Heterocyclic Compounds as CCR2 Antagonists

Abstract

Compounds of formula (I) Q-L-W—C(═X)—Z—P wherein Q is an amine of the formula —N(R 1 )(R 2 ); L is an alkyl or heterocyclyl-alkyl linker; W is a 6- or 7-membered aliphatic ring comprising ring atoms Y 1 and Y 2 which are linked to groups L and C(X) respectively and Y 1 and Y 2 are independently selected from N and C; X is O, N, N—CN or S; Z is NR 3 ; P is an optionally substituted monocyclic or bicyclic aryl or heteroaryl group; and pharmaceutically acceptable salts or solvates thereof, are useful in the treatment of C—C chemokine mediated conditions.

1 - 12 . (canceled) 
     
     
         13 . A method comprising treating human diseases or conditions in which modulating chemokine receptor activity is beneficial by administering to a human in need thereof a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein
 R 2  is selected from hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, cycloalkyl-alkyl of up to 14 ring and chain atoms, heterocyclyl of up to 7 ring atoms, heterocyclyl-alkyl of up to 14 ring and chain atoms, heterocyclyl-cycloalkyl of up to 14 ring atoms, heterocyclyl-heterocyclyl-alkyl of up to 20 ring and chain atoms, heterocyclyl-aryl-alkyl of up to 20 ring and chain atoms, heterocyclyl-aryl of up to 20 ring atoms; aryl-alkyl of up to 14 ring and chain atoms, aryl-heterocyclyl-alkyl of up to 20 ring and chain atoms, aryl-oxy-alkyl of up to 14 ring and chain atoms, aryl-cycloalkyl of up to 14 ring atoms, and aryl-aryl-alkyl of up to 20 ring and chain atoms; 
 and wherein each chain or ring is independently optionally substituted by up to 3 substituents each independently selected from halogen, hydroxy, C 1-6  alkyl, C 1-4 alkoxy optionally substituted by C 1-4 alkoxy, cyano, C 1-4 alkylsulfonyl, trifluoromethyl, carboxy, C 1-4  alkoxycarbonyl, C 1-2 alkyloxycarbonylphenyl, phenyl, NH 2 , NO 2 , ═O, C 1-4  alkylcarbonyl, C 3-7  cycloalkyl-heteroaryl of up to 10 ring atoms, and a nitrogen atom of a heteroaromatic ring may be substituted by an oxide group; and 
 P is a phenyl optionally substituted by 1 or 2 substituents independently selected from halogen, C 1-4  alkyl, cyano, trifluoromethyl, C 1-4  alkoxy, and trifluoromethylthio. 
 
       
     
     
         14 . The method according to  claim 13  wherein said human diseases or conditions are selected from neuropathic pain, asthma, allergic rhinitis, COPD, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, or psoriasis. 
     
     
         15 . The method according to  claim 13 , wherein said disease or condition is neuropathic pain. 
     
     
         16 . The method according to  claim 13 , wherein said disease or condition is diabetic neuropathy. 
     
     
         17 - 26 . (canceled) 
     
     
         27 . The method according to  claim 13 , wherein said disease or condition is post-herpetic neuropathy. 
     
     
         28 . The method according to  claim 13 , wherein said disease or condition is COPD. 
     
     
         29 . The method according to  claim 13 , wherein said disease or condition is asthma. 
     
     
         30 . A method comprising treating human diseases or conditions in which modulating chemokine receptor activity is beneficial by administering to a human in need thereof a pharmaceutical composition comprising (i) a compound of formula (I), or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein
 R 2  is selected from hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, C 2-6  alkenyl, C 2-6  alkynyl, cycloalkyl-alkyl of up to 14 ring and chain atoms, heterocyclyl of up to 7 ring atoms, heterocyclyl-alkyl of up to 14 ring and chain atoms, heterocyclyl-cycloalkyl of up to 14 ring atoms, heterocyclyl-heterocyclyl-alkyl of up to 20 ring and chain atoms, heterocyclyl-aryl-alkyl of up to 20 ring and chain atoms, heterocyclyl-aryl of up to 20 ring atoms; aryl-alkyl of up to 14 ring and chain atoms, aryl-heterocyclyl-alkyl of up to 20 ring and chain atoms, aryl-oxy-alkyl of up to 14 ring and chain atoms, aryl-cycloalkyl of up to 14 ring atoms, and aryl-aryl-alkyl of up to 20 ring and chain atoms; 
 and wherein each chain or ring is independently optionally substituted by up to 3 substituents each independently selected from halogen, hydroxy, C 1-6  alkyl, C 1-4  alkoxy optionally substituted by C 1-4  alkoxy, cyano, C 1-4  alkylsulfonyl, trifluoromethyl, carboxy, C 1-4  alkoxycarbonyl, C 1-2 alkyloxycarbonylphenyl, phenyl, NH 2 , NO 2 , ═O, C 1-4 alkylcarbonyl, C 3-7  cycloalkyl-heteroaryl of up to 10 ring atoms, and a nitrogen atom of a heteroaromatic ring may be substituted by an oxide group; and 
 
         P is a phenyl optionally substituted by 1 or 2 substituents independently selected from halogen, C 1-4  alkyl, cyano, trifluoromethyl, C 1-4  alkoxy, and trifluoromethylthio; and 
         (ii) a pharmaceutically-acceptable diluent or carrier. 
       
     
     
         31 . The method according to  claim 30 , wherein said human diseases or conditions are selected from neuropathic pain, asthma, allergic rhinitis, COPD, inflammatory bowel disease, irritable bowel syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis, or psoriasis. 
     
     
         32 . The method according to  claim 30 , wherein said disease or condition is neuropathic pain. 
     
     
         33 . The method according to  claim 30 , wherein said disease or condition is diabetic neuropathy. 
     
     
         34 . The method according to  claim 30 , wherein said disease or condition is post-herpetic neuropathy. 
     
     
         35 . The method according to  claim 30 , wherein said disease or condition is COPD. 
     
     
         36 . The method according to  claim 30 , wherein said disease or condition is asthma.