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US 6,207,669 B1Granted
Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
AssigneeGlaxo Wellcome Inc.
InventorsGeorge Stuart Cockerill, Malcolm Clive Carter, Stephen Barry Guntrip, Kathryn Jane Smith
Life of this patent
Estimating the term…
Abstract
Substituted heteroaromatic compounds, and in particular substituted bicyclic heteroaromatic compounds in which one ring is a pyridine or pyrimidine of formula (I) are protein tyrosine kinase inhibitors. The compounds are described as are methods for their preparation, pharmaceutical compositions including such compounds and their use in medicine, for example in the treatment of cancer and psoriasis.
Claims29
A compound of formula (I):
- or a salt or solvent thereof;
- wherein X is N;
- Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1-8 alkyl group;
- R1 is selected from the group consisting a phenyl, furan, thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole, isoxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole and imidazole ring or a hydrogenated derivative of the aforementioned, the ring being substituted:
- either (a) by one or more groups selected from dioxolanyl, hydroxy- C1-4 alkyl C1-4 alkylamino-C1-4 alkyl or di(C1-4 alkyl)-amino- C1-4 alkyl;
- or (b) by one or more groups independently selected from M1-M2-M3-M4, M1-M5 or M1-M2-M3′-M6
- wherein
- M1 represents a C1-4 alkyl group, wherein optionally a CH2 group is replaced by a CO group;
- M2 represents NR12 or CR12 and R13 each independently represent H or C1-4 alkyl;
- M3 represents a C1-4 alkyl group;
- M3 represents a C1-4 alkyl group or is absent;
- M4 represents CN, NR12S(O)mR13, S(O)mNR14R1, CONR14R15, S(O)mR13 or CO2R13, in which R12, R13 and m are as hereinbefore defined and R14 and R15 each independently represent H or C1-4 alkyl, or R14 and R15 together with the nitrogen atom to which they are attached represent a 5-or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O or S(O)m in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group;
- M5 represents the group NR14R15 or the group
- in which t represents 2 to 4 and R16 represents OH, OC1-4 alkyl or NR14R15;
- and
- M6 represents a C3-6 cycloalkyl group, the group NR14R15 or a 5- or 6membered heterocyclic ring system containing 1 to 4 heteroatoms selected from N, O or S;
- and R1 is optionally further substituted by one or two halogeno, C1-4 alkyl or C1-4 alkoxy groups;
- R2 represents hydrogen;
- each R5 is independently selected from the group consisting hydrogen, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di-[C1-4 alkylamino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbamoyl, di-carbamoyl, carbamyl, C1-4 alkoxycarbonyl, cyano, nitro and trifluoromethyl, and n is 1, 2 or 3;
- R3 is a group ZR4 wherein Z is joined to R4through a (CH2)p group in which p is 0, 1 or 2 and Z is oxygen, dicarbonyl, OCH2, CH(CN), S(O)m or NRb, wherein Rb is hydrogen or C1-4 alkyl;
- and R4 is an optionally substituted phenyl, dioxolanyl, thienyl, cyclohexyl or pyridyl group;
- wherein any optional substituent on R4 is either (a) selected from the group consisting CH2)qS(O)mC1-4 alkyl, (CH2)qS(O)m-C3-6 cycloalkyl, (CH2)qSO2NR8R9, (CH2)qCO2R8, (CH2)qOR8, (CH2)qCONR8R9, (CH2)qNR8COR9, (CH2)qCOR8, (CH2)qR8, NRSSO2R9 and S(O)mR8;
- wherein q is an integer from 0 to 4 inclusive and m is as defined above;
- and wherein R8 and R9 are independently selected from the group consisting hydrogen, Ci- alkyl, C3-5 cycloalkyl, aryl, a 5-or 6-membered saturated or unsaturated heterocyclic ring which may be the same or
- different and which contains one or more heteroatoms which are selected from N, O or S(O)m, with the proviso that the heterocyclic ring does not contain two adjacent O or S(O)m atoms;
- or (b) is selected from the group consisting halogen, trifluoromethyl, trifluoromethoxy, nitro and cyano;
- and
- represents
25 more elements
A method of treating a disorder mediated by aberrant protein tyrosine kinase activity in a human or animal subject, wherein at least one kinase selected from the group consisting of c-erb-B2, EGFr, and c-erb-B4 exhibits aberrant activity, comprising administering to the human or animal an effective amount of a compound of formula I:
- or a salt or solvate thereof;
- wherein X is N;
- Y is a group W(CH2), (CH2)W, or W, in which W is 0, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1-8 alkyl group;
- R1 is selected from the group consisting of phenyl, furan, thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole, isooxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole and imidazole ring or a hydrogenated derivative of the aforementioned, the ring being substituted:
- either (a) by one or more groups selected from dioxolanyl, hydroxy-C1-4 alkyl, C1-4 alkylamino-C1-4 alkyl, or di-amino-C1-4 alkyl;
- or (b) by one or more groups independently selected from M1-M2-M3-M4, M1-M2-M3′-M6
- wherein
- M1 represents a C1-4 alkyl group, wherein optionally a CH2 group is replaced by a CO group;
- M2 represents NR12 or CR12R13, in which R12 and R13 each independently represent H or C1-4 alkyl;
- M3 represents a C1-4 alkyl group;
- M3 represents a C1-4 alkyl group or is absent;
- M4 represents CN, NR12S(O)mR13, S(O)mNR14R15, CONR14R15, S(O)mR13 or CO2R13, in which R12, R13 and m are as hereinbefore defined and R14 and R15 each independently represent H or C1-4 alkyl, or R14 and R15 together with the nitrogen atom to which they are attached represent a 5-or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O or S(O)m in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group;
- M5 represents the group NR14R15 or the group
- in which t represents 2 to 4 and R16 represents OH, OC1-4 alkyl or NR14R15;
- and
- M6 represents a C3-6 cycloalkyl group, the group NR14R 15 or a 5- or 6-membered heterocyclic ring system containing 1 to 4 heteroatoms selected from N, O or S;
- and R1 is optionally further substituted by one or two halogeno, C1-4 alkyl or C1-4 alkoxy groups;
- R2 represents hydrogen;
- each R5 is independently selected from the group consisting of hydrogen, hydroxy, halogen, C1-4 alky, C1-4 alkoxy, C1-4 alkylamino, di-amino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbonyl, C1-4 alkylcarbamoyl, di-carbamoyl, carbamyl, C1-4 alkoxycarbonyl, cyano, nitro and trifluoromethyl, and n is 1, 2 or 3;
- R3 is a group ZR4 wherein Z is joined to R4through a (CH2)p group in which p is 0, 1 or 2 and Z is oxygen, dicarbonyl, OCH2, CH(CN), S(O)m, or NRb where Rb is hydrogen or C1-4 alkyl;
- and R4 is an optionally substituted phenyl, dioxianyl, thienyl, cyclohexyl, or pyridyl group;
- wherein any optional substituent on R4 is either (a) selected from the group consisting of (CH2)qS(O)m—C1-4 alkyl, (CH2)qS(O)m—C3-6 cycloalkyl, (CH2)qSO2NR8R9, (CH2)qNR6R9, (CH2)qCO2R8, (CH2)qOR8, (CH2)qCONR8R9, (CH2)qNR8COR9, (CH2)qCOR8, (CH2)qR8, NR8SO2R9 and S(O)mR8, wherein q is an integer from 0 to 4 inclusive and m is as defined above;
- and wherein R8 and R9 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, aryl, a 5- or 6- membered saturated or unsaturated heterocyclic ring which may be the same or different and which contains one or more heteroatoms which are selected from N, O or S(O)m with the proviso that the heterocyclic ring does not contain two adjacent O or S(O)m atoms;
- or (b) is selected from the group consisting of halogen, trifluoromethyl, trifluormethoxy, nitro, and cyano;
- and
- represents
23 more elements
A method of treating a disorder mediated by aberrant protein tyrosine kinase activity in a human or animal subject, wherein at least two kinases selected from the group consisting of c-erb-B2, EGFr, and c-erb-B4 exhibits aberrant activity, comprising administering to the human or animal an effective amount of a compound of formula I:
- or a salt or solvate thereof;
- wherein X is N;
- Y is a group W(CH2), (CH2)W, or W, in which W is O, S(O)m wherein m is 0, 1 or 2, or NRa wherein Ra is hydrogen or a C1-8 alkyl group;
- R1 is selected from the group consisting of phenyl, furan, thiophene, pyridine, pyrimidine, pyrazine, pyrrole, oxazole, isooxazole, oxadiazole, thiazole, isothiazole, triazole, tetrazole and imidazole ring or a hydrogenated derivative of the aforementioned, the ring being substituted:
- either (a) by one or more groups selected from dioxolanyl, C1-4 alkyl, C1-4 alkylamino-C1-4 alkyl, or di-amino-C1-4 alkyl;
- or (b) by one or more groups independently selected from M1-M2-M3-M4, M1-M5 or M1M2-M3-M6
- wherein
- M1 represents a C1-4 alkyl group, wherein optionally a CH2 group is replaced by a CO group;
- M2 represents NR12 or CR12R13, in which R12 and R13 each independently represent H or C1-4 alkyl;
- M3 represents a C1-4 alkyl group;
- M3′ represents a C1-4 alkyl group or is absent;
- M4 represents CN, NR12S(O)mR13, S(O)mNR14R15, S(O)mR13, in which R12, R13 and m are as hereinbefore defined and R14 and R15 each independently represent H or C1-4 alkyl, or R14 and R15 together with the nitrogen atom to which they are attached represent a 5-or 6-membered ring optionally containing 1 or 2 additional heteroatoms selected from N, O or S(O)m in which ring any nitrogen atom present may optionally be substituted with a C1-4 alkyl group;
- M5 represents the group NR14R15 or the group
- in which t represents 2 to 4 and R16 represents OH, OC1-4 alkyl or NR14R15;
- and
- M6 represents a C3-6 cycloalkyl group, the group NR14R15, or a 5- or 6-membered heterocyclic ring system containing 1 to 4 heteroatoms selected from N, O or S;
- and R1 is optionally further substituted by one or two halogeno, C1-4 alkyl or C1-4 alkoxy groups;
- R2 represents hydrogen;
- each R5 is independently selected from the group consisting of hydrogen, hydroxy, halogen, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino, di-amino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbonyl, C1-4 alkylcarbamoyl, di-carbamoyl, carbamyl, C1-4 alkoxycarbonyl, cyano, nitro and trifluoromethyl, and n is 1, 2 or 3;
- R3 is a group ZR4 wherein Z is joined to R4through a (CH2)p group in which p is 0, 1 or 2 and Z is oxygen, dicarbonyl, OCH2, CH(CN), S(O)m, or NRb where Rb is hydrogen or C1-4 alkyl;
- and R4 is an optionally substituted phenyl, dioxlanyl, thienyl, cyclohexyl, or pyridyl group;
- wherein any optional substituent on R4 is either (a) selected from the group consisting of (CH2)qs(O)m—C1-4alkyl, (CH2)qS(O)m—C3-6 cycloalkyl, (CH2)qSO2NR8R9, (CH2)NR8R9, (CH2)qCO2R8, (CH2)qOR8, (CH2)qCONR8R9, (CH2)qNR8COR9, (CH2)qCOR8, (CH2)qR8, NR8SO2R9 and S(O)mR8, wherein q is an integer from 0 to 4 inclusive and m is as defined above;
- and wherein R8 and R9 are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, aryl, a 5- or 6- membered saturated or unsaturated heterocyclic ring which may be the same or different and which contains one or more heteroatoms which are selected from N, O or S(O)m with the proviso that the heterocyclic ring does not contain two adjacent O or S(O)m atoms;
- or (b) is selected from the group consisting of halogen, trifluoromethyl, trifluormethoxy, nitro, and cyano;
- and
- represents
23 more elements
Dependencies are inferred from the claim text.