Il-8 receptor antagonists

Abstract

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

What is claimed is: 
     
         1 . A compound according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X is selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, CF 3 , and OCF 3 ; 
         R2 is selected from the group consisting of C 3-6  cycloalkyl, phenyl and heteroaryl, wherein the phenyl or heteroaryl moieties are optionally substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy; or 
         R2 is phenyl substituted by methylenedioxy or phenyl substituted by (di-halo-substituted)-methylenedioxy; 
         R1 is a C 4-8 heterocyclyl(CH 2 ) n — moiety wherein the C 4-8 heterocyclyl is an optionally substituted pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, or azetidin-3-yl, the heterocyclyl moieties being optionally substituted independently, once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, C(O)OR4 and C(O)R5; or 
         R1 is selected from the following ring systems (a-k): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R4 and R5 are, independently, C 1-3 alkyl; 
         n is 0 or 1; and 
         R3 is H or C 1-3 alkyl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . A compound according to  claim 1  wherein X is halogen. 
     
     
         3 . A compound according to  claim 1  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 1-3 alkyl, halogen, OCF 3  and phenyloxy. 
     
     
         5 . A compound according to  claim 4  wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl. 
     
     
         6 . A compound according to  claim 1  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 n is 0. 
     
     
         10 . A compound according to  claim 1  wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety. 
     
     
         11 . A compound according to  claim 1  wherein n is 1, and R1 is a pyrrolidin-3-yl or a ethyl-1-pyrrolidinylcarboxylate moiety. 
     
     
         12 . A compound according to  claim 1  wherein R1 is 3-exo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl or 3-exo-8-azabicyclo[3.2.1]oct-3-yl. 
     
     
         13 . A compound according to  claim 1  wherein the pharmaceutically acceptable salt is a hydrochloride salt. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier or diluent. 
     
     
         15 . A compound according to  claim 1  selected from the group consisting of
 N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-pyridinyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-fluorophenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea; 
 N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(3-fluoro-2-methylphenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(2-ethylphenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-ethylphenyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-ethylphenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-[2-(phenyloxy)phenyl]urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-[2-(phenyloxy)phenyl]urea; 
 ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]-phenyl}sulfonyl)-1-piperidinecarboxylate; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea; 
 N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea; 
 ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea; 
 N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         16 . A compound according to  claim 1  selected from the group consisting of:
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-(3-fluoro-2-methylphenyl)urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2-chloro-3-pyridinyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]-N′-[2-(phenyloxy)phenyl]urea; 
 ethyl 4-{[6-chloro-3-({[(3-fluoro-2-methylphenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 ethyl 4-({6-chloro-2-hydroxy-3-[({[2-(phenyloxy)phenyl]amino}carbonyl)amino]phenyl}sulfonyl)-1-piperidinecarboxylate; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea; 
 N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(4-piperidinylsulfonyl)phenyl]urea; 
 ethyl 4-{[6-chloro-3-({[(2-chloro-3-fluorophenyl)amino]carbonyl}amino)-2-hydroxyphenyl]sulfonyl}-1-piperidinecarboxylate; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea; 
 N-(2-chloro-3-fluorophenyl)-N′-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]urea; and 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea; 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)phenyl]-N′-(2,3-dichlorophenyl)urea; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         17 . A method of synthesizing a compound according to Formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         X is selected from the group consisting of halogen, C 1-3 alkyl, C 1-3 alkoxy, cyano, CF 3 , and OCF 3 ; 
         R2 is selected from the group consisting of C 3-6  cycloalkyl, phenyl and heteroaryl, wherein the phenyl or heteroaryl moieties are optionally substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy; or 
         R2 is phenyl substituted by methylenedioxy or phenyl substituted by (di-halo-substituted)-methylenedioxy; 
         R1 is a C 4-8 heterocyclyl(CH 2 ) n — moiety wherein the C 4-8 heterocyclyl is an optionally substituted pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-4-yl, piperidin-3-yl, or azetidin-3-yl, the heterocyclyl moieties being optionally substituted independently, once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, C(O)OR4 and C(O)R5; or 
         R1 is selected from the following ring systems (a-k): 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R4 and R5 are, independently, C 1-3 alkyl; 
         n is 0 or 1; and 
         R3 is H or C 1-3 alkyl; 
         or a pharmaceutically acceptable salt thereof, 
         comprising the steps of:
 a) oxidizing a sulfide according to Formula (II): 
 
       
       
         
           
           
               
               
           
         
         wherein R1 and X are as defined according to Formula (I), to a sulfone according to Formula (III): 
       
       
         
           
           
               
               
           
         
         
           b) hydrolyzing the sulfone to an aminophenol according to Formula (IV): 
         
       
       
         
           
           
               
               
           
         
         
            and 
           c) exposing the aminophenol to an isocyanate or isocyanate precursor having the formula
   R2C═N═O or R2CON 3 ,
 
 
            to yield the final product, and wherein R2 is as defined for Formula (I); and protecting and de-protecting the R1 moiety by an acid labile protecting group as necessary. 
         
       
     
     
         18 . The process according to  claim 17  wherein the compound of Formula (I) is
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-[2-(phenyloxy)phenyl]urea; or 
 N-{3-[(3-exo)-8-azabicyclo[3.2.1]oct-3-ylsulfonyl]-4-chloro-2-hydroxyphenyl}-N′-(2-chloro-3-fluorophenyl)urea; or a pharmaceutically acceptable salt thereof. 
 
     
     
         19 . The process according to  claim 17  wherein the compound of Formula (I) is
 N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3-pyrrolidinylmethyl)sulfonyl]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-ethylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2,2-difluoro-1,3-benzodioxol-4-yl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-{2-[(trifluoromethyl)oxy]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(2-chloro-3-pyridinyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea; 
 N-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}-N′-[2-(phenyloxy)phenyl]urea; 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-pyrrolidinylsulfonyl]phenyl}urea; or 
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3R)-3-pyrrolidinylsulfonyl]phenyl}urea; or a pharmaceutically acceptable salt thereof. 
 
     
     
         20 . The process according to  claim 17  wherein the compound of Formula (I) is
 N-(2-chloro-3-fluorophenyl)-N′-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}urea; 
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea, or 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′-(3-fluoro-2-methylphenyl)urea, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         21 . The process according to  claim 17  wherein the compound of Formula (I) is
 N-{4-chloro-2-hydroxy-3-[(3S)-3-piperidinylsulfonyl]phenyl}-N′-(3-fluoro-2-methylphenyl)urea, or 
 N-[4-chloro-2-hydroxy-3-(3-piperidinylsulfonyl)-phenyl]-N′-(3-fluoro-2-methylphenyl)urea, 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         22 . The process according to  claim 17  wherein n is 0 and R1 is a piperidine-3-yl or piperidine-4-yl moiety. 
     
     
         23 . The process according to  claim 17  wherein R2 is phenyl optionally substituted, independently once or twice, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, OCF 3  and phenyloxy. 
     
     
         24 . The process according to  claim 17  wherein R2 is selected from the group consisting of 3-fluoro-2-methylphenyl, 2-trifluoromethyloxyphenyl, 2-chloro-3-fluorophenyl, 2-ethylphenyl and 2-phenyloxyphenyl. 
     
     
         25 . The process according to  claim 17  wherein n=0 and R1 is a 3-azetidinyl, 4-piperidinyl, 3-piperidinyl, 3-pyrrolidinyl or ethyl-1-pyrrolidinylcarboxylate. 
     
     
         26 . The process according to  claim 17  wherein R1 is an optionally substituted piperidine-3-yl. 
     
     
         27 . The process according to  claim 26  wherein X is halogen. 
     
     
         28 . The process according to  claim 27  wherein R2 is a phenyl substituted, once or twice, independently, by a substituent selected from the group consisting of C 1-3 alkyl, halogen, CF 3 , OCF 3 , phenyloxy and benzyloxy. 
     
     
         29 . A compound which is
 N-(4-chloro-2-hydroxy-3-{[(3-exo)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]sulfonyl}phenyl)-N′-(3-fluoro-2-methylphenyl)urea;   N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-pyridinyl)urea;   N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(2-chloro-3-fluorophenyl)urea; or   N-[3-(3-azetidinylsulfonyl)-4-chloro-2-hydroxyphenyl]-N′-(3-fluoro-2-methylphenyl)urea; or a pharmaceutically acceptable salt thereof.   
     
     
         30 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         31 . A method of treating a chemokine mediated disease, wherein the chemokine binds to an IL-8 α or β receptor in a mammal, which method comprises administering to said mammal an effective amount of a compound according to  claim 1 .