Cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors

• US 7,354,933 B2
• Filed: 02/02/2004
• Issued: 04/08/2008
• Est. Priority Date: 01/31/2003
• Status: Expired due to Fees

• Current Assignee: Aventis Pharma SA (Sanofi )
• Original Assignee: Aventis Pharma SA (Sanofi )
• Inventors: Ruf, Sven, Bénard, Didier, Ritter, Kurt, Patek, Marcel, El-Ahmad, Youssef, Bouchard, Herve, Nemecek, Conception, Strobel, Hartmut, Nair, Anil, Mauger, Jacques, Hittinger, Augustin, Faitg, Thomas, Lesuisse, Dominique, Malleron, Jean-Luc, Palermo, Mark, Al-Obeidi, Fahad, Harlow, Greg, Bond, Daniel
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US10/770,382
• Publication Number:
  US 20040248884A1
• Time in Patent Office: 1,527 Days
• Field of Search: 546/172, 546/274.4, 548/319.1, 514/314, 514/341, 514/389, 514/391
• US Class Current: 514/314
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/14 containing three or more hetero rings

Abstract

The present invention relates to a cyclic urea compound of formula I:

as defined herein. The invention is also directed to the process for its preparation, pharmaceutical composition comprising it and its pharmaceutical use, as an inhibitor on a protein kinase. Thus, it is useful for preventing or treating a physiological disorder capable of being modulated by inhibiting the activity of a protein kinase, such as a solid tumor.

Claims

1. The compound of formula I:

2. The compound according to claim 1 wherein

p is 0,

R and R1, which may be identical or different, are O or NH,

R2 and R3, which may be identical or different, are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl or heteroaryl,

A1 is single bond, alkyl, allyl or propynyl,

Y and Y1, which may be identical or different, are such that one of Y and Y1 is selected from the group consisting of —

OCF₃, —

S(O)_nCF₃, —

S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃ and —

SO₂NR5R6 and the other of Y and Y1 is selected from the group consisting of —

OCF₃, —

S(O)_nCF₃, —

S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃, —

SO₂NR5R6, hydrogen, halogen, hydroxyl, alkoxy, —

NR5R6, alkyl, aryl, heteroaryl, —

CF₃, —

O-allyl, —

O-propynyl, —

O-cycloalkyl, —

S(O)_n-allyl, —

S(O)_n-propynyl, —

S(O)_n-cycloalkyl, —

CONR5R6 and free, salified or esterified carboxyl,

wherein R5 and R6, which may be identical or different, are selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl and heteroaryl, or R5 and R6 taken together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl containing one or more hetero atoms chosen from O, S, N and NR7,

A2, which may be identical to or different from A1, is defined as A1 or CO or SO₂,

B2 is a saturated or unsaturated heterocyclyl containing 1 or more identical or different hetero atoms chosen from O, S, N and NR7, optionally substituted with one or more identical or different substituents defined as Y2,

R7 is hydrogen, alkyl, cycloalkyl, phenyl, acyl, —

S(O)₂Alk, —

S(O)₂Aryl, S(O)₂heteroaryl or —

S(O)₂NR5R6 radical,

Y2 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —

O-allyl, —

O-propynyl, —

O-cycloalkyl, —

S(O)_n-alkyl, —

S(O)_n-allyl, —

S(O)_n-propynyl, —

S(O)_n-cycloalkyl, —

COOR9, —

OCOR8, —

NR5R6, —

CONR5R6, —

S(O)_n—

R5R6, —

NHCOR8, —

NH—

S(O)_nR8, —

NH—

S(O)_nCF₃ or —

NH—

SO₂—

NR5R6, all these radicals being optionally substituted,

all the carbocyclyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl above are optionally substituted with one or more substituents, which may be identical or different, selected from the group consisting of halogen, cyano, hydroxyl, alkoxy, —

CF₃, nitro, aryl, heteroaryl, —

C(═

O)—

OR9, —

C(═

O)—

R8, —

NR11R12, —

C(═

O)—

NR11R12, —

N(R10)-C(═

O)—

R8, —

N(R10)-C(═

O)—

OR9, N(R10)-C(═

O)—

NR11R12, —

N(R10)-S(O)_n—

R8, —

S(O)_n—

R8, —

N(R10)-S(O)_n—

NR11R12 and —

S(O)_n—

NR11R12, and

all the aryl and heteroaryl above are optionally substituted with one or more substituents selected from the group consisting of alkyl and alkylenedioxy radicals, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof,

with the proviso;

a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

OCF₃ or —

S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other imidazolylalkyl;

b) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

S(O)_n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl;

or

c) when p is 0, R and R1 are oxygen, A1 is single bond, Y and Y1, which may be identical or different, are one is —

SO₂Alk or SO₂NH₂ and the other is NR5R6, A2 is single bond or alkylene and B2 is optionally substituted 5- to 10-membered heterocyclyl, then R2 and R3 are not both hydrogen.

3. The compound according to claim 1 wherein

p is 0,

R and R1, which may be identical or different, are O or NH,

R2 and R3, which may be identical or different, are hydrogen, alkyl, alkenyl, cycloalkyl, phenyl or heteroaryl,

A1 is single bond, alkyl, allyl or propynyl,

Y and Y1, which may be identical or different, are such that one of Y and Y1 is selected from the group consisting of —

OCF₃, —

S(O)_nCF₃, S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃ and —

SO₂NR5R6 and the other from Y and Y1 is selected from the group consisting of —

OCF₃, —

S(O)_nCF₃, S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃, —

SO₂NR5R6, hydrogen, halogen, hydroxyl, alkoxy, NR5R6, alkyl, phenyl, optionally substituted pyrazolyl and optionally substituted pyridyl,

R5 and R6, which may be identical or different, are hydrogen, alkyl, alkenyl, cycloalkyl, heterocyclyl, phenyl or heteroaryl, or R5 and R6 taken together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclyl that contains one or more hetero atoms chosen from O, S, N and NR7, A2, which may be identical to or different from A1, is defined as A1 or is CO or SO₂,

B2 is a saturated or unsaturated 3- to 10-membered heterocyclyl containing one or more hetero atoms, which may be identical or different, chosen from O, S, N and NR7, optionally substituted with one or more substituents, which may be identical or different substituents defined as Y2,

R7 is hydrogen or an alkyl, cycloalkyl or phenyl radical,

Y2 is hydrogen, halogen, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, phenyl, heteroaryl, —

O-cycloalkyl, —

S(O)_n-alk, —

S(O)_n-cycloalkyl, —

COOR9, —

OCOR8, —

NR5R6, —

CONR5R6, S(O)_n—

R5R6, —

NHCOR8 or —

NH—

S(O)_nR8, all these radicals being optionally substituted,

all the alkyl, alkenyl, alkynyl and alkoxy radicals above being linear or branched and contain not more than 6 carbon atoms,

all the cycloalkyl and heterocyclyl radicals above containing not more than 7 carbon atoms,

all the aryl and heteroaryl radicals above containing not more than 10 carbon atoms,

all the carbocyclyl, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl radicals above being optionally substituted with one or more radicals, which may be identical or different, chosen from halogen atoms and cyano, hydroxyl, alkoxy, —

CF₃, nitro, phenyl, heteroaryl, —

C(═

O)—

OR9, —

C(═

O)—

R8, —

NR11R12, —

C(═

O)—

NR11R12, —

N(R10)-C(═

O)—

R8, —

N(R10)-C(═

O)—

OR9, N(R10)-C(═

O)—

NR11R12, —

N(R10)-S(O)_n—

R8, —

S(O)_n—

R8, —

N(R10)-S(O)_n—

NR11R12 and —

S(O)_n—

NR11R12,

all the aryl and heteroaryl radicals above are optionally substituted with one or more radicals chosen from alkyl and alkylenedioxy,

n is 0 to 2,

R8 is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, phenyl or phenylalkyl,

R9 is defined as R8 or is hydrogen,

R10 is hydrogen or alkyl, and

R11 and R12, which may be identical or different, are hydrogen, C₁-C₄ alkyl or phenyl, which are optionally substituted with one or more radicals, which may be identical or different, chosen from halogen, hydroxyl, alkoxy, —

CF₃, nitro, phenyl and free, salified, esterified or amidated carboxyl, or R11 and R12 taken together with the nitrogen atom to which they are attached form a 5- to 7-membered cyclic radical containing one or more hetero atoms chosen from O, S, N and NR7, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof,

with the proviso;

a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

OCF₃ or —

S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other imidazolylalkyl;

b) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

S(O)_n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl;

or

c) when p is 0, R and R1 are oxygen, A1 is single bond, Y and Y1, which may be identical or different, are one is —

SO₂Alk or SO₂NH₂ and the other is NR5R6, A2 is single bond or alkylene and B2 is optionally substituted 5- to 10-membered heterocyclyl, then R2 and R3 are not both hydrogen.

4. The compound according to claim 1 wherein

one of Y and Y1 is hydrogen and the other is chosen from —

OCF₃, —

S(O)_nCF₃, —

S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃ and —

SO₂NR5R6, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof,

with the proviso;

a) when p is 0, R and R1 are oxygen, A1 is single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

OCF₃ or —

S-alk, A2 is single bond or alkyl and B2 is an optionally substituted heterocyclyl, then R2 and R3 are not one hydrogen and the other imidazolylalkyl;

or

b) when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

S(O)_n-alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl.

5. The compound according to claim 1 wherein

one of Y and Y1 is hydrogen and the other is chosen from —

S(O)_nCF₃, —

SO-Alk, —

S(O)₂Alk, —

SO₂CHF₂, —

SO₂CF₂CF₃ and —

SO₂NR5R6, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof,

with the proviso;

when p is 0, R and R1 are oxygen, A1 is a single bond or alkyl, Y and Y1, which may be identical or different, are at least one is —

SO-Alk or —

S(O)₂Alk, A2 is single bond and B2 is an optionally substituted 5- or 6-membered aromatic heterocyclyl, then R2 and R3 are not selected from the group consisting of hydrogen, alkyl, arylalkyl, aryl and heteroaryl.

6. The compound according to claim 1 wherein

one of Y and Y1 is hydrogen and the other is chosen from —

S(O)_nCF₃, —

SO₂CHF₂, —

SO₂CF₂CF₃ and —

SO₂NR5R6, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

7. The compound according to claim 1 wherein

one of Y and Y1 is hydrogen and the other is chosen from —

S(O)_nCF₃, —

SO₂CHF₂ and —

SO₂CF₂CF₃, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

9. The compound according to claim 1 wherein R1 is O.

10. The compound according to claim 1 wherein R is O.

12. The compound according to claim 1 wherein R2 and R3, which may be identical or different, are chosen from hydrogen, alkyl, phenylalkyl, pyridylalkyl and benzothienylalkyl, which are optionally substituted with one or more radicals chosen from halogen, hydroxyl, alkyl and alkoxy containing from one to 4 carbon atoms.

13. The compound according to claim 1 wherein R2 and R3, which may be identical or different, are chosen from hydrogen, alkyl, hydroxyalkyl, phenylalkyl, hydroxyphenylalkyl, pyridylalkyl or thienylbenzothienylallyl.

14. The compound according to claim 1 wherein R2 and R3, which may be identical or different, are chosen from hydrogen, alkyl, hydroxyalkyl, phenylalkyl and hydroxyphenylalkyl.

15. The compound according to claim 1 wherein one of R2 and R3 is chosen from hydrogen and alkyl, and the other R2 and R3 is chosen from among the broadest definitions of R2 and R3.

16. The compound according to claim 1 wherein R2 and R3, which may be identical or different, are hydrogen or alkyl.

17. The compound according to claim 1 wherein R2 and R3, which may be identical or different, are hydrogen or methyl.

18. The compound according to claim 1 wherein A1 is single bond and A2 is chosen from single bond, a linear or branched alkyl containing not more than 6 carbon atoms and allyl, propynyl, C═

O and SO₂ radicals, the other substituents of said compound of formula I are as defined in claim 1.

19. The compound according to claim 1 wherein A1 is single bond and A2 is chosen from single bond, alkyl, allyl, propynyl, C═

O and SO₂.

20. The compound according to claim 1 wherein A1 is single bond and A2 is chosen from alkyl, allyl, propynyl, C═

O and SO₂.

21. The compound according to claim 1 wherein A1 is single bond and A2 is alkyl or C═

O.

22. The compound according to claim 1 wherein A1 is single bond and A2 is C═

O, ethylene or methylene.

23. The compound according to claim 1 wherein A1 is single bond and A2 is methylene.

24. The compound according to claim 1 wherein Y and Y1 are such that one is hydrogen, halogen or amino and the other is chosen from —

OCF₃, —

O—

CF₂—

CHF₂, —

O—

CHF₂, —

O—

CH₂—

CF₃, —

SF₅, —

S(O)_n—

CF₃, —

S(O)_n-alk, —

SO₂CHF₂, —

SO₂CF₂CF₃, —

SO₂NH₂, —

S—

CF₂—

CF₂—

CF₃, —

S-Alk-O-Alk, —

S-Alk-OH, —

S-Alk-CN, —

S-Alk-morpholino, —

S-Alk-pyrrolidinyl and —

S-Alk-piperazinyl, wherein the morpholino, pyrrolidinyl and piperazinyl are optionally substituted with Alk, in which Alk is alkyl containing from 1 to 4 carbon atoms.

25. The compound according to claim 1 wherein Y is hydrogen and Y1 is chosen from —

OCF₃, S(O)_n—

CF₃, —

S(O)_n—

CH3, —

SO₂CHF₂ and —

SO₂NH₂.

26. The compound according to claim 1 wherein Y is hydrogen and Y1 is chosen from —

OCF₃, —

S(O)_n—

CF₃ and —

SO₂CHF₂.

27. The compound according to claim 1 wherein Y is hydrogen and Y1 is chosen from —

OCF₃ and S(O)_n—

CF₃.

28. The compound according to claim 1 wherein Y is hydrogen and Y1 is chosen from —

OCF₃, S—

CF₃ and S(O)2—

CF₃.

29. The compound according to claim 1 wherein B2 is monocyclic or bicyclic heteroaryl chosen from pyridyl, pyrimidinyl, quinolyl, azaindolyl, 1H-pyrrolo[2,3-b]pyridinyl, quinazolyl, thiazolyl, imidazolyl, pyrazolyl, furazanyl, isoxazolyl, morpholinyl, pyrrolidinyl, furyl, piperidyl, thienyl, chromenyl, oxochromenyl, indolyl, pyrrolyl, purinyl, benzoxazinyl, benzimidazolyl and benzofuranyl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

30. The compound according to claim 1 wherein B2 is heteroaryl chosen from 3- or 4-pyridyl, 3- or 4-quinolyl, imidazolyl, thiazolyl, indolyl, pyrazolyl, pyrrolyl, pyrimidyl, purinyl, benzoxazinyl, benzimidazolyl and benzofuranyl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

31. The compound according to claim 1 wherein B2 is heteroaryl chosen from 4-pyridyl, 4-quinolyl, imidazolyl, thiazolyl, pyrazolyl, pyrrolyl, pyrimidyl and purinyl radicals, which are optionally substituted with one or more radicals chosen from the definition of Y2.

32. The compound according to claim 1 wherein B2 is heteroaryl chosen from 3- or 4-pyridyl, pyrimidinyl, 3- or 4-quinolyl, azaindolyl, quinazolyl, thiazolyl, imidazolyl, pyrazolyl, furazanyl and isoxazolyl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

33. The compound according to claim 1 wherein B2 is heteroaryl chosen from 3- or 4-pyridyl, pyrimidyl, 3- or 4-quinolyl, azaindolyl and quinazolyl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

34. The compound according to claim 1 wherein B2 is 4-pyridyl, 4-quinolyl or 1H-pyrrolo[2,3-b]pyrid-4-yl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

35. The compound according to claim 1 wherein Y2 is 2-amino-4-pyridyl in which the amino is optionally substituted as indicated for the radical —

NR5R6 as defined in claim 1.

37. The compound according to claim 1 wherein R5 and R6 are pyridyl, pyrazinyl, pyrimidinyl, thienyl, thiazolyl or oxazolyl, which are all optionally substituted.

40. The compound according to claim 1 in which —

A2-B2-Y2 is selected from the following radicals;

41. The compound according to claim 1 wherein B2 is selected from the group consisting of 4-pyridyl and 4-quinolyl, which are optionally substituted with one or more radicals chosen from the definition of Y2.

44. The compound according to claim 1 wherein Y2 is hydrogen, F, Cl, —

CH₃, —

CH₂CH₃, —

OH, —

OCH₃, —

NH₂, —

NH-Alk or phenyl optionally substituted with —

NR5R6 in which R5 and R6 are as defined in claim 1.

45. The compound according to claim 1 wherein B2 is selected from 4-pyridyl and 4-quinolyl substituted with one or two radicals chosen from F, Cl, —

OH and —

OCH₃.

46. The compound according to claim 1 wherein

47. The compound according to claim 1 wherein —

A2-B2-Y2 are selected from the following radicals;

56. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant.

57. A method for treating a patient suffering from rheumatoid arthritis, comprising administering to the patient a physiologically effective amount of the compound according to claim 1.

58. The compound according to claim 1 wherein

Y and Y1, which may be identical or different, are such that one of Y and Y1 is selected from the group consisting of OCF₃, —

O—

CF₂—

CHF₂, —

O—

CHF₂, —

O—

CH₂—

CF₃, —

S(O)_nCF₃, —

S—

CF₂—

CF₂—

CF₃, —

S(O)_n-alk, —

S-Alk-O-Alk, —

S-Alk-OH, —

S-Alk-CN, —

S-Alk-heterocyclyl, —

SO₂CHF₂, —

SO₂CF₂CF₃, —

SO₂NR5R6 and —

SF₅, in which Alk is alkyl containing from 1 to 4 carbon atoms, and the other of Y and Y1 is chosen from the group consisting of hydrogen, halogen, nitro, —

NR5R6, free or esterified carboxyl, and —

CONR5R6,

or the

8. A compound of formula I wherein

11. The compound of formula I:

36. The compound of formula I:

38. The compound of formula I:

39. The compound of formula I:

42. The compound of formula I:

43. The compound of formula I:

48. The compound of formula (IC):

49. The compound according to claim 48 wherein the radical

50. The compound of formula (IA):

51. The compound according to claim 50 wherein Y1A, B2a, R2A and R3A are as defined in claim 50 and Y2A is halogen, —

OH, -alk, —

Oalk, —

Oacyl, —

NR5AR6A, —

CO2H, —

CO2alk, —

CO—

NR5AR6A, —

S(O)_n—

CF₃, —

NH—

S(O)_n—

CF₃ or phenyl;

alk is a linear or branched alkyl radical containing not more than 6 carbon atoms;

all the alkyl, alkoxy and phenyl are optionally substituted, R5A and R6A, which may be identical or different, are hydrogen, alkyl, cycloalkyl or phenyl, the alkyl and phenyl are optionally substituted, or R5A and R6A taken together with the nitrogen atom to which they are attached form cyclic radical chosen from pyrrolidyl, piperidyl, piperazinyl, morpholinyl, indolinyl, tetrahydroquinolyl and azetidinyl,

all the alkyl, alkoxy and phenyl are optionally substituted with one or more radicals chosen from halogen, —

OH, alk, —

Oalk, —

OCF₃, —

S(O)_n—

CF₃, —

CF₃, —

NH₂, —

NH-Alk and —

N(Alk)₂, and

n is 0 to 2, or

a racemic, enantiomeric or diastereoisomeric isomer form of said compound, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

52. The compound according to claim 50 wherein

Y1A is —

OCF₃, SCF₃ or S(O)2-CF₃,

B2a is a 4-quinolyl or 4-pyridyl radical optionally substituted with one or two radicals chosen from halogen, —

OH, alk, —

Oalk, —

CO2H, —

CO2alk, —

NR5AR6A, —

CF₃, —

OCF₃ and optionally substituted phenyl,

R5A and R6A, which may be identical or different, are hydrogen, alkyl, cycloalkyl or phenyl, the alkyl and phenyl radicals being optionally substituted,

or R5A and R6A taken together with the nitrogen atom to which they are attached forma cyclic radical chosen from pyrrolidyl, piperidyl, piperazinyl, morpholinyl, piperazinyl and azetidinyl radicals,

R2A and R3A, which may be identical or different, are hydrogen or optionally substituted alkyl,

all the alkyl and phenyl radicals being optionally substituted with one or more radicals chosen from halogen, OH, alk, Oalk, OCF₃, S(O)_n—

CF₃, —

CF₃, NH₂, NHalk and N(Alk)₂, or

a racemic, enantiomeric or diastereoisomeric isomer form of said compound, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

53. The compound according to claim 50 wherein

Y1A is —

OCF₃, —

SCF₃ or —

S(O)₂—

CF₃,

B2a is 4-quinolyl or 4-pyridyl optionally substituted with one or two radicals chosen from halogen, —

OH, alk and —

Oalk, and

R2A and R3A, which may be identical or different, are hydrogen or linear or branched alkyl containing not more than 4 carbon atoms optionally substituted with hydroxyl, or

a racemic, enantiomeric or diastereoisomeric isomer form of said compound, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

54. The compound according to claim 50 wherein Y1a is —

OCF₃, —

SCF₃ or —

S(O)₂CF₃, and R2A and R3A, which may be identical or different, are hydrogen or CH3, or a diastereoisomeric isomer form of said compound, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.

55. A compound selected from the group consisting of:

(S)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(S)-5-methyl-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(S)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-methyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-methyl-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-methyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-4-methyl-3-quinol-4-ylmethyl-5-thioxo-1-(4-trifluoromethylsulfanylphenyl)imidazolidin-2-one trifluoroacetate;

(R)-5-isopropyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-isopropyl-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-(4-hydroxybenzyl)-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-(4-hydroxybenzyl)-1-pyrid-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-5-(1-hydroxyethyl)-1-quinol-4-ylmethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

(R)-1-(3-hydroxypyrid-4-ylmethyl)-5-methyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-quinol-4-ylmethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

5,5-dimethyl-1-(3-methylpyrid-4-ylmethyl)-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethoxyphenyl)imidazolidine-2,4-dione trifluoroacetate;

1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate

1-(3-hydroxypyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethanesulfonylphenyl)imidazolidine-2,4-dione trifluoroacetate;

{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl} cyclopropanecarboxamide trifluoroacetate;

5,5-dimethyl-1-[2-(pyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

compound with trifluoroacetic acid;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}isobutyramide;

compound with trifluoroacetic acid;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide;

compound with trifluoroacetic acid;

1-(2-aminopyrid-4-ylmethyl)-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione hydrochloride;

{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}pyridine-2-carboxamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-piperid-1-ylpropionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-[4-(2-hydroxyethyl)piperazin-1-yl]propionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-morpholin-4-ylpropionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-pyrrolidin-1-ylpropionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(4-methylpiperazin-1-yl)propionamide trifluoroacetate;

1-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-phenylurea;

1-[2-(6-ethylpyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

5,5-dimethyl-1-[2-(4-methylpyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

5,5-dimethyl-1-[2-(6-methylpyrid-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

1-[2-(4,6-dimethylpyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethyl sulfanylphenyl)-imidazolidine-2,4-dione;

1-[2-(3,5-dichloropyrid-2-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione;

5,5-dimethyl-1-[2-(pyrid-4-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

5,5-dimethyl-1-[2-(pyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(2-oxoazepan-1-yl)propionamide;

3-(benzylmethylamino)-N-{4-[5,5-dimethyl-2,4-di-oxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide;

4,5-diacetoxy-6-acetoxymethyl-2-(3-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)-imidazolidin-1-ylmethyl]pyrid-2-yl}thioureidoacetic acid;

5,5-dimethyl-1-[2-(5-methylpyrid-2-ylamino)pyridin-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3,5-dimethoxybenzamide trifluoroacetate;

5,5-dimethyl-1-[2-(pyrazin-2-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(3-methylpiperid-1-yl)propionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(3,5-dimethylpiperid-1-yl)propionamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-methoxybenzamide trifluoroacetate;

{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}pyrazine-2-carboxamide trifluoroacetate;

{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}thiophene-2-carboxamide trifluoroacetate;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-4-methylbenzamide;

compound with trifluoroacetic acid;

1-isoquinolin-5-yl-5,5-dimethyl-3-(4-trifluoro-methylsulfanylphenyl)imidazolidine-2,4-dione;

3-(4-acetylpiperazin-1-yl)-N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide;

3-[4-(2-diethylaminoethyl)piperazin-1-yl]-N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}propionamide;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(2,6-dimethylmorpholin-4-yl)propionamide;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-3-(4-pyrrolidin-1-ylpiperid-1-yl)propionamide;

N-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-yl}-2-(4-pyrrolidin-1-ylpiperid-1-yl)acetamide;

5,5-dimethyl-1-[2-(4-methylpyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

5,5-dimethyl-1-[2-(6-morpholin-4-ylpyrid-3-ylamino)pyrid-4-ylmethyl]-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

1-[2-(2,6-dimethylpyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione;

methyl 5-{4-[5,5-dimethyl-2,4-dioxo-3-(4-trifluoromethylsulfanylphenyl)imidazolidin-1-ylmethyl]pyrid-2-ylamino}pyridine-2-carboxylate;

1-[2-(2,6-dimethoxypyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)imidazolidine-2,4-dione;

1-[2-(6-fluoropyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione; and

1-[2-(6-methoxypyrid-3-ylamino)pyrid-4-ylmethyl]-5,5-dimethyl-3-(4-trifluoromethylsulfanylphenyl)-imidazolidine-2,4-dione, or

a racemic, enantiomeric or diastereoisomeric isomer form of the compound of formula I, or an addition salt with a mineral or organic acid or with a mineral or organic base thereof.