IL-8 receptor antagonists

Abstract

This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.  
     
         1 . A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 a or b receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         wherein  
         X is oxygen or sulfur;  
         R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;  
         R 1  is independently selected from hydrogen; halogen; nitro; cyano; C 1-10  alkyl; halosubstituted C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ;(CR 8 R 8 )q S(O) t R 4 ;hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryl C 2-10  alkenyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10  alkenyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 1-4 alkyloxy; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 H; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; (CR 8 R 8 )q C(O)OR 11 ; (CR 8 R 8 )q OC(O)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 , (CR 8 R 8 )q NHS(O) 2 R 13 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two R 1  moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;  
         t is 0, or an integer having a value of 1 or 2;  
         s is an integer having a value of 1 to 3;  
         R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclic C 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
         Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )qS(O) t R 4 , (CR 8 R 8 )qOR 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; arylC 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heteroaryl C 2-10  alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )qC(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )qC(O)R 11; C   2-10  alkenylC(O)R 11 ; (CR 8 R 8 )qC(O)OR 11 ; C 2-10 alkenylC(O)OR 11 ; (CR 8 R 8 )qOC(O)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )qNHS(O) 2 R b ; (CR 8 R 8 )qS(O) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
         q is 0 or an integer having a value of 1 to 10;  
         m is an integer having a value of 1 to 3;  
         R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
         R 8  is hydrogen or C 1-4  alkyl;  
         R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
         R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
         R 12  is hydrogen; C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
         R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
         R b  is NR 6 R 7 , alkyl, aryl, aryl C 1-4  alkyl, aryl C 2-4  alkenyl, heteroaryl, heteroaryl C 1-4  alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4  alkyl, heterocyclic C 2-4  alkenyl, or camphor, all of which groups may be optionally substituted;  
         or a pharmaceutically acceptably salt thereof.  
       
     
     
         2 . The method according to  claim 1  wherein the ionizable hydrogen has a pKa of 3 to 10.  
     
     
         3 . The method according to  claim 2  wherein R is hydroxy, carboxylic acid, thiol, —SR 2 —OR 2 , —NH—C(O)R a , —C(O)NR 6 R 7 , —NHS(O) 2 R b , —S(O) 2 NHR c , NHC(X)NHR b , or tetrazolyl; 
 wherein R 2  is a substituted aryl, heteroaryl, or heterocyclic moiety which ring has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;  
 R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
 R a  is an alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, all of which may be optionally substituted;  
 R b  is a NR 6 R 7 , alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, heterocyclic C 2-4 alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; cyano, halosubstituted C 1-4  alkyl; C 1-4  alkyl; C 1-4  alkoxy; C 1-4  amino, NR 9 C(O)R a ; C(O)NR 6 R 7 , S(O) 3 H, or S(O) m ′R a  (wherein m′ is 0, 1, or 2) or C(O)OC 1-4  alkyl;  
 R 9  is hydrogen or a C 1-4  alkyl;  
 R c  is alkyl, aryl, arylC 1-4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4 alkenyl, heterocyclic, heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro,cyano, halosubstituted C 1-4  alkyl, C 1-4  alkyl, C 1-4  alkoxy, C 1-4  amino, NR 9 C(O)R a , C(O)NR 6 R 7 , S(O) 3 H, or C(O)OC 1-4  alkyl.  
 
     
     
         4 . The method according to  claim 3  wherein the R 2  is optionally substituted one to three times by halogen, nitro, halosubstituted C 1-10  alkyl, C 1-10  alkyl, C 1-10  alkoxy, hydroxy, SH, —C(O)NR 6 R 7 , —NH—C(O)R a , —NHS(O)R b , S(O)NR 6 R 7 , C(O)OR 8 , or a tetrazolyl ring.  
     
     
         5 . The method according to  claim 3  wherein R is OH, —NHS(O) 2 R b  or C(O)OH.  
     
     
         6 . The method according to  claim 1  wherein R 1  is halogen, cyano, nitro, CF 3 , C(O)NR 4 R 5 , alkenyl C(O)NR 4 R 5 , C(O) R 4 R 10 , alkenyl C(O)OR 12 , heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR 4 R 5 .  
     
     
         7 . The method according to  claim 1  wherein Y is halogen, C 1-4  alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR 4 R 5 , thioC 1-4 alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C 1-4 alkyl, hydroxy alkyl.  
     
     
         8 . The method according to  claim 1  wherein R is OH, SH, or NHS(O) s R b  and R 1  is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.  
     
     
         9 . The compound according to claims  1  or  8  wherein Y is mono-substituted in the 2′-position or 3′-position, or is disubstituted in the 2′- or 3′-position of a monocyclic ring.  
     
     
         10 . The compound according to claims  1 ,  8  or  9  wherein n amd m are each equal to 1 or more.  
     
     
         11 . The method according to  claim 1  wherein R is a carboxylic acid, and R 1  is hydrogen, or R 1  is substituted in the 4-position.  
     
     
         12 . The method according to  claim 1  wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulo-nephritis, or thrombosis, alzheimers disease, graft vs. host reaction, or allograft rejections.  
     
     
         13 . The method according to  claim 1  wherein the compound, or a pharmaceutically accepatable salt is: 
 N-(2-Hydroxy-4nitrophenyl)-N′-(2-methoxyphenyl)urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2-bromophenyl)urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2-phenylphenyl)urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2-methylthiophenyl)urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2,3-dichlorophenyl)urea  
 N-(2-Hydroxy 4-nitro phenyl) N′-(2-chloro phenyl) urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2,3-methylenedioxyphenyl)urea  
 N-(2-Hydroxy-4-nitrophenyl)-N′-(2-methoxy-3-chlorophenyl)urea  
 N-(2-hydroxy 4-nitro phenyl) N′-(2-phenyloxy phenyl) urea  
 N-(3-Chloro-2-hydroxyphenyl)-N′-(bromophenyl)urea  
 N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N′-(2-bromophenyl)urea  
 N-(3-Nitro-2-hydroxyphenyl)-N′-(2-bromophenyl)urea  
 N-(2-Hydroxy-4-cyanophenyl)-N′-(2-bromophenyl)urea  
 N-(2-Hydroxy-3,4-dichlorophenyl)-N′-(2-bromophenyl)urea  
 N-(3-Cyano-2-hydroxyphenyl)-N′-(2-bromophenyl)urea  
 N-(2-Hydroxy-4-cyanophenyl)-N′-(2-methoxyphenyl)urea  
 N-(2-Hydroxy-4-cyanophenyl)-N′-(2-phenylphenyl)urea  
 N-(2-Hydroxy-4-cyanophenyl-N′-(2,3-dichlorophenyl)urea  
 N-(2-Hydroxy-4-cyanophenyl)-N′-(2-methylphenyl)urea  
 N-(2-Hydroxy-3-cyano-4-methylphenyl)-N′-(2-bromophenyl)urea  
 N-(4-Cyano-2-hydroxyphenyl)-N′-(2-trifluoromethylphenyl)urea  
 N-(3-Trifluoromethyl-2-hydroxyphenyl)-N′-(2-bromophenyl)urea  
 N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N′-(2-bromophenyl)urea  
 N-(2-hydroxy 4-nitro phenyl) N′-(2-iodo phenyl) urea  
 N-(2-hydroxy 4-nitro phenyl) N′(2-bromo phenyl) thiourea  
 N-(2-phenylsulfonamido)-4-cyanophenyl-N′(2-bromo phenyl)urea  
 (E)-N-[3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N′-(2-bromophenyl)urea  
 N-(2-Hydroxy,3,4dichlorophenyl)-N′-(2-methoxyphenyl)urea  
 N-(2-Hydroxy,3,4dichlorophenyl)-N′-(2-phenylphenyl)urea  
 N-(2-Hydroxy-3,4-dichlorophenyl)-N′-(2,3-dichlorophenyl)urea  
 N-(2-Hydroxy-5-nitrophenyl)-N′-(2,3-dichlorophenyl)urea; or  
 N-(2-Hydroxy-3-cyanophenyl)-N′-(2,3 dichlorophenyl)urea.  
 
     
     
         14 . A compound of the formula::  
       
         
           
           
               
               
           
         
         X is oxygen or sulfur;  
         R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;  
         R 1  is independently selected from hydrogen; halogen; nitro; cyano; C 1-10  alkyl; halosubstituted C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ;(CR 8 R 8 )q S(O) t R 4 ;hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryl C 2-10  alkenyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10  alkenyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4  alkyl; heterocyclicC 1-4 alkyloxy; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; (CR 8 R 8 )q C(O)OR 11 ; (CR 8 R 8 )q OC(O)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; (CR 8 R 8 )q NHS(O) 2 R 13 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two R 1  moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;  
         t is 0, or an integer having a value of 1 or 2;  
         s is an integer having a value of 1 to 3;  
         R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclicC 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
         Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )qS(O) t R 4 , (CR 8 R 8 )qOR 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; arylC 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heteroaryl C 2-10  alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )qC(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )qC(O)R 11 ; C 2-10  alkenylC(O)R 11 ; (CR 8 R 8 )qC(O)OR 11 ; C 2-10 alkenylC(O)OR 11 ; (CR 8 R 8 )qOC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q NHS(O) 2 R b ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
         q is 0 or an integer having a value of 1 to 10;  
         n is an integer having a value of 1 to 3;  
         m is an integer having a value of 1 to 3;  
         R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
         R 8  is hydrogen or C 1-4  alkyl;  
         R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
         R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
         R 12  is hydrogen, C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
         R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
         R b  is NR 6 R 7 , alkyl, aryl, aryl C 1-4  alkyl, aryl C 2-4  alkenyl, heteroaryl, heteroaryl C 1-4  alkyd heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4  alkyl, If heterocyclic C 2-4  alkenyl, or camphor, all of which groups may be optionally substituted;  
         E is optionally selected from  
         
           
             
             
                 
                 
             
           
         
         the asterix * denoting point of attachment of the ring, with at least one E being present; or a pharmaceutically acceptably salt thereof.  
       
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 14  and a pharmaceutically acceptable carrier or diluent.  
     
     
         16 . A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 a or b receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula according to  claim 14 .  
     
     
         17 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein  
         X is oxygen or sulfur;  
         R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;  
         R 1  is independently selected from hydrogen; halogen; nitro; cyano; C 1-10  alkyl; halosubstituted C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; S(O) t R 4 ;(CR 8 R 8 )q S(O) t R 4 ; hydroxy; hydroxy substituted C 1-4  alkyl; aryl; aryl C 1-4  alkyl; aryl C 2-10  alkenyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10  alkenyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC-4alkyloxy; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; (CR 8 R 8 )q C(O)OR 11 ; (CR 8 R 8 )q OC(Q)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 , (CR 8 R 8 )q NHS(O) 2 R 13 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two R 1  moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;  
         q is 0 or an integer having a value of 1 to 10;  
         t is 0, or an integer having a value of 1 or 2;  
         s is an integer having a value of 1 to 3;  
         R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclicC 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
         Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )qS(O) t R 4 , (CR 8 R 8 )qOR 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; arylC 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heteroaryl C 2-10  alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )qC(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )qC(O)R 11 ; C 2-10  alkenylC(O)R 11 ; (CR 8 R 8 )qC(O)OR 11 ; C 2-10 alkenylC(O)OR 11 ; (CR 8 R 8 )qOC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q NHS(O) 2 R b ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
         n is an integer having a value of 1 to 3;  
         m is an integer having a value of 1 to 3;  
         R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
         R 8  is hydrogen or C 1-4  alkyl;  
         R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
         R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
         R 12  is hydrogen, C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
         R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
         R b  is NR 6 R 7 , alkyl, aryl, aryl C 1-4  alkyl, aryl C 2-4  alkenyl, heteroaryl, heteroaryl C 1-4  alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4  alkyl, heterocyclic C 2-4  alkenyl, or camphor, all of which groups may be optionally substituted;  
         E is optionally selected from  
         
           
             
             
                 
                 
             
           
         
         the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptably salt thereof.  
       
     
     
         18 . A pharmaceutical composition comprising a compound according to  claim 17  and a pharmaceutically acceptable carrier or diluent.  
     
     
         19 . A method of treating a chemokine mediated disease state, wherein the chemokine binds to an U-8 a or b receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula according to  claim 17 .  
     
     
         20 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein  
         X is oxygen or sulfur;  
         R a  is an alkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, all of which may be optionally substituted;  
         R b  is a NR 6 R 7 , alkyl, aryl, arylC 1-4 alkyl, aryl C 2-4 alkenyl, heteroaryl, heteroarylC 1-4 alkyl, heteroarylC 2-4  alkenyl, heterocyclic, or heterocyclic C 1-4 alkyl, or a heterocyclic C 2-4 alkenyl moiety, camphor, all of which may be optionally substituted one to three times independently by halogen; nitro; halosubstituted C 1-4  alkyl; C 1-4  alkyl; C 1-4  alkoxy; NR 9 C(O)R a ; S(O) m ′ R a , C(O)NR 6 R 7 , S(O) 3 H, or C(O)OC 1-4  alkyl;  
         R 6  and R 7  are independently hydrogen, or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur, which ring may be optionally substitued;  
         R 9  is hydrogen or a C 1-4  alkyl, preferably hydrogen;  
         R 1  is independently selected from hydrogen; halogen; nitro; cyano; C 1-10  alkyl; halosubstituted C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ;(CR 8 R 8 )q S(O) t R 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryl C 2-10  alkenyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10  alkenyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclic C 1-4 alkyloxy; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; (CR 8 R 8 )q C(O)OR 11 ; (CR 8 R 8 )q OC(O)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 , (CR 8 R 8 )q NHS(O) 2 R 13 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two R 1  moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;  
         t is 0, or an integer having a value of 1 or 2;  
         s is an integer having a value of 1 to 3;  
         R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4 alkyl, heterocyclic, heterocyclicC 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
         Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1-10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )qS(O) t R 4 , (CR 8 R 8 )qOR 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryloxy; arylC 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heteroaryl C 2-10  alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )qC(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )qC(O)R 11 ; C 2-10 alkenylC(O)R 11 ; (CR 8 R 8 )qC(O)OR 11 ; C 2-10 alkenylC(O)OR 11 ; (CR 8 R 8 )qOC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q NHS(O) 2 R b ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 ; (CR 8 R 8 )qC(N 4 )R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
         q is 0 or an integer having a value of 1 to 10;  
         n is an integer having a value of 1 to 3;  
         m is an integer having a value of 1 to 3;  
         R 8  is hydrogen or C 1-4  alkyl;  
         R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
         R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
         R 12  is hydrogen, C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
         R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
         or a pharmaceutically acceptably salt thereof.  
       
     
     
         21 . The compound according to  claim 20  wherein R 1  is substituted in the 3-position, the 4-position or di substituted in the 3,4-position by an electron withdrawing moiety.  
     
     
         22 . The compound according to  claim 20  or  21  wherein Y is mono-substituted in the 2′-position or 3′-position, or is disubstituted in the 2′- or 3′-position of a monocyclic ring.  
     
     
         23 . The compound according to  claim 20  or  21  wherein n amd m are each equal to 1 or more.  
     
     
         24 . The compound according to  claim 20  which is 
 N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N′-phenyl urea  
 N-[(2-Phenylsulfamido) 4-cyanophenyl]-N′-(2-bromo phenyl) urea  
 N-(2-(Amino sulfonamido phenyl) phenyl) N′-(2-bromo phenyl) urea N-(2-(Amino sulfonyl styryl) phenyl) N′-(2-bromo phenyl) urea 2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N′-(2-bromo phenyl) urea N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N′-(2-bromo phenyl) urea N-(2-(Amino sulfonyl (2-thiophene) phenyl) N′-(2-bromo phenyl) urea N-(2-(Amino sulfonyl (3-tolyl) phenyl) N′-(2-bromo phenyl) urea N-(2-(Amino sulfonyl (8-quinolinyl)) phenyl)  
 N′-(2-bromo phenyl) urea N-(2-(Amino sulfonyl benzyl) phenyl) N′-(2-bromo phenyl) urea  
 N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N′-(2-bromophenyl)urea  
 N-(2-Bromophenyl)-N′-[2-dimethylaminosulfonylamino]phenyl]urea N-[2-(Phenethylsulfonylamino)phenyl]-N′-(2-bromophenyl)urea N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N′-(2-bromophenyl)ureaN-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N′-(2-bromophenyl)urea  
 N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-([2-[1S)-10-Camphorsulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-[[2-( 1R)-10-Camphorsulfonylamino]phenyl]-N′-(2-bromophenyl)urea  
 N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N′-(2-bromophenyl)urea  
 N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]-N′-(2-bromophenyl)urea; or N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N′-(2-bromo phenyl) urea.  
 
     
     
         25 . A pharmaceutical composition comprising a compound according to any of  claims 20  to  24  and a pharmaceutically acceptable carrier or diluent.  
     
     
         26 . A compound of the formula:  
       
         
           
           
               
               
           
         
         wherein  
         X is oxygen or sulfur;  
         X 1  is oxygen or sulfur;  
         R 1  is independently selected from hydrogen; halogen; nitro; cyano; C 1-10  alkyl; halosubstituted C 1-10 alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10 alkoxy; azide; S(O) t R 4 ;(CR 8 R 8 )q S(O) t R 4 ; hydroxy; hydroxy substituted C 1-4 alkyl; aryl; aryl C 1-4  alkyl; aryl C 2-10  alkenyl; aryloxy; aryl C 1-4  alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C 2-10  alkenyl; heteroaryl C 1-4  alkyloxy; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 1-4 alkyloxy; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )q NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)R 11 ; C 2-10  alkenyl C(O)R 11 ; C 2-10  alkenyl C(O)OR 11 ; (CR 8 R 8 )q C(O)OR 11 ; (CR 8 R 8 )q OC(O)R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 , (CR 8 R 8 )q NHS(O) 2 R 13 ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , or two R 1  moieties together form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;  
         t is 0, or an integer having a value of 1 or 2;  
         s is an integer having a value of 1 to 3;  
         R 4  and R 5  are independently hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 1-4  alkyl, heterocyclic, heterocyclic C 1-4  alkyl, or R 4  and R 5  together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;  
         Y is hydrogen; halogen; nitro; cyano; halosubstituted C 1 - 10  alkyl; C 1-10  alkyl; C 2-10  alkenyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; azide; (CR 8 R 8 )qS(O) t R 4 , (CR 8 R 8 )qOR 4 ; hydroxy; hydroxy substituted C 1-4  alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylC 1-4  alkyloxy; aryl C 2-10  alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1-4  alkyloxy; heteroaryl C 2-10  alkenyl; heterocyclic, heterocyclic C 1-4 alkyl; heterocyclicC 2-10  alkenyl; (CR 8 R 8 )qNR 4 R 5 ; C 2-10  alkenyl C(O)NR 4 R 5 ; (CR 8 R 8 )qC(O)NR 4 R 5 ; (CR 8 R 8 )q C(O)NR 4 R 10 ; S(O) 3 R 8 ; (CR 8 R 8 )qC(O)R 11 ; C 2-10  alkenylC(O)R 11 ; (CR 8 R 8 )qC(O)OR 11 ; C 2-10 alkenylC(O)OR 11 ; (CR 8 R 8 )qOC(O) R 11 ; (CR 8 R 8 )qNR 4 C(O)R 11 ; (CR 8 R 8 )q NHS(O) 2 R b ; (CR 8 R 8 )q S(O) 2 NR 4 R 5 , (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 11 ; or two Y moieties together may form O—(CH 2 ) s O— or a 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally substituted;  
         q is 0 or an integer having a value of 1 to 10;  
         n is an integer having a value of 1 to 3;  
         m is an integer having a value of 1 to 3;  
         R 6  and R 7  are independently hydrogen or a C 1-4  alkyl group, or R 6  and R 7  together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;  
         R 8  is hydrogen or C 1-4  alkyl;  
         R 10  is C 1-10  alkyl C(O) 2 R 8 ;  
         R 11  is hydrogen, optionally substituted C 1-4  alkyl, optionally substituted aryl, optionally substituted aryl C 1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 1-4 alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1-4 alkyl;  
         R 12  is hydrogen, C 1-10  alkyl, optionally substituted aryl or optionally substituted arylalkyl;  
         R 13  is suitably C 1-4  alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclic, or heterocyclicC 1-4 alkyl;  
         R b  is NR 6 R 7 , alkyl, aryl, aryl C 1-4  alkyl, aryl C 2-4  alkenyl, heteroaryl, heteroaryl C 1-4  alkyl, heteroarylC 2-4  alkenyl, heterocyclic, heterocyclic C 1-4  alkyl, heterocyclic C 1-4  alkenyl, or camphor, all of which groups may be optionally, substituted; provided that 
 when n=1 than Y is substituted in the 2- or 3-position;  
 when n=2 than Y is di-substituted in the 2′-3′-position, the 2′-5′-position, the 2′-6′ position, the 3′-5′ or the 3′-6′ position;  
 when n=3 than Y is trisubstituted in the 2′-3′-5′ or the 2′-3′-6′-positions; further provided that  
 when X 1  is O. m=2, R 1  is 2-t-butyl, 4-methyl, and n=3 than Y is not 2′-OH,3′-t-butyl, 5′-methyl;  
 when X 1  is O, m=1, R 1  is 4-methyl, and n=2 than Y is not 2′-OH, 5′-methyl; 
 when X1 is O, m=1, R 1  is hydrogen, and n=2 than Y is not 2′-6′-diethyl;  
 when X 1  is O, m=1, R 1  is 6-OH, and n=2 than Y is not 2′-5′-methyl;  
 when X 1  is S, m=1, R 1  is 4-ethyl, and n=1 than Y is not 2-methoxy;,  
 or a pharmaceutically acceptably salt thereof.  
 
 
       
     
     
         27 . The compound according to  claim 26  wherein R 1  is substituted in the 3-position, the 4-position or di-substituted in the 3,4-position by an electron withdrawing moiety.  
     
     
         28 . The compound according to  claim 26  or  27  wherein Y is mono-substituted in the 2′-position or 3′-position, or is disubstituted in the 2′ or 3′ position of a monocyclic ring.  
     
     
         29 . The compound according to  claim 26  or  27  wherein n amd m are each equal to 1 or more.  
     
     
         30 . A pharmaceutical composition comprising a compound according to any of  claims 26  to  29  and a pharmaceutically acceptable carrier or diluent.  
     
     
         31 . A process for producing a cyano phenol derivative of the formula:  
       
         
           
           
               
               
           
         
         wherein R 1  is as defined for Formula (I) above, which method comprises 
 a) reacting a compound of the formula:  
                     
 wherein X is halogen with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.  
 
       
     
     
         32 . The process according to claim  31  wherein the temperature is about 60 to about 80° C., and X is bromine.