IP Library › Granted Patent US 8,188,078

Granted Patent B2

US 8,188,078 · App. 12/761,973 · Granted May 29, 2012

6-aryl/heteroalkyloxy benzothiazole and benzimidazole derivatives, method for preparing same, application thereof as drugs, pharmaceutical compositions and novel use in particular as C-MET inhibitors

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Quick Facts

Patent No.: US 8,188,078
App. No.: 12/761,973
Granted: May 29, 2012
Kind: B2

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Abstract

The disclosure relates to compounds of formula (I): wherein A, W, R, R 5 , and R 6 are as defined in the disclosure, or a salt thereof, and to their use as drugs, in particular as c-Met inhibitors.

Claims (133)

1. A compound of formula (Ia):

Wherein:

R represents a hydrogen atom, a halogen atom or an alkyl radical,

A represents NH or S;

R6 represents an aryl or heteroaryl radical optionally substituted with one or more radicals, which may be identical or different, selected from halogen atoms, hydroxyl, alkoxy, NR3R4 radicals, and alkyl, phenyl and phenylalkyl radicals, these last three radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals; and

W represents a hydrogen atom or the radical COR7 in which R7 represents:

a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, hydroxyl, phenyl, heteroaryl, NR3R4, CONR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

an alkoxy radical optionally substituted with a hydroxyl, alkoxy, phenyl, heteroaryl, NR3R4, CONR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, phenylalkoxy, cycloalkylalkoxy radicals, and heteroaryl, heterocycloalkyl, NR3R4, CONR3R4 and phenyl radicals optionally substituted as indicated below; or alternatively R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O, S, N and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

wherein R3 and R4, identical or different, are such that one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl, CO2Alk radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, NH2, NHalk, N(alk)2 radicals and heteroaryl, heterocycloalkyl, and phenyl radicals optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals; or alternatively R3 and R4 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O, S, N and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

the heterocycloalkyl, heteroaryl, aryl and phenyl radicals defined above as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHalk, N(alk)2, free or esterified carboxyl radicals and alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, (heterocycloalkyl)alkyl, (phenyl)alkyl, (heteroaryl)alkyl, —CO-heterocycloalkyl, —CO-phenyl, —CO-heteroaryl, —S-heterocycloalkyl, —S-aryl, —S-heteroaryl, —O-heterocycloalkyl, —O-aryl and —O-heteroaryl radicals, such that in these last-mentioned radicals, the heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;

and wherein:

-R6 bears at least one halogen atom;

-R7 does not represent a methoxy radical;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

2. A compound of formula (Ia) according to claim 1 :

wherein:

R represents a hydrogen atom, a halogen atom or an alkyl radical;

A represents NH or S;

R6 represents an aryl or heteroaryl radical optionally substituted with one or more radicals, which may be identical or different, selected from halogen atoms, hydroxyl, alkoxy, NR3R4 radicals and alkyl, phenyl and phenylalkyl radicals, these last three radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals; and

W represents a hydrogen atom or the radical COR7 in which R7 represents:

a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, hydroxyl, phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

an alkoxy radical optionally substituted with an alkoxy, phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, phenylalkoxy, cycloalkylalkoxy radicals, and heteroaryl, heterocycloalkyl, NR3R4, CONR3R4 and phenyl radicals optionally substituted as indicated below; or alternatively R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O, S, N and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

the heterocycloalkyl, heteroaryl, aryl and phenyl radicals defined above as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHalk, N(alk)2, free or esterified carboxyl radicals and alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, (hetero cycloalkyl) alkyl, (phenyl) alkyl, (heteroaryl)alkyl, —CO-heterocycloalkyl, —CO-phenyl, —CO-heteroaryl, —S-heterocycloalkyl, —S-aryl, —S-heteroaryl, —O-heterocycloalkyl, —O-aryl and —O-heteroaryl radicals, such that in these last-mentioned radicals, the heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;

and wherein:

R6 bears at least one halogen atom;

R7 does not represent a methoxy radical;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

3. The compound of formula (Ia) according to claim 1 , wherein:

R represents a hydrogen atom, a halogen atom or an alkyl radical;

A represents NH or S;

R6 represents an aryl or heteroaryl radical optionally substituted with one or more radicals, which may be identical or different, selected from halogen atoms, hydroxyl, alkoxy, NR3R4 radicals and alkyl, phenyl and phenylalkyl radicals, these last three radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals;

W represents a hydrogen atom or the radical COR7 in which R7 represents:

a cycloalkyl radical or an alkyl radical optionally substituted with an alkoxy, hydroxyl, phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

an alkoxy radical optionally substituted with a phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

and wherein:

R6 bears at least one halogen atom;

R7 does not represent a methoxy radical;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

4. The compound of formula (Ia) according to claim 1 , wherein:

R represents a hydrogen atom, a halogen atom or an alkyl radical;

A represents NH or S;

R6 represents a phenyl or heteroaryl radical optionally substituted with one or more radicals, which may be identical or different, selected from halogen atoms, hydroxyl, alkoxy, NR3R4 radicals and alkyl, phenyl and phenylalkyl radicals, these last three radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals; and

W represents a hydrogen atom or the radical COR7 in which R7 represents:

a cycloalkyl radical or an alkyl radical optionally substituted with a phenyl, heteroaryl, NR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

an alkoxy radical optionally substituted with NR3R4;

or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, phenylalkoxy, cycloalkylalkoxy, heteroaryl, heterocycloalkyl, NR3R4, CONR3R4 and phenyl radicals optionally substituted as indicated below; or alternatively R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

wherein R3 and R4, identical or different, are such that one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a cycloalkyl, CO2Alk radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and phenyl radical itself optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl and alkoxy radicals; or alternatively R3 and R4 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

the heterocycloalkyl, heteroaryl and phenyl radicals defined above as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHalk, N(alk)2, free or esterified carboxyl radicals and alkyl, cycloalkyl, heterocycloalkyl, phenyl, phenylalkyl and heteroaryl radicals, these last-mentioned heterocycloalkyl, phenyl, phenylalkyl and heteroaryl radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

5. The compound of formula (Ia) according to claim 1 , wherein:

R represents a hydrogen atom, a halogen atom or an alkyl radical;

A represents NH or S;

R6 represents a phenyl or pyridyl radical optionally substituted with one or more radicals, which may be identical or different, selected from halogen atoms and hydroxyl, alkoxy, NH2, NHalk, N(alk)2, alkyl and phenyl radicals optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals;

W represents a hydrogen atom or the radical COR7 in which R7 represents a cycloalkyl radical or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, phenylalkoxy, cycloalkylalkoxy, heteroaryl, heterocycloalkyl, NR3R4, CONR3R4 and phenyl radicals optionally substituted as indicated below; or alternatively R1 and R2 form with the nitrogen atom to which they are attached a radical selected from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino and piperazinyl radicals, optionally substituted as indicated below;

wherein R3 and R4, identical or different, are such that one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a CO2Alk radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, NH2, NHalk, N(alk)2 and phenyl radicals optionally substituted as indicated below; or alternatively R3 and R4 form with the nitrogen atom to which they are attached a radical selected from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino and piperazinyl radicals, optionally substituted as indicated below;

the heterocycloalkyl, heteroaryl and phenyl radicals defined above as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHalk, N(alk)2, free or esterified carboxyl, alkyl, phenyl and phenylalkyl radicals in which the phenyl radical is itself optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

6. A compound of formula (Ia) according to claim 1 , wherein:

R represents a hydrogen atom, a fluorine atom or a methyl radical;

A represents NH or S;

R6 represents a phenyl or pyridyl radical optionally substituted with 1 to 3 substituents, which may be identical or different, selected from halogen atoms and alkyl radicals themselves optionally substituted with one or more halogen atoms;

W represents a hydrogen atom or the radical COR7 in which R7 represents:

a cycloalkyl radical or an alkyl radical optionally substituted with NR3R4;

an alkoxy radical optionally substituted with an alkoxy radical, or NR3R4;

or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an alkyl radical optionally substituted with a radical selected from the hydroxyl radical; alkoxy; phenylalkoxy optionally substituted on phenyl; cycloalkylalkoxy; CONR3R4; and pyrrolyl, pyridyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidyl, and azepanyl radicals, these radicals themselves are optionally substituted on carbon or nitrogen atoms with one or more radicals selected from the radicals oxo ═O, free or esterified carboxyl, alkyl or phenylalkyl with phenyl optionally substituted;

wherein R3 and R4, identical or different, are such that one of R3 and R4 represents a hydrogen atom or an alkyl radical and the other of R3 and R4 represents a hydrogen atom, a CO2Alk radical or an alkyl radical optionally substituted with a phenyl radical itself optionally substituted; or alternatively R3 and R4 form with the nitrogen atom to which they are attached a radical selected from pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, azepinyl, morpholino and piperazinyl radicals, these radicals themselves are optionally substituted on carbon or nitrogen atoms with one or more radicals selected from the radicals oxo ═O, free or esterified carboxyl, alkyl or phenylalkyl with phenyl optionally substituted;

the phenyl radicals defined above are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkoxy, alkyl; NH2, NHalk, N(alk)2 and free or esterified carboxyl radicals;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

7. The compound of formula (Ia) according to claim 1 , wherein:

R represents a hydrogen atom or a fluorine atom;

A represents NH or S;

W represents a hydrogen atom or the radical COR7 in which R7 represents a cycloalkyl radical or a radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents an alkyl radical optionally substituted with a pyrrolyl, pyridyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidyl, or azepanyl radical, these radicals themselves are optionally substituted on carbon or nitrogen atoms with one or more radicals selected from the radicals oxo ═O, free or esterified carboxyl, alkyl or phenylalkyl with phenyl optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

8. A compound of formula (Ib):

wherein

R represents a hydrogen atom, a halogen atom or an alkyl radical,

A represents NH or S;

W represents a hydrogen atom or the radical COR7 in which R7 represents:

an alkoxy radical optionally substituted with a hydroxyl, alkoxy, phenyl, heteroaryl, NR3R4, CONR3R4 or heterocycloalkyl radical, themselves optionally substituted as indicated below;

or the radical NR1R2 in which R1 and R2 are such that one of R1 and R2 represents a hydrogen atom or an alkyl radical and the other of R1 and R2 represents a hydrogen atom, a cycloalkyl radical or an alkyl radical optionally substituted with one or more radicals, which may be identical or different, selected from hydroxyl, alkoxy, phenylalkoxy, cycloalkylalkoxy radicals, and heteroaryl heteroalkyl, NR3R4 CONR3R4 and phenyl radicals optionally substituted as indicated below; or alternatively R1 and R2 form with the nitrogen atom to which they are attached a cyclic radical optionally containing one or more other heteroatoms selected from O, S, N and NH, said radical including the NH that it possibly contains are optionally substituted as indicated below;

the heterocycloalkyl, heteroaryl, aryl and phenyl radicals defined above as well as the cyclic radicals that R1 and R2 or R3 and R4 can form with the nitrogen atom to which they are attached, are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl, oxo, alkoxy, NH2, NHalk, N(alk)2, free or esterified carboxyl radicals and alkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, (heterocycloalkyl)alkyl, (phenyl) alkyl, (heteroaryl)alkyl, —CO-heterocycloalkyl, —CO-phenyl, —CO-heteroaryl, —S-heterocycloalkyl, —S-aryl, —S-heteroaryl, —O-heterocycloalkyl, —O-aryl and —O-heteroaryl radicals, such that in these last-mentioned radicals, the heterocycloalkyl, phenyl and heteroaryl radicals are themselves optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, oxo, alkyl and alkoxy radicals containing from 1 to 4 carbon atoms, NH2, NHalk and N(alk)2; and

X1, X2 and X3, which may be identical or different, are such that one represents a halogen atom and the other two, identical or different, are selected from hydrogen atom, halogen atoms, hydroxyl, alkoxy, NR3R4 radicals, and alkyl, phenyl and phenylalkyl radicals, these last three radicals themselves are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, alkyl, alkoxy, NH2, NHalk and N(alk)2 radicals;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

9. A compound selected from the group consisting of:

1-{6-[1-(2,6-dichlorophenyl)ethoxy]-1H-benzimidazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-benzimidazol-2-yl}-3-(2-morpholin-4-ylethyl)urea trifluoroacetate;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1H-benzimidazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichlorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[(1R*)-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichlorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[(1R*)-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(3-morpholin-4-ylpropyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-[3-(dimethylamino)propyl]urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(3-piperidin-1-ylpropyl)urea;

1-{3-[4-(2-chloro-6-fluorobenzyl)piperazin-1-yl]propyl}-3-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}urea;

1-(3-azepan-1-ylpropyl)-3-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-piperidin-1-ylethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-pyrrolidin-1-ylethyl)urea;

1-[2-(1-benzylpiperidin-4-yl)ethyl]-3-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-[2-(1-methylpyrrolidin-2-yl)ethyl]urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-[2-(4-methylpiperazin-1-yl)ethyl]urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-[2-(2,6-dimethylpiperidin-1-yl)ethyl]urea;

1-{6-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-(2-morpholin-4-ylethyl)urea;

1-{6-[(1R*)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(4-methylpiperazin-1-yl)ethyl]urea;

1-{6-[(1R*)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-(2-hydroxyethyl)urea;

1-{6-[(1R*)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-(2-hydroxyethyl)urea;

1-{6-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(4-ethylpiperazin-1-yl)ethyl]urea;

1-{6-[(1R*)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(4-ethylpiperazin-1-yl)ethyl]urea;

1-{6-[(1R*)-1-(2,3-dichloro-6-fluorophenyl)ethoxy]-1,3-benzothiazol-2-yl}-3-[2-(4-methylpiperazin-1-yl)ethyl]urea;

1-{6-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea;

1-{6-[(1R*)-1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(morpholin-4-yl)ethyl]urea;

1-{6-[1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(4-methylpiperazin-1-yl)ethyl]urea;

1-{6-[(1R*)-1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(4-methylpiperazin-1-yl)ethyl]urea; and

1-{6-[(1R*)-1-(2,3-dichloro-6-fluorophenyl)ethoxy]-5-fluoro-1,3-benzothiazol-2-yl}-3-[2-(pyrrolidin-1-yl)ethyl]urea;

or an addition salt thereof with a mineral or organic acid or with a mineral or organic base.

10. A pharmaceutical composition comprising a compound of formula (Ia) according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable support.

11. A pharmaceutical composition comprising a compound of formula (I) according to claim 9 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable support.

12. A method of inhibiting the activity of protein kinase MET which comprises contacting said protein kinase with a compound of formula (Ia) according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 wherein the protein kinase is in a cell culture.

14. The method according to claim 12 wherein the protein kinase is in a mammal.

15. A pharmaceutical composition comprising a compound of formula Ib according to claim 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable support.

Assignments (2)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

Reel/Frame 028413/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 13, 2010

From: NEMECEK, CONCEPTION; WENTZLER, SYLVIE

To: SANOFI-AVENTIS

Reel/Frame 025131/0091 →