IL-8 Receptor Antagonists

• US 20090298810A1
• Filed: 04/20/2007
• Published: 12/03/2009
• Est. Priority Date: 04/21/2006
• Status: Active Grant

• Current Assignee: GlaxoSmithKline LLC (GSK plc)
• Original Assignee: Smithkline Beecham Corporation (GSK plc)
• Inventors: Busch-Petersen, Jakob
• Granted Patent: US 8,097,626 B2
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 451/04 with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 453/02 : containing not further condensed quinuclidine ring systems
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

This invention relates to novel compounds and compositions thereof, useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (II-8).

Claims

1. A compound according to Formula (I):

2. A compound according to claim 1 wherein X is halogen.

3. A compound according to claim 2 wherein X is chlorine.

4. A compound according to claim 1 wherein R2 is phenyl, optionally substituted, independently, once or twice, by a substituent selected from the group consisting of C_1-3alkyl, halogen, OCF₃ and phenyloxy.

5. A compound according to claim 1 wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl or 2-phenoxyphenyl.

6. A compound according to claim 5 wherein R2 is 3-fluoro-2-methylphenyl, or 2-chloro-3-fluorophenyl.

7. A compound according to claim 1 wherein R2 is pyridyl, optionally substituted once by halogen.

8. A compound according to claim 7 wherein R2 is 2-chloro-3-pyridyl.

9. A compound according to claim 1 wherein the R1 ring is selected from the group consisting of:

octahydro-5H-pyrrolo[3,2-c]pyridyl;

1-azabicyclo[2.2.2]octane-3-aminyl;

3,7-diazabicyclo[3.3.1]nonyl;

8-azabicyclo[3.2.1]octyl;

3-oxo-8-azabicyclo[3.2.1]octyl;

3-(hydroxyimino)-8-azabicyclo[3.2.1]octyl;

3,8-diazabicyclo[3.2.1]octyl;

3-(alkylamino)-8-azabicyclo[3.2.1]octyl;

5,6-dihydroimidazo[1,2-a]pyrazinyl;

3,8-diazabicyclo[3.2.1]octyl;

1,8-diazaspiro[4.5]decyl; and

2,5-diazabicyclo[2.2.1]heptyl;

10. A compound according to claim 1 wherein R1 is selected from the group consisting of:

2,5-diazabicyclo[2.2.1]heptan-2-yl;

1,8-diazaspiro[4.5]decan-8-yl;

3,8-diazabicyclo[3.2.1]octan-3-yl;

,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl;

3-amino-8-azabicyclo[3.2.1]octane;

3,8-diazabicyclo[3.2.1]octan-3-yl;

3-(hydroxyimino)-8-azabicyclo[3.2.1]octan-8-yl;

3-oxo-8-azabicyclo[3.2.1]octan-8-yl;

8-azabicyclo[3.2.1]octan-3-aminyl;

3,7-diazabicyclo[3.3.1]nonan-3-yl;

1-azabicyclo[2.2.2]octan-3-aminyl; and

octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl.

11. A compound according to claim 1 which is:

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-{2-[(phenylmethyl)oxy]phenyl}urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-{4-chloro-3-[(1S,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)-N′

-{2-[(phenylmethyl)oxy]phenyl}urea;

N-(4-chloro-3-{[(1S,4S)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(cyclopropylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(hydroxyimino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-[2-(phenyloxy)phenyl]urea;

N-(3-{[(1R,5S)-3-(butylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-4-chloro-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-(3-{[(1R,5S)-3-(butylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-4-chloro-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(propylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-3-({(1R,5S)-3-[(cyclopropylmethyl)amino]-8-azabicyclo[3.2.1]oct-8-yl}sulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-3-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-(4-chloro-3-{[(1S,4S)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)urea;

N-(3-{[(1R,5S)-3-(butylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-4-chloro-2-hydroxyphenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-{4-chloro-3-[(1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-pyridinyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(2-chloro-3-pyridinyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5R)-3-(phenylmethyl)-3,8-diazabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-[2-(phenyloxy)phenyl]urea;

N-[4-chloro-3-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-ethylphenyl)urea;

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-ethylphenyl)urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-{2-[(trifluoromethyl)oxy]phenyl}urea;

6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxy-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]benzenesulfonamide;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(2,2-difluoro-1,3-benzodioxol-4-yl)urea;

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-ethylphenyl)urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-ethylphenyl)urea;

N-{4-chloro-3-[(1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-ethylphenyl)urea;

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-ylsulfonyl]-2-hydroxyphenyl}-N′

-{2-chloro-3-fluorophenyl}urea;

N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxybenzenesulfonamide;

N-{4-chloro-3-[(1S,5S)-3,7-diazabicyclo[3.3.1]non-3-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]benzenesulfonamide;

N-[(3S)-1-azabicyclo[2.2.2]oct-3-yl]-6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxybenzenesulfonamide;

N-(4-chloro-2-hydroxy-3-{[(1R,5R)-8-(phenylmethyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-3-[(1R,5S)-3,7-diazabicyclo[3.3.1]non-3-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-pyridinyl)urea;

6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxy-N-[(3-endo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]benzenesulfonamide;

N-(2-chloro-3-fluorophenyl)-N′

-[4-chloro-2-hydroxy-3-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-ylsulfonyl)phenyl]urea;

N-[4-chloro-2-hydroxy-3-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-ylsulfonyl)phenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-[4-chloro-2-hydroxy-3-(octahydro-5H-pyrrolo[3,2-c]pyridin-5-ylsulfonyl)phenyl]-N′

-(2-chloro-3-pyridinyl)urea;

N-(4-chloro-3-{[(1S,4S)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}-2-hydroxyphenyl)-N′

-{2-[(phenylmethyl)oxy]phenyl}urea;

N-[(3-exo)-8-azabicyclo[3.2.1]oct-3-yl]-6-chloro-3-({[(2,2-difluoro-1,3-benzodioxol-4-yl)amino]carbonyl}amino)-2-hydroxybenzenesulfonamide;

or

N-[(1R,5S)-8-azabicyclo[3.2.1]oct-3-yl]-6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxybenzenesulfonamide;

or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 11 which is:

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-ylsulfonyl]-2-hydroxyphenyl}-N′

-{2-chloro-3-fluorophenyl}urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-{2-[(phenylmethyl)oxy]phenyl}urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-{4-chloro-3-[(1S,4R)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(1,8-diazaspiro[4.5]dec-8-ylsulfonyl)-2-hydroxyphenyl]-N′

-(2-chloro-3-fluorophenyl)urea;

N-(2-chloro-3-fluorophenyl)-N′

-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-(2-hydroxyethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)urea;

N-{4-chloro-3-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylsulfonyl]-2-hydroxyphenyl}-N′

-[2-(phenyloxy)phenyl]urea;

N-(4-chloro-2-hydroxy-3-{[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}phenyl)-N′

-{2-[(phenylmethyl)oxy]phenyl}urea;

N-(4-chloro-3-{[(1S,4S)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(cyclopropylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(hydroxyimino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-[2-(phenyloxy)phenyl]urea;

N-(3-{[(1R,5S)-3-(butylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-4-chloro-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

or

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 which is:

N-{4-chloro-3-[(1R,5S)-3,8-diazabicyclo[3.2.1]oct-8-ylsulfonyl]-2-hydroxyphenyl}-N′

-{2-chloro-3-fluorophenyl}urea;

N-(4-chloro-3-{[(1S,4S)-5-(cyclopropylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(methylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(cyclopropylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-(hydroxyimino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

N-(4-chloro-3-{[(1R,5S)-3-(ethylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

N-[4-chloro-3-(3,8-diazabicyclo[3.2.1]oct-3-ylsulfonyl)-2-hydroxyphenyl]-N′

-[2-(phenyloxy)phenyl]urea;

N-(3-{[(1R,5S)-3-(butylamino)-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}-4-chloro-2-hydroxyphenyl)-N′

-(2-chloro-3-fluorophenyl)urea;

or

N-(4-chloro-2-hydroxy-3-{[(1R,5S)-3-oxo-8-azabicyclo[3.2.1]oct-8-yl]sulfonyl}phenyl)-N′

-(3-fluoro-2-methylphenyl)urea;

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

20. A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 β

receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound according to claim 1.

21. The method according to claim 20 wherein the mammal is afflicted with a chemokine mediated disease selected from the group consisting of psoriasis, atopic dermatitis, osteoarthritis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer'"'"'s disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, viral diseases such as rhinovirus and undesired hematopoietic stem cell release.

22. The method according to claim 21 wherein the mammal is afflicted with asthma, chronic obstructive pulmonary disease, or adult respiratory distress syndrome.

23. The method according to claim 22 wherein the mammal is afflicted with chronic obstructive pulmonary disease.

26. A method of synthesizing a compound according to claim 1 comprising the steps of:

a) hydrolyzing a benzoxazole according to formula (II);

30. The compound according to claim 9 wherein each R1 ring system having an R3 substituent group is optionally substituted independently, by C_1-6alkyl, C_1-6alkoxy, C_3-7cycloalkyl, C_3-7cycloalkyl C_1-3-alkyl, or phenylC_1-3-alkyl;

and wherein for each R1 ring system having a Z1 substituent group, Z1 is CHNR8, and the R8 moiety is selected from a C_1-5alkyl, C_3-5cycloalkyl or C_3-5cycloalkylC_1-5 alkyl.

31. The compound according to claim 10 wherein each R1 ring system having an R3 substituent group is optionally substituted independently by methyl, ethyl, propyl, butyl, C₂H₄OH, C₃H₆OH, cyclopropyl, cyclopropylmethyl, or phenylmethyl;

and wherein for each R1 ring system having a Z1 substituent group, Z1 is CHNR8, and the R8 moiety is selected from methyl, ethyl, propyl, butyl, cyclopropyl or cyclopropylmethyl.

32. A pharmaceutical composition comprising a compound according to claim 11 and a pharmaceutically acceptable carrier or diluent.

15-19. -19. (canceled)

24-25. -25. (canceled)

27. An intermediate according to formula (II) or (III):

28. (canceled)

29. (canceled)