1-pyrazolo[4,3-c]isoquinoline derivatives, preparation thereof and therapeutic use thereof

1. A compound of formula (I):

in which:

R 1 represents a phenyl group which is optionally substituted by one or more halogen atoms;

R 2 represents:

a hydrogen or halogen atom or a cyano group;

a group —C(═O)Y in which Y represents a hydrogen atom or a group —NH 2 or —OR a ;

a group —C(═S)NH 2 ;

a group —C(═NH)NH—OH;

a group —CH 2 OH or —CH 2 F;

a group —CH═N—OH;

a group —CH═CH 2 or —C≡C—R a ;

a group

where R a represents a hydrogen atom or a (C 1 -C 4 )alkyl group;

R 3 represents a hydrogen atom or a (C 1 -C 4 )alkyl group;

R 4 represents an —NH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl or (C 3 -C 7 )cycloalkyl group.

2. The compound according to claim 1 , wherein R 1 represents a 2,6-difluoro-phenyl group and R 3 represents a hydrogen atom.

3. The compound according to claim 1 , wherein R 2 is selected from: H, —C(═O)H, —C(═O)NH 2 , —CH═N—OH, —CH 2 OH, —CH═CH 2 , —F, —C≡CH, —C(═O)OCH 3 , —C(═S)NH 2 , —CN,

4. The compound according to claim 1 , wherein R 4 is selected from: —CH 3 , —CH 2 CH 3 , —CF 3 or the cyclopropyl group.

5. The compound according to claim 1 selected from the following list:

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}1-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol;

5-(2,6-difluorophenyl)-3-{[1-(trifluoromethanesulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino }-7-vinyl-1H-pyrazolo[4,3-c]isoquinoline;

5-(2,6-difluorophenyl)-7-fluoro-3-{[1-(methyl sulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino }-7-ethynyl-1H-pyrazolo[4,3-c]isoquinoline;

methyl 5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3c] isoquinoline-7-carboxylate;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbothioamide;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline;

5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c] isoquinoline-7-carbonitrile;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile;

5-(2,6-difluorophenyl)-3-[1-(ethylsulphonyl)piperidin-4-yl]amino-1H-pyrazolo[4,3-c]isoquinoline-7-carbonitrile;

5-(2,6-difluorophenyl)-3-{[1-(cyclopropylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide;

5-(2,6-difluorophenyl)-3-{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde;

5-(2,6-difluorophenyl)-N-hydroxy-3{[1-(methylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboximidamide;

[5-(2,6-difluorophenyl)-7-(fluoromethyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-1H-pyrazolo[4,3-c]isoquinolin-3-amine;

5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carboxamide;

5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde;

5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde oxime;

5-(2,6-difluorophenyl)-3-{[1-(ethylsulphonyl)piperidin-4-yl]amino}-1H-pyrazolo[4,3-c]isoquinolin-7-yl]methanol;

5-(2,6-difluorophenyl)-3-[(1-sulphamoylpiperidin-4-yl)amino]-2H-pyrazolo[4,3-c]isoquinoline-7-carboxamide;

4-({5-(2,6-difluorophenyl)-7-[(E/Z)-(hydroxyimino)methyl]-1H-pyrazolo[4,3-c]isoquinolin-3-yl}amino)piperidine-1-sulphonamide;

5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]isoquinolin-3-amine;

5-(2,6-difluorophenyl)-N-[1-(methylsulphonyl)piperidin-4-yl]-7-(2H-1,2,3-triazol-4-yl)-1H-pyrazolo[4,3-c]isoquinolin-3-amine;

4-{[7-cyano-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide;

4-{[5-(2,6-difluorophenyl)-7-(hydroxymethyl)-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide;

4-{[5-(2,6-difluorophenyl)-7-fluoro-1H-pyrazolo[4,3-c]isoquinolin-3-yl]amino}piperidine-1-sulphonamide.

6. The compound according to claim 1 , in the form of a base or an acid addition salt.

7. A process for preparing a compound of formula:

in which:

R 1 represents a phenyl group which is optionally substituted by one or more halogen atoms;

R 3 represents a hydrogen atom or a (C 1 -C 4 )alkyl group;

R 4 represents an —NH 2 , (C 1 -C 4 )alkyl, (C 1 -C 4 )fluoroalkyl or (C 3 -C 7 )cycloalkyl group, and X represents a hydrogen or fluorine atom or a group cyano; —C(═O)H; —CH═CH 2 ; —C≡C—SiMe s ; —COOR a , R a representing a hydrogen atom or a (C 1 -C 4 )alkyl group; or the group

comprising:

(i) coupling the compounds P 1 and P 2 in the presence of a palladium complex and optionally of a base:

(ii) deprotecting the product obtained in the preceding step (i), or else comprising:

(i′) reacting the compound P′ 4 of formula:

with R 4 SO 2 Cl,

(ii′) deprotecting the product obtained in the preceding step (i),

where PG represents a protective group for the NH function of the pyrazole ring.

8. A process for preparing a compound of formula (I):

in which R 1 , R 3 and R 4 are as defined in claim 1 , and R 2 represents one of the following groups: —C(═O)NH 2 , —C(═S)NH 2 , —C(O)H, —CH═N—OH, —CH 2 OH, —CH 2 F, —C≡CH,

from a compound of formula:

in which X represents a group —CN, —CHO, —CH 2 OH, —C≡CH or —C≡C—SiMe 3 and A represents a hydrogen atom or a protective group PG protecting the NH function of the pyrazole ring, comprising:

(i)

hydrolyzing the group X=—CN to group R 2 =—C(═O)NH 2 or —C(═O)OH; or

converting the group X=—CN to group R 2 =—C(═S)NH 2 in the presence of ammonium sulphide with microwaves; or

reducing the group X=—CN to group R 2 =—C(O)H; or

converting the group X=—C(═O)H to group R 2 =—CH═N—OH in the presence of NH 2 OH; or

reducing the group X=—C(═O)H to group R 2 =—CH 2 OH; or

converting the group X=—C≡C—SiMe 3 to group R 2 =—C≡CH; or

fluorinating the group X=—CH 2 OH to group R 2 =—CH 2 F; or

converting the group X=—C≡CH to group

by cycloaddition in the presence of trimethylsilyl azide N 3 SiMe 3 ; and

(ii) where appropriate, deprotecting the product obtained in the preceding step (i).

9. A pharmaceutical composition comprising the compound according to claim 1 and at least one pharmaceutically acceptable excipient.

10. An anticancer agent comprising the compound of claim 1 .

11. A compound of formula:

or of formula

in which:

R 1 represents a phenyl group which is optionally substituted by one or more halogen atoms;

R 2 represents:

a hydrogen or halogen atom or a cyano group;

a group —C(═O)Y in which Y represents a hydrogen atom or a group —NH 2 or OR a ;

a group —C(═S)NH 2 ;

a group —C(═NH)NH—OH;

a group —CH 2 OH or —CH 2 F;

a group —CH═N—OH;

a group —CH═CH 2 or —C≡C—R a ;

a group

where R a represents a hydrogen atom or a (C i -C 4 )alkyl group;

R 3 represents a hydrogen atom or a (C i -C 4 )alkyl group;

R 4 represents an —NH 2 , (C i -C 4 )alkyl, (C i -C 4 )fluoroalkyl or (C 3 -C 7 )cycloalkyl group;

X represents a hydrogen or fluorine atom, a group cyano; —C(═O)H; —CH═CH 2 ; —C≡C—SiMe 3 ; —C≡CH , —COOR a , where R a represents a hydrogen atom or a (C 1 -C 4 )alkyl group, or the group

PG represents a protective group for the NH function of the pyrazole group;

B represents a hydrogen atom or a protective group PG′ for the amine function.

12. The compound according to claim 11 , in which PG represents SEM or SO 2 NMe 2 and PG′ represents BOC.

13. The compound according to claim 11 , in which PG' represents BOC.