Biphenyl Derivatives and Their Use in Treating Hepatitis C

• US 20080255105A1
• Filed: 09/18/2006
• Published: 10/16/2008
• Est. Priority Date: 09/16/2005
• Status: Active Grant

• Current Assignee: Arrow Therapeutics Ltd. (Astrazeneca PLC), Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Arrow Therapeutics Ltd. (Astrazeneca PLC)
• Inventors: Lumley, James, Wheelhouse, Christopher James, Thomas, Alexander James Floyd, Salter, James Iain, Mathews, Neil, Angell, Richard Martyn, Pilkington, Christopher John, Bushnell, David John, Carter, Malcolm Clive
• Granted Patent: US 8,008,303 B2
• Time in Patent Office: Days
• US Class Current: 514/227.8
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: C07D 205/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 237/28 Cinnolines
• CPC Class Codes: C07D 279/12 not condensed with other rings
• CPC Class Codes: C07D 295/135 with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/26 Sulfur atoms
• CPC Class Codes: C07D 307/38 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

A compound which is a biphenyl derivative of formula (I), or a pharmaceutically acceptable salt thereof wherein: R₁ is a C₁-C₆ alkyl group or a moiety -A₁, -L₁-A₁, -A₁-A₁′, -L₁-A₁-A₁′, -A₁-L₁-A₁′, -A₁-Y₁-A₁′, -A₁-Het₁-A₁′, -L₁-A₁-Y₁-A₁′, -L₁-A₁-Het₁-A₁′, -L₁-Het₁-A₁, -L₁-Y₁-A₁, -L₁-Y₁-Het₁-A₁, -L₁-Het₁-Y₁-A₁, -L₁-Y₁-Het₁-L₁′, -A₁-Y₁-Het₁-A₁′, -A₁-Het₁-Y₁-A₁′, -A₁-Het₁-L₁-A₁′, -A₁-L₁-Het₁-A₁′ or -L₁-Het₁-L₁′; -A and B are the same or different and each represent a direct bond or a —CO—NR′—, —NR′—CO—, —NR′—CO₂—, —CO—, —NR′—CO—NR″—, —NR′—S(O)₂—, —S(O)₂—NR′—, —SO₂—, —NR′—, —NR′—CO—CO—, —CO—O—, —O—CO—, —(C₁-C₂ alkylene)-NR′— or —(C₁-C₂ hydroxyalkylene)-NR′-moiety, wherein R′ and R″ are the same or different and each represent hydrogen or C₁-C₄ alkyl; —R₂ and R₃ are the same or different and each represent C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy or halogen; n and m are the same or different and each represent 0 or 1; R₄ is a C₁-C₆ alkyl group or a moiety -A₄, -L₄-A₄, -A₄-A₄′, -L₄-A₄-A₄′, -A₄-L₄-A₄′, -A₄-Y₄-A₄′, -A₄-Het₄-A₄′, -L₄-A₄-Y₄-A₄′, -L₄-A₄-Het₄-A₄′, -L₄-Het₄-A₄, -L₄-Y₄-A₄, -L₄-Y₄-Het₄-A₄, -L₄-Het₄-Y₄-A₄, -L₄-Y₄-Het₄-L₄′, -A₄-Y₄-Het₄-A₄′, -A₄-Het₄-Y₄-A₄′, -A₄-Het₄-L₄-A₄′, -A₄-L₄-Het₄-A₄′ or -L₄-Het₄-L₄′, each A₁, A₄, A₁′ and A₄′ are the same or different and represent a phenyl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocyclyl or C₃-C₈ carbocyclyl moiety; each L₁ and L₄ is the same or different and represents a C₁-C₄ alkylene or a C₁-C₄ hydroxyalkylene group; each Y₁ and Y₄ is the same or different and represents —CO—, —SO— or —S(O)₂—; each L₁′ and L₄′ is the same or different and represents hydrogen or a C₁-C₄ alkyl group; and each Het₁ and Het₄ is the same or different and represents —O—, —S— or —NR′—, wherein R′ is hydrogen or a C₁-C₄ alkyl group, the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R₁ and R₄ 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 R₁ and R₄ being unsubstituted or substituted by (a) a single unsubstituted substituent selected from —(C₁-C₄ alkyl)-X₁, —CO₂R′, —SO₂NR′R″, —S(O)₂—R′, —CONR′R″, —NR′—CO—R′″, —NR′—S(O)₂—R′″, —CO—NR′—(C₁-C₄ alkyl)-NR′R″ and —CO—O—(C₁-C₄ alkyl)-NR′R″ and/or (b) 1, 2 or 3 unsubstituted substituents selected from —(C₁-C₄ alkyl)-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano, nitro and —NR′R″, wherein X₁ is —CO₂R′, —SO₂—R′, —NR′—CO₂—R″, —NR′—S(O)₂—R′″, —CONR′R″ or —SO₂—NR′R″, each X₂ is the same or different and is cyano, nitro or —NR′R″, each R′ and R″ is the same or different and represents hydrogen or C₁-C₄ alkyl and each R′″ is the same or different and represents C₁-C₄ alkyl.

Claims

1. A compound which is a biphenyl derivative of formula (I), or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein the phenyl, heteroaryl, heterocyclyl and carbocyclyl moieties in R₁ and R₄ are unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

(C₁-C₂ alkyl)-X₁, —

CO₂R′

″

, —

SO₂R′

″

, —

SO₂NR′

R′

″

, —

CONR′

R′

″

, —

NR′

—

CO—

R′

″

, —

NR′

—

SO₂—

R′

″ and

—

CO—

NR′

—

(C₁-C₂ alkyl)-NR′

R′

″ and

/or (b) 1, 2 or 3 unsubstituted substituents selected from —

(C₁-C₂ alkyl)-X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and —

NR′

R″

, wherein X₁ is —

CO₂R′

″

, —

NR′

—

CO₂—

R′

″

, —

NR′

—

S(O)₂—

R′

″

or —

SO₂NR′

R″

, each X₂ is the same or different and is cyano or —

NR′

R″

, each R′ and

R″

are the same or different and represent hydrogen or C₁-C₄ alkyl and each R′

″

is the same or different and represents C₁-C₄ alkyl.

3. A compound according to claim 1, wherein each A₁ moiety is the same or different and represents a non-fused 5- to 6-membered heterocyclyl or C₃-C₈ carbocyclyl group, or a phenyl or 5- to 6-membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group.

4. A compound according to claim 1, wherein when A₁ is other than a non-fused phenyl ring, it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from —

CH₂—

X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and —

NR′

R″

, wherein each X₂ is the same or different and is cyano or —

NR′

R″

, and each R′ and

R″

is the same or different and represents hydrogen or C₁-C₄ alkyl.

5. A compound according to claim 1, wherein each A₁′

moiety is the same or different and represents a non-fused phenyl, C₃-C₈ carbocyclyl, 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group.

6. A compound according to claim 1, wherein each A₁′

moiety is unsubstituted or substituted by (a) a single unsubstituted —

SO₂—

R′

″

or —

SO₂—

NR′

R″

substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy and —

NR′

R″

, wherein each R′ and

R″

are the same or different and are selected from hydrogen and C₁-C₄ alkyl, and R′

″

represents C₁-C₄ alkyl.

7. A compound according to claim 1, wherein each A₄ moiety is the same or different and is a non-fused 5- to 6-membered heterocyclyl or C₃-C₈ carbocyclyl group, or a phenyl or 5- to 6-membered heteroaryl group which is optionally fused to a phenyl ring or to a 5- to 6-membered heteroaryl or 5- to 6-membered heterocyclyl group.

8. A compound according to claim 1, wherein each A₄ moiety is unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

CO₂R′

″ and

—

CONR′

R″ and

/or (b) 1, 2 or 3 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, —

NR′

R″

, C₁-C₄ haloalkyl, C₁-C₄ haloalkoxy and cyano, wherein R′

represents hydrogen or C₁-C₄ alkyl and R′

″

represents C₁-C₄ alkyl.

9. A compound according to claim 1, wherein each A₄′

moiety is the same or different and represents a non-fused phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocyclyl or C₃-C₆ carbocyclyl group.

10. A compound according to claim 1, wherein each A₄′

moiety is unsubstituted or substituted by (a) an unsubstituted —

SO₂—

(C₁-C₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy and —

NR′

R″

, wherein each R′ and

R″

are the same or different and are selected from hydrogen and C₁-C₄alkyl.

11. A compound according to claim 1, wherein L₁ and L₄ are the same or different and each represent a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group.

12. A compound according to claim 1, wherein Y₁ and Y₄ are each —

CO—

.

13. A compound according to claim 1, wherein L₁′

is hydrogen or a C₁-C₂ alkyl group and/or L₄′

is a C₁-C₂ alkyl group.

14. A compound according to claim 1, wherein Het₁ represents —

O—

, —

NR′

—

or —

S—

, wherein R′

is hydrogen or C₁-C₂ alkyl and/or Het₄ represents —

O—

or —

NH—

.

15. A compound according to claim 1, wherein R₁ is a C₁-C₆ alkyl group or a moiety selected from the group consisting of -A₁, -L₁-A₁, -A₁-A₁′

, -L₁-A₁-A₁, -A₁-L₁-A₁, -A₁-Y₁-A₁′

, -A₁-Het₁-A₁′

, -L₁-A₁-Het₁-A₁, -L₁-Y₁-Het₁-A₁′

, -L₁-Het₁-Y₁-A₁′

, -L₁-Y₁-Het₁-L₁′

, -A₁-Het₁-L₁-A₁′

, -A₁-L₁-Het₁-A₁′ and

-L-Het₁-L₁′

.

16. A compound according to claim 1 wherein A represents a —

(C₁-C₂ alkylene)-NR′

—

, —

CO—

NR′

—

, —

NR′

—

CO—

, —

CO—

, —

CO—

O—

or —

O—

CO—

group, in which R′

is hydrogen or C₁-C₂ alkyl.

17. A compound according to claim 1, wherein B represents a direct bond, —

CO—

NR′

—

, —

NR′

—

CO—

, —

NR′

—

CO₂—

, —

NR′

—

S(O)₂—

, —

S(O)₂—

NR′

—

, —

CO—

, —

NR′

—

, —

(C₁-C₂ alkylene)-NR′

—

, —

NR′

—

CO—

NR″

—

or —

NR′

—

CO—

CO—

, wherein R′ and

R″

are the same or different and represent hydrogen or C₁-C₂ alkyl, provided that when B represents a direct bond, R₄ is -A₄ or -A₄-A₄′

.

18. A compound according to claim 1, wherein R₂ and R₃ are the same or different and represent C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen.

19. A compound according to claim 1, wherein R₄ is a C₁-C₅ alkyl group or a moiety -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-Y₄-A₄′

or -L₄-Het₄-L₄′

.

20. A compound according to claim 1, wherein:

R₁ is a C₂-C₆ alkyl group or a moiety selected from the group consisting of -A₁, -L₁-A₁, -A₁-A₁′

, -L₁-A₁-A₁′

, -A₁-L₁-A₁′

, -A₁-CO-A₁′

, -L₁-A₁-Het₁-A₁′

, -L₁-Het₁-CO-A₁′

, -L₁-CO-Het₁-L₁′

, -A₁-Het₁-L₁-A₁′

, -A₁-L₁-Het₁-A₁′ and

-L₁-Het₁-L₁′

;

A represents a —

(C₁-C₂ alkylene)-NH—

, —

CO—

NH—

, —

NH—

CO—

, —

CO—

, —

CO—

O—

or —

O—

CO group;

B represents —

CO—

NH—

, —

NH—

CO—

, —

NH—

CO₂—

, —

NH—

, —

CO—

, —

NH—

S(O)₂—

, —

S(O)₂—

NH—

, —

(C₁-C₂ alkylene)-NH—

, —

NH—

CO—

NH—

, —

N(CH₃)—

CO—

, —

NH—

CO—

CO—

or a direct bond, provided that when B represents a direct bond, R₄ is -A₄ or -A₄-A₄′

;

R₂ is C₁-C₄ alkyl;

R₃ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅ alkyl group or a moiety -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-CO-A₄′

or -L₄-Het₄-L₄′

;

each A₁ moiety is the same or different and represents a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[1,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, 1H-benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group, wherein (i) when A₁ is a phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

CH₂—

X₁, —

CO₂—

R′

″

, —

SO₂NR′

R′

″

, —

CONR′

R′

″

, —

NR′

—

CO—

R′

″

, —

NR′

—

SO₂—

R′

″ and

—

CO—

NR′

—

(C₁-C₂ alkyl)-NR′

R′

″

, and/or (b) 1 or 2 unsubstituted substituents selected from —

CH₂—

X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and —

NR′

R″

, wherein X₁ is —

CO₂R′

″

, —

NR′

—

CO₂—

R′

″

or —

SO₂—

NR′

R′

″

, each X₂ is the same or different and is cyano or —

NR′

R″

, each R′ and

R″

are the same or different and represent hydrogen or C₁-C₄ alkyl and each R′

″

is the same or different and represents C₁-C₄ alkyl and (ii) when A₁ is other than a phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy and hydroxy;

each A₁′

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 —

SO₂—

(C₁-C₄ alkyl) or —

SO₂—

NR′

R″

substituent, wherein R′ and

R″

are the same or different and each represent hydrogen or C₁-C₄ alkyl and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl and C₁-C₂ hydroxyalkyl;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolidinyl, azetidinyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomorpholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted —

CONR′

R′

″

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R′

″

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R′

″

represents C₁-C₄alkyl;

each A₄′

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) a single unsubstituted —

SO₂—

(C₁-C₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

each L₁ and L₄ are the same or different and represent a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group

L₁′

represents hydrogen or a C₁-C₂ alkyl group;

L₄′

represents a C₁-C₂ alkyl group;

Het₁ represents —

O—

, —

NR′

—

or —

S—

, wherein R′

is hydrogen or C₁-C₂ alkyl; and

Het₄ represents —

O—

or —

NH—

.

21. A compound according to claim 1, wherein:

R₁ is a C₂-C₆ alkyl group or a moiety selected from the group consisting of -A₁, -L₁-A₁, -A₁-A₁′

, -L₁-A₁-A₁, -A₁-L₁-A₁′

, -A₁-CO-A₁′

, -L₁-A₁-Het₁-A₁, -L₁-Het₁-CO-A₁′

, -L₁-CO-Het₁-L₁′

, -A₁-Het₁-L₁-A₁′

, -A₁-L₁-Het₁-A₁′ and

-L₁-Het₁-L₁′

;

A represents a —

(C₁-C₂ alkylene)-NH—

, —

CO—

NH—

, —

NH—

CO—

, —

CO—

, —

CO—

O—

or —

O—

CO—

group;

B represents —

CO—

NH—

, —

NH—

CO—

, —

NH—

CO₂—

, —

NH—

, —

CO—

, —

NH—

S(O)₂—

, —

(C₁-C₂ alkylene)-NH—

, —

NH—

CO—

NH—

, —

N(CH₃)—

CO—

, —

NH—

CO—

CO—

or a direct bond, provided that when B represents a direct bond, R₄ is -A₄ or -A₄-A₄′

;

R₂ is C₁-C₄ alkyl;

R₃ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy or halogen;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅ alkyl group or a moiety selected from the group consisting of -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-CO-A₄′ and

-L₄-O-L₄′

;

each A₁ moiety is the same or different and represents a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[1,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, 1H-benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group, wherein (i) when A₁ is a phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

CH₂—

X₁, —

CO₂—

R′

″

, —

SO₂NR′

R′

″

, —

CONR′

R′

″

, —

NR′

—

CO—

R′

″

, —

NR′

—

SO₂—

R′

″ and

—

CO—

NR′

—

(C₁-C₂ alkyl)-NR′

R′

″

, and/or (b) 1 or 2 unsubstituted substituents selected from —

CH₂—

X₂, halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano and —

NR′

R″

, wherein X₁ is —

CO₂R′

″

, —

NR′

—

CO₂—

R′

″

or —

SO₂—

NR′

R′

″

, each X₂ is the same or different and is cyano or —

NR′

R″

, each R′ and

R″

are the same or different and represent hydrogen or C₁-C₄ alkyl and each R′

″

is the same or different and represents C₁-C₄ alkyl and (ii) when A₁ is other than a phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy and hydroxy;

each A₁′

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 —

SO₂—

(C₁-C₄ alkyl) substituent and/or (b) 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl and C₁-C₂ hydroxyalkyl;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl, C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomorpholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted —

CONR′

R′

″

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R′

″

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R′

″

represents C₁-C₄ alkyl;

each A₄′

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 which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

each L₁ and L₄ are the same or different and represent a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group

L₁′

represents hydrogen or a C₁-C₂ alkyl group;

L₄′

represents a C₁-C₂ alkyl group; and

Het₁ represents —

O—

, —

NR′

—

or —

S—

, wherein R′

is hydrogen or C₁-C₂ alkyl.

22. A compound according to claim 1, wherein:

R₁ is a C₂-C₆ alkyl group or a moiety selected from the group consisting of -A₁, -L₁-A₁, -A₁-A₁′

, -L₁-A₁-A₁′

, -A₁-L₁-A₁′

, -A₁-CO-A₁′

, -L₁-A₁-Het₁-A₁′

, -L₁-Het₁-CO-A₁′

, -L₁-CO-Het₁-L₁′

, -A₁-Het₁-L₁-A₁′

, -A₁-L₁-Het₁-A₁′ and

-L₁-Het₁-L₁′

;

R₂ is C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkyl or halogen;

R₃ is C₁-C₄ alkyl;

A represents a —

(C₁-C₂ alkylene)-NH—

, —

CO—

NH—

, —

NH—

CO—

, —

CO—

, —

CO—

O—

or —

O—

CO—

group;

B represents —

CO—

NH—

, —

NH—

CO—

, —

NH—

CO₂—

, —

NH—

, —

CO—

, —

NH—

S(O)₂—

, —

(C₁-C₂ alkylene)-NH—

, —

NH—

CO—

NH—

, —

N(CH₃)—

CO—

, —

NH—

CO—

CO—

or a direct bond, provided that when B represents a direct bond, R₄ is -A₄ or -A₄-A₄′

;

n and m are the same or different and each represent 0 or 1;

R₄ is a C₁-C₅alkyl group or a moiety selected from the group consisting of -A₄, -A₄-A₄′

, -L₄-A₄, -A₄-L₄-A₄′

, -A₄-CO-A₄′

- and -L₄-O-L₄′

;

each A₁ moiety is the same or different and represents a phenyl, pyrrolidinyl, indazolyl, pyridyl, indolyl, benzimidazolyl, piperidinyl, thienyl, imidazolyl, furanyl, benzo[1,3]dioxolanyl, piperazinyl, benzothiazolyl, S,S-dioxo-thiomorpholinyl, 1H-benzo[d]imidazol-2(3H)-onyl, cyclopropyl or quinoxalinyl group, wherein (i) when A₁ is a phenyl ring it is unsubstituted or substituted by (a) a single unsubstituted substituent selected from —

CH₂—

X₁, —

CO₂—

R′

″

, —

SO₂NR′

R′

″

, —

CONR′

R′

″

, —

NR′

—

CO—

R′

″

, —

NR′

—

SO₂—

R′

″ and

—

CO—

NR′

—

(C₁-C₂ alkyl)-NR′

R′

″ and

/or (b) 1 or 2 unsubstituted substituents selected from —

CH₂—

X₂ halogen, C₁-C₄ alkyl C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxyy C₁-C₄ hydroxyalkyl, hydroxy, cyano and —

NR′

R″

, wherein X₁ is —

CO₂R′

″

, —

NR′

—

CO₂—

R′

″

or SO₂—

NR′

R′

″

, each X₂ is the same or different and is cyano or —

NR′

R″

, each R′ and

R″

are the same or different and represent hydrogen or C_1-4alkyl and each R′

″

is the same or different and represents C₁-C₄ alkyl and (ii) when A₁ is other than a phenyl group it is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from halogen, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₂ haloalkyl, C₁-C₂ haloalkoxy and hydroxy;

each A₁′

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 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, hydroxy, C₁-C₂ alkyl, C₁-C₂ haloalkyl and C₁-C₂ hydroxyalkyl;

each A₄ moiety is the same or different and is phenyl, furanyl, imidazolyl, pyrazolyl, tetrahydrofuranyl, piperazinyl, piperidinyl, pyrrolidin-2-onyl, thiadiazolyl, isothiazolyl C₃-C₈ cycloalkyl, morpholinyl, thienyl, pyridyl, pyrrolyl, S,S-dioxo-thiomorpholinyl, tetrahydropyranyl, thiazolyl, oxadiazolyl or indazolyl group, each A₄ moiety being unsubstituted or substituted by (a) a single unsubstituted —

CONR′

R′

″

substituent and/or (b) 1 or 2 unsubstituted substituents selected from fluorine, chlorine, bromine, —

NR′

R′

″

, C₁-C₄ alkyl, C₁-C₂ alkoxy, C₁-C₂ haloalkyl and cyano, wherein R′

is hydrogen or C₁-C₄ alkyl and R′

″

represents C₁-C₄ alkyl;

each A₄′

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 which is unsubstituted or substituted by 1 or 2 unsubstituted substituents selected from chlorine, fluorine, bromine, C₁-C₂ alkyl and C₁-C₂ haloalkyl;

each L₁ and L₄ are the same or different and represent a C₁-C₃ alkylene group or a C₁-C₃ hydroxyalkylene group

L₁′

represents hydrogen or a C₁-C₂ alkyl group;

L₄′

represents a C₁-C₂ alkyl group; and

Het₁ represents —

O—

, —

NR′

—

or —

S—

, wherein R′

is hydrogen or C₁-C₂ alkyl.

23. A compound according to claim 21 wherein R₁ is -A₁-L₁-A₁′

.

24. A compound according to claim 23, wherein A₁ is phenyl, L₁ is —

CH₂— and

A₁′

is a morpholino or piperazinyl group which is unsubstituted or substituted by a —

S(O)₂—

(C₁-C₄ alkyl) substituent.

25. A compound according to claim 24, wherein when A₁′

is a piperazinyl group it is a moiety

26. A compound according to claim 25, wherein R₄ is -A₄ or -A₄-L₄-A₄′

.

27. A compound according to claim 26, wherein when R₄ is A₄ it is C₃-C₆ cycloalkyl or when R₄ is -A₄-L₄-A₄′

, A₄ is phenyl, L₄ is —

CH₂— and

A₄′

. is a group

28. A compound according to claim 27, wherein A is —

CO—

NH— and

/or B is —

NH—

CO—

NH—

, —

NH—

CO—

or —

CO—

NH—

.

31. A pharmaceutical composition comprising a biphenyl derivative of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutical acceptable diluent or carrier.

32. A pharmaceutical composition according to claim 31, which further comprises interferon and/or ribavirin.

34. A method of treating or preventing an HCV infection in a patient, which method comprises administering to said patient an effective amount of a biphenyl derivative of claim 1, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, further comprising administering interferon and/or ribavirin.

29-30. -30. (canceled)

33. (canceled)