Benzimidazole and imidazopyridine derivatives and use thereof as a medicament

1. A compound of the formula

in racemic, enantiomeric form or any combinations of these forms wherein

A is —C(O)—;

X is —CH═;

R a and R b are independently selected from the group consisting of hydrogen or (C 1 -C 6 )alkyl;

R 1 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl optionally substituted by hydroxy or at least one halo; (C 1 -C 6 )alkenyl and —(CH 2 ) n —X 1 ;

R 2 is selected from the group consisting of (C 1 -C 8 )alkyl optionally substituted by hydroxy or at least one halo; (C 2 -C 4 alkenyl and —(CH 2 ) n —X 1 ;

each X 1 independently is selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, adamantyl, heterocycloalkyl, aryl and heteroaryl,

the (C 3 -C 7 )cycloalkyl, heterocycloalkyl, aryl and heteroaryl being unsubstituted or substituted by at least one member selected from the group consisting of —CH 2 n —V 1 —Y 1 , halo, nitro, cyano and aryl;

V 1 is —O—, —S— or a covalent bond;

Y 1 is (C 1 -C 6 )alkyl optionally substituted by at least one halo;

n is an integer from 0 to 6 and n′ is an integer from 0 to 2 (it being understood that when n is equal to 0, then X 1 is not alkoxy);

or R 1 and R 2 form together with the nitrogen atom to which they are attached, a heterobicycloalkyl or a heterocycloalkyl optionally substituted by at least one member selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl optionally substituted by hydroxy, (C 1 -C 6 )alkoxy-carbonyl, heterocycloalkyl and —C(O)NV 1 ′Y 1 ′, V 1 ′ and Y 1 ′ independently are hydrogen or (C 1 -C 6 )alkyl; or R 1 and R 2 together form a member selected from the group consisting of

R 3 is selected from the group consisting of -Z 3 , —C(R Z3 )(R′ Z3 )-Z 3 , —C(R Z3 )(R′ Z3 )—(CH 2 ) p —Z 3 or —C(O)-V′ 3

R Z3 and R′ Z3 are independently hydrogen or (C 1 -C 6 ) alkyl,

Z 3 is selected from the group consisting of Z 3a , Z 3b , Z 3c , Z 3d , or Z 3e ;

Z 3a is (C 1 -C 6 )alkyl;

Z 3b is selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkylamino or di((C 1 -C 6 )alkyl)amino;

Z 3c is aryl or heteroaryl;

Z 3d is selected from the group consisting of (C 1 -C 6 ) alkoxy-carbonyl, amino-carbonyl, C 1 -C 6 )alkylamino-carbonyl, di((C 1 -C 6 )alkyl)amino-carbonyl, (C 1 -C 6 )alkyl-C(O)—NH—, (C 3 -C 7 )cycloalkyl, heterocycloalkyl;

the (C 3 -C 7 )cycloalkyl and heterocycloalkyl being optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkoxy optionally substituted by at least one halo, (C 1 -C 4 alkyl optionally substituted by at least one halo, (C 1 -C 6 )alkyl-carbonyl, (C 1 -C 6 )alkoxy-carbonyl, amino-carbonyl, (C 1 -C 6 )alkylamino-carbonyl, di((C 1 -C 6 )alkyl)amino-carbonyl and oxy,

the aryl and heteroaryl radicals being optionally substituted by at least one member selected from the group consisting of halo, cyano, nitro, azido, oxy, (C 1 -C 6 )alkoxy-carbonyl-(C 1 -C 6 )alkenyl, (C 1 -C 6 )alkylamino-carbonyl-(C 1 -C 6 )alkenyl, —SO 2 —NR 31 R 32 , heterocycloalkyl, heteroaryl or —(CH 2 ) p —V 3 Y 3 ;

R 31 , and R 32 form together with the nitrogen atom to which they are attached, a heterocycloalkyl;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —O—C(O)—, —SO 2 —, —SO 2 NH—, —NR′ 3 —SO 2 —, —NR′ 3 —, —NR′ 3 —C(O), —C(O)—NR′ 3 , —NH—C(O)—NR′ 3 —or a covalent bond;

Y 3 is selected from the group consisting of hydrogen; (C 1 -C 6 )alkyl optionally substituted by at least one halo; aryl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkyl and (C 1 -C 6 )alkoxy; aryl-(C 1 C 4 )alkyl optionally substituted by at least one member selected from the group consisting of halo, nitro, (C 1 -C 6 )alkyl and (C 1 -C 1 )alkoxy;

Z 3e is

Z′ 3 is aryl optionally substituted by one member selected from the group consisting of halo, nitro and —(CH 2 ) p′ —V′ 3 —Y′ 3 ;

V′ 3 is selected from the group consisting of —O—, —C(O)—, [—C(O)—], —C(O)—O—, —C(O)—NR′ 3 —, —NH—C(O)—NR′ 3 —or a covalent bond;

Y′ 3 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least one halo;

R′ 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

p is selected from the group consisting of an integer from 1 to 4; p′ and p″ are independently an integer from 0 to 4;

R′ 4 is —(CH 2 )—R′ 4

R′ 4 is selected from the group consisting of guanidine; heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl; or —NW 4 W′ 4

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s′-Z 4 ;

Z 4 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl optionally substituted by at least one member selected from the group consisting of (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, hydroxy; (C 2 -C 6 )alkenyl; (C 3 -C 7 )cycloalkyl optionally substituted by at least one (C 1 -C 6 )alkyl; cyclohexene; heteroaryl and aryl;

the aryl and heteroaryl radicals being optionally substituted by at least one member selected from the group consisting of —(CH 2 ) s″ —V 4 —Y 4 , hydroxy, halo, nitro and cyano;

V 4 is selected from the group consisting of —O—, —S—, —NH—C(O)—, —NV 4′ — or a covalent bond;

Y 4 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least one halo;

V 4 ′ is hydrogen or (C 1 -C 6 )alkyl;

s″ is an integer from 0 to 4;

or Z 4 is

s and s′ are independently an integer from 0 to 6;

and i) when R 3 is —C(O)-Z′3 and R 4 is —(CH 2 ) s —NW 4 W′ 4 and W 4 and W′ 4 are independently hydrogen or (C 1 -C 6 )alkyl, then —(CH 2 ) s is neither ethylene nor —(CH 2 )—CH((C 1 -C 4 alkyl)-, ii) when R 3 is -Z′ 3c and Z′ 3c is phenyl or naphthyl, ten phenyl and naphthyl are not substituted by cyano; and it being understood that when R 3 is -Z 3d then Z 3d only is one (C 1 -C 7 ) cycloalkyl or heterocycloalkyl;

and iii) when A is —C(O)—; X═—CH—, Z 3 ═—C(O)-Z′ 3 -, R 4 is —(CH 2 ) s—R′ 4 and s is an integer from 1 to 6, either R 1 is hydrogen or alkenyl and R 2 is alkenyl, or R 1 is —CH 2 ) n —X 1 and R 2 is —(CH,) n —X 1 ;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 wherein R 3 is —C(O)-Z′ 3 ;

R 1 and R 2 are independently (C 1 -C 8 )alkyl;

Z′ 3 is phenyl optionally substituted by at least one member selected from the group consisting of halo, nitro and —(CH 2 ) p″ —V′ 3 —Y′ 3

V′ 3 is selected from the group consisting of —O—, —C(O)—O— or a covalent bond;

V′ 3 is hydrogen or (C 1 -C 6 )alkyl;

p′ is 0;

R 4 is —(CH 2 ) s —R′ 4 and R′ 4 —NW 4 W′ 4

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s ′-Z 4 and Z 4 is hydrogen;

s is an integer from 2 to 4; s′ is an integer from 0 to 4;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 1 wherein

R 1 is selected from the group consisting of hydrogen, (C 1 -C 8 )alkyl optionally substituted by hydroxy, (C 2 -C 6 )alkenyl or —(CH 2 ) n —X 1 ;

R 2 is selected from the group consisting of (C 1 -C 8 )alkyl optionally substituted by hydroxy, (C 2 -C 6 )alkenyl or —(CH 2 ) n —X 1 ;

each X 1 is independently selected from the group consisting of (C 1 -C 6 )alkoxy, (C 3 -C 7 )cycloalkyl, aryl or heteroaryl,

the aryl being optionally substituted by at least one —(CH 2 ) n′ —V 1 —Y 1 or halo;

V 1 is —O— or a covalent bond;

Y 1 is (C 1 -C 6 )alkyl optionally substituted by at least one halo or aryl;

or R 1 and R 2 form together with the nitrogen atom to which they are attached, a heterocycloalkyl optionally substituted by at least one member selected from the group consisting of hydroxy, (C 1 -C 6 )alkyl optionally substituted by hydroxy, (C 1 -C 6 )alkoxy-carbonyl, heterocycloalkyl and —C(O)NV 1 ′Y 1 ′, V 1 ′ and Y 1 ′ independently are hydrogen or (C 1 -C 6 )alkyl,

or R 1 and R 2 together form a member selected from the group consisting of

R 3 is selected from the group consisting of -Z 3 , —C(R Z3 )(R′ Z3 )-Z 3 or —C(R Z3 )(R Z3 )—(CH 2 ) p -Z 3 ;

R 4 is —(CH 2 ) s —R′ 4

R′ 4 is selected from the group consisting of heterocycloalkyl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl or aralkyl; a heteroaryl containing at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl; or —NW 4 W′ 4

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s′ -Z 4 ;

Z 4 is selected from the group consisting of hydrogen, (C 3 -C 7 )cycloalkyl or aryl;

s is an integer from 0 to 5; s′ is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 wherein having at least one of the following characteristics:

(C 3 -C 7 )cycloalkyl of X 1 is cyclopropyl

aryl of X 1 is phenyl;

heteroaryl of X 1 is pyridine;

heterocycloalkyl that R 1 and R 2 form together with the nitrogen atom to which they are attached is selected from the group consisting of pyrrolidine, piperidine, azepane, azacyclooctane, morpholine, piperazine and decahydroisoquinoline;

heterocycloalkyl of R′ 4 , optionally substituted by (C 1 -C 6 )alkyl or benzyl, is selected from the group consisting of pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl;

heteroaryl of R′ 4 is imidazolyl;

cycloalkyl of Z 4 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

aryl of Z 4 is phenyl; or a pharmaceutically acceptable salt thereof.

5. A compound of claim 3 , wherein R 4 is —(CH 2 ) s —R′ 4 , R′ 4 is pyrrolidinyl or piperidinyl; or —NW 4 W′ 4

W 4 is hydrogen or (C 1 -C 8 )alkyl;

W′ 4 is —(CH 2 ) s -Z 4 and Z 4 is hydrogen;

s is an integer from 2 to 4; s′ is an integer from 0 to 4; or a pharmaceutically acceptable salt thereof.

6. A compound of claim 3 wherein R 1 and R 2 are independently (C 1 -C 8 )alkyl; or a pharmaceutically acceptable salt thereof.

7. A compound of claim 3 wherein

R 3 is -Z 3 and Z 3 is Z 3c , Z 3d or Z 3e ;

Z 3d is (C 3 -C 7 )cycloalkyl or heterocycloalkyl; or a pharmaceutically acceptable salt thereof.

8. A compound of claim 7 , wherein

Z 3c is a heteroaryl selected from the group consisting of thienyl, furyl, indolyl, dihydroindolyl, pyridyl, benzothienyl and benzofuryl; or an aryl selected from the group consisting of phenyl, naphthyl and fluorenyl;

the heteroaryl being optionally substituted by at least one (C 1 -C 6 )alkyl-carbonyl or (C 1 -C 6 )alkoxy-carbonyl;

the aryl being optionally substituted by at least one member selected from the group consisting of halo, cyano, nitro, azido, (C 1 -C 6 )alkoxy-carbonyl-(C 1 -C 6 )alkenyl, oxy, —SO 2 —NR 31 R 32 , heterocycloalkyl, heteroaryl, or —(CH 2 ) p′ —V 3 —Y 3 ;

R 31 and R 32 form together with the nitrogen atom to which they are attached piperidine;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 —, —SO 2 NH—, —NR′ 3 —, —NR′ 3 —C(O)—, —C(O)—NR′ 3 , —NH—C(O)—NR′ 3 — or a covalent bond;

Y 3 is selected from the group consisting of hydrogen; (C 1 -C 6 )alkyl optionally substituted by at least one halo, phenyl; or benzyl;

R′ 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

Z 3d is cyclopropyl, cyclohexyl or piperidinyl, each being unsubstituted or substituted by (C 1 -C 6 )alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

9. A compound of claim 7 , wherein

R 3 is -Z 3 and Z 3 is Z 3c , Z 3d or Z 3e ;

Z 3c is heteroaryl selected from the group consisting of thienyl, indolyl and benzothienyl; or aryl is phenyl or naphthyl;

the heteroaryl being optionally substituted by at least one oxy;

the aryl radical being optionally substituted by at least one member selected from the group consisting of halo, nitro, heteroaryl or —(CH 2 ) p′ —V 3 —Y 3 ;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 —, —SO 2 NH—, —NR′ 3 —C(O)—, —C(O)—NR′ 3 —, —NH—C(O)—NR′ 3 —or a covalent bond;

Y 3 is selected from the group consisting of hydrogen; (C 1 -C 6 )alkyl optionally substituted by at least one halo, phenyl; or benzyl;

R′ 3 is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy;

Z 3d is cyclopropyl or piperidinyl, each optionally substituted by (C 1 -C 6 )alkoxy-carbonyl; or a pharmaceutically acceptable salt thereof.

10. A compound of claim 9 , wherein

Z 3 is Z 3c or Z 3e;

Z 3c is phenyl optionally substituted by at least one-member selected from the group consisting of nitro or —(CH 2 ) p′ —V 3 —Y 3 ;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 —, —SO 2 NH—, —NR′ 3 C(O)—, —C(O)—NR′ 3 — or a covalent bond;

Y 3 is selected from the group consisting of hydrogen; (C 1 -C 6 )alkyl; phenyl; or benzyl;

R′ 3 is hydrogen;

Z 3e is

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 3 wherein R 3 is —C(R Z3 )(R′ Z3 )-Z 3 and Z 3 is Z 3b , Z c , Z 3d or Z 3e ; or a pharmaceutically acceptable salt thereof.

12. A compound of claim 11 , wherein

R 3 is —C(R Z3 )(R′ Z3 )- 3 Z; and Z 3 is Z 3b or R 3c ;

R 23 and R 23′ are hydrogens;

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 12 wherein

Z 3b is (C 1 -C 6 )alkoxy;

Z 3c is heteroaryl selected from the group consisting of thienyl, furyl, pyridyl, benzothienyl and dihydrobenzofuryl; or phenyl or naphthyl,

the aryl being optionally substituted by at least one of halo or —(CH 2 ) p′ —V 3 Y 3 ;

V 3 is selected from the group consisting of —O—, —O—, —C(O)—, —C(O)—O—, —SC 2 —, SO 2 NH—, —NR′ 3 —C(O)—or —C(O)—NR′ 3 ,

Y 3 is selected from the group consisting of hydrogen (C 1 -C 6 )alkyl optionally substituted by at least one halo;

R+ 3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

14. A compound of claim 12 , wherein

R 3 is —C(R Z3 )(R′ Z3 )-Z 3 , Z 3 is Z 3b or Z 3c ;

Z 3b is (C 1 -C 6 )alkoxy;

Z 3c , is heteroaryl selected from the group consisting of thienyl, furyl, dihydrobenzofuryl; or phenyl;

the phenyl being optionally substituted by at least one of nitro or —(CH 2 ) p′ —V 3 —Y 3 ;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 —, SO 2 NH or —C(O)—NR′ 3 —,

Y 3 is hydrogen or (C 1 -C 6 )alkyl optionally substituted by at least one halo;

R′ 3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

15. A compound of claim 14 , wherein

Z 3 is Z 3c ;

Z 3c , is furyl or phenyl unsubstituted or substituted by at least one —(CH) p′ —V 3 —Y 3 ;

V 3 is selected from the group consisting of —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 —, —SO 2 NH— or —C(O)—NR′ 3 —,

Y 3 is hydrogen; or (C 1 -C 6 )alkyl optionally substituted by at least one halogen;

R′ 3 is hydrogen;

or a pharmaceutically acceptable salt thereof.

16. A compound of claim 11 , wherein

R 3 is —C(R Z3 )(R′ Z3 )-Z 3 , Z 3 is Z 3d or Z 3e ;

R Z3 and R′ Z3 are hydrogen or (C 1 -C 6 )alkyl;

Z 3d is (C 1 -C 6 )alkoxy-carbonyl, (C 3 -C 7 )cycloalkyl or heterocycloalkyl;

Z 3c is

or a pharmaceutically acceptable salt thereof.

17. A compound of claim 16 wherein

Z 3d is selected from the group consisting of (C 1 -C 6 )alkoxy-carbonyl, cyclohexyl or tetrabydrofuranyl,

or a pharmaceutically acceptable salt thereof.

18. A compound of claim 16 wherein Z 3 is Z 3d or Z 3e ;

Z 3d is (C 1 -C 6 )alkoxy-carbonyl;

Z 3c is

or a pharmaceutically acceptable salt thereof.

19. A compound of claim 18 wherein Z 3 is

or a pharmaceutically acceptable salt thereof.

20. A compound of claim 3 wherein R 3 is —C(R Z3 )(R′ Z3 )—(CH 2 ) p -Z 3 and Z 3 is Z 3b , Z 3c or Z 3d ; or a pharmaceutically acceptable salt thereof.

21. A compound of claim 20 , wherein R 3 is —C(R Z3 )(R′ Z3 )—(CH 2 ) p -Z 3 and Z 3 is Z 3b ; or a pharmaceutically acceptable salt thereof.

22. A compound of claim 21 , wherein R Z3 and R′ Z3 are independently hydrogen or (C 1 -C 6 )alkyl;

Z 3b is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio or di((C 1 -C 6 )alkyl)amino; or a pharmaceutically acceptable salt thereof.

23. A compound of claim 21 , wherein

R Z3 and R′ Z3 are independently hydrogen or (C 1 -C 6 )alkyl;

Z 3b is (C 1 -C 6 )alkoxy or (C 1 -C 6 )alkylthio; or a pharmaceutically acceptable salt thereof.

24. A compound of claim 20 , wherein R 3 is —C(R Z3 )(R′ Z3 )—(CH 2 ) p -Z 3 and Z 3 is Z 3c or Z 3d ; or a pharmaceutically acceptable salt thereof.

25. A compound of claim 24 , wherein

R Z3 and R′Z Z3 are independently hydrogen or (C 1 -C 6 )alkyl,

Z 3c is indolyl or phenyl unsubstituted or substituted by at least one of halo or —(CH 2 ) p′ —V 3 —Y 3 ;

V 3 is —SO 2 NH—,

Y 3 is hydrogen; or (C 1 -C 6 )alkyl,

Z 3d is selected from the group consisting of (C 1 -C 6 )alkoxy-carbonyl, amino-carbonyl, (C 1 -C 6 )alkyl-amino-carbonyl, (C 1 -C 6 )alkyl-C(O)—NH—, or piperidinyl, morpholinyl, pyrrolidine or imidazolidinyl; or a pharmaceutically acceptable salt thereof.

26. A compound of claim 24 , wherein

Z 3 is Z 3d ;

R Z3 and R′ Z3 are independently hydrogen or (C 1 -C 6 )alkyl;

Z 3d is selected from the group consisting of (C 1 -C 6 )alkoxy-carbonyl, amino-carbonyl, (C 1 -C 6 )alkylamino-carbonyl, (C 1 -C 6 )alkyl-C(O)—NH— or heterocycloalkyl, optionally substituted by oxy; or a pharmaceutically acceptable salt thereof.

27. A process for the preparation of a compound of claim 1 comprising reacting a compound of the formula

in which A, X, R 1 , R 2 , R 4 have the meaning of claim 1 , with an isothiocyanate of the formula R 3 N═C═S in which R 3 has the meaning indicated in claim 1 , in the presence of a coupling agent or yellow mercury (II) oxide in the presence of sulfur, for a period of 3 to 48 hours, in a protic or aprotic solvent, at a temperature of 50 to 80° C.

28. A pharmaceutical composition comprising at least one compound of claim 1 , in combination with a pharmaceutically acceptable carrier.