Cyclic pyrimidin-4-carboxamides as ccr2 receptor antagonists for treatment of inflammation, asthma and copd

Abstract

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD. Formula (I), wherein A is selected from among a single bond, ═CH—, —CH 2 —, —O—, —S—, and —NH—; wherein n is 1, 2 or 3; wherein Z is C or N, the other variables are as defined in the claims, as well as in form of their acid addition salts with pharmacologically acceptable acids.

1 . A compound according to formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is -L 1 -R 7 , 
         wherein L 1  is a linker selected from a bond or a group selected from among —C 1 -C 2 -alkylene, and —C 1 -C 2 -alkenylene which optionally comprises one or more groups selected from —O—, —C(O)—, and —NH— in the chain and which is optionally substituted by a group selected from among —OH, —NH 2 , —C 1 -C 3 -alkyl, O—C 1 -C 6 -alkyl, and —CN, 
         wherein R 7  is a ring selected from among —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, —C 5 -C 10 -aryl, and —C 5 -C 10 -heteroaryl, 
         wherein the ring R 7  is optionally substituted with one or more groups selected from among —CF 3 , —O—CF 3 , —CN, and -halogen, 
         or wherein the ring R 7  is optionally substituted with one or more groups selected from among —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, —C 1 -C 6 -alkenyl, and —C 1 -C 6 -alkynyl, optionally being substituted by one or more groups selected from among —OH, —NH 2 , —C 1 -C 3 -alkyl, —O—C 1 -C 6 -alkyl, —CN, —CF 3 , —OCF 3 , halogen, and ═O, 
         or wherein the ring R 7  is optionally further bi-valently substituted on two neighbouring ring atoms, such that an annellated ring is formed by one or more groups selected from among —C 1 -C 6 -alkylene, —C 2 -C 6 -alkenylene and —C 4 -C 6 -alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, O and S, the bivalent group being optionally substituted by one or more groups selected from —OH, —NH 2 , —C 1 -C 3 -alkyl, —O—C 1 -C 6 -alkyl, —CN, —CF 3 , —OCF 3 , halogen, and ═O; 
         wherein R 2  is selected from among —H, -halogen, —CN, —O—C 1 -C 4 -alkyl, —C 1 -C 4 -alkyl, —CH═CH 2 , —C≡CH, —CF 3 , —OCF 3 , —OCF 2 H, and —OCFH 2 ; 
         wherein R 3  is selected from among —H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, —OCH 3 , and —CN; 
         wherein R 4  and R 5  are independently selected from among an electron pair, —H, and a group selected from among —C 1 -C 6 -alkyl, —NH 2 , —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, and —C(O)—N(R 8 ,R 8′ ), with R 8  and R 8′  independently being selected from among —H, and —C 1 -C 6 -alkyl, 
         and wherein R 4  and R 5  if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF 3 , —CN, —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —O—C 3 -C 8 -cycloalkyl, —O—C 3 -C 8 -heterocyclyl, —O—C 5 -C 10 -aryl, —O—C 5 -C 10 -heteroaryl, —C 0 -C 6 -alkylene-CN, —C 0 -C 4 -alkylene-O—C 1 -C 4 -alkyl, —C 0 -C 4 -alkylene-O—C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-O—C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-O—C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-O—C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-Q-C 0 -C 4 -alkyl-N(R 9 ,R 9′ ), —C 0 -C 4 -alkylene-N(R 10 )-Q-C 1 -C 4 -alkyl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-N(R 10 )-Q—C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-Q-N(R 11 ,R 11′ ), —C 0 -C 4 -alkylen-N(R 12 )-Q-N(R 13 ,R 13′ ), —C 0 -C 4 -alkylen-R 14 , —C 0 -C 4 -alkylene-Q-C 1 -C 6 -alkyl, —C 0 -C 4 -alkylene-Q-C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-Q-C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-Q-C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-Q-C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-O-Q-N(R 15 ,R 15′ ), and —C 0 -C 4 -alkylene-N(R 16 )-Q-O—(R 17 ), 
         wherein Q is selected from among —C(O)—, and —SO 2 —, 
         wherein R 12 , R 16 , are independently selected from among —H, —C 1 -C 6 -alkyl, and —C 3 -C 6 -cycloalkyl, 
         wherein R 9 , R 9′ , R 10 , R 11 , R 11′ , R 13 , R 13′ , R 15 , R 15′ , are independently selected from among —H, —C 1 -C 6 -alkyl, and —C 3 -C 6 -cycloalkyl, 
         or wherein R 9  and R 9′ , R 11  and R 11′ , R 13  and R 13′ , R 15  and R 15′  together form a —C 2 -C 6 -alkylene group, 
         wherein R 14  and R 17  are independently selected from among —H, —C 1 -C 6 -alkyl, —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, and —C 3 -C 8 -heterocyclyl, wherein said —C 3 -C 8 -heterocyclyl optionally comprises nitrogen and/or —SO 2 — in the ring, 
         and wherein R 14  and R 17  are optionally substituted with one or more groups selected from among —OH, —OCH 3 , —CF 3 , —OCF 3 , —CN, -halogen, —C 1 -C 4 -alkyl, ═O, and —SO 2 —C 1 -C 4 -alkyl, 
         or wherein R 4  and/or R 5  are independently a group of the structure -L 2 -R 18 , 
         wherein L 2  is selected from among —NH— and —N(C 1 -C 4 -alkyl)-, 
         wherein R 18  is selected from among —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, and —C 3 -C 8 -heterocyclyl, 
         wherein R 18  is optionally substituted by one or more groups selected from among halogen, —CF 3 , —OCF 3 , —CN, —OH, —O—C 1 -C 4 -alkyl, —C 1 -C 6 -alkyl, —NH—C(O)—C 1 -C 6 -alkyl, —N(C 1 -C 4 -alkyl)-C(O)—C 1 -C 6 -alkyl, —C(O)—C 1 -C 6 -alkyl, —S(O) 2 —C 1 -C 6 -alkyl, —NH—S(O) 2 —C 1 -C 6 -alkyl, —N(C 1 -C 4 -alkyl)-S(O) 2 —C 1 -C 6 -alkyl, and —C(O)—O—C 1 -C 6 -alkyl, and wherein R 4 , R 5  and R 18  are optionally further substituted by spiro-C 3 -C 8 -cycloalkyl or spiro-C 3 -C 8 -heterocyclyl such that together with R 4 , R 5  and/or R 18  a spirocycle is formed, wherein said spiro-C 3 -C 8 -heterocyclyl optionally comprises one or more groups selected from among nitrogen, —C(O)—, —SO 2 —, and —N(SO 2 —C 1 -C 4 -alkyl)- in the ring, or wherein R 4 , R 5  and R 18  are optionally further bi-valently substituted by one or more spirocyclic or annellated ring forming groups selected from among —C 1 -C 6 -alkylene, —C 2 -C 6 -alkenylene, and —C 4 -C 6 -alkynylene, in which one or two carbon centers may optionally be replaced by one or two hetero atoms selected from among N, O and S and which may optionally be substituted by one or more groups on one ring atom or on two neighbouring ring atoms selected from among —OH, —NH 2 , —C 1 -C 3 -alkyl, O—C 1 -C 6 -alkyl, —CN, —CF 3 , —OCF 3 , and halogen; 
         wherein R 6  is selected from among —H, —C 1 -C 4 -alkyl, —OH, —O—C 1 -C 4 -alkyl, -halogen, —CN, —CF 3 , and —OCF 3 ; 
         wherein A is selected from among a single bond, ═CH—, —CH 2 —, —O—, —S—, and —NH—; 
         wherein n is 1, 2 or 3; 
         wherein Z is C or N, 
         as well as in form of their acid addition salts with pharmacologically acceptable acids. 
       
     
     
         2 . The compound of  claim 1 ,
 wherein   R 1  is -L 1 -R 7 ,   and wherein L 1  is a bond or a group selected from among methylene, ethylene, methenylene, and ethenylene,   and wherein R 7  is a ring selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridyl, and furanyl,   wherein L 1  if different from a bond is optionally substituted with one or more groups selected from among methyl, and ethyl,   wherein L 1  if different from a bond optionally comprises one or more —O— atoms,   wherein the ring R 7  is optionally substituted with one or more groups selected from among —F, —Cl, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, -t-butyl, —CF 3 , —O—CF 3 , —CN, —O-methyl, furanyl and phenyl, wherein said furanyl and said phenyl are optionally independently substituted by one or more groups selected from among —C 1 -C 3 -alkyl, halogen, —OCH 3 , —CF 3 , and —OCF 3 ,   or wherein the ring R 7  is bi-valently substituted by one or more groups selected from among   
       
         
           
           
               
               
           
         
         on two neighbouring ring atoms, such that an annellated ring is formed. 
       
     
     
         3 . The compound of  claim 1 , wherein R 1  is selected from among 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein R 2  is selected from among —H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH 2 , —C≡CH, and —OCH 3 . 
     
     
         5 . The compound of  claim 1 , wherein R 2  is selected from among —H, -Methyl, -Ethyl, —Br, and —OCH 3 . 
     
     
         6 . The compound of  claim 1 , wherein R 3  is selected from among —H, and -methyl. 
     
     
         7 . The compound of  claim 1 , wherein R 4  and R 5  are independently selected from among an electron pair, —H, and a group selected from among-1-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and —C(O)—N(R 8 ,R 8′ ), with R 8  and R 8′  independently being selected from among —H and —C 1 -C 6 -alkyl,
 wherein R 4  and R 5  if different from an electron pair, and —H are optionally independently substituted with one or more groups selected from among -fluoro, -methyl, -ethyl, propyl, -1-propyl, -butyl, -1-butyl, -t-butyl, -hydroxy, —CF 3 , —OCF 3 , —CN, —O—CH 3 , —O—C 2 H 5 , —O—C 3 H 7 , —CH 2 —CN, —CH 2 —O—CH 3 , —(CH 2 ) 2 —O—CH 3 , —C(O)—CH 3 , —C(O)—C 2 H 5 , —C(O)—C 3 H 7 , —COOH, —C(O)—NH 2 , —C(O)—NH—CH 3 , —C(O)—N(CH 3 ) 2 , —NH—C(O)—CH 3 , —N(CH 3 )C(O)—CH 3 , —NH—C(O)—C 2 H 5 , —N(CH 3 )—C(O)—C 2 H 5 , —NH—C(O)—C 3 H 7 , —N(CH 3 )—C(O)—C 3 H 7 , —NH—SO 2 —CH 3 , —N(CH 3 )—SO 2 —CH 3 , —N(C 2 H 5 )—SO 2 —CH 3 , —N(C 3 H 7 )—SO 2 —CH 3 , —NH—SO 2   −  C 2 H 5 , —N(CH 3 )—SO 2 —C 2 H 5 , —N(C 2 H 5 )—SO 2 —C 2 H 5 , —N(C 3 H 7 )—SO 2 —C 2 H 5 , —H—SO 2 —C 3 H 7 , —N(CH 3 )—SO 2 —C 3 H 7 , —N(C 2 H 5 )—SO 2 —C 3 H 7 , —N(C 3 H 7 )—SO 2 —C 3 H 7 , —NH—SO 2 —C 3 H 5 , —N(CH 3 ) SO 2 —C 3 H 5 , —N(C 2 H 5 )—SO 2 —C 3 H 5 , —N(C 3 H 7 )—SO 2 —C 2 H 5 , —CH 2 —NH—SO 2 —CH 3 , —CH 2 —N(CH 3 ) SO 2 —CH 3 , —CH 2 —NH—SO 2 —C 2 H 5 , —CH 2 —N(CH 3 )—SO 2 —C 2 H 5 , —CH 2 —NH—SO 2 —C 3 H 7 , —CH 2 —N(CH 3 )—SO 2 —C 3 H 7 , —CH 2 —NH—SO 2 —C 3 H 5 , —CH 2 —N(CH 3 )—SO 2 —C 3 H 5 , —NH—C(O)—NH 2 , —N(CH 3 )—C(O)—NH 2 , —NH—C(O)—NH—CH 3 , —N(CH 3 )—C(O)—NH—CH 3 , —NH—C(O)—N(CH 3 ) 2 , —N(CH 3 )—C(O)—N(CH 3 ) 2 , —SO 2 —NH 2 , —SO 2 —NH(CH 3 ), —SO 2 —N(CH 3 ) 2 , —C(O)—NH—C 2 H 5 , —C(O)—N(CH 3 )—C 2 H 5 , —C(O)—N(CH 3 )—C 3 H 7 , —C(O)—N(CH 3 )—C 4 H 9 , —C(O)—NH—CH(CH 3 )—C 2 H 5 , —C(O)—N(CH 3 )—CH(CH 3 )—C 2 H 5 , —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—NH—CH 3 , —CH 2 —C(O)—N(CH 3 ) 2 , —N(CH 3)—SO   2 —N(CH 3 ) 2 , -phenyl, -pyridin-4-yl, —CH 2 -3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl, 
 
       
         
           
           
               
               
           
         
         or wherein R 4  and R 5  are independently a group of the structure -L 2 -R 18 , 
         wherein L 2  is selected from among —NH—, —N(CH 3 )—, and —N(C 2 H 5 )—, 
         and wherein R 18  is selected from among -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl, -octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and -tetrahydro-naphthyridinyl, 
         wherein R 18  is optionally substituted by one or more groups selected from among —F, —CF 3 , —OCF 3 , —CN, —OH, —O—CH 3 , —CH 3 , —NH—C(O)—CH 3 , —N(CH 3 )—C(O)—CH 3 , —C(O)—CH 3 , —S(O) 2 —CH 3 , —NH—S(O) 2 —CH 3 , —N(CH 3 )—S(O) 2 —CH 3 , and —C(O)—O—C 2 H 5 , 
         and wherein R 4 , R 5  and R 18  are optionally further bi-valently substituted by one or more groups selected from among 
       
       
         
           
           
               
               
           
         
         on one ring atom or on two neighboring ring atoms, such that spirocyclic or annellated rings are formed. 
       
     
     
         8 . The compound of  claim 1 , wherein R 4  is selected from among 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein R 5  is selected from among an electron pair, —H, and —C(O)—NH 2 . 
     
     
         10 . The compound of  claim 1 , wherein R 6  is selected from among —H, —CH 3 , —C 2 H 5 , —O—CH 3 , —O—C 2 H 5 , —F, —CF 3 , and —OCF 3 . 
     
     
         11 . The compound of  claim 1 , wherein R 6  is H or —O—CH 3 . 
     
     
         12 . The compound of  claim 1 , wherein A is selected from a single bond, ═CH—, —CH 2 , —O— or —NH—. 
     
     
         13 . The compound of  claim 1 , wherein A is selected from among —O— and —NH—. 
     
     
         14 . The compound of  claim 1 , wherein A is —NH—. 
     
     
         15 . The compound of  claim 1 , wherein Z is C or N. 
     
     
         16 . (canceled) 
     
     
         17 . A method for the treatment of inflammatory diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmacologically acceptable salt thereof. 
     
     
         18 . The method according to  claim 17 , wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. 
     
     
         19 . The method according to  claim 18 , wherein the diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis. 
     
     
         20 . A method for the treatment of neurologic diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmacologically acceptable salt thereof. 
     
     
         21 . A method for the treatment of immune related diseases comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmacologically acceptable salt thereof. 
     
     
         22 . A method for the treatment of cardiovascular diseases, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmacologically acceptable salt thereof. 
     
     
         23 . A method for the treatment of diabetic nephropathy comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to  claim 1  or a pharmacologically acceptable salt thereof. 
     
     
         24 . The method according to  claim 20  wherein the neurologic disease is neuropathic pain. 
     
     
         25 . The method according to  claim 21  wherein the immune related disease is diabetes mellitus. 
     
     
         26 . The method according to  claim 22  wherein the cardiovascular disease is atherosclerosis.