), 4-hydroxycarbonyl- phenyl boronic acid (2.2Ig), cesium carbonate (4.26g) and tetrakis(triphenylphosphine)palladium° (catalytic quantity), in 1:2 aqueous DME (75ml) was heated to reflux for 18h. The cooled reaction was then evaporated to dryness and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia;

800:8:1 to 100:8:1 gave a yellow crystalline solid (3.4g)

Intermediate 14

4'-[4-(l,l-Dioxo-llambda*6*-thiomorpholm-4-ylmethyl)-phen ylcarbamoyl]-6-methyl- biphenyl-3-carboxylic acid methyl ester ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-methyl ester (1.59g) in toluene (50ml) was treated with oxalyl chloride (8ml) and DMF (6 drops). The mixture was stirred at 2OC for 2h. and then was evaporated to dryness. The residue was then dissolved in dichloromethane (50ml) containing triethylamine (0.85ml) and was treated with 4-(l,l- dioxo-llambda*6*-thiomoipholin-4-ylmemyl)-phenylamine (1.4g). This mixture was stirred at 2OC for 18h. and was then partitioned between IM sodium hydroxide and dichloromethane. The dried extracts were evaporated giving the title compound as a colourless foam (2.72g). Intermediate 15

4'-[4-(1 , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-ρhenylcarbamoyl]-6-meth yl- biphenyl-3-carboxylic acid

4'-[4-(l,l-Dioxo-llambda*6*-thiomorρholin-4-ylmethyl)-ph enylcarbamoyl]-6-methyl- biphenyl-3-carboxylic acid methyl ester (1.09g) was heated to reflux in IM sodium hydroxide (20ml) and THF (20ml) for 3h. The mixture was then allowed to cool, and the THF evaporated. The aqueous residue was extracted with dichloromethane, and was then acidified. The resultant white solid was collected by filtration and dried (950mg).

Example 120

Biρhenyl-3,4'-dicarboxylic acid 4'- {[4-(l , 1 -dioxo- 1 lambda* 6* -thiomorpholin-4- ylmethyl)-phenyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide] This compound was prepared by an analogous method to Example 121

Example 121

6-Methyl-biphenyl-S^'-dicarboxylic acid 4'-cyclopropylamide 3-{[4-(l,l-dioxo- 1 lambda* 6* -thiomorpholin-4-yhnethyl)-phenyl] -amide}

4'-[4-(1 , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methy l- biphenyl-3-carboxylic acid (35mg) N-methylmorpholine (0.01ml), 1- hydroxybenzotriazole (lOrng) cyclopropylamine (5mg) and l-ethyl-3-(3-

(dimethylaminopropyl)carbodiimide hydrochloride (14mg) in dry DMF (0.5ml) was stirred at 2OC for 18h. The mixture was then added to water (6ml) and after a further 15mins stirring, the solid was collected by filtration, washed (water 2x1 ml and pet ether 2xlml) and dried giving the title compound as a colourless solid (27mg). ¹ H NMR (DMSO,δ) 0.57-0.60 (m, 2H) 0.66-0.71 (m, 2H) 2.31 (s, 3H) 2.88-3.00 (m, 5H) 3.13 (m ,4H) 3.66 (s, 2H) 7.33 (d, 2H) 7.41-7.43 (m, IH) 7.54-7.58 (d, 2H) 7.74- 7.81 (m, 4H) 8.04 (d, 2H) 8.46 (d, IH) 10.34 (s, IH). LC-MS ES+ = 518

Example 122

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'- {[4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-

4-ylmethyl)-ρhenyl] -amide} 3-[(3-methyl-butyl)-amide]

This compound was prepared by an analogous method to Example 121

Example 123

6-Methyl-biphenyl-3 ,4 ' -dicarboxylic acid 3 - { [4-( 1 , 1 -dioxo- 1 lambda*6 * -thiomorpholin-

4-ylmethyl)-phenyl]-amide} 4'-(3-fluoro-benzylamide)

The following compound was prepared in an analogous fashion to Example 121 except that 3-fluorobenzylamine was used. The title compound was isolated as a colourless solid (llmg)

¹ H NMR (DMSO,δ) 2.33 (s, 3H) 2.90 (m ,4H) 3.12 (m ,4H) 3.66 (s, 2H) 4.51 (d, 2H)

7.05-7.19 (m, 4H) 7.32-7.48 (m, 3H) 7.58 (d, 2H) 7.78-7.88 (m, 4H) 8.06 (d, 2H) 9.14

(t, IH) 10.35 (s, IH)

LC-MS ES+ = 586

Examples 124 to 128 were prepared by an analogous method to Example 121

Example 124

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4 ^l -{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl] -amide} 3-[(tetrahydro-furan-2-ylmethyl)-amide]

Example 125

6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 4 ¹ - { [4-( 1 , 1 -dioxo- 1 lambda* 6 * -thiomorpholin-

4-ylmethyl)-phenyl] -amide} 3-[(2-piperidin-l-yl-ethyl)-amide]

Example 126

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl]-amide} 3-[(2-methoxy-ethyl)-amide]

Example 127 6-Methyl-biphenyl-3,4'-dicarboxylic acid 4 ^l -{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl]-amide} 3-{[2-(3H-imidazol-4-yl)-ethyl]-amide}

Example 128

2'-Methyl-5'-(4-pyrrolidin-l-yl-piperidine-l-carbonyl)-bi plienyl-4-carboxylic acid [4- (l,l-dioxo-llambda*6*-tbJomorpholin-4-ylmethyl)-phenyl]-amid e

Example 129

6-Methyl-biphenyl-3,4'-dicarboxylic acid bis-{[4-(l,l-dioxo-llambda*6*- thiomoφholin-4-ylmethyl)-phenyl]-amide} The following compound was prepared in an analogous fashion to Example 123 except that 4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenylamin e was used. The title compound was isolated as a colourless solid (21mg).

¹ H NMR (DMSO,δ) 2.36 (s, 3H) 2.88 (m, 8H) 3.12 (m, 8H) 3.65 (m, 4H) 7.30-7.35 (m,

4H) 7.55 (d, IH) 7.61 (d, 2H) 7.75-7.82 (m, 4H) 7.92-7.95 (m, 2H) 8.08 (d, 2H) 10.28 (s, IH) 10.38 (s,lH). LC-MS ES+ = 701

Example 130

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-dimethylamino-phenyl)-amide] 4'-{[4- (1,1 -dioxo- 1 lambda* 6* -thiomorpholin-4-yhnethyl)-phenyl] -amide} This compound was prepared by an analogous method to Example 121

Example 131

4'-(Cyclopropanecarbonyl-ammo)-2'-methyl-biphenyl-3-carbo xylic acid [4-(l , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

This compound was prepared from intermediates generated from coupling A/Bl and synthesised in an analogous fashion to example 114.

Core 6

Route B

Intermediate 16

5 ' -tert-Butoxycarbonylamino-2 ' -methyl-biphenyl-4-carboxylic acid

5'-tert-Butoxycarbonylammo-2'-methyl-biphenyl-4-carboxyli c acid ethyl ester (6.3g) was stirred in ethanol (75ml) and IM sodium hydroxide (30ml) at 2OC for 18h. The mixture was then acidified and the ethanol evaporated. The pale beige solid thus formed was collected by filtration and dried (4.26g)

Intermediate 17

{4'-[4-(l,l-Dioxo-llambda*6*-thiomoφholin-4-ylmethyl)-ph enylcarbamoyl]-6- methyl-biphenyl-3-yl}-carbamic acid tert-butyl ester

A mixture of 5' -tert-butoxycarbonylamino-2' -methyl-biphenyl-4-carboxylic acid (500mg), 4-(l.l -dioxo- llambda*6*-thiomorpholin-4-yhnethyl)-phenylamine (367mg), triethylamine (0.64ml) and O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (869mg) in dry DMF (20ml) was stirred at 2OC for 18h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol;

1:1 removed high Rf impurities and further elution with ethyl acetate gave the title compound as a pale yellow solid (693mg).

Intermediate 18 S'-Amino^'-methyl-biphenyM-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

A solution of {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-carbamic acid tert-butyl ester (685mg) in ethanol (25ml) and 6M HCl (25ml) was stirred at 2OC for 18h. The mixture was then basifϊed and the ethanol evaporated. The colourless solid thus formed was collected by filtration and dried (434mg).

Example 132 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (Route A) A mixture of 5'-amino-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (Intermediate 13)(50mg) and triethylamine (llmg) in dry dichloromethane (ImI) was treated with cyclopropanecarbonyl chloride (12mg) with stirring for 2h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (44mg)

¹ H NMR (DMSO, δ) 0.77-.80 (m, 4H) 1.74-1.79 (m, IH) 2.20 (s, 3H) 2.88 (m, 4H) 3.11 (m, 4H) 3.65 (s, 2H) 7.24 (d, IH) 7.33 (d, 2H) 7.48-7.55 (m, 4H) 7.77 (d, 2H) 8.02 (d, 2H) 10.22 (s, IH) 10.32 (s, IH). LC-MS ES+ = 518.

Examples 133 to 135 were prepared from intermediates generated from coupling A/Bl and synthesised in an analogous fashion to example 114.

Examplel33

Furan-2-carboxylic acid {3 ^l -[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-2-methyl-biphenyl-4-yl}-amide

Example 134

4'-(2-Methoxy-benzoylamino)-2'-πiethyl-biphenyl-3-carbox ylic acid [4-(l , 1-dioxo- llambda*6*-thiomorpholm-4-ylmethyl)-phenyl]-amide

Examplel35 2'-Methyl-biphenyl-3,4'-dicarboxylic acid 3-{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl]-amide} 4'-[(4-moφholin-4-yl-phenyl)-amide]

Examples 136 to 148 were prepared by an analogous method to Example 121

Example 136

6-Methyl-biphenyl-3,4'-dicarboxylic acid 4'-{[3-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl]-amide} 3-[(4-morpholin-4-yl-phenyl)-amide]

Example 137 ό-Methyl-biphenyl-S^'-dicarboxylic acid 4^[4-(l,l-dioxo-llambda*6*-trnomorpholin- 4-ylmethyl)-phenyl] -amide} 3-{[3-(2-oxo-pyrrolidin-l-yl)-propyl]-amide}

Example 138

6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 4'- { [4-( 1 , 1 -dioxo- 1 lambda* 6* -thiomorpholin- 4-ylmethyl)-phenyl]-arnide} 3- {[4-(3-ethyl-2,6-dioxo-piperidin-3-yl)-phenyl]-amide}

Example 139

6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 4'- { [4-( 1 , 1 -dioxo- 1 lambda* 6* -thiomorpholin- 4-ylmethyl)-phenyl] -amide} 3-[(4-[l,2,4]triazol-l-yl-phenyl)-amide]

Example 140

6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 4'- { [4-( 1 , 1 -dioxo- 1 lambda* 6*-thiomorpholin-

4-ylmethyl)-phenyl] -amide} 3-{[4-(moipholine-4-carbonyl)-phenyl]-amide}

Example 141

6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 4'- { [4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-

4-ylmethyl)-phenyl]-amide} 3-[(4-methylcarbamoyl-phenyl)-aniide]

Example 142

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-[(4-dimethylcarbamoyl-phenyl)-amide] 4'- { [4-( 1 , 1 -dioxo- 1 lambda*6* -thiomorpholm-4-ylmethyl)-phenyl]-amide}

Example 143 θ-Methyl-biphenyl-S^'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*-tHomorpholin- 4-ylmethyl)-phenyl]-amide} 3-[(5-ethyl-[l,3,4]thiadiazol-2-yl)-amide]

Example 144

6-Methyl-biphenyl-3,4 ^l -dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylniethyl)-phenyl]-amide} 3- {[4-(piperidine- 1 -carbonyl)-phenyl]-amide}

Example 145

6-Metb.yl-biphenyl-3,4 ^l -dicarboxylic acid 4 ^l -{[4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl] -amide} 3-[(3-methyl-isothiazol-5-yl)-amide]

Example 146

6-Methyl-biphenyl-S^'-dicarboxylic acid 3-cyclohexylmethyl-amide 4'-{[4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide}

Example 147

6-Methyl-biphenyl-3,4'-dicarboxylic acid 3-cycloheptylamide 4'-{[4-(l,l-dioxo- llambda ^H! 6*-thiomorpholin-4-ylmethyl)-phenyl]-amide}

Example 148 ό-Methyl-biphenyl-S^'-dicarboxylic acid 3-cyclopentylamide 4'-{[4-(l,l-dioxo- 1 lambda* 6 *-thiomoφholin-4-ylmethyl)-phenyl] -amide}

Core 7

Intermediate 19 4-(l,l-Dioxo-llarnbda*6*-thiomoφholin-4-ylmethyl)-N-[4-(4,4 ,5,5-tetrarnethyl- [l,3,2]dioxaborolan-2-yl)-phenyl]-benzamide

A mixture of 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaboroloan-2-yl)-phenylamin e (60mg), 4-

(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-benzoic acid (73mg), EDAC

(53mg), HOBT (37mg) and N-methylmorpholine (0.06ml) in dry DMF (2ml) was stirred at 2OC for 18h. The mixture was then diluted with water (6ml) and the resulting colourless solid collected by filtration and dried (130mg).

Intermediate 20

Cyclopropanecarboxylic acid (3-bromo-4-methyl-phenyl)-amide

A mixture of 3-bromo-4-methylaniline (lOOmg), cyclopropanecarbonyl chloride (98mg) and N-methylmorpholine (0.12ml) in dry dichloromethane (2ml) was stirred at 2OC for 18h. The mixture was then partitioned between saturated sodium bicarbonate solution and dichloromethane. The dried extracts were evaporated giving a solid which was used without purification in the next synthetic step (120mg).

Example 149

N-[5 ' -(Cyclopropanecarbonyl-amino)-2'methyl-biphenyl-4-yl] -4-( 1 , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-benzamide

A mixture of 4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-N-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-benzamide (70mg), cyclopropanecarboxylic acid (3-bromo-4-methyl-phenyi)-amide (38mg) in DME (4ml) and water (1.5ml) containing cesium carbonate (50mg) and tetrakis(triphenylphosphine) palladium ' ' (lOmg) was heated to reflux for 18h. The cooled mixture was then partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 0-30% DCM:EtOH:NH3; 20:8:1 in DCM gave the title compound as a tan solid (6mg)

¹ H NMR (DMSO, δ) 0.60-0.72 (m, 4H) 1.64-1.74 (m, IH) 2.13 (s, 3H) 2.83 (m, 4H) 3.06 (m, 4H) 3.71 (s, 2H) 7.12 (d, IH) 7.24 (d, 2H) 7.38-7.56 (m, 4H) 7.78 (d, 2H) 7.88 (d, 2H) 10.09 (s, IH) 10.25 (s, IH). LC-MS ES+ = 518.

Examples 150 and 151 were prepared by analogous methods to Example 149

Example 150

N-[5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-yl ]-4-(l , 1 -dioxo- llambda*6*-thiomorpholm-4-ynnethyl)-benzamide

Example 151

4'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-ben zoylamino]-6-methyl- biphenyl-3-carboxylic acid (4-morpholin-4-yl-phenyl)-amide

Core 8

Intermediate 21

(3-Bromo-4-methyl-phenyl)-carbamic acid tert-butyl ester

A solution of 3-bromo-4-methyl aniline (3.4g) in methanol (100ml) was treated with triethylamine (5.1ml) and Boc anhydride (6.6g) and was stirred at 2OC for 18h. The solvent was then evaporated and the residue partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a brown oil (5.47g).

Intermediate 22

5'-tert-Butoxycarbonylamino-2'-methyl-biphenyl-4-carboxyl ic acid ethyl ester

A mixture of (3-bromo-4-methyl-phenyl)-carbamic acid tert-butyl ester (5.3g) 4- ethoxycarbonyl-phenyl boronic acid (3.54g), cesium carbonate (5.95g) and tetrakis(triphenylphosphine)palladium° (catalytic quantity), in 1:2 aqueous DME

(120ml) was heated to reflux for 18h. The mixture was then allowed to cool and was then partitioned between IM HCl and dichloromethane. The dried extracts were then evaporated giving the title compound as a yellow/orange foam (6.63g).

Intermediate 23

5'-Amino-2'-methyl-biphenyl-4-carboxylic acid ethyl ester

5'-tert-Butoxycarbonylamino-2'-methyl-biphenyl-4-carboxyl ic acid ethyl ester (6.6g) was stirred in ethanol (120ml) and 6M HCl (50ml) at 2OC for 2 days. The ethanol was evaporated and the residue basified and then extracted with dichloromethane. The dried extracts were evaporated giving the title compound as a pale brown crystalline solid (4g).

Intermediate 24 2'-Methyl-5'-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carb oxylic acid ethyl ester

A stirred solution of 5'-amino-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (520mg) in dry THF (25ml) containing triethylamine (0.57ml) was treated with 4-

morpholine-carbonyl chloride (0.26ml). After 18h. the mixture was partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1:1 gave the title compound as a yellow oil (416mg).

¹ H NMR (CDCl ₃ ,δ) 1.39 (t, 3H) 2.18 (s, 3H) 3.46 (t, 4H) 3.73 (t, 4H) 4.38 (q, 2H) 6.28 (s, IH) 7.17-7.31 (m, 3H) 7.36 (d, 2H) 8.04 (d, 2H).

Intermediate 25 2'-Methyl-5'-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carb oxylic acid

2'-Methyl-5'-[(morpholine-4-carbonyl)-amino]-biphenyl-4-c arboxylic acid ethyl ester (416mg) was stirred in ethanol (15ml) and IM sodium hydroxide (4ml) at 2OC for 18h. The mixture was then acidified and extracted with dichloromethane. The dried extracts were then evaporated giving the title compound as a beige solid (295mg).

¹ H NMR (DMSO,δ) 2.23 (s, 3H) 3.49 (m, 4H) 3.67 (m, 4H) 7.24 (d, IH) 7.45-7.84 (m, 4H) 8.07 (d, 2H) 8.62 (s, IH).

Example 152

Morpholine-4-carboxylic acid {4 ' - [4-( 1 , 1 -dioxo- 1 lambda* 6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

A mixture of 2'-methyl-5'-[(morpholine-4-carbonyl)-amino]-biphenyl-4-carb oxylic acid (40mg), 4-(l , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (28mg), triethylamine (0.033ml) and O-benzotriazol-l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (67mg) in dry DMF (3ml) was stirred at 2OC for 18h. The mixture was then partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 200:8:1 gave an off-white solid (32mg).

¹ H NMR (DMSO,δ) 2.20 (s, 3H) 2.88 (m, 4H) 3.13 (m, 4H) 3.43 (m, 4H) 3.60-3.66 (m+s, 6H) 7.18 (d, IH) 7.22 (d, 2H) 7.38-7.52 (m, 4H) 7.78 (d, 2H) 8.02 (d, 2H) 8.57 (s, IH) 10.33 (s, IH).

Examples 153 and 154 were prepared by analogous methods to Example 155.

Example 153

Furan-2-carboxylic acid {4 ^l -[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl] -6-methyl-biphenyl-3 -yl} -amide

Example 154

5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo-

1 lambda* 6 *-thiomorpholin-4-ylmethyl)-phenyl] -amide

Intermediate 26

2'-Methyl-5'-[(thiophene-2-carbonyl)-amino]-biphenyl-4-ca rboxylic acid ethyl ester A mixture of 5'-amino-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (280mg) and thiophene-2-carbonyl chloride (161mg) in dichloromethane (5ml) containing triethylamine (222mg) was stirred at 2OC for 18h. The mixture was then partitioned between water and dichloromethane. The dried extracts were then evaporated giving the title compound as a colourless solid (425mg)

Intermediate 27

2 ' -Methyl-5 ' - [(thiophene-2-carbonyl)-amino] -biphenyl-4-carboxylic acid 2'-Methyl-5'-[(thiophene-2-carbonyl)-amino]-biphenyl-4-carbo xylic acid ethyl ester (425mg) in THF (10ml) and sodium hydroxide (IM ₅ 20ml) was heated to reflux for 4h. The solvent was then evaporated and the residue acidified. The resulting precipitate was collected by filtration and dried (321mg).

Example 155

Thiophene-2-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thioniorpholin-4-ylinethyl)- phenylcarbamoyl]-6-methyl-biphenyl-3-yl} -amide (Route B) 2'-Methyl-5'-[(thiophene-2-carbonyl)-amino]-biphenyl-4-carbo xylic acid (45mg), 4- (l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-ph.enylamine (32mg), EDAC (25mg), HOBT (18mg) and N-methylmorpholine (27mg) in dry DMF (0.5ml) was stirred at 2OC for 18h. The mixture was then diluted with water (6ml) and the resulting colourless solid collected by filtration and dried (62mg). ¹ H NMR (DMSO, δ) 2.25 (s, 3H) 2.90 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H) 7.24 (m, IH) 7.26-7.35 (m, 3H) 7.54 (d, 2H) 7.68-7.88 (m, 6H) 8.05 (d, 2H) 10.27 (s, IH) 10.34 (s, IH). LC-MS ES+ = 560.

Example 156

N-{4'-[4-(l,l-Dioxo-llambda*6*-thiomorρholin-4-ylmethyl) -phenylcarbamoyl]-6- methyl-biphenyl-3 -yl} -nicotinamide

This compound was prepared by an analogous method to Example 155.

Example 157

1 -Methyl- lH-pyrrole-2-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-tMomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl} -amide (Route B) This material was prepared as described for Example 155 via the intermediates T- methyl-5 ' - [( 1 -methyl- 1 H-ρyrrole-2-carbonyl)-ammo]-biphenyl-4-carboxylic acid ethyl ester and 2'-methyl-5'-[(l-methyl-lH-pyrrole-2-carbonyl)-amino]-biphen yl-4- carboxylic acid. The title compound was isolated as a white solid (49mg)

¹ H NMR (DMSO, δ) 2.24 (s, 3H) 2.90 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H) 3.88 (s, 3H) 6.10 (dd, IH) 7.01-7.05 (m, 2H) 7.25-7.35 (m, 3H) 7.53 (d, 2H) 7.67 (m, 2H) 7.79 (d, 2H) 8.04 (d, 2H) 9.78 (s, IH) 10.34 (s, IH).

LC-MS ES+ = 557.

Example 158

5 ^l -(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- llambda*6*-thiomorph.olm-4-ylmethyl)-phenyl]-amide (Route A) This material was prepared as described for Example 132 except that cyclohexanecarbonyl chloride was used. The title compound was obtained as a colourless solid (35mg)

¹ H NMR (DMSO, δ) 1.15-1.4 (m, 6H) 1.65-1.85 (m, 4H) 2.20 (s, 3H) 2.28-2.32 (m, IH) 2.74 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H) 7.24 (d, IH) 7.33 (d, 2H) 7.48-7.55 (m, 4H) 7.78 (d, 2H) 8.03 (d, 2H) 9.84 (s, IH) 10.34 (s, IH). LC-MS ES+ = 560.

Example 159

5'-(4-Fluoro-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- 1 lambda*6*-tm ^' omorpholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to compound 160

Example 160

2'-Methyl-5'-(4-methyl-benzoylamino)-biphenyl-4-carboxyli c acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (Route B)

This material was prepared as described for Example 155 via the intermediates T- methyl-5'-(4-methyl-benzoylamino)-biphenyl-4-carboxylic acid ethyl ester and T- methyl-5'-(4-methyl-benzoylamino)-biphenyl-4-carboxylic acid. The title compound was isolated as a white solid (15mg)

¹ H NMR (DMSO, δ)2.25 (s, 3H) 2.40 (s, 3H) 2.88 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H)

7.30-7.36 (m, 5H) 7.54 (d, 2H) 7.74-7.91 (m, 6H) 8.04 (d, 2H) 10.21 (s, IH) 10.35 (s,

IH).

LC-MS ES+ = 568.

Examples 160 and 162 were prepared by an analogous method to compound 160

Example 161

5'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-benzoy lamino]-2 ^l -methyl- biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)- phenyl] -amide

Example 162

5'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-ben zoylamino]-2'-methyl- biphenyl-4-carboxylic acid 3-chloro-benzylamide

Example 163

5'-(3-Cyclohexyl-propionylamino)-2'-methyl-biphenyl-4-car boxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (Route B)

This material was prepared as described for Example 155 via the intermediates 5'-(3- cyclohexyl-propionylamino)-2'-methyl-biphenyl-4-carboxylic acid ethyl ester and 5'-

(3-cyclohexyl-proρionylamino)-2'-methyl-biphenyl-4-carbo xylic acid. The title compound was isolated as a white solid (55mg)

¹ H NMR (DMSO, δ) 0.80-0.91 (m, 2H) 1.05-1.26 (m, 6H) 1.46 (q, 2H) 1.61-1.69 (m,

4H) 2.16 (s, 3H) 2.20-2.27 (m, IH) 2.85 (m, 4H) 3.08 (m, 4H) 3.62 (s, 2H) 7.20 (d, IH) 7.23 (d, 2H) 7.44-7.51 (m, 4H) 7.74 (d, 2H) 7.98 (d, 2H) 9.88 (s, IH) 10.31 (s, IH).

LC-MS ES+ = 588.

Examples 164 to 167 were prepared by analogous methods to Example 163

Example 164

5'-(Cycloheptanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-yhnethyl)-phenyl]-amide

Example 165 5'-(2-Cyclohexyl-acetylamino)-2'-methyl-biphenyl-4-carboxyli c acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 166

5'-(2-Cyclopentyl-acetylamino)-2'-methyl-biphenyl-4-carbo xylic acid [4-(l , 1 -dioxo-

1 lambda* 6 *-thiomoφholin-4-ylmethyl)-phenyl] -amide

Example 167

5'-(Cyclopentanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid [4-(l,l-dioxo- Uambda*6*-thiom.orpholin-4-ylmethyl)-phenyl]-amide

Examples 168 and 169 were prepared in an analogous fashion to Example 60 using an intermediate analogous to the Intermediate 6.

Example 168

3 '-(Cyclopropanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 169

3'-(Cyclobutanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

Examples 170 and 171 were prepared by an analogous method to example 163

Example 170

Tetrahydro-pyran-4-carboxylic acid {4'-[4-( 1 , 1 -dioxo- 1 lambda*6*-thiomorpholin-4- ylmethyl)-phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

Example 171

2'-Methyl-5 '-(2-tetrahydro-pyran-4-yl-acetylamino)-biphenyl-4-carboxyli c acid [4-(l , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 172

3'-(Cyclopropanecarbonyl-amino)-2,4'-dimethyl-biphenyl-4- carboxylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-yhnethyl)-phenyl]-amide

Check

Examples 173 to 179 were prepared by analogous methods to example 163

Example 173

2'-Methyl-5'-[(l-trifluoromethyl-cyclopropanecarbonyl)-am ino]-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-a mide

Example 174

5'-[(I -Cyano-cyclopropanecarbonyl)-amino]-2'-methyl-biphenyl-4-car boxylic acid [4- (1,1 -dioxo- 1 lambda*6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

Example 175

2'-Methyl-5'-[(l -methyl-cyclopropanecarbonyl)-amino]-biphenyl-4-carboxylic acid [4-

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

Example 176

5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid [4-(l,l-dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide

Example 177 Thiazole-4-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-6-methyl-biphenyl-3-yl}-amide

Example 178

5'-(2-Cyclopropyl-acetylamino)-2'-methyl-biphenyl-4-carbo xylic acid [4-( 1 , 1 -dioxo- 1 lambda*6*-thiomorpriolin-4-ylmethyl)-phenyl]-amide

Example 179

Thiazole-5-carboxylic acid {4'-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-6-methyl-biphenyl-3-yl} -amide

Examples 180 and 181 were prepared by analogous methods to example 182

Example 180

5'- Acetylamino-2'-methyl-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 181

5'-(2-Ethyl-butyrylamino)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1-dioxo- Uambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 182 5'-Butyrylamino-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorρholin-4-ylmethyl)-phenyl]-amide (Route A) A mixture of 5'-amino-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (54mg),butyric acid (llmg), EDAC (24mg), HOBT (16mg) and N-methylmorpholine (24mg) in dry DMF (ImI) was stirred at 2OC for 18h. The mixture was then diluted with water (6ml) and the resulting colourless solid collected by filtration and dried (42mg).

¹ H NMR (DMSO, δ) 0.92 (t, 3H) 1.61 (q, 2H) 2.21 (s, 3H) 2.29 (t, 2H) 2.90 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H) 7.25 (d, IH) 7.33 (d, 2H) 7.48-7.56 (m, 4H) 7.78 (d, 2H) 8.03 (d, 2H) 9.89 (s, IH) 10.32 (s, IH) , LC-MS ES+ = 520

Examples 183 and 184 were prepared by analogous methods to Example 182

Example 183 5'-Isobutyrylamino-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 184

5'-(2,2-Dimethyl-propionylamino)-2'-methyl-biphenyl-4-car boxylic acid [4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-yhnethyl)-phenyl]-amide

Intermediate 28 (3-Bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester

A mixture of 3-bromo-4-trifluoromethoxy-phenylamine (250mg) and Boc anhydride (430mg) in methanol (4ml) containing triethylamine (0.26ml) was stirred at 2OC for 18h. The mixture was then partitioned between IM HCL and ethyl acetate. The dried extracts were then evaporated giving the title compound as an off-white solid (250mg).

Intermediate 29

5 '-tert-Butoxycarbonylamino-2'-trifluoromethoxy-biphenyl-4-ca ^boxylic acid ethyl ester

A mixture of (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (250mg), 4-ethoxycarbonyl-phenyl boronic acid (136mg), cesium carbonate (228mg) and tetrakis(triphenylpb.osphine)palladium° (catalytic quantity), in 1 :2 aqueous DME (15ml) was heated to reflux for 18h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a pale yellow solid (217mg)

Intermediate 30

5'-tert-Butoxycarbonylamino-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid

5 ' -tert-Butoxycarbonylamino-2 ' -trifluoromethoxy-biphenyl-4-carboxylic acid ethyl ester (200mg) in ethanol (7ml) and 2M sodium hydroxide (4ml) was stirred at 2OC for

18h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (128mg)

Intermediate 31

{4'-[4-(l , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6- trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester

A mixture of 5 ' -tert-butoxycarbonylamino-2 ' -trifluoromethoxy-biphenyl-4-carboxylic acid (100mg) 4-(l,l-dioxo-llambda ^:|! 6*-thiomorpholin-4-ynnethyl)-phenylamine (61mg), N-methylmorpholine (0.06ml), 1-hydroxybenzotriazole (34mg) and l-ethyl-3- (3-(dimethylaminopropyl)carbodiimide hydrochloride (48mg) in dry DMF (2ml) was stirred at 2OC for 18h. The mixture was then added to water and the resulting colourless precipitate collected by filtration and dried ( 140mg) .

Intermediate 32

5 '-Amino-2 '-trifluoromethoxy-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- 1 lambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

{4'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-ph enylcarbamoyl]-6- trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester (140mg) was stirred in 1:1 trifluoroacetic acid:dichloromethane (6ml) at 2OC for Ih. The mixture was then basified and extracted with ethyl acetate. The dried extracts were then evaporated giving a dark gum (105mg).

Example 185

5 '-(Cyclopropanecarbonyl-amino)-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid [4-

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

5' -Amino-2 '-trifluorornethoxy-biphenyl-4-carboxylic acid [4-(l,l -dioxo- llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide (50mg) in dichloromethane (ImI) containing N-methylmorpholine (0.03ml) was treated with cyclopropanecarbonyl chloride (9mg), the mixture being stirred for 18h. The solvent was then evaporated and the residue purified on silica gel. Elution with dichloromethane:ethanol:0.880 ammonia; 800:8:1 to 100:8:1 gave a colourless solid (46mg).

¹ H NMR (DMSO,δ) 0.84 (d, 4H) 1.80-1.85 (m, IH) 2.89 (m, 4H) 3.13 (m, 4H) 3.66 (s, 2H) 7.33 (d, 2H) 7.38 (m, IH) 7.47 (d, 2H) 7.60-7.81 (m, 4H) 8.06 (d, 2H) 10.37 (s, IH) 10.57 (s, IH). LC-MS ES+ = 588

Intermediate 33 2'-Methoxy-5'-nitro-biphenyl-4-carboxylic acid ethyl ester

A mixture of 2-bromo-l-methoxy-4-nitro-benzene (Ig), 4-ethoxycarbonyl-phenyl boronic acid (836mg), cesium carbonate (1.4g) and tetrakis(triphenylphosphine)palladium ⁰ (catalytic quantity), in 1 :2 aqueous DME (45ml) was heated to reflux for 18h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a yellow solid (997mg).

Intermediate 34

5'-Amino-2'methoxy-biphenyl-4-carboxylic acid ethyl ester hydrochloride

2'-Methoxy-5'-nitro-biphenyl-4-carboxylic acid ethyl ester (600mg) in ethanol 90ml) and 2M HCl (2.5ml) was hydrogenated at RTP for 3h. The mixture was then filtered through celite and the solvent evaporated. The dark solid residue was dissolved in 1:1 aqueous acetonitrile, filtered through celite again and evaporated giving the title compound as a red solid (595mg).

Intermediate 35 5'-(Cyclopropanecarbonyl-amino)-2'-methoxy-biphenyl-4-carbox ylic acid ethyl ester

A mixture of 5'-amino-2'methoxy-biphenyl-4-carboxylic acid ethyl ester hydrochloride (1 OOmg), N-methylmorpholine (0. ImI) and cyclopropanecarbonyl chloride (29mg) in dry THF (3ml) was stirred at 2OC for 18h. The mixture was then evaporated and the residue partitioned between sodium bicarbonate solution and ethyl acetate. The dried extracts were then evaporated giving the title compound as a dark oil (88mg)

Intermediate 36

5'-(Cyclopropanecarbonyl-amino)-2'-methoxy-biphenyl-4-car boxylic acid

A mixture of 5'-(cyclopropanecarbonyl-amino)-2'-methoxy-biρhenyl-4-carbo xylic acid ethyl ester (88mg) in ethanol (7ml) and 2M sodium hydroxide (4ml) was stirred at 2OC for 18h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (55mg)

Example 186

5 ' -(Cyclopropanecarbonyl-amino)-2 ' -methoxy-biphenyl-4-carboxylic acid [4-(l , 1 - dioxo- 1 lambda* 6*-thiomporpholin-4-ylmethyl)-phenyl] -amide

A mixture of 5' -(cyclopropanecarbonyl-amino)-2' -methoxy-biphenyl-4-carboxylic acid (50mg), 4-(l,l-dioxo-llambda ^:|! 6*-thiomoipholin-4-ylmethyl)-phenylamine (38mg), N-

methylmorpholine (0.03ml), 1-hydroxybenzotriazole (21mg) and l-ethyl-3-(3- (dimethylaminopropyl)carbodiimide hydrochloride (30mg) in dry DMF (ImI) was stirred at 2OC for 18h. The mixture was then added to water and the resulting colourless precipitate collected by filtration and dried (38mg). ¹ H NMR (DMSO,δ) 0.74-0.81 (m, 4H) 1.70-1.80 (m, IH) 2.88 (m, 4H) 3.13 (m, 4H) 3.36 (s, 3H) 3.66 (s, 2H) 7.10 (d, IH) 7.36 (d, 2H) 7.56-7.65 (m, 4H) 7.70 (d, 2H) 8.00 (d, 2H) 10.16 (s, IH) 10.29 (s, IH). LC-MS ES+ = 534

Example 187

5'-(Cyclohexanecarbonyl-amino)-2'-methoxy-biphenyl-4-carb oxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to Example 186

Example 188

5'-(3-Ethyl-ureido)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to Example 189

Example 189

5'-(3-Cyclohexyl-ureido)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (Route A) This material was prepared as described for Example 132 except that ¹ isocyanatocyclohexane was used. The title compound was obtained as a colourless solid (40mg)

¹ H NMR (DMSO, δ) 1.15-1.34 (m, 4H) 1.64-1.83 (m, 6H) 2.18 (s, 3H) 2.90 (m, 4H) 3.12 (m, 4H) 3.33 (m, IH) 3.66 (s, 2H) 6.04 (d, IH) 7.17 (d, IH) 7.24-7.35 (m, 4H) 7.48 (d, 2H) 7.78 (d, 2H) 7.97-8.04 (2H) 8.30 (s, IH) 10.30 (s, IH) LC-MS ES+ = 575.

Example 190

2 ^l -Methyl-5'-(2-oxo-propionylamino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-plienyl]-aniide This compound was prepared by an analogous method to Example 189

Example 191

5'-(Cyclohexanecarbonyl-amino)-2'-fluoro-biphenyl-4-carbo xylic acid [4-(l,l-dioxo- llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to Example 194 except that a fluorinated core was used.

Example 192

5'-(Cyclohexanecarbonyl-amino)-2'-trifluoromethoxy-biphen yl-4-carboxylic acid [4- (1,1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide This compound was prepared by an analogous method to Example 185.

Intermediate 37

2'-Chloro-5'-nitro-biphenyl-4-carboxylic acid ethyl ester

A mixture of 2-bromo-l-chloro-4-nitro-benzene (2.5g), 4-ethoxycarbonyl-phenyl boronic acid (2.05g), cesium carbonate (3.44g) and tetrakis(triphenylphosphine)palladium° (catalytic quantity), in 1 :2 aqueous DME (45ml) was heated to reflux for 18h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated to give the product as a white solid (3.0Ig). This material was used in the next stage without further purification.

Intermediate 38

5'-Amino-2'-chloro-biphenyl-4-carboxylic acid ethyl ester hydrochloride

2'-CMoro-5'-nitro-biphenyl-4-carboxylic acid ethyl ester (1.04g) in ethanol 30ml) and 2M HCl (5.0ml) was hydrogenated at RTP for 3h. The mixture was then filtered through celite and the solvent evaporated to give the title compound as a dark red solid (1.02g) which was used in the next stage without further purification.

Intermediate 39 5 ' -(Cyclohexanecarbonyl-amino)^ ' -chloro-biphenyl-4-carboxylic acid ethyl ester

A mixture of 5'-amino-2'-chloro-biphenyl-4-carboxylic acid ethyl ester hydrochloride (521mg), triethylamine (0.49ml) and cyclohexanecarbonyl chloride (0.26ml) in dry THF (25ml) was stirred at 2OC for 18h. The mixture was then evaporated and the residue partitioned between water and dichloromethane. The organic layer was washed with water, dried (MgSO ₄ ), filtered and evaporated under reduced pressure to give the product (714mg) as a yellow oil.

Intermediate 40 5'-(Cyclohexanecarbonyl-amino)-2'-chloro-biphenyl-4-carboxyl ic acid

A mixture of 5'-(cyclohexanecarbonyl-amino)-2'-chloro-biphenyl-4-carboxyl ic acid ethyl ester (200mg) in ethanol (15ml) and IM sodium hydroxide (7.5ml) was stirred at 2OC for 18h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (176mg).

Example 193

5 ' -(Cyclohexanecarbonyl-amino)^ ' -chloro-biphenyl-4-carboxylic acid [4-(l , 1 -dioxo- 1 lambda* 6* -thiomporρholin-4-yhnethyl)-phenyl] -amide

A mixture of 5' -(cyclohexanecarbonyl-amino)-2' -chloro-biphenyl-4-carboxylic acid (lOOmg), 4-(l,l-dioxo-llambda*6*-thiomorpholin-4-yhnethyl)-phenylamin e (67mg), triethylamine (0.098ml) and HBTU (159mg) in dry DMF (5ml) was stirred at 2OC for

18h. The mixture was then evaporated to dryness and purified via reversed-phase preparative HPLC (eluting with acetonitrile/water) to afford the title compound as an orange solid (35mg).

¹ H NMR (DMSO,δ) 0.90-1.40 (m, 6H), 1.42-1.73 (m, 4H), 2.09-2.24 (m, IH), 2.65- 2.78 (m, 4H), 2.90-3.00 (m, 4H), 3.49 (s, IH), 7.18 (d, 2H), 7.30-7.54 (m, 5H), 7.58- 7.69 (m, 2H), 7.88 (d, 2H), 9.89 (s, IH), 10.19 (s, IH).

Example 194 2'-Chloro-5 '-(cycloproρanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide This compound was prepared by an analogous method to Example 193.

Example 195 5'-(Cyclobutanecarbonyl-amino)-2 ^l -methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide This compound was prepared by an analogous method to Example 165

Example 196 3'-(Cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-(l,l-dioxo- 1 lambda* 6* -thiomorpholin-4-yhnethyl)-phenyl] -amide This compound was prepared by an analogous method to Example 60 using an intermediate analogous to Intermediate 6.

Core 12

Intermediate 41 5'-Hydroxymethyl-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

4'-[4-(1 , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-6-methy l- biphenyl-3-carboxylic acid methyl ester (565mg) in dry THF (6ml) was treated with a solution of lithium borohydride (2M in THF, 3.5ml). The mixture was stirred at 2OC for 18h. and was then treated with methanol (5ml). The mixture was then evaporated and the residue partitioned between water and ethyl acetate. The dried extracts were evaporated giving the title compound as a colourless crystalline solid (505mg).

Intermediate 42

5'-Formyl-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda ^ϊl! 6*- thiomorpholin-4-ylmethyl)-phenyl]-amide

5'-Hydroxymethyl-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide (500mg) in dichloromethane (30ml) was treated with manganese dioxide (3g) and the mixture stirred at 2OC for 18h. The suspension was then filtered through celite and the mother liquor evaporated giving the title compound as a colourless oil (480mg)

Example 197

5'-[(3-Bromo-phenylammo)-methyl]-2'-methyl-biphenyl-4-car boxylic acid [4-(l,l- dioxo- 1 lambda*6*-miomoφholin-4-ylmethyl)-phenyl]-amide This compound was prepared by an analogous method to Example 198.

Example 198

5 ' - [(3-Bromo-phenylamino)-methyl] -2 'methyl-biphenyl-4-carboxylic acid [4-( 1 , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

5'-Formyl-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide (40mg) and 3-bromo-aniline (18mg) were stirred together in dry dichloromethane (10ml) containing 3 A molecular sieves. The mixture was then heated to 4OC for 4h. Sodium (triacetoxy)borohydride (50mg) and glacial acetic acid (ImI) were then added and stirring continued at 2OC for 18h. The sieves were then removed by filtration and the mother liquor evaporated. The residue was purified on silica gel. . Elution with dichloromethane:ethanol:0.880 ammonia; 200:8: 1 gave the title compound as a pale yellow solid (32mg). ¹ H NMR (DMSO,δ) 2.25 (s, 3H) 2.88 (m, 4H) 3.13-3.18 (m, 4H) 3.66 (s, 2H) 4.29 (d, 2H) 6.57-6.67 (m, 3H) 6.76 (s, IH) 6.96 (t, IH) 7.25-7.35 (m, 5H) 7.49 (d, 2H) 7.78 (d, 2H) 8.02 (d, 2H) 10.33 (s, IH) LC-MS ES+ - 618

Examples 199 to 201 were prepared by analogous methods to Example 198

Example 199

5'-[(3-Chloro-benzylamino)-methyl]-2'-methyl-biphenyl-4-c arboxylic acid [4-(l , 1 - dioxo- 1 lambda*6*-tWomoφholin-4-ylmethyl)-phenyl]-amide

Example 200

5'-{[l-Hydroxymetb.yl-2-(3H-imidazol-4-yl)-etb.ylamino]-m ethyl}-2'-methyl-biphenyl- 4-carboxylic acid [4-(l,l-dioxo-llambda*6*-thiomoφholin-4-ylmetliyl)-phenyl]- amide

Example 201

5 ^l -[(lH-Indazol-6-ylamino)-methyl]-2'-methyl-biphenyl-4-carbox ylic acid [4-(l,l- dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Example 202

5'-(4-Chloro-benzenesulfonylammo)-2'-methyl-biphenyl-4-ca rboxylic acid [4-(l,l- dioxo-llambda*6*-thiomoφholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to Example 203.

Example 203

2'-Methyl-5 '-(6-morpholin-4-yl-pyridine-3 -sulfonylamino)-biphenyl-4-carboxylic acid

[4-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (RouteB)

This material was prepared as described for Example 155. The title compound was isolated as a colourless solid (3 lmg).

¹ H NMR (DMSO, δ) 2.16 (s, 3H) 2.90 (m, 4H) 3.13 (m, 4H) 3.58-3.66 (m, 10H) 6.91- 6.98 (m, 2H) 7.05-7.10 (m, IH) 7.22 (d, IH) 7.33 (d, 2H) 7.40 (d, 2H) 7.75-7.79 (m, 3H) 8.01 (d, 2H) 8.38 (dd, IH) 10.14 (s, IH) 10.33 (s, IH). LC-MS ES+ = 676

Example 204

5 ^l -(5-Chloro-thiophene-2-sulfonylamino)-2'-methyl-biphenyl-4-c arboxylic acid [4-( 1,1- dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

This compound was prepared by an analogous method to Example 203

Core 13

Intermediate 43 3-Bromo-4-methyl-benzonitrile

3-Bromo-4-methyl-benzoic acid (3g) in toluene (75ml) was treated with oxalyl chloride (1 OmI) and DMF (4 drops). The mixture was then stirred at 2OC for 3h. and then the solvent evaporated giving a yellow solid. This in turn was dissolved in THF (30ml) containing N-methyl-morpholine (1.5ml). Aqueous ammonia (0.880, 40ml) was then added and the mixture stirred for 18h. The THF was then evaporated and the resulting amide intermediate collected by filtration as a colourless solid (2.9g). This material was then suspended in thionyl chloride (35ml) and was heated to 85C for 6h. The excess reagent was then evaporated and the residue purified on silica gel. Elution with 5-50% ethyl acetate in hexane gave the title compound as a white solid (1.4g)

Intermediate 44 5 ' -Cyano-2 ' -methyl-biphenyl-4-carboxylic acid ethyl ester

A mixture of 3-bromo-4-methyl-benzonitrile (600mg), 4-(ethoxycarbonylphenyl) boronic acid (594mg), cesium carbonate (995mg) and tetrakis(triphenylphosphine) palladium (0), 5 mol% (180mg) was heated to reflux under nitrogen in DME (30 ml) and water (15ml) for 18 h. The reaction mixture was then cooled to room temperature and filtered. The resulting filtrate was then evaporated and purified on silica gel, gradient elution with 10-20% ethyl acetate in petrol gave the title compound as a pale yellow solid (867mg).

Intermediate 45 5'-Cyano-2'-methyl-biphenyl-4-carboxylic acid

A mixture of 5'-Cyano-2'-methyl-biphenyl-4-carboxylic acid ethyl ester (850mg) and sodium hydroxide (2M, 15ml) in ethanol (30ml) was stirred at 2OC for 18h. The ethanol was then evaporated and the residue acidified. The resulting solid was collected by filtration and was then purified on silica gel. Gradient elution with 0-30% 20:8:1 CH ₂ Cl ₂ / EtOH / NH ₃ in CH ₂ Cl ₂ gave the title compound as a white solid (665mg).

Intermediate 46

5'-Cyano-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide A mixture of 5'-cyano-2'-methyl-biphenyl-4-carboxylic acid (lOOmg), 4-(l,l-dioxo- „ llambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (lOlmg), EDAC (81mg), HOBT (57mg) and N-methylmorpholine (0.09ml) in dry DMF (2ml) was stirred at 2OC for 18h. Water (8ml) was then added and the resulting solid collected by filtration and dried (160mg).

Intermediate 47

5 ' -(N-Hydroxycarbamimidoyl)-2 ' -methyl-biphenyl-4-carboxylic acid [4-( 1 , 1 -dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

Hydroxylamine hydrochloride (47mg) and sodium methoxide (37mg) were stirred in methanol (5ml) for Ih. The mixture was filtered and the mother liquor treated with 5'- Cyano-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo-llambda*6*-thiomorpholin- 4-ylmethyl)-phenyl] -amide (155mg). The mixture was then heated to reflux for 18h. On cooling a colourless solid was formed which was collected by filtration and dried (138mg).

Example 205

5'-(5-Cyclopropyl-[ 1 ,2,4]oxadiazol-3-yl)-2'-methyl-biphenyl-4-carboxylic acid [4-(l , 1 - dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide 5'-(N-Hydroxycarbamimidoyl)-2'-methyl-biphenyl-4-carboxylic acid [4-(l,l-dioxo- llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (50mg) and cyclopropylcarbonyl chloride (0.02ml) was heated in a microwave at 150C for 40min.

The solvent was then evaporated and the residue purified on silica gel. Gradient elution with 0-30% 20:8:1 CH ₂ Cl ₂ / EtOH / NH ₃ in CH ₂ Cl ₂ gave the title compound as a white solid (24mg).

¹ H NMR (DMSO, δ) 1.18-1.32 (m, 4H) 2.34 (s, 3H) 2.34-2.43 (m, IH) 2.89 (m ,4H) 3.12 (m, 4H) 3.66 (s, 2H) 7.33 (d, 2H) 7.52-7.60 (m, 3H) 7.78-7.81 (m, 3H) 7.92 (dd, IH) 8.07 (d, 2H) 10.35 (s, IH). LC-MS ES+ = 543 Example 206

5'-(5-Cyclohexyl-[l,2,4]oxadiazol-3-yl)-2'-methyl-bipheny l-4-carboxylic acid [4-(l,l- dioxo- 1 lambda* 6* -thiomorpholin-4-ylmethyl)-phenyl] -amide This material was prepared as described for Example 209 except that cyclohexanecarbonyl chloride was used. The title compound was obtained as a white solid (15mg).

¹ H NMR (DMSO, δ) 1.20-1.45 (m, 6H) 1.60-1.80 (m, 4H) 2.05-2.12 (m, IH) 2.35 (s, 3H) 2.89 (m, 4H) 3.10 (m, 4H) 3.66 (s, 2H) 7.33 (d, 2H) 7.52-7.60 (m, 3H) 7.78-7.81 (m, 3H) 7.92 (dd, IH) 8.07 (d, 2H) 10.35 (s, IH). LC-MS ES+ = 585.

Example 207

5'-(5-Isopropyl-[l,2,4]oxadiazol-3-yl)-2'-methyl-biphenyl -4-carboxylic acid [4-(l,l- dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide This material was prepared as described for Example 205 except that isobutyryl chloride was used. The title compound was obtained as a white solid (14mg).

¹ H NMR (DMSO, δ) 1.39 (d, 6H) 2.35 (s, IH) 2.89 (m, 4H) 3.12 (m, 4H) 3.66 (s, 2H) 7.33 (d, 2H) 7.52-7.60 (m, 3H) 7.78-7.81 (m, 3H) 7.92 (dd, IH) 8.07 (d, 2H) 10.35 (s, IH).

Examples 208 to 233 can be prepared in an analogous fashion to Examples 1 or 87.

Example 208 6-Methyl-biphenyl-3 ,4'-dicarboxylic acid 3 -cyclopropylamide 4 ¹ - { [4-(2-diethylamino- ethylcarbamoyl)-phenyl]-amide}

Example 209 Furan-2-carboxylic acid [4'-(3-chloro-benzylcarbamoyl)-6-methyl-biphenyl-3-yl]-amide

Example 210 5'-tert-Butoxycarbonylamino-2'-methyl-biphenyl-4-carboxylic acid ethyl ester Example 211

5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid (lH-indazol-6-yl)- amide

Example 212

5'-(4-Bromo-benzoylamino)-2'-methyl-biphenyl-4-carboxylic acid (4-oxazol-5-yl- phenyl)-amide

Example 213 Thiophene-2-carboxylic acid [4'-(lH-indazol-6-ylcarbamoyl)-6-methyl-biphenyl-3-yl]- amide

Example 214 lH-Pyrazole-4-carboxylic acid [6-methyl-4'-(3-methyl-benzylcarbamoyl)-biphenyl-3- yl]-amide

Example 215 N-[6-Methyl-4'-(3-methyl-benzylcarbamoyl)-biphenyl-3-yl]-iso nicotinamide

Example 216

5'-(Cyclopropanecarbonyl-amino)-2 ^l -methyl-biphenyl-4-carboxylic acid 3-chloro- benzylamide

Example 217 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid 4-(4-methyl- piperazin- 1 -yl)-benzylamide

Example 218

5'-(Cyclopropanecarbonyl-amino)-2'-niethyl-biphenyl-4-car boxylic acid (4- [ 1 ,2,4]triazol- 1 -yl-phenyl)-amide

Example 219

5'-(Cyclohexanecarbonyl-amino)-2 ^l -methyl-biph.enyl-4-carboxylic acid (4- [ 1 ,2,4]triazol- 1 -yl-phenyl)-amide

Example 220 5'-(Cyclopropanecarbonyl-ammo)-2'-methyl-biphenyl-4-carboxyl ic acid [4-(3-ethyl-2,6- dioxo-piperidin-3-yl)-phenyl]-amide

Example 221

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carbo xylic acid [4-(3-ethyl-2,6- dioxo-piperidin-3-yl)-phenyl]-amide

Example 222

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biplienyl-4-carb oxylic acid (4- dimethylaminomethyl-phenyl)-amide

Example 223

5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid (4- dimethylaminomethyl-phenyl)-amide

Example 224

5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid (2-piperidin-l- ylmethyl-phenyl)-amide

Example 225 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (3- dimethylaminomethyl-phenyl)-amide

Example 226

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carbo xylic acid (4-morρholin-4- ylmethyl-phenyl)-amide

Example 227

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carbo xylic acid (4-ρyrrolidin-l- ylmethyl-phenyl)-amide

Example 228 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (4-piperidin-l- ylmethyl-phenyl)-amide

Example 229

5'-(Cycloproρanecarbonyl-amino)-2'-methyl-biphenyl-4-car boxylic acid (4-piperidin- 1 - ylmethyl-ρhenyl)-amide

Example 230

5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carb oxylic acid (4-pyrrolidin- 1 -ylmethyl-phenyl)-amide

Example 231

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carbo xylic acid (4-isoxazol-5- yl-phenyl)-amide

Example 232

5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carbo xylic acid (4- hydroxymethyl-phenyl)-amide

Example 233 Furan-2-carboxylic acid [4'-(lH-indol-6-ylcarbamoyl)-6-methyl-biphenyl-3-yl]-amide

(4' - {4-[4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethyl]-phenylcarbamoyl} -6- trifluoromethoxy-biphenyl-3-yl)-carbamic acid tert-butyl ester.

A mixture of 5 '-tert-butoxycarbonylamino-2 '-trifluoromethoxy-biphenyl-4-carboxylic acid (300mg), 4-[4-(propane-l-sulfonyl)-piperazin-l-ylmethyl]-phenylamine (224mg), EDAC (144mg), HOBT (102mg) and N-Methylmorpholine (166ul) in dry DMF (3ml) was stirred for lόhrs. This mixture was the diluted with water (12ml) and the tan solid produced collected and dried (459mg). LCMS- ES+ = 677

5'-Amino-2'-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4-(propane-l-sulfonyl)- piperazin-l-ylmethyl]-phenyl}-amide

(4' - {4-[4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethyl]-phenylcarbamoyl} -6- trifluoromethoxy-biphenyl-3-yl)-carbamic acid tert-butyl ester (459mg) in DCM (4ml) andTrifluoroacetic Acid (4ml) was stirred for 2hrs. The mixture was evaporated and the residue partitioned between EtOAc and saturated potassium carbonate. The dried extracts were then evaporated giving the title compound as a tan foam (374mg). LCMS- ES+ = 577

Example 234

(R)-Piρeridine-2-carboxylic acid (4'-{4-[4-(propane-l-sulfonyl)-piperazin-l-ylmethyl]- phenylcarbamoyl} -6-trifluoromethoxy-biphenyl-3 -yl)-amide.

A cold (-10) stirred solution of (R)-N-Boc-2-piperidinecarboxylic acid (39.7mg) in dry THF (4ml) and N,N-Diisopropylethylamine (60.4ul) was treated dropwise with isobutylchloroforniate (22.5ul) for 10 minutes. 5'-Amino-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid {4-[4-(propane-l-sulfonyl)-piperazin-l-ylmethyl]-phenyl}-ami de (50mg) in dry THF (ImI) was then added and the reaction mixture allowed to warm to room temperature, stirring under nitrogen for 16 hours.

The mixture was then evaporated and the residue purified on silica gel. Gradient elution with 0%-20% 20DCM:8EtOH:lNH3 in DCM over 35 mins gave a tan solid (45mg). LCMS- ES+ = 788

The above material (45mg) was dissolved in DCM (2ml) and was then treated with trifluoroacetic acid (2ml) and the mixture stirred for 2 hours. The mixture was evaporated and the residue partitioned between EtOAc and saturated potassium carbonate. The dried extracts were then evaporated and the residue purified on silica gel. Gradient elution with 0%-35% 20DCM:8EtOH:lNH3 in DCM over 30 mins. Gave the title compound as an off-white solid (35mg). LCMS- ES+ = 688

¹ H NMR (DMSO, δ) 0.97-1.03 (t,3H) 1.38-1.48 (m,4H) 1.66-1.78 (m,4H) 2.45 (m,4H) 2.52-2.63 (m,lH) 2.99-3.01 (m,2H) 3.18 (m,4H) 3.26 (m,2H) 3.51 (m,2H) 7.29-7.32 (d,2H) 7.45-7.49 (d,lH) 7.60-7.64 (d,2H) 7.76-7.87 (m,3H) 7.93-7.94 (m,lH) 8.05-8.08 (d,2H) 9.95 (s,lH) 10.35 (s,lH)

{4'-[4-(4-Methanesulfonyl-piperazin-l-ylmethyl)-phenylcar bamoyl]-6- trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester.

A mixture of 5'-tert-butoxycarbonylamino-2'-trifluoromethoxy-biphenyl-4-c arboxylic acid (50mg), 4-(4-methanesulfonyl-piperazin-l-ylmethyl)-phenylamine (35.2mg), HBTU (49.6mg) and N-Methylmorpholine (3OuI) in dry DMF (3ml) was stirred for 16hrs. The reaction mixture was then diluted with water (6ml) and the resulting solid collected by filtration and dried to giving a tan solid (80mg). LCMS- ES+ = 649

Example 235 5'-(3-Cyclohexyl-ureido)-2'-trifluoromethoxy-biphenyl-4-carb oxylic acid [4-(4- methanesulfonyl-piperazin- 1 -ylmethyl)-phenyl] -amide

{4'-[4-(4-Methanesulfonyl-piperazin-l-ylmethyl)-phenylcar bamoyl]-6- trifluoromethoxy-biphenyl-3-yl}-carbamic acid tert-butyl ester (80mg) in DCM (3ml)

and trifluoroacetic acid (3ml) was stirred for 2hrs. The reaction mixture was then evaporated giving a brown oil which was used without further purification in the next step.

LCMS- ES+ = 549

The crude amine (95mg), cylcohexylisocyanate (62mg) and N-Methylmorpholine (6OuI) in dry DMF (3ml) was stirred at room temperature for 48 hours. The reaction mixture was then diluted with water (6ml) and the solid formed collected by filtration. This material was then purified on silica gel. Gradient elution with 0%-30% 20DCM:8EtOH: 1NH3 in DCM over 35 mins gave the title compound as an off-white solid (26mg). LCMS- ES+ = 674

¹ H NMR (DMSO, δ) 1.16-1.34 (m,6H) 1.55-1.83 (m,5H) 2.47-2.51 (m,4H) 2.89 (s,3H) 3.13 (m,4H) 3.51 (m,2H) 6.21-6.24 (d,lH) 7.29-7.75 (m,4H) 7.59-7.66 (m,3H) 7.76- 7.79 (m,2H) 8.03-8.66 (d,2H) 8.66 (s,lH) 10.37 (s,lH)

Example 236

(S)-Pyrrolidine-2-carboxylic acid (4'-{4-[4-(propane-l-sulfonyl)-piperazin-l-yhnethyl]- phenylcarbamoyl}-6-trifluoromethoxy-biphenyl-3-yl)-amide

A cold (-10) stirred solution of (S)-N-Boc-2-pyrrolidinecarboxylic acid (30mg) in dry THF (4ml) and N,N-diisopropylethylamine (36μl) was treated dropwise with isobutylchloroformate (18μl) for 10 minutes. 5'-Amino-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid {4-[4-(propane-l-sulfonyl)-piperazin-l-yhnethyl]-phenyl}-ami de (40mg) in dry THF (ImI) was then added and the reaction mixture allowed to warm to room temperature, stirring under nitrogen for 16 hours.

The mixture was then evaporated and the residue partitioned between EtOAc and 0.5M HCl. The dried extracts were evaporated and the residue used without further purification. LCMS- ES+ = 774

The above material was dissolved in DCM (2ml) and treated with trifluoroacetic acid (2ml) for 2h. The mixture was evaporated and the residue partitioned between satd.

potassium carbonate solution and EtOAc. The dried extracts were evaporated giving the title compound as a tan solid (47mg)

¹ HNMR (DMSO, δ) 0.87-0.93 (t,3H) 1.56-1.63 (m,4H) 1.65-1.68 (m,lH) 2.36 (m,4H) 2.84-2.96 (m,4H) 3.09 (m,4H) 3.41 (m,2H) 3.69-3.73 (m,lH) 7.19-7.22 (d,2H) 7.37- 7.40 (d,lH) 7.52-7.55 (d, 2H) 7.66-7.74 (d,2H) 7.76-7.78 (d,lH) 7.83-7.84 (m,lH) 7.96- 7.99 (d,2H) 10.25-10.27 (m,2H) LCMS- ES+ = 674

Example 237 5'-(Cyclopropanecarbonyl-amino)-2'-trifluoromethoxy-biphenyl -4-carboxylic acid {4- [4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethylj-phenyl} -amide.

A stirred solution of 5'-amino-2'-trifluoromethoxy-biphenyl-4-carboxylic acid {4-[4- (propane-l-sulfonyl)-piperazin-l-ylmethyl]-phenyl}-amide (50mg) in dry THF (ImI) was treated with N,N-diisopropylethylamine (60μl) followed by cyclopropane carbonyl chloride (18mg). After 16h the mixture was evaporated and the residue purified by chromatography. Gradient elution with 0%-30% 20DCM:8EtOH:lNH3 in DCM over 35 mins gave the title compound as an off-white solid (18mg).

¹ H NMR (DMSO, δ) 0.65-0.70 (d,4H) 0.82-0.88 (t,3H) 1.51-1.67 (m,3H) 2.30 (m,4H)

2.84-2.90 (m,2H) 3.03 (m,4H) 3.35 (m,2H) 7.14-7.17 (d,2H) 7.30-7.34 (m,lH) 7.45-

7.48 (d, 2H) 7.55-7.63 (m,3H) 7.70-7.71 (m,lH) 7.89-7.92 (d,2H) 10.19 (s,lH) 10.36

(S ₅ IH)

LCMS- ES+ = 645.

Example 238

(S)-Piperidine-2-carboxylic acid (4 ' - {4- [4-(propane- 1 -sulfonyl)-piperazin- 1 -yhnethyl] - phenylcarbamoyl} -6-trifluoromethoxy-biphenyl-3 -yl)-amide.

A cold (-10) stirred solution of (S)-N-Boc-2-piperidinecarboxylic acid (39.7mg) in dry THF (4ml) and N,N-diisopropylethylamine (60.4μl) was treated dropwise with isobutylchloroformate (22.5μl) for 10 minutes. 5'-Amino-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid {4-[4-(propane- 1 -sulfonyl)-piperazin- 1 -yhnethyl] -phenyl} -amide

(50mg) in dry THF (ImI) was then added and the reaction mixture allowed to warm to room temperature, stirring under nitrogen for 16 hours.

The mixture was then evaporated and the residue purified on silica gel. Gradient elution with 0%-20% 20DCM:8EtOH: 1NH3 in DCM over 35 mins gave a tan solid (83mg). LCMS- ES+ = 788

The above material (78mg) was dissolved in DCM (2ml) and was then treated with trifluoroacetic acid (2ml) and the mixture stirred for 2 hours. The mixture was evaporated and the residue partitioned between EtOAc and saturated potassium carbonate. The dried extracts were then evaporated and the residue purified on silica gel. Gradient elution with 0%-35% 20DCM:8EtOH:lNH3 in DCM over 30 mins gave the title compound as a tan solid (69mg).

¹ H NMR (DMSO, δ) 1.01-1.07 (t,3H) 1.49-1.60 (m,4H) 1.70-1.96 (m,4H) 2.49 (m,4H) 2.73 (m,lH) 3.04-3.07 (m,2H) 3.13 (m,4H) 3.55 (m,2H) 7.33-7.37 (d,2H) 7.52-7.56 (d,lH) 7.65-7.68 (d, 2H) 7.80-7.95 (m,4H) 8.09-8.13 (d,2H) 10.15 (s,lH) 10.40 (s,lH) LCMS- ES+ = 688

Example 239

4-Methyl-piperazine-l-carboxylic acid {4'-[4-(4-methanesulfonyl-ρiperazin-l- ylmethyl)-ρhenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-yl }-amide

The product of the initial deprotection step described in Example 235 (50mg) in DCM (4ml) was treated with triphosgene (15mg) and N-methyl morpholine (20 μl). The mixture was then heated to 50C for 30mins. After cooling to room temperature N- methylpiperazine (11 μl) was added and stirring continued for 16h. The mixture was then evaporated and the residue purified on silica gel. Gradient elution with 0%-35% 20DCM:8EtOH:lNH3 in DCM over 30 mins gave the title compound as an off-white solid (4mg).

¹ H NMR (DMSO, δ) 2.00 (s,3H) 2.12 (m,4H) 2.30 (m,4H) 2.67 (s,3H) 2.91 (m,4H) 3.26 (m,4H) 3.30 (m,2H) 7.08-7.11 (d,2H) 7.11-7.21 (d,lH) 7.38-7.58 (m, 6H) 7.83- 7.86 (d,2H) 8.93 (s,lH) 10.15 (s,lH)

LCMS- ES+ = 676

{4 ' - [4-(4-Dimethylsulfamoyl-piper azin- 1 -ylmethyl)-phenylcarbamoyl] -6- trifluoromethoxy-biphenyl-3-yl}-carboxylic acid tert-butyl ester A mixture of 5'-tert-butoxycarbonylamino-2'-trifluoromethoxy-biphenyl-4-c arboxylic acid (300mg), 4-(4-amino-benzyl)-piperazine-l -sulfonic acid dimethylamide (226mg), EDAC (144mg) and HOBT (103mg) in dry DMF (3ml) containing N-methyl morpholine (0.166ml) was stirred for 16h. The mixture was then added to water (12ml) and the resulting solid collected by filtration and dried and used in the following step without purification (558mg) LCMS- ES+ = 678.

5 ' - Amino-2 ' -trifluoromethoxy-biphenyl-4-caeboxylic acid [4-(4-dimethylsulfarnoyl- piperazin- 1 -ylmethyl)-phenyl] -amide

{4'-[4-(4-Dimethylsulfamoyl-piperazin-l-ylmethyl)-ρhenyl carbaπioyl]-6- trifluoromethoxy-biphenyl-3-yl}-carboxylic acid tert-butyl ester (555mg) was dissolved in DCM (4ml) and was then treated with trifluoroacetic acid (4ml) and the mixture stirred for 2 hours. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 0%-40% 20DCM:8EtOH: 1NH3 in DCM over 40 mins gave an off-white solid (327mg). LCMS- ES+ = 578.

Example 240 5'-(2-Methylamino-acetylamino)-2'-trifluoromethoxy-biphenyl- 4-carboxylic acid [4-(4- dimethylsulfamoyl-piperazin- 1 -ylmethyl)-phenyl] -amide

A mixture of (tert-butoxycarbonyl-methyl-amino)-acetic acid (33mg), 5'-amino-2'- trifluoromethoxy-biphenyl-4-carboxylic acid [4-(4-dimethylsulfamoyl-piperazin- 1 - ylmethyl)-ρhenyl]-amide (50mg) and EEDQ (43mg) in dry THF (ImI) was stirred at room temp for 48h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 0%-30% 20DCM:8EtOH:lNH3 in DCM over

30 mins gave an off-white solid (63mg).

This material was dissolved in DCM (2ml) and was then treated with trifluoroacetic acid (2ml) and the mixture stirred for 2 hours. The mixture was evaporated and the residue partitioned between satd. potassium carbonate solution and EtOAc. The dried extracts were evaporated giving the title compound as a tan solid (49mg).

¹ H NMR (DMSO, δ) 2.18 (s,3H) 2.24-2.34 (m,4H) 2.41-2.42 (s,6H) 3.06-3.08 (m,4H)

3.20 (m,2H) 3.40 (m,2H) 3.50 (t,lH) 7.19-7.22 (d,2H) 7.39-7.51 (d,lH) 7.54-7.66 (d,

2H) 7.69-7.81 (m,4H) 7.95-7.99 (d,2H) 10.26 (s,lH) LCMS- ES+ = 649.

(S)-2-(4'-Ethoxycarbonyl-6-trifluoromethoxy-biphenyl-3-yl carbamoyl)-azetidine-l- carboxylic acid tert-butyl ester

A mixture of 5'-amino-2'-trifluoromethoxy-biρhenyl-4-carboxylic acid (150mg), (S)- azetidine-l,2-dicarboxylic acid 1 -tert-butyl ester (93mg), HBTU (262mg) and N-methyl morpholine (0.14ml) in dry DMF (3ml) was stirred at room temp for 18h. The mixture was then partitioned between water and DCM. The dried organic layer was evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1 : 1 gave a pale orange oil (188mg).

(S)-2-(4'-Carboxy-6-trifluoromethoxy-biphenyl-3-ylcarbamo yl)-azetidine-l-carboxylic acid tert-butyl ester

A mixture of (S)-2-(4'-Ethoxycarbonyl-6-trifluoromethoxy-biphenyl-3-ylcar bamoyl)- azetidine-1-carboxylic acid tert-butyl ester (188mg) in ethanol (15ml) and sodium hydroxide (2M, 5ml) was stirred at room temp for 18h. The mixture was acidified and

the ethanol evaporated. The residue was extracted with DCM and the dried extracts evaporated giving the crude acid as a pale orange gum (154mg).

(S)-2-{4'-[4-(4-Methanesulfonyl-piperazin-l-yhnethyl)-phe nylcarbamoyl]-6- trifluoromethoxy-biphenyl-3-ylcarbamoyl} -azetidine- 1-carboxylic acid tert-butyl ester

A mixture of (S)-2-(4'-Carboxy-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl) -azetidine- 1-carboxylic acid tert-butyl ester (50mg), 4-(4-methanesulfonyl-ρiperazin-l-ylmethyl)- phenylamine (29mg), HBTU (61mg) and N-methyl morpholine (0.033ml) in dry DMF (3ml) was stirred at room temp for 18h. Water (10ml) was then added and the cream solid collected by filtration and used without purification or characterisation.

Example 241

(S)-2-{4'-[4-(4-Methanesulfonyl-piperazin-l-ylmethyl)-phe nylcarbamoyl]-6- trifluoromethoxy-biphenyl-S-ylcarbamoylJ-azetidme-l-carboxyl ic acid

A mixture of (S)-2-{4'-[4-(4-Methanesulfonyl-piperazin-l-ylmethyl)- phenylcarbamoyl]-6-trifluoromethoxy-biphenyl-3-ylcarbamoyl}- azetidine-l-carboxylic acid tert-butyl ester in dioxan (5ml) was treated with cone, hydrochloric acid (3ml) and the mixture stirred at room temp for 18h. The mixture was then carefully basified with solid potassium carbonate and the mixture then was extracted with DCM. The residue was then purified on silica gel. Elution initially with DCM:EtOH:ammonia; 200:8:1 gave a colourless foam (impure). Further purification eluting with DCM:MeOH:AcOH:water; 90:10:1:1 gave a colourless gum (nmr suggests probably acetate salt of desired product). This material was then dissolved in

DCM:EtOH:ammonia;25:8 : 1 and then passed down an SCX cartridge giving the title compound as a colourless solid (14mg). This material is still not entirely pure as shown by ¹ H NMR. No further purification of this material was carried out.

4-[2-(l , 1 -dioxo- 1 lambda*6*-thiomorpholin-4-yl)-ethyl]-phenylamine A mixture of 4-(2-amino-ethyl)-phenylamine (Ig) and ethenesulfonyl-ethene (0.74ml) in NMP (2.5ml) containing triethylamine (1.02ml) was heated to 11OC for 30mins. The mixture was then allowed to cool and the solid produced was collected by filtration, washed with ether, and dried, giving the title compound as a pale yellow solid (1.59g).

Example 242 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid {4-[2-(l,l- dioxo- 1 lambda* 6* -thiomorpholin-4-yl)-ethyl] -phenyl} -amide

A mixture of 5'-(Cyclohexanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid (40mg), 4-[2-(l,l-dioxo-llambda*6*-thiomorpholin-4-yl)-ethyl]-phenyl amine (30mg), EDAC (23mg), HOBT (16mg) and N-Methyhnorpholine (26μl) in dry DMF (ImI) was stirred for lόhrs. This mixture was then diluted with water (8ml) and the tan solid produced collected and dried (45mg).

¹ H NMR (DMSO ₅ δ) 1.18-1.43 (m,6H) 1.68-1.82 (m,6H) 2.20 (s,3H) 2.32 (m,lH) 2.73 (m,2H) 2.98-3.09 (m,4H) 3.09-3.11 (m,4H) 3.59-3.64 (m,2H) 7.22-7.26 (d,3H) 7.47- 7.58 (m,4H) 7.70-7.73 (d,2H) 8.01-8.04 (d,2H) 9.82 (s,lH) 10.25 (s,lH). LCMS- ES+ = 574.

Example 243 5'-Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxyl ic acid [4-(4-propane- 1 -sulfonyl-piperazin- 1 -ylmethyl)-phenyl] -amide

A mixture of 5'-(Cyclopropanecarbonyl-amino)-2'-methyl-biphenyl-4-carboxy lic acid (50mg), 4-(4-propane-l -sulfonyl-piperazin- l-ylmethyl)-phenylamine (50mg), HBTU (64mg) and N-methyl morpholine (0.04ml) in dry DMF (3ml) was stirred at room temp for 18h. Water (6ml) was added and the resulting solid collected by filtration. This material was then purified on silica gel. Gradient elution with 0%-30% 20DCM:8EtOH:lNH3 in DCM over 30 mins gave the title compound as an yellow solid (43mg).

¹ H NMR (DMSO, δ) 0.63-0.66 (d,4H) 0.81-0.87 (t,3H) 1.50-1.65 (m,4H) 2.06 (s,3H) 2.29-2.63 (m,4H) 3.02 (m,4H) 3.35 (m,2H) 7.12-7.17 (d,2H) 7.33-7.38 (m,3H) 7.41 (s, IH) 7.61-7.64 (d,2H) 7.86-7.89 (d,2H) 10.08 (s,lH) 10.18 (s,lH) LCMS- ES+ = 575.

3-Bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzenesulf onamide To stirred, cold (OC) chlorosulfonic acid was added l-bromo-2-methoxy-benzene (Ig) dropwise. The mixture was then allowed to warm to room temp and was stirred for Ih.

The mixture was then cooled again (OC) and ice was added carefully until no further effervescence was seen. This was further diluted with water and extracted with DCM.

The dried extracts were evaporated giving a pale yellow gum. This material was then dissolved in DCM (15ml) and was treated with 4-morpholin-4-yl-phenylamine (1.43g) and was stirred for 18h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with DCM then DCM:EtOH:NH3; 800:8:1 and finally 400:8:1 gave an off-white solid (1.4g).

¹ H NMR (DMSO, δ) 3.06 (t, 4H), 3.75 (t, 4H), 3.95 (s, 3H), 6.88 (d, 2H), 6.98 (d, 2H), 7.28 (d, IH), 7.69 (dd, IH), 7.88 (d, IH), 9.84 (br. s, IH).

2 ' -Methoxy-5 ' -(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid. A mixture of 3-bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzenesulfona mide (460mg) and 4-carboxy-phenyl boronic acid (196mg) in saturated sodium bicarbonate solution (4ml) and DME (8ml) was heated to reflux in the presence of tetrakis(triphenylphosphine)palladium° for 16h. The mixture was allowed to cool and was evaporated. The residue was then suspended in water and 2M HCl added until the effervescence ceased. The resulting light grey solid was collected and dried (490mg) ¹ H NMR (DMSO ₅ δ) 2.93 (t, 4H), 3.61 (t, 4H), 3.75 (s, 3H) ₅ 6.75 (d, 2H) ₅ 6.87 (d, 2H), 7.17 (d, IH), 7.40 (d, 2H) ₅ 7.52 (d, 2H) ₅ 7.60 (dd, IH), 7.90 (d, IH) ₅ 9.62 (br. s, IH).

Example 244

2 ' -Methoxy-5 ' -(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-( 1 , 1 - dioxo-llambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide

2'-Methoxy-5'-(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4- carboxylic acid (80mg) ₅ 4-(l ₅ l-dioxo-llambda*6*-thiomoφholin-4-ylmethyl)-phenylamine (41mg), EDAC (65mg) and HOBT (46mg) were stirred in dry DMF (ImI) containing N- methylmorpholine (56μl) for 18h. Water (10ml) was then added and the solid collected by filtration. This material was purified by chromatography. Elution with DCM:EtOH:NH3; 400:8:1 gave the title compound as an off-white solid (31mg). ¹ H NMR (DMSO ₅ δ) 2.89 (m, 4H) ₅ 3.03 (t, 4H) ₅ 3.12 (m, 4H) ₅ 3.66 (s, 2H), 3.71 (t, 4H) ₅ 3.85 (S ₅ 3H) ₅ 6.85 (d, 2H) ₅ 6.98 (d, 2H) ₅ 7.31 (m, 3H) ₅ 7.54 (m ₅ 3H) ₅ 7.71 (dd ₅ IH) ₅ 7.78 (d, 2H) ₅ 8.00 (d, 2H), 9.72 (br. s, IH) ₅ 10.33 (br. s, IH) LCMS- ES+ = 692.

Example 245

2 ' -Methoxy-5 ' -(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4- methanesulfonyl-piperazin-l-yhnethyl)-phenyl]-amide

This compound was prepared as described for Example 244 except that 4-(4- methanesulfonyl-piperazin-l-ylmethyl)-phenylamine (46mg) was used. The title compound was an off-white solid (35mg)

¹ HNMR (DMSO ₅ δ) 2.47 (m, 4H) ₅ 2.89 (s, 3H) ₅ 3.03 (t, 4H), 3.13 (m, 4H), 3.51 (s, 2H) ₅ 3.71 (t, 4H), 3.85 (s, 3H) ₅ 6.86 (d, 2H) ₅ 6.98 (d, 2H) ₅ 7.30 (m, 3H) ₅ 7.55 (m, 3H), 7.69 (dd, IH) ₅ 7.77 (d, 2H) ₅ 8.01 (d ₅ 2H) ₅ 9.82 (br. s, IH) ₅ 10.32 (br. S ₅ IH)

LCMS- ES+ = 721

Example 246

2 ' -Methoxy-5 ' -(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4- propane-2-sulfonyl-piperazin- 1 -ylmethyl)-phenyl]-amide

This compound was prepared as described for Example 244 except that 4-(4-propane-2- sulfonyl-piperazin-l-ylmethyl)-phenylamine (51mg) was used. The title compound was an off-white solid (34mg)

¹ H NMR (DMSO, δ) 1.23 (d, 6H) ₅ 2.41 (m, 4H) ₅ 3.03 (t, 4H) ₅ 3.26 (m, 4H) ₅ 3.42 (m, IH), 3.50 (s, 2H), 3.73 (t, 4H) ₅ 3.85 (s, 3H) ₅ 6.85 (d, 2H) ₅ 6.98 (d, 2H) ₅ 7.30 (m, 3H) ₅ 7.55 (m ₅ 3H) ₅ 7.71 (dd, IH) ₅ 7.77 (d, 2H) ₅ 8.00 (d, 2H) ₅ 9.72 (br. s ₅ IH) ₅ 10.32 (br. s, IH) LCMS- ES+ = 749

Example 247

2'-Methoxy-5'-(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl -4-carboxylic acid [4-(4- dimethylsulfamoyl-piperazin- 1 -ylmethyl)-phenyl] -amide

This compound was prepared as described for Example 244 except that 4-(4-amino- benzyl)-piperazine-l -sulfonic acid dimethylamide (51mg) was used. The title compound was an off-white solid (49mg)

¹ H NMR (DMSO, δ) 2.43 (m, 4H) ₅ 2.77 (s, 6H), 3.03 (t, 4H), 3.17 (m, 4H), 3.50 (s, 2H) ₅

3.71 (t ₅ 4H) ₅ 3.85 (s, 3H) ₅ 6.85 (d, 2H) ₅ 6.98 (d, 2H) ₅ 7.29 (m, 3H) ₅ 7.55 (m, 3H) ₅ 7.71

(dd, IH), 7.77 (d, 2H) ₅ 8.01 (d, 2H) ₅ 9.72 (br. S ₅ IH) ₅ 10.32 (br. s, IH).

LCMS- ES+ = 750.

Example 248

2'-Methoxy-5 '-(4-morpholin-4-yl-phenylsulfamoyl)-biphenyl-4-carboxylic acid [4-(4- propane-l-sulfonyl-piperazin-l-ylmethyl)-phenyl]-amide

This compound was prepared as described for Example 244 except that 4-(4-propane-l- sulfonyl-piperazin-l-ylmethyl)-phenylamine (36mg) was used. The title compound was a pale orange solid (20mg)

¹ H NMR (DMSO ₅ δ) 1.00 (t, 3H) ₅ 1.71 (m, 2H) ₅ 2.45 (m, 4H) ₅ 3.02 (m, 6H), 3.18 (m,

4H) ₅ 3.51 (s, 2H) ₅ 3.70 (m, 4H), 3.86 (s, 3H), 6.85 (d, 2H), 6.98 (d, 2H), 7.29 (m ₅ 3H) ₅

7.55 (m, 3H), 7.71 (dd, IH) ₅ 7.77 (d, 2H), 8.01 (d, 2H), 9.71 (br. s, IH), 10.30 (br. s,

IH).

LCMS- ES+ = 749

Example 249

2 '-Chloro-5 '-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxylic acid [4-(4-methyl- piperazin- 1 -ylmethyl)-phenyl] -amide

A mixture of 2'-Chloro-5'-(cyclohexanecarbonyl-amino)-biphenyl-4-carboxyl ic acid

(103mg), 4-(4-methyl-piρerazin-l-ylmethyl)-phenylamine (59mg) and HBTU (148mg) in dry DMF (1 OmI) containing triethylamine (362μl) was stirred at room temp for 18h.

Most of the DMF was evaporated and the residue diluted with water. The resulting solid was collected by filtration. This material was then purified by reverse phase Prep HPLC giving the title compound as a yellow solid (51mg)

¹ H NMR (DMSO, δ) 1.10-1.81 (1OH, m), 2.17 (3H, s), 2.24-2.28 (9H, m), 3.43 (2H, s),

7.29 (2H, d), 7.41-7.61 (2H, m), 7.67 (IH, dd), 7.71-7.81 (2H, m), 8.05 (2H ₅ d,), 8.83

(2H, m), 10.13 (IH, s), 10.36 (IH, s).

LCMS- ES+ = 544,546.

(R)-2-(6-Chloro-4'-ethoxycarbonyl-biρhenyl-3-ylcarbainoy l)-pyrrolidine-l-carboxylic acid tert-butyl ester

A mixture of 5'-amino-2'-chloro-biphenyl-4-carboxylic acid ethyl ester (800mg), (R)-

N-Boc-2-pyrrolidinecarboxylic acid (608mg) and HBTU (1.46g) in dry DMF (30ml) containing N-methylmorpholine (1.26ml) was stirred at room temp for 18h. Silica gel

(5g) was then added and the mixture evaporated. The residue was purified by chromatography. Elution with 12:1 petrol:ethyl acetate gave a viscous brown gum

(987mg)

¹ H NMR (DMSO, δ) 1.14-1.43 (12H, m), 1.66-1.99 (2H, m), 2.10-2.30 (IH, m), 3.32- 3.57 (3H, m), 4.14-4.45 (3H, m), 739-7.41 (2H, m), 7.72-7.82 (2H, d), 8.02-8.11 (3H, m), 10.15 (IH, s).

(R)-2-(4'-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-pyrrol idine-l-carboxylic acid tert-butyl ester (R)-2-(6-Chloro-4'-ethoxycarbonyl-biphenyl-3-ylcarbamoyl)-py rrolidine-l-carboxylic acid tert-butyl ester (985mg) in 2M NaOH (5ml) and ethanol (7ml) was stirred at room temp for 18h. The ethanol was then evaporated and the residue acidified with HCl. The resulting yellow solid was collected by filtration and dried (672mg). Material used without purification in next step.

(R)-2-{6-Chloro-4'-[4-(4-methanesulfonyl-piperazin-l-yhne thyl)-phenylcarbamoyl]- biphenyl-S-ylcarbamoylJ-pyrrolidine-l-carboxylic acid tert-butyl ester.

A mixture of (R)-2-(4'-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-pyrrolidi ne-l- carboxylic acid tert-butyl ester (lOOmg), 4-(4-methanesulfonyl-piperazin-l-ylmethyl)- phenylamine (86mg) and HBTU (121mg) in dry DMF (4ml) containing N- methylmorpholine (69μl) was stirred at room temp for 18h.

The mixture was then evaporated and the residue purified by chromatography. Elution

DCM:EtOH:NH3; 300:8:1 gave a light brown oil (118mg).

Example 250

(R)-Pyrrolidine-2-carboxylic acid {6-chloro-4'-[4-(4-methanesulfonyl-piperazin-l- ylmethyl)-ρhenylcarbamoyl]-biphenyl-3-yl}-amide The above Boc-protected amine (112mg) was stirred in THF (3ml) and TFA (5ml) for 18h. The mixture was then evaporated and the residue purified by chromatography. Elution DCM:EtOH:NH3; 150:8:1 gave an off-white solid (12mg). ¹ H NMR (DMSO ₅ δ) 1.58-1.92 (3H ₅ m) ₅ 1.96-2.16 (IH ₅ m) ₅ 2.47-2.52 (4H, m), 2.88 (3H, s), 3.05-3.19 (4H ₅ m), 3.31-3.49 (2H ₅ m), 3.51 (2H, s) ₅ 3.73 (IH ₅ dd), 7.32 (2H ₅ d) ₅ 7.42-7.49 (2H ₅ m) ₅ 7.72-7.83 (4H ₅ m), 8.01-8.12 (3H ₅ m) ₅ 10.10 (IH ₅ s), 10.31 (IH ₅ s).

(R)-2-(6-Chloro-4'-ethoxycarbonyl-biphenyl-3-ylcarbamoyl) -piperidine-l-carboxylic acid tert-butyl ester

A mixture of 5'-amino-2'-chloro-biρhenyl-4-carboxylic acid ethyl ester (750mg), (R)- N-Boc-2-piperidinecarboxylic acid (664mg) and HBTU (1.37g) in dry DMF (40ml) containing N-methylmorpholine (1.2ml) was stirred at room temp for 18h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 5:1 petrol: ethyl acetate gave a yellow oil (310mg)

(R)-2-(4'-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-piperi dine-l-carboxylic acid tert- butyl ester

(R)-2-(6-Chloro-4 '-ethoxycarbonyl-biphenyl-3 -ylcarbamoyl)-piperidine- 1 -carboxylic acid tert-butyl ester (306mg) in 2M NaOH (6ml) and ethanol (10ml) was stirred at room temp for 18h. The ethanol was then evaporated and the residue acidified with HCl. The resulting off-white solid was collected by filtration and dried (143mg). Material used without purification in next step.

(R)-2- {6-Chloro-4' -[4-(4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethyl)- ρhenylcarbamoyl]-biphenyl-3-ylcarbamoyl}-piperidine-l-carbo xylic acid tert-butyl ester.

A mixture of (R)-2-(4'-Carboxy-6-chloro-biphenyl-3-ylcarbamoyl)-piperidin e- 1 - carboxylic acid tert-butyl ester (73 mg), 4-(4-(propane-l-sulfonyl)-piperazin-l-

ylmethyl)-phenylamine (118mg) and HBTU (91mg) in dry DMF (4ml) containing N- methylmorpholine (52μl) was stirred at room temp for 18h.

The mixture was then evaporated and the residue used crude in the next step (130mg).

Example 251

(R)-Piρeridine-2-carboxylic acid {6-chloro-4'-[4-(4-(propane-l-sulfonyl)-piperazin-l- ylmethyl)-phenylcarbarnoyl] -biphenyl-3 -yl} -amide

The above Boc-protected amine (130mg) was stirred in THF (3ml) and TFA (5ml) for 18h. The mixture was then evaporated and the residue purified by chromatography. Elution DCM:EtOH:NH3; 250:8:1 gave a brown solid (15mg).

¹ HNMR (DMSO, δ) 1.03 (3H, t), 1.22-1.88 (1OH, m), 2.35-2.48 (4H, m), 2.91-3.09 (3H, m), 3.11-3.25 (4H, m), 3.50 (2H, s), 7.30 (2H, d), 7.47-7.63 (3H, m), 7.69-7.82 (3H, m), 7.82 (IH, d), 8.06 (2H, d), 9.89 (IH, brs), 10.34 (IH, s).

5'-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2'- chloro-biphenyl-4- carboxylic acid ethyl ester.

A mixture of 5'-amino-2'-chloro-biphenyl-4-carboxylic acid ethyl ester (750mg), (tert- butoxycarbonyl-methyl-amino)-acetic acid (589mg) and HBTU (1.37g) in dry DMF (40ml) containing N-methylmorpholine (0.79ml) was stirred at room temp for 18h. The mixture was then evaporated and the residue was purified by chromatography. Elution with 4:1 petrol:ethyl acetate gave a pale brown oil (494mg)

5'-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2'-chl oro-biphenyl-4- carboxylic acid 5'-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2'-chl oro-biphenyl-4- carboxylic acid ethyl ester (494mg) in 2M NaOH (10ml) and ethanol (15ml) was stirred at room temp for 18h. The ethanol was then evaporated and the residue acidified with HCl. The colourless solid formed was collected by filtration and dried (420mg). ¹ HNMR (DMSO, δ) 1.25-1.47 (9H, m), 2.87 (3H, m), 3.98 (2H, m), 7.45-7.81 (5H, m), 8.05 (2H, d), 10.26 (IH, m).

({6-Chloro-4'[4-(4-methanesulfonyl-piperazin-l-ylmethyl)- phenylcarbamoyl]- biphenyl-3-ylcarbamoyl}-methyl)-methyl-carbamic acid tert-butyl ester.

A mixture of 5'-[2-(tert-Butoxycarbonyl-methyl-amino)-acetylamino]-2'-chl oro- biphenyl-4-carboxylic acid (85mg), 4-(4-methanesulfonyl-piperazin-l-ylrnethyl)- phenylamine (81mg) and HBTU (120mg) in dry DMF (4ml) containing N- methylmoφholine (65μl) was stirred at room temp for 18h. The mixture was then evaporated and the residue used crude in the next step (161mg). LCMS- ES+ = 669

Example 252

2'-Chloro-5 '-(2-methylamino-acetylamino)-biphenyl-4-carboxylic acid [4-(4- methanesulfonyl-piperazin- 1 -ylmethyl)-phenyl]-amide

The above Boc-protected amine (160mg) was stirred in THF (2ml) and TFA (4ml) at 45C for 18h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 3%-20% 20DCM:8EtOH:lNH3 in DCM over 30 mins gave material which appeared pure by TLC but was multi-peak by HPLC. This material was then purified by reverse phase Prep HPLC giving the title compound as a yellow solid (28mg)

¹ HNMR (DMSO ₃ δ) 2.36 (3H, s), 2.42-2.51 (4H ₃ m), 2.88 (3H, s), 3.05-3.17 (4H, m), 4.14 (2H, d), 7.30 (2H ₃ d) ₃ 7.49-7.65 (3H ₃ m), 7.68 -7.86 (4H, m), 8.05 (2H ₃ d), 8.31 (IH ₃ s), 10.37 (IH, s). LCMS- ES- = 569

2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid ethyl ester A mixture of 5'-amino-2'-chloro-biphenyl-4-carboxylic acid ethyl ester (350mg) and cyclohexyl isocyanate (0.32ml) in dry THF(15ml) containing triethylamine (0.62ml) was stirred at room temp for 48h. The mixture was then evaporated and the residue partitioned between water and DCM. The dried extracts were evaporated giving the crude title compound as a white solid (616mg, >100%, contaminated with dicyclohexyl- urea)

2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid

The above ester (600mg) in 2M NaOH (12ml) and ethanol (20ml) was stirred at room temp for 18h. The ethanol was then evaporated and the residue acidified with HCl. The colourless solid formed was collected by filtration and dried (500mg).

Example 253

2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid {4-[4~(propane-l- sulfonyl)-piperazin- 1 -ylmethyl]-phenyl} -amide A mixture of 2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid (150mg), 4-(4-(propane-l-sulfonyl)-piperazin-l-ylmethyl)-phenylamine (236mg) and HBTU (228mg) in dry DMF (5ml) containing N-methylmorpholine (0.13ml) was stirred at room temp for 18h. The mixture was then evaporated and the residue purified by chromatography. Gradient elution with 3%-20% 20DCM:8EtOH:lNH3 in DCM over 30 mins gave a white solid (38mg)

¹ H NMR (DMSO, δ) 0.91-1.89 (16H, m), 2.37-2.49 (4H, m), 2.97-3.10 (2H, m), 3.11- 3.22 (4H ₅ m), 3.50 (2H, m), 7.23-7.46 (4H, m), 7.52-7.61 (3H, m), 7.78 (2H, d), 8.04 (2H, d), 8.55 (IH, s), 10.33 (IH, s).

Example 254

2 ' -Chloro-5 ' -(3 -cyclohexyl-ureido)-biρhenyl-4-carboxylic acid {4- [4-(prop ane-2- sulfonyl)-piperazin- 1 -ylmethyl] -phenyl} -amide

This material was prepared as described for Example 253 except that 4-(4-(propane-2- sulfonyl)-piperazin-l-ylmethyl)-phenylamine was used. The title compound was isolated as a white solid (21mg)

¹ H NMR (DMSO, δ) 0.91-0.96 (12H, m), 1.44-1.93 (5H, m), 2.32-2.46 (4H, m), 2.94-

3.05 (IH, m), 3.19-3.29 (4H ₃ m), 3.50 (2H, s), 7.21-7.66 (7H, m), 7.74 (2H, d), 8.05

(2H, d), 8.56 (IH, s), 10.34 (IH, s).

Example 255

2'-Chloro-5'-(3-cyclohexyl-ureido)-biphenyl-4-carboxylic acid [4- (4dimethylsulfamoyl-piperazin- 1 -ylmethyl] -phenyl} -amide This material was prepared as described for Example 253 except that 4-(4-amino- benzyl)-piperazine-l -sulfonic acid dimethylamide was used. The title compound was isolated as a white solid (27mg).

¹ HNMR (DMSO, δ) 1.06-1.43 (6H, m), 1.45-1.89 (5H, m), 2.35-2.51 (4H, m), 2.78 (6H, s), 3.08-3.25 (4H, m), 3.40-3.56 (2H, m), 6.20 (IH, d), 7.20-7.49 (4H, m), 7.51- 7.64 (3H, m), 7.76 (2H, d), 8.04 (2H, d), 8.61 (IH, s), 10.34 (IH, s).

3 -Nitro-4-trifluoromethoxybenzoic acid

To a stirred solution of 4-trifluoromethoxybenzoic acid (2.96g) in concentrated sulphuric acid (19ml) at room temperature was added a mixture of concentrated nitric acid (8.5ml) and concentrated sulphuric acid (8.5ml) drop-wise. After 15 min a white precipitate had formed. The reaction was slowly poured onto ice (approx. 100ml). Once the ice had melted the resulting suspension was filtered, and the residue washed with water (3 x 10ml) and then dried in vacuo to give the title compound as a white solid (3.4Ig). ¹ H NMR (DMSO, δ) 7.87 (dd, IH), 8.36 (dd, IH), 8.59 (d, IH), 14.05 (br. s). LCMS- ES- = 250

3 - Amino-4-trifluoromethoxybenzoic acid

A solution of 3-nitro-4-trifluoromethoxybenzoic acid (3g) in methanol (240ml) was hydrogenated at 5O ⁰ C and 50 bar using H-cube apparatus. The methanol solution was evaporated giving the title compound as a white solid (2.58g). ¹ H NMR (DMSO ₅ δ) 5.63 (br. s, 2H), 7.13 (dd, IH), 7.20 (dd, IH), 7.42 (d, IH), 12.85 (br. s).

3-Bromo-4-trifluoromethoxybenzoic acid

To a stirred solution of 3-amino-4-trifluoromethoxybenzoic acid (2g) in a mixture of water (16ml) and 48% HBr (12ml) at O ⁰ C was added a solution of sodium nitrite (0.64g) in water (8ml) drop-wise. After 15 min at 0°C the reaction mixture was diluted with water (12ml) and carefully poured onto a stirred solution of copper (I) bromide (1.32g) in 48% HBr (8ml) at room temperature. The resulting suspension was filtered, and the residue washed with water (3 x 5ml) and dried in vacuo to give the title compound as a beige solid (2.08g). ¹ H NMR (DMSO, δ) 7.87 (dd, IH), 8.26 (dd, IH), 8.46 (d, IH) ₅ 13.70 (br. s, IH). LCMS- ES- = 284.

3-Bromo-N-(4-morpholin-4-ylphenyl)-4-trifluoromethoxy-benzam ide A solution of 3-bromo-4-trifluoromethoxybenzoic acid (515mg), N-(4- aminophenyl)morpholine (323mg), EDAC (763mg), HOBT (538mg) and N- methylmorpholine (597μl) in DMF (5ml) was stirred at room temperature. After Ih, water (10ml) was added and the resulting suspension filtered. The residue was dried in vacuo and then purified by flash column chromatography, eluting with 2 : 1 petroleum ether : ethyl acetate. The title compound was isolated as an off-white solid (532mg). ¹ H NMR (DMSO, δ) 3.07 (t, 4H) ₅ 3.80 (t, 4H) ₅ 6.84 (d, 2H), 7.31 (dd, IH), 7.42 (d, 2H) ₅ 7.68 (s, IH) ₅ 7.76 (dd, IH) ₅ 8.07 (s, IH). LCMS- ES+ = 446.

5'-(4-Morpholino-4-ylphenylcarbamoyl)-2'-trifluoromethoxy -biphenyl-4-carboxylic acid

A mixture of 3-bromo-iV ^: -(4-morpholin-4-ylphenyl)-4-trifluoromethoxybenzamide (505mg), 4-carboxyphenylboronic acid (207mg) and tetrakis(triphenylphosphine)palladium (65mg) in DME (5ml) and a saturated aqueous

solution OfNa ₂ CO ₃ (2.5ml) was heated to reflux. After 16h the reaction was allowed to cool to room temperature and then concentrated to dryness to yield a brown residue.

The residue was taken up in water (10ml) and treated with a 2M aqueous solution of

HCl until no further effervescence occurred. The resulting suspension was filtered and the residue washed with water (3 x 3ml) and dried in vacuo to give the title compound as a light brown solid (565mg).

¹ H NMR (DMSO ₅ δ) 3.14 (t, 4H), 3.80 (t, 4H), 7.01 (d, 2H), 7.68 (m, 6H), 8.12 (d, 2H),

8.21 (s, IH).

LCMS- ES+ = 487.

Example 256

6-Trifruoromethoxy-biphenyl-3,4'-dicarboxylic acid 4'- {[4-(4-methanesulfonyl- piperazin- 1 -ylmethyl)-ρhenyl] -amide} 3 - [(4-morpholin-4-yl-phenyl)-amide]

A mixture of 5'-(4-Morpholino-4-ylphenylcarbamoyl)-2'-trifluoromethoxy-bi phenyl-4- carboxylic acid ( 1 OOmg), 4-(4-methanesulfonyl-piperazin- 1 -ylmethyl)-phenylamine

(57mg) EDAC (86mg) and HOBT (61mg) in dry DMF (ImI) containing N- methylmorpholine (68μl) was stirred at room temp for 18h.

The mixture was then evaporated and the residue purified by chromatography. Elution

DCM:EtOH:NH3; 200:8:1 gave a white solid (54mg). ¹ H NMR (DMSO, δ) 2.55 (m, 4H), 2.89 (s, 3H), 3.09 (m, 8H), 3.52 (s, 2H), 3.76 (t, 4H) ₅

6.97 (d, 2H) ₅ 7.32 (d, 2H) ₅ 7.67 (m, 3H), 7.77 (m, 4H), 8.15 (m, 4H) ₅ 10.26 (br. s, IH),

10.37 (br. S ₅ IH).

3-Bromo-4-methoxy-N-(4-morpholin-4-yl-plienyl)-benzamide A mixture of 3-bromo-4-methoxy-benzoic acid (500mg), N-(4- aminophenyl)morpholine (385mg), EDAC (828mg), HOBT (583mg) and N- methylmorpholine (714μl) in DMF (5ml) was stirred at room temperature for 18h. The mixture was then diluted with water (30ml) and the resulting solid collected by filtration and dried (818mg)

2'-Methoxy-5'-(4-morpholin-4-yl-ρhenylcarbamoyl)-bipheny l-4-carboxylic acid A mixture of 3-Bromo-4-methoxy-N-(4-morpholin-4-yl-phenyl)-benzamide (788mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (564mg) in 2:1 DMErwater (15ml) containing cesium carbonate (1.3Ig) and tetrakis(triphenylphosphine)palladium° (232mg) was heated to reflux for 18h.

The mixture was cooled and then evaporated. The residue was then stirred in ethanol (10ml) and 2M NaOH (5ml) at room temp for 16h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (1.19g)

LCMS- ES+ = 461.

Example 257 ό-Methoxy-biphenyl-S^'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'- ( {4-[4-(propane- 1 -sulfonyl)-piperazin- 1 -ylmethyl]-phenyl} -amide)

A mixture of 2'-Methoxy-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4- carboxylic acid (lOOmg), 4-(4-(propane-l-sulfonyl)-piperazin-l-ylmethyl)-phenylamine (68mg), EDAC (48mg), HOBT (34mg) and N-methylmorpholine (56μl) in DMF (ImI) was stirred at room temperature for 18h. The mixture was then evaporated and the residue purified by reverse phase preparative HPLC giving the title compound as an off- white solid (42mg).

¹ H NMR (DMSO, δ) 1.00 (t, 3H), 1.71 (m, 2H), 2.46 (m, 4H), 3.01 (m, 2H), 3.06 (m, 4H), 3.18 (m, 4H), 3.51 (s, 2H), 3.75 (t, 4H), 3.89 (s, 3H), 6.95 (d, 2H), 7.30 (m, 3H), 7.64 (d, 2H), 7.73 (d, 2H), 7.79 (d, 2H), 8.04 (m, 4H), 10.02 (br. S, IH), 10.30 (br. S, IH).

Example 258

6-Methoxy-biphenyl-3,4'-dicarboxylic acid 3-[(4-morpholin-4-yl-phenyl)-amide] 4'-

( {4-[4-(propane-2-sulfonyl)-piperazin-l -ylmethyl] -phenyl} -amide) This material was prepared as described for Example 257 except that 4-(4-(propane-2- sulfonyl)-piperazin-l-ylmethyl)-phenylamine was used. The title compound was isolated as a white solid (31mg)

¹ H NMR (DMSO, δ) 1.28 (d, 6H), 2.46 (m, 4H), 3.05 (m, IH), 3.13 (t, 4H), 3.30 (t, 4H),

3.55 (s, 2H), 3.80 (t, 4H), 3.94 (s, 3H), 6.99 (d, 2H), 7.35 (m, 3H), 7.68 (d, 2H), 7.80 (m, 4H), 8.08 (m, 4H), 10.06 (br. s, IH), 10.34 (br. s, IH).

Example 259

6-Methoxy-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(4-dimethylsulfamoyl- piperazin-1- ylmethyl)-phenyl] -amide} 3-[(4-moφholin-4-yl-phenyl)-amide] This material was prepared as described for Example 257 except that 4-(4-amino- benzyl)-piperazine-l -sulfonic acid dimethylamide was used. The title compound was isolated as a white solid (28mg)

¹ H NMR (DMSO, δ) 2.44 (m, 4H), 2.77 (s, 6H), 3.08 (t, 4H), 3.18 (t, 4H), 3.50 (s, 2H), 3.75 (t, 4H), 3.89 (s, 3H), 6.95 (d, 2H), 7.30 (m, 3H), 7.63 (d, 2H), 7.75 (m, 4H), 8.04 (m, 4H), 10.01 (br. s, IH), 10.29 (br. s, IH).

3-Bromo-4-m6thoxy-N-(2-methyl-4-morpholin-4-yl-phenyl)-be nzamide

A mixture of 3-bromo-4-methoxy-benzoic acid (247mg), 2-methyl-4-morpholin-4-yl- phenylamine (205mg), EDAC (410mg), HOBT (289mg) and N-methylmorpholine (353μl) in DMF (5ml) was stirred at room temperature for 18h. The mixture was then diluted with water (30ml) and the resulting solid collected by filtration and dried (464mg)

¹ H NMR (DMSO, δ) 2.22 (s, 3H), 3.07 (t, 4H), 3.79 (t, 4H), 3.90 (s, 3H), 6.72 (m, 2H), 6.,89 (d, IH), 7.19 (br. s, IH), 7.38 (d, IH), 7.75 (dd, IH), 8.00 (d, IH).

2 ' -Methoxy-5 ' -(2-methyl-4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carb oxylic acid

A mixture of 3-Bromo-4-methoxy-N-(2-methyl-4-morpholin-4-yl-phenyl)-benza mide

(432mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (311mg) in 2:1 DME:water

(15ml) containing cesium carbonate (697mg) and tetrakis(triphenylphosphme)palladium° (127mg) was heated to reflux for 18h. The mixture was cooled and then evaporated. The residue was then stirred in ethanol

(10ml) and 2M NaOH (5ml) at room temp for 16h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (561mg)

¹ H NMR (DMSO, δ) DiDsD D3.11 (t, 4H), 3.76 (t, 4H), 3.88 (s, 3H), 6.87 (m, 2H), 7.16 (d, IH), 7.28 (d, IH), 7.63 (m, 3H), 8.04 (m, 3H), 9.73 (br. s, IH)

Example 260

6-Methoxy-biphenyl-3,4'-dicarboxylic acid 3-[(2-methyl-4-morpholin-4-yl-phenyl)- amide] 4' -( {4-[4-(propane- 1 -sulfonyl)-piperazin-l -ylmethyl] -phenyl} -amide) A mixture of 2'-Methoxy-5'-(2-methyl-4-morpholin-4-yl-phenylcarbamoyl)-bi ρhenyl- 4-carboxylic acid (60mg), 4-(4-(propane-l-sulfonyl)-piperazin-l-ylmethyl)- phenylamine (39mg), EDAC (50mg), HOBT (35mg) and N-methylmorpholine (43μl) in DMF (ImI) was stirred at room temperature for 18h. The mixture was then evaporated

and the residue purified by chromatography. Elution DCM:EtOH:NH3; 400:8:1 gave a white solid (53mg).

¹ H NMR (DMSO, δ)~it, 3H), 1.71 (m, 2H), 2.19 (s, 3H), 2.45 (m, 4H), 3.01 (m, 4H), 3.13 (t, 2H), 3.18 (m, 4H), 3.51 (s, 2H) ₅ 3.76 (t, 4H), 3.89 (s, 3H), 6.84 (m, 2H), 7.15 (d, IH), 7.30 (m, 3H), 7.75 (m, 4H), 8.05 (m, 4H), 9.70 (br. s, IH), 10.33 (br. s, IH)

3-Bromo-4-methoxy-N-[4-(4-methyl-piperazin-l-yl)-phenyl]- benzamide

A mixture of 3-bromo-4-methoxy-benzoic acid (500mg), 4-(4-methyl-piperazin-l-yl)- phenylamine (413mg), EDAC (828mg), HOBT (534mg) and N-methylmorpholine (712μl) in DMF (3ml) was stirred at room temperature for 18h. The mixture was then diluted with water (30ml) and the resulting solid collected by filtration and dried (840mg)

¹ H NMR (DMSO, δ) 2.78 (s, 3H), 3.27 (m, 4H), 3.41 (m, 4H, merged with water peak), 3.94 (s, 3H), 7.00 (d, 2H), 7.25 (d, IH), 7.67 (d, 2H), 8.03 (dd, IH), 8.24 (d, IH), 10.11 (br. s, IH).

2'-Methoxy-5'-[4-(4-methyl-piperazin-l-yl)-phenylcarbamoy l]-biphenyl-4-carboxylic acid

A mixture of 3-Bromo-4-methoxy-N-[4-(4-methyl-piperazin-l-yl)-phenyl]-ben zamide (748mg) and 4-(ethoxycarbonyl)-phenyl boronic acid (538mg) in 2: 1 DME:water

(15ml) containing cesium carbonate (1.21mg) and tetrakis(triρhenylphosphine)palladium° (220mg) was heated to reflux for 18h.

The mixture was cooled and then evaporated. The residue was then stirred in ethanol

(8ml) and 2M NaOH (4ml) at room temp for 16h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting solid was collected by filtration and dried (528mg)

¹ H NMR (DMSO, δ) 2.69 (s, 3H), 3.16 (m, 4H), 3.38 (m, 4H, merged with water peak),

3.88 (s, 3H), 6.99 (d, 2H), 7.28 (d, IH), 7.69 (m, 4H), 8.03 (m, 4H).

Example 261

6-Methoxy-biphenyl-3,4'-dicarboxylic acid 3- {[4-(4-(l , 1 -dioxo- 1 lambda*6*- thiomorpholin-4-yl)-phenyl] -amide} 4 ' - { [4-(4-methyl-piperazin- 1 -yl)-ρhenyl] -amide}

A mixture of 2'-Methoxy-5'-[4-(4-methyl-piperazin-l-yl)-phenylcarbamoyl]- biphenyl- 4-carboxylic acid (lOOmg), 4-(l,l-dioxo-llambda*6*-thiomorpholin-4-yl)-phenylamine (50mg), EDAC (84mg), HOBT (59mg) and N-methylmorpholine (73μl) in DMF (ImI) was stirred at room temperature for 18h. The mixture was then evaporated and the residue purified by chromatography. Elution DCM:EtOH:NH3 ; 200:8: 1 gave an off- white solid (61mg).

¹ H NMR (DMSO, δ) 2.23 (s, 3H), 2.48 (t, 4H), 3.12 (m, 8H), 3.78 (m, 4H), 3.89 (s, 3H) ₅ 6.93 (d, 2H), 7.06 (d, 2H), 7.29 (d, IH), 7.61 (d, 2H), 7.72 (m, 4H), 8.03 (m, 4H), 9.99 (br. s, IH), 10.16 (br. s, IH).

3-Bromo-N-[4-(l,l-dioxo-llambda*6*-thiomorpholin-4-yhneth yl)-phenyl]-4-methoxy- benzamide

A mixture of 3-bromo-4-methoxy-benzoic acid (500mg), 4-(l,l-dioxo-llambda*6*- thiomorpholin-4-yhnethyl)-phenylamine (519mg), EDAC (830mg), HOBT (585mg) and N-methylmorpholine (712μl) in DMF (3ml) was stirred at room temperature for

18h. The mixture was then diluted with water (30ml) and the resulting solid collected by filtration and dried (882mg)

¹ H NMR (DMSO, δ) 3.02 (m, 4H), 3.26 (m, 4H), 3.80 (s, 2H), 4.10 (s, 2H), 7.42 (d, IH), 7.47 (d, 2H), 7.89 (d, 2H), 8.17 (dd, IH), 8.39 (d, IH), 10.35 (br. s, IH).

5 '-[4-(1 , 1 -Dioxo- 1 lambda*6*-thiomorpholin-4-ylmethyl)-phenylcarbamoyl]-2'- methoxy-biphenyl-4-carboxylic acid

A mixture of 3-Bromo-N-[4-(l , 1 -dioxo-1 lambda*6*-thiomoφholin-4-ylmethyl)- phenyl]-4-methoxy-benzamide (930mg) and 4-carboxyphenyl boronic acid (408mg) in 2:1 DME: satd. sodium bicarbonate solution (7.5ml) containing tetrakis(triphenylphosphine)palladium° (116mg) was heated to reflux for 18h. The reaction was allowed to cool to room temperature and then concentrated to dryness to yield a dark residue. The residue was taken up in water (10ml) and treated with 2M HCl until no further effervescence occurred. The resulting suspension was filtered and the residue washed with water (3 x 3ml) and dried in vacuo to give the title compound as a light grey solid (989mg).

¹ H NMR (DMSO, δ) 2.87 (m, 4H), 3.12 (m, 4H), 3.64 (s, 2H), 3.88 (s, 3H), 7.29 (m, 2H), 7.60 (m, 3H), 7.76 (m, 2H), 8.00 (m, 4H), 10.23 (br. s, IH).

Example 262

6-Methoxy-biphenyl-3,4'-dicarboxylic acid 4'-{[4-(l,l-dioxo-llambda*6*- thiomorpholin-4-ylmethyl)-phenyl]-amide} 4'{[4-(4-methanesulfonyl-piperazin-l- ylmethyl)-phenyl]-amide}

A mixture of 5'-[4-(l,l-Dioxo-llambda*6*-thiomorpholin-4-ylmethyl)- phenylcarbamoyl]-2'-methoxy-biphenyl-4-carboxylic acid (lOOmg), 4-(4- methanesulfonyl-piperazin-l-ylmethyl)-phenylamme (54mg) EDAC (77mg) and HOBT (54mg) in dry DMF (ImI) containing N-methylmorpholine (66μl) was stirred at room temp for 18h. The mixture was then evaporated and the residue purified by chromatography. Elution DCM:EtOH:NH3; 200:8:1 gave an off-white solid (59mg). ¹ H NMR (DMSO, δ) 2.53 (m, 4H), 2.94 (m, 7H), 3.18 (m, 8H), 3.57 (s, 2H), 3.71 (s, 2H), 3.96 (s, 3H), 7.37 (m, 5H), 7.82 (m, 6H), 8.11 (m, 4H), 10.25 (br. s, IH), 10.37 (br. s, IH).

2'-Chloro-5 '-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-carboxylic acid ethyl ester

A mixture of 6-chloro-biphenyl-3,4'-dicarboxylic acid 4'-ethyl ester (800mg), N-(4- ammophenyl)morpholine (469mg), EDAC (504mg), HOBT (355mg) and N-

methylmorpholine (578μl) in DMF (10ml) was stirred at room temperature. After Ih, water (80ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Elution with 1:1 ethyl acetate:petrol gave a yellow crystalline solid (437mg).

2'-Chloro-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl- 4-carboxylic acid The above ester (778mg) was stirred in ethanol (20ml) and 2M NaOH (10ml) at room temp for 18h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting pale pink solid was collected by filtration and dried (740mg)

Example 263

6-Chloro-biphenyl-3,4'-dicarboxylic acid 4'-({4-[4-(butane-l-sulfonyl)piperazin-l- ylmethyl]-phenyl} -amide) 3-[(4-morpholin-4-yl-phenyl)-amide]

A mixture of 2'-chloro-5'-(4-morpholin-4-yl-phenylcarbamoyl)-biphenyl-4-c arboxylic acid (57mg), 4[-4-(butane- 1 -sulfonyl)-piperazin- 1 -ylmethyl]-phenylamine (53mg), EDAC (33mg), HOBT (23mg) and N-methylmorpholine (37μl) in DMF (ImI) was stirred at room temperature. After 18h, water (10ml) was added and the resulting suspension filtered and dried giving the title compound as an off-white solid (31mg) ¹ H NMR (DMSO, δ) 0.91 (t, 3H), 1.39 (q, 2H), 1.65 (m, 2H), 2.47 (m, 4H), 3.07 (m, 4H), 3.19 (brs, 4H), 3.33 (s, 2H) ₅ 3.75 (m, 4H), 6.98 (d, 2H), 7.34 (d, 2H), 7.62 (d, 2H), 7.72 (d, 2H), 7.78 (m, 3H), 8.09 (m, 4H), 10.21 (s, IH), 10.37 (s, IH) LCMS- ES+ = 730, 732.

2'-Chloro-5'-(2-fluoro-4-morpholin-4-yl-phenylcarbamoyl)- biphenyl-4-carboxylic acid ethyl ester

A mixture of 6-chloro-biphenyl-3,4'-dicarboxylic acid 4'-ethyl ester (213mg), 3-fiuoro- 4-morpholin-4-yl-phenylamine (179mg), EDAC (174mg), HOBT (123mg) and N- methylmorpholine (200μl) in DMF (3ml) was stirred at room temperature. After 18h, water (30ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Elution with 1 : 1 ethyl acetate:petrol gave a brown oil (235mg).

2'-Chloro-5'-(2-fluoro-4-morpholin-4-yl-phenylcarbamoyl)- biphenyl-4-carboxylic acid

The above ester (233mg) was stirred in ethanol (4ml) and 2M NaOH (2ml) at room temp for 18h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting colourless solid was collected by filtration and dried (198mg)

Example 264

6-Chloro-biphenyl-S^'-dicarboxylic acid 3-[(3-fluoro-4-morpholin-4-yl-phenyl)-amide]

4'-({4-[4-(propane-l-sulfonyl)-piperazin-l-ylmethyl]-phen yl}-amide)

A mixture of 2'-chloro-5'-(2-fluoro-4-morpholin-4-yl-phenylcarbamoyl)-bip henyl-4- carboxylic acid (45mg), 4-(4-(propane-l-sulfonyl)-piperazin-l-yhnethyl)-ρhenylamine (39mg), EDAC (25mg), HOBT (18mg) and N-methylmorpholine (43μl) in DMF (ImI) was stirred at room temperature for 18h. Water (10ml) was added and the resulting suspension filtered and dried giving the title compound as an off-white solid (57mg) ¹ H NMR (DMSO, δ) 1.00 (t, 3H) ₅ 1.69 (q, 2H), 2.45 (bs, 2H), 2.99 (m, 8H), 3.18 (m, 4H), 3.51 (s, 2H), 3.75 (m, 4H), 7.06 (t, IH), 7.33 (d, 2H), 7.46 (d, IH), 7.72 (d, 2H), 7.77 (m, 4H), 8.08 (m, 4H), 10.38 (s, IHO, 10.42 (s, IH) LCMS- ES+ = 735, 737.

2'-Chloro-5'-[4-(4-methanesulfonyl-piperazin-l-ylmethyl)- phenylcarbamoyl]-biphenyl- 4-carboxylic acid ethyl ester A mixture of 6-chloro-biphenyl-3,4'-dicarboxylic acid 4'-ethyl ester (152mg), 4-(4- methanesulfonyl-piperazin-l-ylmethyl)-phenylamine (175mg), EDAC (125mg), HOBT (88mg) and N-methyhnorpholine (143μl) in DMF (3ml) was stirred at room temperature. After Ih, water (30ml) was added and the resulting suspension filtered. The residue was then purified by chromatography. Gradient elution with 30-100% ethyl acetate in petrol gave a beige solid (240mg).

2 ' -Chloro- 5 ' - [4-(4-methanesulfonyl-piperazin- 1 -ylmethyl)-phenylcarbamoyl]-biphenyl- 4-carboxylic acid

The above ester (237mg) was stirred in ethanol (4ml) and 2M NaOH (2ml) at room temp for 18h. The ethanol was then evaporated and the residue acidified with 2M HCl. The resulting colourless solid was collected by filtration and dried (229mg)

Example 265

6-Chloro-biphenyl-S^'-dicarboxylic acid 3- {[4-(4-methanesulfonyl-piperazin- 1 - ylmethyl)-phenyl]-amide} 4'-[(4-morpholin-4-yl-phenyl)-amide] A mixture of 2 ' -chloro-5 ' - [4-(4-methanesulfonyl-piperazin- 1 -ylmethyl)- phenylcarbamoyl]-biphenyl-4-carboxylic acid (53mg), N-(4-aminophenyl)morpholine (23mg), EDAC (25mg), HOBT (18mg) and N-methylmorpholine (43 μl) in DMF (ImI) was stirred at room temperature. After 18h, water (10ml) was added and the resulting suspension filtered. This material was then purified by reverse phase Prep HPLC giving the title compound as an off-white solid (39mg) ¹ H NMR (DMSO, δ) 2.47 (m, 4H), 2.88 (s, 3H), 3.10 (m, 8H), 3.51 (s, 2H), 3.76 (m, 4H), 6.99 (d, 2H), 7.32 (d, 2H), 7.71 (m, 7H) ₅ 8.07 (m, 4H), 10.21 (s, IH), 10.40 (s, IH) LCMS- ES+ = 689, 691.

Activity 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 ⁰ C in a 5% CO ₂ environment and split twice a week on seeding at 2 x 10 ⁶ cells/flask on day 1 and 1 x 10 ⁶ 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 11 MO- OSS), 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 IC ₅₀ . Wells G12 and H12 were left empty in the clear plate as the blank. Plates were then incubated at 37 ⁰ C in a 5% CO ₂ 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 37 ⁰ C with 5% CO ₂ for 72h.

At the end of the incubation time, the cells in the white plate were harvested by washing 23.5mM beetle luciferin (Promega E1603), 26mM ATP (Sigma O-2060) in 10OnM Tris buffer pH 7.8 aliquoted and stored at -80C 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 MgSO ₄ (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 IC ₅₀ , 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 TD ₅₀ , 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 run minus background against drug concentration.