WO1999035132A1 - Composes heterocycliques - Google Patents

Composes heterocycliques Download PDF

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Publication number
WO1999035132A1
WO1999035132A1 PCT/GB1999/000076 GB9900076W WO9935132A1 WO 1999035132 A1 WO1999035132 A1 WO 1999035132A1 GB 9900076 W GB9900076 W GB 9900076W WO 9935132 A1 WO9935132 A1 WO 9935132A1
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WO
WIPO (PCT)
Prior art keywords
amine
methanesulphonyl
ethyl
indazol
fluorobenzyl
Prior art date
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PCT/GB1999/000076
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English (en)
Inventor
George Stuart Cockerill
Karen Elizabeth Lackey
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Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU19786/99A priority Critical patent/AU1978699A/en
Publication of WO1999035132A1 publication Critical patent/WO1999035132A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine.
  • the invention relates to quinoline, quinazoline, pyridopyridine and pyridopyrimidine derivatives which exhibit protein tyrosine kinase inhibition.
  • Protein tyrosine kinases catalyse the phosphorylation of specific tyrosyl residues in various proteins involved in the regulation of cell growth and differentiation (A.F. Wilks, Progress in Growth Factor Research, 1990, 2, 97-111 ; S.A. Courtneidge, Dev. Supp.l, 1993, 57-64; J.A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R.F. Paulson, Semin. Immunol., 1995, 7(4), 267-277; A.C. Chan, Curr. Opin. Immunol., 1996, 8(3), 394-401). Protein tyrosine kinases can be broadly classified as receptor (e.g.
  • non-receptor e.g. c-src, lck, zap70
  • Protein tyrosine kinases such as c-erbB-2, c-src, c-met, EGFr and PDGFr have been implicated in human malignancies. Elevated EGFr activity has, for example, been implicated in non-small cell lung, bladder and head and neck cancers, and increased c-erbB-2 activity in breast, ovarian, gastric and pancreatic cancers. Inhibition of protein tyrosine kinases should therefore provide a treatment for tumours such as those outlined above.
  • P56lck and zap 70 are indicated in disease conditions in which T cells are hyperactive e.g. rheumatoid arthritis, autoimmune disease, allergy, asthma and graft rejection.
  • the process of angiogenesis has been associated with a number of disease states (e.g. tumourogenesis, psoriasis, rheumatoid arthritis) and this has been shown to be controlled through the action of a number of receptor tyrosine kinases (L.K. Shawver, DDT, 1997, 2(2), 50-63).
  • the present invention envisages that other disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition, including preferential inhibition, of the appropriate protein tyrosine kinase activity.
  • protein tyrosine kinase may not always provide optimal treatment of, for example tumours, and could in certain cases even be detrimental to subjects since protein tyrosine kinases provide an essential role in the normal regulation of cell growth.
  • protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, c- rnet, tie-2, PDGFr, c-src, lck, Zap70, and fyn.
  • protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, c- rnet, tie-2, PDGFr, c-src, lck, Zap70, and fyn.
  • a further object of the present invention is to provide compounds useful in the treatment of protein tyrosine kinase related diseases which minimise undesirable side-effects in the recipient.
  • the present invention relates to heterocyclic compounds which may be used to treat disorders mediated by protein tyrosine kinases and in particular have anti-cancer properties. More particularly, the compounds of the present invention are potent inhibitors of protein tyrosine kinases such as such as EGFr, c-erbB-2, c-erbB-4, c- met, tie-2, PDGFr, c-src, lck, Zap70, and fyn, thereby allowing clinical management of particular diseased tissues.
  • protein tyrosine kinases such as such as EGFr, c-erbB-2, c-erbB-4, c- met, tie-2, PDGFr, c-src, lck, Zap70, and fyn
  • the present invention envisages, in particular, the treatment of human malignancies, for example breast, non-small cell lung, ovary, stomach, and pancreatic tumours, especially those driven by EGF-R or erbB-2, using the compounds of the present invention.
  • the invention includes compounds which are highly active against the c-erbB-2 receptor protein tyrosine kinase often in preference to the EGF receptor kinase hence allowing treatment of c-erbB-2 driven tumours.
  • the invention also includes compounds which are highly active against both c-erbB-2 and EGF receptor kinases hence allowing treatment of a broader range of tumours.
  • the present invention envisages that disorders mediated by protein tyrosine kinase activity may be treated effectively by inhibition of the appropriate protein tyrosine kinase activity in a relatively selective manner, thereby minimising potential side effects.
  • X is N or CH
  • Y is CR 1 and V is N; or Y is N and V is CR 1 ; or Y is CR 1 and V is CR 2 ; or Y is CR 2 and V is CR 1 ;
  • R 1 represents a group Q-M-, wherein M is a C M alkylene group in which any carbon atom, other than a carbon atom immediately adjacent the group Q, may be replaced by an oxygen or sulphur atom or by a group NR 6 ; or wherein M is a C 5 alkylene group in which any carbon atom, other than a carbon atom immediately adjacent the group Q, may be replaced by an oxygen or sulphur atom or by a group NR 6 ;
  • Q represents a group of formula Z-(CH 2 ) P -NR 6 - wherein p is 1 to 4 and Z is selected from the group comprising NR 6 S(0) m R 10 , S(0) m NR 8 R 9 , CONR 8 R 9 , NR 6 COR 7 , S(0) m R 10 and C0 2 R 7 ;
  • R 11 represents NR 8 R 9 or OR 10 ;
  • R 6 , R 7 , R 8 and R 9 each independently represent H or C alkyl, and R 10 represents C ⁇ alkyl; m is 1 or 2; and n is 1 or 2;
  • R 2 is selected from the group comprising hydrogen, halo, hydroxy, C ⁇ alkyl, C 1-4 alkoxy, C ⁇ alkylamino and di[C ⁇ alkyljamino;
  • U represents phenyl, pyridyl, pyrimidinyl or 3H-imidazolyl or a 9- or 10-membered bicyclic heterocyclic moiety containing one or two nitrogen atoms and optionally containing a further heteroatom selected from oxygen, nitrogen and sulphur, U being substituted by an R 3 group and optionally substituted by up to three independently selected R 4 groups;
  • R 3 is selected from a group comprising benzyl, halo-, dihalo- and trihalobenzyl, benzoyi, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
  • R 3 represents a group of formula
  • each R 5 is independently selected from halogen, C ⁇ alkyl and C ⁇ alkoxy; and n is 0 to 3;
  • each R 4 is independently hydroxy, halogen, C M alkyl, C ⁇ alkenyl, C ⁇ alkynyl, C 1-4 alkoxy, amino, C M alkylamino, di[C ⁇ alkyljamino, C ⁇ alkylthio, C ⁇ alkylsulphinyl, C-,. 4 alkylsulphonyl, C M alkylcarbonyl, carboxy, carbamoyi, C ⁇ alkoxycarbonyl, C M alkanoylamino, N-(C ⁇ alkyl)carbamoyl, N,N-di(C ⁇ alkyl)carbamoyl, cyano, nitro and trifluoromethyl.
  • the group R 1 may be at the 6- or 7-position; the compounds in which R 1 is in the 6-position are of particular interest in the context of c-erbB-2 and/or EGFr activity.
  • the group R 1 may be at the 6- or 7-position; the compounds in which R 1 is in the 6-position are of particular interest in the context of c-erbB-2 and/or EGFr activity.
  • Ring systems (1), (2), (5) and (6) are preferred; ring systems (2) and (6) are more preferred.
  • Alkyl groups containing three or more carbon atoms may be straight, branched or cyclised; preferably they are straight or branched. References to a specific alkyl group such as "butyl” is intended to refer to the straight chain (n-) isomer only. References to other generic terms such as alkoxy, alkylamino etc. are to be interpreted analogously.
  • R 4 and R 5 are as follows: halo is, for example, fluoro, chloro, bromo or iodo; preferably it is fluoro, chloro or bromo, more preferably fluoro or chloro;
  • C ⁇ alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl; preferably it is methyl, ethyl, propyl, isopropyl or butyl, more preferably methyl;
  • C 2 _ 4 alkenyl is, for example, ethenyl, prop-1-enyl or prop-2-enyl; preferably it is ethenyl;
  • C 2 . 4 alkynyl is, for example, ethynyl, prop-1-ynyl or prop-2-ynyl; preferably it is ethynyl;
  • C ⁇ alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy; preferably it is methoxy, ethoxy, propoxy, isopropoxy or butoxy; more preferably it is methoxy;
  • C ⁇ alkylamino is, for example, methylamino, ethylamino or propylamino; preferably it is methylamino; di[C ⁇ alkyljamino is, for example, dimethylamino, diethylamino, N-methyl-N- ethylamino or dipropylamino; preferably it is dimethylamino;
  • C ⁇ alkylthio is, for example, methylthio, ethylthio, propylthio or isopropylthio, preferably methylthio;
  • C M alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl or isopropylsulphinyl, preferably methylsulphinyl;
  • C ⁇ alkylsulphonyl is, for example, methanesulphonyl, ethylsulphonyl, propylsulphonyl or isopropylsulphonyl, preferably methanesulphonyl;
  • C ⁇ alkylcarbonyl is, for example methylcarbonyl, ethylcarbonyl or propyicarbonyl
  • C ⁇ alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl;
  • C ⁇ alkanoylamino (where the number of carbon atoms includes the CO functionality) is, for example, formamido, acetamido, propionamido or butyramido;
  • N-(C alkyl)carbamoyl is, for example, N-methylcarbamoyl or N-ethylcarbamoyl;
  • N,N-di(C 1 ⁇ l alkyl)carbamoyl is, for example, N,N-dimethylcarbamoyl, N-methyl-N- ethylcarbamoyl or N,N-diethylcarbamoyl.
  • a suitable value for U when it is a 9- or 10-membered bicyclic heterocyclic moiety containing 1 or 2 nitrogen heteroatoms and optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur is, for example, a benzo- fused heterocyclic moiety such as indolyl, indolinyl, isoindolyl, isoindolinyl, indoiizinyl, 1H-benzimidazolyl, 2,3-dihydro-1 H-benzimidazolyl, 1 H-indazolyl, 2,3-dihydro-1 H- indazolyl, benzoxazolyl, 2,3-dihydrobenzoxazolyl, benzo[c]isoxazolyl, benzo[d]isoxazolyl, 2,3-dihydrobenzo[d]isoxazolyl, benzothiazoyl, 2,3- dihydrobenzothiazolyl, ' benzo[c]isothi
  • X is N
  • Y is CR 1
  • V is CR 2 (ring system (2) above).
  • X is N
  • Y is CR 1
  • V is N (ring system (6) above).
  • R 2 represents hydrogen or C ⁇ alkoxy.
  • R 2 represents hydrogen or methoxy.
  • R 2 represents hydrogen
  • p is 1 or 2.
  • M represents a C ⁇ alkylene group in which any carbon atom, other than a carbon atom immediately adjacent the group Q, may be replaced by an oxygen or sulphur atom or by a group NR 6 , wherein R 6 is methyl or hydrogen, preferably hydrogen; or M represents a C 5 alkylene group in which any carbon atom, other than a carbon atom immediately adjacent the group Q, may be replaced by an oxygen or sulphur atom or by a group NR 6 .
  • M represents a C 2 alkylene group; or M represents a C 5 alkylene group.
  • M represents a C Z alkylene group in which a carbon atom, other than the carbon atom immediately adjacent the group Q, is replaced by an oxygen atom or NH group (preferably the carbon atom furthest from the group Q is replaced); or M represents a C 5 alkylene group in which a carbon atom, other than the carbon atom immediately adjacent the group Q, is replaced by an oxygen atom or NH group (preferably the carbon atom furthest from the group Q is replaced).
  • M represents a -CH 2 - group.
  • M represents a -CH 2 CH 2 CH 2 0- group; or M represents a -CH 2 CH 2 CH 2 CH 2 0- group.
  • R 6 represents methyl or hydrogen, more preferably hydrogen.
  • Z represents a group S(0) m NR 8 R 9 , NR 6 S(0) m R 10 or S(0) m R 10 ; wherein m is 1 or 2, more preferably 2; R 8 and R 9 are independently methyl or hydrogen, more preferably both are hydrogen; R 10 is methyl; R 6 is methyl or hydrogen, more preferably hydrogen.
  • Q represents a CH 3 S0 2 (CH 2 ) 2.3 NH, CH 3 SO(CH 2 ) 2 . 3 NH, CH 3 S0 2 (CH 2 ) 2 . 3 N(CH 3 ), CH 3 SO(CH 2 ) 2 . 3 N(CH 3 ), CH 3 S0 2 NH(CH 2 ) 2.3 NH or CH 3 S0 2 NH(CH 2 ) 2 . 3 N(CH 3 ) group.
  • Q represents a group CH 3 S0 2 CH 2 CH 2 NH.
  • Q represents a group CH 3 S0 2 CH 2 CH 2 N(CH 3 ).
  • Z represents a group CONR 8 R 9 ; wherein R 8 and R 9 are independently methyl or hydrogen, more preferably both are hydrogen.
  • Z represents a group C0 2 R 7 ; wherein R 7 is methyl or hydrogen.
  • Q represents NH 2 COCH 2 NH or NH 2 COCH 2 N(CH 3 ). In a further preferred embodiment Q represents a group of formula
  • R 6 represents methyl or hydrogen, more preferably hydrogen; m is 2; and R 10 is methyl.
  • R 11 is NR 8 R 9 , wherein R 8 and R 9 are independently methyl or hydrogen, more preferably both are hydrogen.
  • R 11 is OR 10 , wherein R 10 is tert-butyl.
  • R 1 is CH 3 SO 2 CH 2 CH 2 NHCH 2 .
  • R 1 is selected from the group comprising H0 2 CCH 2 NHCH 2 , NH 2 COCH 2 NHCH 2 or NH 2 COCH 2 N(CH 3 ) CH 2 .
  • R 1 is selected from the group comprising CH 3 SO 2 CH 2 CH 2 N(CH 3 )CH 2 or HO 2 CCH 2 N(CH 3 )CH 2 .
  • R 1 is selected from the group comprising CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 0 or
  • R 1 is selected from the group comprising CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 0 or CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 CH 2 O.
  • R 1 is CH 3 SO 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 O.
  • R 1 is a group of formula
  • R 1 is a group of formula
  • n is 2.
  • the group Q is a thiomorpholine-1- oxide-4-yl group.
  • U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1 H-indazolyl, 2,3-dihydro-1 H-indazolyl, 1 H- benzimidazolyl, 2,3-dihydro-1 H-benzimidazolyl or 1 H-benzot azolyl group, substituted by an R 3 group and optionally substituted by up to three independently selected R 4 groups.
  • U represents a phenyl, indolyl or 1 H-indazolyl group substituted by an R 3 group and optionally substituted by up to three, preferably one or two, independently selected R 4 groups.
  • U represents a phenyl or indazolyl group substituted by an R 3 group and optionally substituted by up to three, preferably one or two, independently selected R 4 groups.
  • the R 3 and R 4 groups may be bound to the ring system U by either a carbon atom or a heteroatom of the ring system.
  • the ring system itself may be bound to the bridging NH group by a carbon atom or a heteroatom but is preferably bound by a carbon atom.
  • the R 3 and R 4 groups may be bound to either ring when U represents a bicyciic ring system, but these groups are preferably bound to the ring which is not bound to the bridging NH group in such a case.
  • R 3 represents benzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
  • R 3 represents benzyl, halo-, dihalo- and trihalobenzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
  • R 3 represents a group of formula
  • Hal is Br or Cl, particularly Cl, more especially wherein the Hal substituent is in the position marked with a star in the ring as shown.
  • R 3 represents benzyloxy, fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl.
  • R 3 represents fluorobenzyloxy (especially 3- fluorobenzyloxy). In another especially preferred embodiment R 3 represents fluorobenzyl (especially 3- fluorobenzyl.
  • the ring U is not substituted by an R 4 group; in an especially preferred embodiment U is phenyl or indazolyl unsubstituted by an R 4 group.
  • U is substituted by an R 4 group, preferably halo, more preferably chloro.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl, fluorobenzyloxyphenyl, benzenesulphonylphenyl, benzylindazolyl or phenoxyphenyl.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl, fluorobenzyloxyphenyl, fluorobenzyloxy(chlorophenyl), benzenesulphonylphenyl, benzylindazolyl or phenoxyphenyl.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl, 3-fluorobenzyloxyphenyl, benzenesulphonylphenyl or benzylindazolyl.
  • the group U together with the substituent(s) R 3 and R 4 represents fluorobenzylindazolyl (especially 3- fluorobenzylindazolyl).
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl or benzylindazolyl.
  • the group U together with the substituent(s) R 3 and R 4 represents 3-fluorobenzyloxyphenyl, 3-fluorobenzyiindazolyl or benzenesulphonylphenyl.
  • U together with the substituent(s) R 3 and R 4 represents 3-fluorobenzylindazolyl.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR 2 , wherein R 2 is hydrogen or methoxy; Y is CR 1 wherein R 1 is a CH 3 S0 2 CH 2 CH 2 NHCH 2 , NH 2 COCH 2 NHCH 2 , NH 2 COCH 2 N(CH 3 )CH 2 , HO 2 CCH 2 NHCH 2 , prolinamido-methyl or proline(t-butyl- ester)-methyl group; U is phenyl or indazolyl; R 3 is benzyl or benzyloxy; and R 4 is not present.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR 2 , wherein R 2 is hydrogen or methoxy; Y is CR 1 wherein R 1 is CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 O, CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 0, CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 O or CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 CH 2 O; U is phenyl or indazolyl; R 3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R 4 is not present or is halo (especially chloro).
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR 2 , wherein R 2 is hydrogen or methoxy; V is CR 1 wherein R 1 is a CH 3 S0 2 CH 2 CH 2 NHCH 2 , NH 2 COCH 2 NHCH 2 , NH 2 COCH 2 N(CH 3 )CH 2 , H0 2 CCH 2 NHCH 2 , prolinamido-methyl or proline(t-butyl- ester)-methyl group; U is phenyl or indazolyl; R 3 is benzyl or benzyloxy; and R 4 is not present.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR 2 , wherein R 2 is hydrogen or methoxy; V is CR 1 wherein R 1 is CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 O, CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 0, CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 CH 2 O or CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 CH 2 0; U is phenyl or indazolyl; R 3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R 4 is not present or is halo (especially chloro).
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is N; Y is CR 1 wherein R 1 is a CH 3 S0 2 CH 2 CH 2 NHCH 2) NH 2 COCH 2 NHCH 2 , NH 2 COCH 2 N(CH 3 )CH 2 ,
  • U is phenyl or indazolyl;
  • R 3 is benzyl or benzyloxy; and
  • R 4 is not present.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is N; Y is CR 1 wherein R 1 is CH 3 S0 2 CH 2 CH 2 NHCH 2 CH 2 CH 2 O, CH 3 S0 2 CH 2 CH 2 N(CH 3 )CH 2 CH 2 CH 2 0,
  • Preferred compounds of the present invention include:
  • Especially preferred compounds of the present invention include:
  • salts or solvates thereof particularly pharmaceutically acceptable salts or solvates thereof.

Abstract

Cette invention concerne des composés hétéro-aromatiques substitués qui correspondent à la formule (I) dans laquelle X représente N ou CH. Dans cette formule, Y représente CR1 et V représente N, ou encore Y représente N et V représente CR1, ou encore Y représente CR1 et V représente CR2, ou encore Y représente CR2 et V représente CR1. R1 représente un groupe Q-M-, étant entendu que M est un groupe alcylène C¿1-4? dans lequel tout atome de carbone, autre qu'un atome de carbone à proximité immédiate du groupe Q, peut être remplacé par un atome d'oxygène ou de soufre ou par un groupe NR?6¿. M peut encore représenter un groupe alcylène C¿5? dans lequel tout atome de carbone, autre qu'un atome de carbone à proximité immédiate du groupe Q, peut être remplacé par un atome d'oxygène ou de soufre ou par un groupe NR?6¿.
PCT/GB1999/000076 1998-01-12 1999-01-11 Composes heterocycliques WO1999035132A1 (fr)

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GBGB9800575.4A GB9800575D0 (en) 1998-01-12 1998-01-12 Heterocyclic compounds

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WO2000021955A1 (fr) * 1998-10-08 2000-04-20 Astrazeneca Ab Derives de quinazoline
GB2345486A (en) * 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
WO2001004111A1 (fr) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilino-quinazolines comme inhibiteurs de la proteine tyrosine kinase
WO2001021597A1 (fr) * 1999-09-21 2001-03-29 Astrazeneca Ab Derives therapeutiques de quinazoline
WO2001021596A1 (fr) * 1999-09-21 2001-03-29 Astrazeneca Ab Derives de quinazoline et leur utilisation comme produits pharmaceutiques
WO2001055116A2 (fr) * 2000-01-28 2001-08-02 Astrazeneca Ab Composes chimiques
US6294532B1 (en) 1997-08-22 2001-09-25 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
WO2002000649A1 (fr) * 2000-06-28 2002-01-03 Astrazeneca Ab Derives de la quinazoline substitues et leur utilisation comme inhibiteurs
WO2002076977A2 (fr) * 2001-03-23 2002-10-03 Bayer Corporation Inhibiteurs de rho-kinase
WO2002076976A2 (fr) * 2001-03-23 2002-10-03 Bayer Corporation Inhibiteurs de rho-kinase
WO2003064413A1 (fr) * 2002-02-01 2003-08-07 Astrazeneca Ab Composes de quinazoline
US6869962B2 (en) 2002-06-14 2005-03-22 Agouron Pharmaceuticals, Inc. Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use
WO2005026156A1 (fr) * 2003-09-16 2005-03-24 Astrazeneca Ab Derives de quinazoline
US6890924B2 (en) 2000-06-22 2005-05-10 Pfizer Inc Substituted bicyclic derivatives for the treatment of abnormal cell growth
US6924290B2 (en) 2002-01-23 2005-08-02 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
US6927220B2 (en) 2001-04-13 2005-08-09 Pfizer Inc Bicyclic-substituted 4-amino-pyridopyrimidine derivatives
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