CYCLIC PYRIMIDIN-4-CARBOXAMIDES AS CCR2 RECEPTOR ANTAGONISTS FOR TREATMENT OF INFLAMMATION, ASTHMA AND COPD

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.