IP Library Granted Patent US 8,546,395
Granted Patent B2
US 8,546,395 · App. 13/128,998 · Granted Oct 1, 2013

6-cycloamino-3-(1

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Quick Facts
Patent No.
US 8,546,395
App. No.
13/128,998
Granted
Oct 1, 2013
Kind
B2
Abstract

The invention relates to 6-cycloamino-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine derivatives corresponding to the general formula (I) in which R 2 represents an aryl group optionally substituted with one or more halogen atoms or C 1-6 -alkyl, C 1-6 -alkyloxy, C 1-6 -alkylthio, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkyloxy and —CN groups or R 2 represents a group chosen from C 1-6 -alkyl, C 1-6 -fluoroalkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl groups; A represents a C 1-7 -alkylene group; B represents a C 1-7 -alkylene group; L represents either a nitrogen atom optionally substituted with an R c or R d group, or a carbon atom substituted with an R e1 group and an R d group or two R e2 groups; the carbon atoms of A and of B being optionally substituted with one or more R f groups, which may be identical to or different from one another. Preparation process and therapeutic use.

Claims (127)

1. A compound of general formula (I):

or in the form of a base or of an addition salt with an acid, in which:

R 2 represents an aryl group optionally substituted with one or more substituents chosen from halogen atoms and C 1-6 -alkyl, C 1-6 -alkyloxy, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkyloxy and —CN groups or R 2 represents a C 1-6 -alkyl, C 1-6 -fluoroalkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl group;

A represents a C 1-7 -alkylene group optionally substituted with one or two R a groups;

B represents a C 1-7 -alkylene group optionally substituted with an R b group;

L represents either a nitrogen atom optionally substituted with an R c or R d group, or a carbon atom substituted with an R e1 group and an R d group or two R e2 groups;

the carbon atoms of A and B being optionally substituted with one or more R f groups, which may be identical to or different from one another;

R a , R b and R c are defined such that:

two R a groups may together form a C 1-6 -alkylene group;

R a and R b may together form a bond or a C 1-6 -alkylene group;

R a and R c may together form a bond or a C 1-6 -alkylene group;

R b and R c may together form a bond or a C 1-6 -alkylene group;

R d represents a group chosen from a hydrogen atom and C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, C 1-6 -alkylthio-C 1-6 -alkyl, C 1-6 -fluoroalkyl or benzyl groups;

R e1 represents an —NR 4 R 5 group or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents chosen from a fluorine atom and C 1-6 -alkyl, C 1-6 -alkyloxy and hydroxyl groups;

two R e2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more R f groups, which may be identical to or different from one another;

R f represents a C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -fluoroalkyl, phenyl or benzyl group;

R 4 and R 5 represent, independently of one another, a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl group; and

R 7 and R 8 represent, independently of one another, a hydrogen atom or a C 1-6 -alkyl group.

2. The compound according to claim 1 , wherein:

R 2 represents a phenyl optionally substituted with one or more halogen atoms or C 1-6 -alkyl or C 1-6 -fluoroalkyl groups.

3. The compound according to claim 1 , wherein:

R 2 represents a group chosen from C 1-6 -alkyl, C 1-6 -fluoroalkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl groups.

4. The compound according to claim 1 , wherein:

R 7 and R 8 represent, independently of each other, a hydrogen atom or a methyl group.

5. The compound according to claim 1 , wherein:

A represents a C 1-7 -alkylene group optionally substituted with one or two R a groups;

B represents a C 1-7 -alkylene group optionally substituted with an R b group;

L represents a nitrogen atom optionally substituted with an R c or R d group;

the carbon atoms of A and of B being optionally substituted with one or more R f groups, which may be identical to or different from each other;

two R a groups may together form a C 1-6 -alkylene group;

R a and R b may together form a bond or a C 1-6 -alkylene group;

R a and R c may together form a bond or a C 1-6 -alkylene group;

R b and R c may together form a bond or a C 1-6 -alkylene group;

R d represents a group chosen from a hydrogen atom and C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, C 1-6 -alkylthio-C 1-6 -alkyl, C 1-6 -fluoroalkyl or benzyl groups; and

R f represents a C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -fluoroalkyl or phenyl group.

6. The compound according to claim 1 , wherein:

A represents a C 1-7 -alkylene group optionally substituted with one or two R a groups;

B represents a C 1-7 -alkylene group optionally substituted with an R b group;

L represents a carbon atom optionally substituted with two R e2 groups;

the carbon atoms of A and of B being optionally substituted with one or more R f groups, which may be identical to or different from each other;

two R e2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally comprising an oxygen atom, this cyclic monoamine being optionally substituted with one or more R f groups, which may be identical to or different from one another; and

R f represents a C 1-6 -alkyl group.

7. The compound according to claim 1 , wherein:

A represents a C 1-7 -alkylene group;

B represents a C 1-7 -alkylene group;

L represents a carbon atom substituted with an R e1 group and an R d group;

R d represents a hydrogen atom;

R e1 represents an —NR 4 R 5 group or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more R f groups, which may be identical to or different from one another; and

R f represents a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl group.

8. The compound according to claim 1 , wherein:

R 2 represents a methyl group;

the cyclic amine formed by —N-A-L-B— represents an (R)-3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl or (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl group; and

R 7 and R 8 represent a hydrogen atom.

9. The compound according to claim 1 , wherein:

R 2 represents a 3-fluorophenyl or a 4-fluorophenyl group;

the cyclic amine formed by —N-A-L-B— represents an (R)-3-methylpiperazin-1-yl, 3,3-dimethylpiperazin-1-yl, (cis)-3,5-dimethylpiperazin-1-yl, 4-isopropylpiperazin-1-yl, 6,9-diazaspiro[4.5]dec-9-yl, 3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, 3-hydroxymethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, (R)-4-(2-hydroxypropyl)-piperazin-1-yl, (S)-4-(2-hydroxypropyl)piperazin-1-yl, 4-(1-hydroxy-2-methylpropan-2-yl)-piperazin-1-yl, 4-(2-hydroxy-2-methylpropyl)piperazin-1-yl, 4-(3-hydroxy-3-methylbutyl)-piperazin-1-yl, (R)-3-phenylpiperazin-1-yl, (S)-3-phenylpiperazin-1-yl, 4-benzylpiperazin-1-yl, (cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl, (cis)-5-(2-hydroxyethyl)hexahydro-pyrrolo[3,4-c]pyrrol-2(1H)-yl, (4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, (4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl, or (1S,4S)-5-methyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl group; and

R 7 and R 8 represent, independently of each other, a hydrogen atom or a methyl group.

10. The compound according to claim 1 , wherein:

R 2 represents a 4-fluorophenyl group;

the cyclic amine formed by —N-A-L-B— represents a 2,9-diazaspiro[5.5]undec-9-yl group; and

R 7 and R 8 represent a hydrogen atom.

11. The compound according to claim 1 , wherein:

R 2 represents a 4-fluorophenyl group;

the cyclic amine formed by —N-A-L-B— represents a 4-(pyrrolidin-1-yl)-piperidin-1-yl group;

R 7 and R 8 represent a hydrogen atom.

12. The compound according to claim 1 , chosen from:

1. 2-Methyl-6-[(R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

2. 6-(3,3-Dimethylpiperazin-1-yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

3. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

4. 6-(4-Isopropylpiperazin-1-yl)-2-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

5. 2-Methyl-6-[(cis)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

6. 2-(4-Fluorophenyl)-6-[(3R)-3-methylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

7. {4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-piperazin-2-yl}methanol;

8. 6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

9. 6-(3,3-Dimethylpiperazin-1-yl)-2-(3-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

10. 6-(3,3-Dimethylpiperazin-1-yl)-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

11. 6-[(cis)-3,5-Dimethylpiperazin-1-yl]-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

12. 2-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;

13. 2-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}ethanol;

14. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

15. 2-(4-Fluorophenyl)-6-(4-isopropylpiperazin-1-yl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

16. (R)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;

17. (S)-1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}propan-2-ol;

18. 6-(6,9-Diazaspiro[4.5]dec-9-yl)-2-(4-fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

19. 2-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-1-ol;

20. 1-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

21. 1-{4-[2-(3-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

22. 1-{4-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylpropan-2-ol;

23. 4-{4-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]piperazin-1-yl}-2-methylbutan-2-ol;

24. (R)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

25. (S)-2-(4-Fluorophenyl)-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine and the trihydrochloride thereof;

26. 2-(4-Fluorophenyl)-8-methyl-6-[3-phenylpiperazin-1-yl]-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

27. 6-(4-Benzylpiperazin-1-yl)-2-(4-fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)-imidazo[1,2-b]pyridazine;

28. (cis)-2-(4-Fluorophenyl)-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

29. (cis)-2-(4-Fluorophenyl)-8-methyl-6-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

30. (cis)-2-{5-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;

31. (cis)-2-{5-[2-(4-Fluorophenyl)-8-methyl-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}ethanol;

32. 2-(4-Fluorophenyl)-8-methyl-6-((4aR,7aR)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

33. 2-(4-Fluorophenyl)-8-methyl-6-((4aS,7aS)-1-methyloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

34. 2-(4-Fluorophenyl)-6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine;

35. 9-[2-(4-Fluorophenyl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazin-6-yl]-2,9-diazaspiro[5.5]undecane;

36. 2-(4-Fluorophenyl)-6-(4-pyrrolidin-1-ylpiperidin-1-yl)-3-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-b]pyridazine.

13. A pharmaceutical composition comprising the compound according to claim 1 , in the form of a base or an addition salt with a pharmaceutically acceptable acid.

14. The pharmaceutical composition according to claim 13 further comprising, at least one pharmaceutically acceptable excipient.

15. A process for preparing the compound according to claim 1 , which comprises reacting a compound of general formula (II):

in which R 2 , R 7 and R 8 are as defined according to claim 1 and X 6 represents a leaving group, with an amine of general formula (III):

in which A, L and B are as defined according to claim 1 .

16. A process for preparing the compound according to claim 1 , comprising deprotecting a compound of general formula (V):

in which R 2 , A, L, B, R 7 and R 8 are as defined according to claim 1 and PG represents a benzene or toluenesulphonyl group, using a base.

17. A method for inhibiting casein kinase I epsilon and/or casein kinase delta comprising adding a solution comprised of said casein kinase I epsilon or casein kinase delta a compound of the formula

or in the form of a base or of an addition salt with an acid, in which:

R 2 represents an aryl group optionally substituted with one or more substituents chosen from halogen atoms and C 1-6 -alkyl, C 1-6 -alkyloxy, C 1-6 -alkylthio, C 1-6 -fluoroalkyl, C 1-6 -fluoroalkyloxy and —CN groups or R 2 represents a C 1-6 -alkyl, C 1-6 -fluoroalkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl group;

A represents a C 1-7 -alkylene group optionally substituted with one or two R a groups;

B represents a C 1-7 -alkylene group optionally substituted with an R b group;

L represents either a nitrogen atom optionally substituted with an R c or R d group, or a carbon atom substituted with an R e1 group and an R d group or two R e2 groups;

the carbon atoms of A and B being optionally substituted with one or more R f groups, which may be identical to or different from one another;

R a , R b and R c are defined such that:

two R a groups may together form a C 1-6 -alkylene group;

R a and R b may together form a bond or a C 1-6 -alkylene group;

R a and R c may together form a bond or a C 1-6 -alkylene group;

R b and R c may together form a bond or a C 1-6 -alkylene group;

R d represents a group chosen from a hydrogen atom and C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -alkyloxy-C 1-6 -alkylthio-C 1-6 -alkyl, C 1-6 -fluoroalkyl or benzyl groups;

R e1 represents an —NR 4 R 5 group or a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more substituents chosen from a fluorine atom and C 1-6 -alkyl, C 1-6 -alkyloxy and hydroxyl groups;

two R e2 groups form, with the carbon atom that bears them, a cyclic monoamine optionally comprising an oxygen atom, the cyclic monoamine being optionally substituted with one or more R f groups, which may be identical to or different from one another;

R f represents a C 1-6 -alkyl, C 3-7 -cycloalkyl, C 1-6 -alkyloxy-C 1-6 -alkyl, hydroxy-C 1-6 -alkyl, C 1-6 -fluoroalkyl, phenyl or benzyl group;

R 4 and R 5 represent, independently of one another, a hydrogen atom or a C 1-6 -alkyl, C 3-7 -cycloalkyl or C 3-7 -cycloalkyl-C 1-6 -alkyl group; and

R 7 and R 8 represent, independently of one another, a hydrogen atom or a C 1-6 -alkyl group.

Assignments (2)
CHANGE OF NAME Recorded Jun 20, 2012
From: SANOFI-AVENTIS
To: SANOFI
Reel/Frame 028413/0927 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 28, 2011
From: PACAUD, CHRISTOPHE; PUECH, FREDERIC
To: SANOFI-AVENTIS
Reel/Frame 026984/0197 →