Benzimidazole derivatives and their use as a medicament

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, in racemic, enantiomeric form or any combination of these forms and in which:

A is —C(O)—;

Y is —NH—;

R 1 and R 2 are, independently, hydrogen, (C 1 -C 8 )alkyl or (C 5 -C 9 )bicycloalkyl optionally substituted by at least one (C 1 -C 6 )alkyl

or R 1 and R 2 form, together with the nitrogen atom to which they are attached, a heterocycloalkyl, a heterobicycloalkyl or the groups

said group being optionally substituted by at least one:

—(CH 2 ) n″ —X″—Y″, oxo, hydroxy, halo, nitro or cyano;

wherein X″ is —O—, —C(O)—, —C(O)—O— or a covalent bond;

Y″ is (C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, arylalkyl, or aryl or heteroaryl optionally substituted by at least one: (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl-carbonyl, halo, hydroxy, nitro, cyano, CF 3 , OCF 3 , amino, (C 1 -C 6 )alkylamino or di((C 1 -C 6 )alkyl)amino; or

Y″ is

wherein n″ is an integer from 0 to 4;

R 3 is —(CH 2 ) p —W 3 —(CH 2 ) p′ —Z 3

wherein W 3 is a covalent bond, —CH(OH)— or —C(O)—;

Z 3 is (C 1 -C 6 )alkyl, adamantyl, aryl, heteroaryl,

the aryl being optionally substituted by at least one —(CH 2 ) p″ —V 3 —Y 3 , halo, nitro, cyano, N 3 , or hydroxy;

wherein V 3 is —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 — or a covalent bond;

Y 3 is (C 1 -C 6 )alkyl optionally substituted by at least one halo, amino, (C 1 -C 6 )alkylamino, di((C 1 -C 6 )alkyl)amino, phenylcarbonylmethyl, heterocycloalkyl or aryl;

p, p′, and p″ represent, independently, an integer from 0 to 4;

R 4 is —(CH 2 ) s —R″ 4

wherein R″ 4 is a heterocycloalkyl including at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl or aralkyl; a heteroaryl including at least one nitrogen atom and optionally substituted by (C 1 -C 6 )alkyl; or —NW 4 W′ 4

wherein W 4 is hydrogen, (C 1 -C 8 )alkyl or (C 3 -C 7 )cycloalkyl;

W′ 4 is —(CH 2 ) s′ -Q 4 -Z 4 ;

Q 4 is a covalent bond, —CH 2 —CH(OH)—[CH 2 ] t —[O] t′ —[CH 2 ] t″ — or —C(O)—O—;

t, t′, and t″ are, independently, 0 or 1;

Z 4 is hydrogen, (C 1 -C 8 )alkyl optionally substituted by at least one: (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyldithio or hydroxy; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl;

(C 3 -C 7 )cycloalkyl optionally substituted by at least one: (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy-carbonyl or (C 1 -C 6 )hydroxyalkyl; cyclohexene; adamantyl; heteroaryl; aryl optionally substituted by at least one —(CH 2 ) q″ —V 4 —Y 4 , hydroxy, halo, nitro, or cyano;

wherein V 4 is —O—, —S—, —NH—C(O)— or a covalent bond;

Y 4 is (C 1 -C 6 )alkyl optionally substituted by di((C 1 -C 6 )alkyl)amino or at least one halo; amino; (C 1 -C 6 )alkylamino; di((C 1 -C 6 )alkyl)amino; aralkyl; or heterocycloalkyl;

q″ is an integer from 0 to 4;

or Z 4 is a group of the formula

s and s′ represent, independently, an integer from 0 to 6.

2. The compound of claim 1 , wherein:

R 1 and R 2 , together with the nitrogen atom to which they are attached, form a heterocycloalkyl which is piperidine, piperazine, diazepane, thiazolidine or morpholine;

the cycloalkyl of Y″ is cyclopentyl or cyclohexyl;

the heterocycloalkyl of Y″ is piperidine, pyrrolidine or morpholine;

the arylalkyl of Y″ is benzyl;

the aryl of Y″ is phenyl;

the heteroaryl of Y″ is pyridine, pyrazine, furan or thiophene; or

a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein:

the aryl of Z 3 is phenyl or naphthyl;

the heteroaryl of Z 3 is benzo[b]thiophene or benzo[b]furan;

the heterocycloalkyl of Y 3 is pyrrolidine;

the aryl of Y 3 is phenyl; or

a phamaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein:

the heterocycloalkyl of R″ 4 is piperazine, piperidine, morpholine or pyrrolidine;

the aralkyl which optionally substitutes the heterocycloalkyl of R″ 4 is benzyl;

the heteroaryl of R″ 4 is imidazole;

the (C 3 -C 7 )cycloalkyl of Z 4 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

the heteroaryl of Z 4 is pyridine, thiophene, indole or furan;

the aryl of Z 4 is phenyl or naphthyl;

the aralkyl of Y 4 is benzyl;

the heterocycloalkyl of Y 4 is pyrrolidine;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein:

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

or R 1 and R 2 form, together with the nitrogen atom to which they are attached, piperidine, piperazine, diazepane, thiazolidine, morpholine, or the groups

said groups being optionally substituted by at least one —(CH 2 ) n″ —X″—Y″ wherein:

X″ is —C(O)—, —C(O)—O— or a covalent bond;

Y″ is (C 1 -C 6 )alkyl, di(alkyl)amino, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, morpholine, benzyl, pyridine, pyrazine, furan, thiophene or phenyl, said phenyl being optionally substituted by at least one (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylcarbonyl and halo; or

Y″ is

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein:

R 3 is —(CH 2 ) p —W 3 —(CH 2 ) p′ Z 3 , wherein:

W 3 is a covalent bond, —CH(OH)— or —C(O)—;

Z 3 is (C 1 -C 6 )alkyl, phenyl, naphthyl, benzo[b]thiophene, benzo[b]furanyl

the phenyl being optionally substituted by at least one —(CH 2 ) p″ —V 3 —Y 3 , halo, nitro or cyano;

wherein V 3 is —O—, —S—, —C(O)—, —C(O)—O—, —SO 2 — or a covalent bond;

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

di((C 1 -C 6 )alkyl)amino; phenylcarbonylmethyl; pyrrolidine or phenyl;

p, p′, and p″ are, independently, an integer from 0 to 2;

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein R 4 is —(CH 2 ) s —R″ 4 , wherein:

R″ 4 is piperidine optionally substituted by benzyl; piperazine optionally substituted by benzyl; or —NW 4 W′ 4 , wherein:

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

W′ 4 is —(CH 2 ) s′ -Q 4 Z 4 ;

Q 4 is a covalent bond, —CH 2 —CH(OH)—, —CH 2 —CH(OH)—CH 2 —O—, —CH 2 —CH(OH)—CH 2 —, —CH 2 —CH(OH)—CH 2 —O—CH 2 — or —C(O)—O—;

Z 4 is hydrogen; (C 1 -C 8 )alkyl optionally substituted by (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkyldithio or one or two hydroxy; (C 2 -C 6 )alkenyl; (C 2 -C 6 )alkynyl; cyclopropyl optionally substituted with alkoxycarbonyl; cyclobutyl; cycloheptyl optionally substituted with hydroxyalkyl; cyclohexyl optionally substituted with one or more alkyl; cycloheptyl; cyclohexene; adamantyl; pyridine; thiophene; indole; furan; naphthyl; or phenyl optionally substituted by at least one —(CH 2 ) q″ —V 4 —Y 4 , hydroxy, halo or cyano; wherein V 4 is —O— or a covalent bond; and Y 4 is a (C 1 -C 6 )alkyl, di((C 1 -C 6 )alkyl)amino or pyrrolidine;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein:

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

R 3 is —(CH 2 ) p —W 3 —(CH 2 ) p′ —Z 3 , wherein:

W 3 is a covalent bond; Z 3 is phenyl substituted by at least one —(CH 2 ) p″ —V 3 —Y 3 or halo;

V 3 is —O— or —S—; and Y 3 is a (C 1 -C 6 )alkyl; p, p′, and p″ represent 0;

R 4 is —(CH 2 ) s —R″ 4

R″ 4 is —NW 4 W′ 4

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

W′ 4 is —(CH 2 ) s″ -Q 4 -Z 4 ;

Q 4 is a covalent bond;

Z 4 is hydrogen; (C 1 -C 8 )alkyl optionally substituted by hydroxy; (C 3 -C 7 )cycloalkyl; heteroaryl; or aryl optionally substituted by at least one —(CH 2 ) q″ —V 4 —Y 4 ;

V 4 is —O— or a covalent bond;

Y 4 is (C 1 -C 6 )alkyl or di((C 1 -C 6 )alkyl)amino;

q″ is 0; s is an integer from 2 to 4, and s′ is an integer from 1 to 2;

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 8 , wherein the (C 3 -C 7 )cycloalkyl is cyclopentyl or cyclohexyl; the heteroaryl is pyridine; and the aryl is phenyl; or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. A method of treating endometriosis, fibroma, polycystic ovary syndrome, cancer of the breast, the ovary and the endometrium, gonadotropic hypophyseal desensitization during medically-assisted procreation protocols, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

12. A method of treating benign prostatic hyperplasia or prostate cancer comprising administering to a subject in need thereof a sufficient amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

13. A method of treating precocious puberty comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.