Process and intermediates for the production of CCR2 antagonists

1. A process for the production of a compound of formula (I),

wherein

R 1 is selected from the group consisting of

R 2 is selected from the group consisting of —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 ;

R 3 is selected from the group consisting of —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH 3 , and —CN;

R 4 and R 5 are independently selected from the group consisting of an electron pair, —H, —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 the group consisting of —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 the group consisting of -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 —C(O)— or —SO 2 —,

wherein R 12 , R 16 , are independently selected from the group consisting of —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 the group consisting of —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 the group consisting of —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 the group consisting of —OH, —OCH 3 , —CF 3 , —OCF 3 , —CN, -halogen, —C 1 -C 4 -alkyl, ═O, and —SO 2 —C 1 -C 4 -alkyl,

or R 4 and/or R 5 are independently a group of the structure -L 2 -R 18 ,

wherein L 2 is —NH— and/or N(C 1 -C 4 -alkyl)-,

wherein R 18 is —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl or —C 3 -C 8 -heterocyclyl,

wherein R 18 is optionally substituted by one or more groups selected from the group consisting of 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;

R 6 is selected from the group consisting of —H, —C 1 -C 4 -alkyl, —OH, —O—C 1 -C 4 -alkyl, -halogen, —CN, —CF 3 , and —OCF 3 ;

A is —NH—;

n is 1, 2 or 3;

Z is C or N,

characterized in that a compound of formula II

in which R 2 , R 3 , R 4 , R 5 , R 6 , Z, and n have the meaning as in formula I, is coupled with a primary amine selected from the group consisting of

2. The process for the production of the compound of formula (I) according to claim 1 ,

wherein

R 2 is selected from the group consisting of —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH 2 , —CCH, and —OCH 3 ;

R 3 is —H, -methyl, and/or —OCH 3 ;

R 4 is selected from the group consisting of

R 5 is —H or —C(O)—NH 2 ;

R 6 is selected from the group consisting of —H, —CH 3 , —C 2 H 5 , —O—CH 3 , —O—C 2 H 5 , —F, —CF 3 , and —OCF 3 ; and

Z is C.

3. An intermediate compound selected from the group consisting of

4. The intermediate according to claim 3 , wherein the intermediate is

5. The intermediate according to claim 3 , wherein the intermediate is

6. The intermediate according to claim 3 , wherein the intermediate is

7. The intermediate according to claim 3 , wherein the intermediate is

8. The intermediate according to claim 3 , wherein the intermediate is

9. The intermediate according to claim 3 , wherein the intermediate is