Patent EA-002632-B1 (EA)
Title: Isoquinolines, process for preparing thereof and use as urokinase inhibitors
Inventor: BARBER CHRISTOPHER GORDON
IPC: A61K31/472
Filed: 1998-10-05
Abstract: 1. A compound of formula (I):   or a pharmaceutically acceptable salt thereof, wherein one of R<1> and R<2> is H and the other is N=C(NH2)2 or NHC(=NH)NH2, R<3> is H, halogen, C1-6 alkyl optionally substituted by one or more halogen, or C1-6 alkoxy optionally substituted by one or more halogen, R<4>, R<5>, R<6> and R<7> are each independently H, OH, halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, CO(C1-6 alkyl optionally substituted by one or more halogen), (Cm-alkylene)CO2R<8>, O(Cn-alkylene)CO2R<8>, O(Cn-alkylene)CN, (Cn-alkylene)CN, (Cm-alkylene)CONR<9>R<10>, (Cm-alkylene)NR<9>COR<10>, O(Cn-alkylene)CONR<9>R<10>, (Cm-alkylene)NR<9>SO2R<11>, (Cm-alkylene)S(O)pR<11>, (Cm-alkylene)SO2NR<9>R<10>, CH=CHCOR<8>, CH=CHCONR<9>R<10>, CH=CHSO2R<8>, CH=CHSO2NR<9>R<10>, CH=CHSO2-aryl, or a group of formula X-aryl or X-Het, or, where two of R<4>, R<5>, R<6> and R<7> are attached to adjacent carbon atoms, they can be taken together to form an -O(Cn-alkylene)O-moiety, R<8> is H, C1-6 alkyl optionally substituted by one or more halogen, or aryl(C1-6 alkylene), R<9> and R<10> are each independently H, C1-6 alkyl optionally substituted by one or more halogen, aryl(C1-6 alkylene), aryl, heteroaryl or heteroaryl(C1-6 alkylene), or R<9> and R<10> may be linked together by an alkylene moiety to form, with the atoms to which they are attached, a 4- to 7-membered ring optionally incorporating an additional hetero-group selected from an O or S atom or a NR<12> group, R<11> is aryl, heteroaryl, or C1-6 alkyl optionally substituted by one or more halogen, R<12> is H, C1-6 alkyl optionally substituted by one or more halogen, or CO(C1-6 alkyl optionally substituted by one or more halogen), X is a direct link, Cn-alkylene, O, (Cn-alkylene)O, O(Cn-alkylene), CH(OH), C(C1-6 alkyl)OH, CO, S(O)p(Cm-alkylene), (Cm-alkylene)S(O)p, CH=CH, or C [triple bond] C, "aryl" is phenyl or naphthyl optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen and OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, CO(C1-6 alkyl optionally substituted by one or more halogen), (Cm-alkylene)CO2R<13>, O(Cn-alkylene)CO2R<13>, (Cm-alkylene)CONR<14>R<15>, (Cm-alkylene)NR<14>COR<15>, O(Cn-alkylene)CONR<14>R<15>, (Cm-alkylene)S(O)pR<13>, (Cm-alkylene)SO2NR<14>R<15>, (Cm-alkylene)NR<14>SO2R<16>, CH=CHSO2R<13>, CH=CHSO2NR<14>R<15>, CH=CHSO2aryl<1>, CH=CHCOR<13>, and CH=CHCONR<14>R<15>, "heteroaryl" is an optionally benzo-fused 5- or 6-membered heterocyclic group linked by any available atom in the heterocyclic or benzo-ring (if present), which heterocyclic group is selected from dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl, said "heteroaryl" group being optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, CO(C1-6 alkyl optionally substituted by one or more halogen), (Cm-alkylene)CO2R<13>, O(Cn-alkylene)CO2 R<13>, (Cm-alkylene)-CONR<14>R<15>, (Cm-alkylene)NR<14>COR<15>, O(Cn-alkylene)CONR<14>R<15>, (Cm-alkylene)NR<14>SO2R<16>, (Cm-alkylene)S(O)pR<13>, (Cm-alkylene)SO2NR<14>R<15>, CH=CHCOR<13>, CH=CHCONR<14>R<15>, CH=CHSO2R<13>, CH=CHSO2NR<14>R<15>, or CH=CHSO2aryl<1>, "Het" is an optionally benzo-fused 5- or 6-membered heterocyclic group linked to the "X" moiety by any available atom in the heterocyclic or benzo-ring (if present), which heterocyclic group is selected from dioxolyl, dioxolanyl, furyl, thienyl, pyrrolyl, oxazolyl, oxazinyl, thiazinyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl, or a fully unsaturated, partially or fully saturated analogue thereof, such "Het" group being optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen and OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, CO(C1-6 alkyl optionally substituted by one or more halogen), (Cm-alkylene)CO2R<13>, O(Cn-alkylene)CO2R<13>, (Cm-alkylene)CONR<14>R<15>, (Cm-alkylene)NR<14>COR<15>, O(Cn-alkylene)CONR<14>R<15>, (Cm-alkylene)NR<14>SO2R<16>, (Cm-alkylene)S(O)pR<13>, (Cm-alkylene)SO2NR<14>R<15>, CH=CHCOR<13>, CH=CHCONR<14>R<15>, CH=CHSO2R<13>, CH=CHSO2NR<14>R<15>, and CH=CHSO2aryl<1>, "aryl<1> " is phenyl or naphthyl optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, CO(C1-6 alkyl optionally substituted by one or more halogen), (Cm-alkylene)CO2R<13>, O(Cn-alkylene)CO2R<13>, (Cm-alkylene)CONR<14>R<15>, (Cm-alkylene)NR<14>COR<15>, O(Cn-alkylene)CONR<14>R<15>, (Cm-alkylene)S(O)pR<13>, (Cm-alkylene)SO2NR<14>R<15>, (Cm-alkylene)NR14SO2R<16>, CH=CHSO2R<13>, CH=CHSO2NR<14>R<15>, CH=CHCOR<13>, and CH=CHCONR<14>R<15>, R<13> is H, C1-6 alkyl optionally substituted by one or more halogen, or aryl<2> (C1-6 alkylene), R<14> and R<15> are each independently H, C1-6 alkyl optionally substituted by one or more halogen, aryl<2> (C1-6 alkylene), aryl<2>, heteroaryl<1> or heteroaryl<1> (C1-6 alkylene), or R<14> and R<15> may be linked together by an alkylene moiety to form, with the atoms to which they are attached, a 4- to 7-membered ring optionally incorporating an additional hetero-group selected from an O or S atom or a NR<12> group, R<16> is aryl<2>, heteroaryl<1>, or C1-6 alkyl optionally substituted by one or more halogen, "aryl<2> " is phenyl or naphthyl optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, or CO(C1-6 alkyl optionally substituted by one or more halogen), "heteroaryl<1> " is an optionally benzo-fused 5- or 6-membered heterocyclic group linked by any available atom in the heterocyclic or benzo-ring (if present), which heterocyclic group is selected from dioxolyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyranyl, said "heteroaryl<1> " group being optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, or CO(C1-6 alkyl optionally substituted by one or more halogen), wherein the "C-alkylene" linking groups in the definitions above are linear or branched, and are optionally substituted by one or more (C1-6 alkyl optionally substituted by one or more halogen) groups, m is an integer from 0 to 3, n is an integer from 1 to 3, and p is an integer from 0 to 2. 2. A compound or salt according to Claim 1 wherein R<1> is N=C(NH2)2 or NHC(=NH)NH2 and R<2> is H. 3. A compound or salt according to Claim 1 or 2 wherein R<3> is H, halogen or C1-6 alkyl optionally substituted by one or more halogen. 4. A compound or salt according to any of preceding Claims wherein R<4> is H, OH, halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, (Cm-alkylene)CONR<9>R<10>, O(Cn-alkylene)CONR<9>R<10>, (Cm-alkylene)SO2NR<9>R<10>, or a group of formula X-aryl or X-Het. 5. A compound or salt according to any of preceding Claims wherein R<5> is H, halogen, or C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH. 6. A compound or salt according to any of preceding Claims wherein R<6> is H, halogen, C1-6 alkyl optionally substituted by one or more substituents independently selected from halogen or OH, C1-6 alkoxy optionally substituted by one or more halogen, CN, O(Cn-alkylene)CN, (Cn-alkylene)CN, (Cm-alkylene)CONR<9>R<10>, (Cm-alkylene)CO2R<8>, (Cm-alkylene)SO2NR<9>R<10>, (Cm-alkylene)S(O)pR<11> or a group of formula X-aryl or X-Het. 7. A compound or salt according to any of preceding Claims wherein R<7> is H. 8. A compound or salt according to any of preceding Claims wherein R<3> is H, Cl, Br or methyl optionally substituted by one or more halogen. 9. A compound or salt according to any of preceding Claims wherein R<4> is H, Br, OH, CN, C1-6-alkoxy, C1-6 alkyl optionally substituted by one or more OH, SO2NR<9>R<10>, CONR<9>R<10>, OCH2CONR<9>R<10>, OCH2-aryl, Het or aryl. 10. A compound or salt according to any of preceding Claims wherein R<5> is H, Br or methyl optionally substituted by one or more halogen. 11. A compound or salt according to any of preceding Claims wherein R<6> is H,Cl, Br, C1-6 alkyl optionally substituted by one or more OH, C1-6-alkoxy, CN, (Cm-alkylene)CONR<9>R<10>, (Cm-alkylene)CO2R<8>, (Cm-alkylene)S(O)pR<11>, (Cm-alkylene)SO2NR<9>R<10> or a group of formula X-aryl or X-Het, where X is a direct link, CH=CH, CH(OH), CO, OCH2, CH2O or CH2. 12. A compound or salt according to any of preceding