WO1999035132A1 - Heterocyclic compounds - Google Patents

Heterocyclic compounds 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
Application number
PCT/GB1999/000076
Other languages
French (fr)
Inventor
George Stuart Cockerill
Karen Elizabeth Lackey
Original Assignee
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.)
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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/en

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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

Substituted heteroaromatic compounds of formula (I) wherein X is N or CH; Y is CR1 and V is N; or Y is N and V is CR1; or Y is CR1 and V is CR2; or Y is CR2 and V is CR1; R1 represents a group Q-M-, wherein M is a C¿1-4? 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¿.

Description

HETEROCYCLIC COMPOUNDS
The present invention relates to a series of substituted heteroaromatic compounds, methods for their preparation, pharmaceutical compositions containing them and their use in medicine. In particular, 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. EGFr, c-erbB-2, c-met, tie-2, PDGFr, FGFr) or non-receptor (e.g. c-src, lck, zap70) kinases. Inappropriate or uncontrolled activation of many of these kinase, i.e. aberrant protein tyrosine kinase activity, for example by over-expression or mutation, has been shown to result in uncontrolled cell growth.
Aberrant activity of 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.
Aberrant protein tyrosine kinase activity has also been implicated in a variety of other disorders: psoriasis, (Dvir et al, J.Cell.Biol; 1991 , 1_13, 857-865), fibrosis, atherosclerosis, restenosis, (Buchdunger et al, Proc.Natl.Acad.Sci. USA; 1991 , 92, 2258-2262), auto-immune disease, allergy, asthma, transplantation rejection (Klausner and Samelson, Cell; 1991 , 64, 875-878), inflammation (Berkois, Blood; 1992, 79(9), 2446-2454), thrombosis (Salari et al, FEBS; 1990, 263(1), 104-108) and nervous system diseases (Ohmichi et al, Biochemistry, 1992, 31_, 4034-4039). Inhibitors of the specific protein tyrosine kinases involved in these diseases eg PDGF-R in restenosis and EGF-R in psoriasis, should lead to novel therapies for such disorders. 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).
It is therefore a general object of the present invention to provide compounds suitable for the treatment of disorders mediated by protein tyrosine kinase activity, and in particular treatment of the above mentioned disorders.
In addition to the treatment of tumours, 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.
Broad spectrum inhibition of 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.
It is another object of the present invention to provide compounds which preferentially inhibit protein tyrosine kinases, such as EGFr, c-erbB-2, c-erbB-4, c- rnet, tie-2, PDGFr, c-src, lck, Zap70, and fyn. There is also perceived to be a benefit in the preferential inhibition involving small groups of protein tyrosine kinases, for example groups including two or more of c-erbB-2, c-erbB-4, EGF-R, lck and zap70.
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.
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. For example, 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. However, 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.
More particularly, 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.
Accordingly, the present invention provides a compound of formula (I)
Figure imgf000005_0001
or a salt or solvate thereof;
wherein X is N or CH;
Y is CR1 and V is N; or Y is N and V is CR1; or Y is CR1 and V is CR2; or Y is CR2 and V is CR1;
R1 represents a group Q-M-, wherein M is a CM 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 NR6; or wherein M is a C5 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 NR6;
Q represents a group of formula Z-(CH2)P-NR6- wherein p is 1 to 4 and Z is selected from the group comprising NR6S(0)mR10, S(0)mNR8R9, CONR8R9, NR6COR7, S(0)mR10 and C02R7;
or Q represents a group of formula
Figure imgf000006_0001
or Q represents a group of formula
>11
N-
wherein R11 represents NR8R9 or OR10;
or Q represents a group of formula
Figure imgf000006_0002
wherein R6, R7, R8 and R9 each independently represent H or C alkyl, and R10 represents C^ alkyl; m is 1 or 2; and n is 1 or 2;
R2 is selected from the group comprising hydrogen, halo, hydroxy, C^ alkyl, C1-4 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 R3 group and optionally substituted by up to three independently selected R4 groups;
R3 is selected from a group comprising benzyl, halo-, dihalo- and trihalobenzyl, benzoyi, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
or R3 represents a group of formula
Figure imgf000007_0001
wherein each R5 is independently selected from halogen, C^ alkyl and C^ alkoxy; and n is 0 to 3;
each R4 is independently hydroxy, halogen, CM alkyl, C^ alkenyl, C^ alkynyl, C 1-4 alkoxy, amino, CM alkylamino, di[C^ alkyljamino, C^ alkylthio, C^ alkylsulphinyl, C-,.4 alkylsulphonyl, CM alkylcarbonyl, carboxy, carbamoyi, C^ alkoxycarbonyl, CM alkanoylamino, N-(C^ alkyl)carbamoyl, N,N-di(C^ alkyl)carbamoyl, cyano, nitro and trifluoromethyl.
Solvates of the compounds of formula (I) are also included within the scope of the present invention.
The definitions for X, Y and V thus give rise to a number of possible basic ring systems for the compounds of formula (I). In particular the compounds may contain the following basic ring systems:
Figure imgf000008_0001
It will be seen that for compounds containing the basic ring system (1) the group R1 may be at the 6- or 7-position; the compounds in which R1 is in the 6-position are of particular interest in the context of c-erbB-2 and/or EGFr activity.
It will be seen that for compounds containing the basic ring system (2) the group R1 may be at the 6- or 7-position; the compounds in which R1 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.
Suitable values for the various groups listed above within the definitions for R\ R2,
R4 and R5 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; C2_4 alkenyl is, for example, ethenyl, prop-1-enyl or prop-2-enyl; preferably it is ethenyl;
C2.4 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;
CM 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(C1^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]isothiazolyl, benzo[d]isothiazolyl, 2,3- dihydrobenzo[d]isothiazolyl, 1H-benzotriazolyl, benzo[c]furazanyl, benzo[c][1 ,2,3]thiadiazolyl, benzo[d][1 ,2,3]oxadiazolyl, benzo[d][1 ,2,3]thia- diazolyl, quinolyl, 1 ,2-dihydroquinolinyl, 1 ,2,3,4-tetrahydroquinolinyl, isoquinolyl, 1 ,2,3,4-tetrahydroisoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyi, 4H-1 ,4-benzoxazinyl, 2,3-dihydro-4H-1 ,4-benzoxazinyl, 4H-1 ,4-benzothiazinyl or 2,3-dihydro-4H-1 ,4-benzothiazinyl.
In an especially preferred embodiment X is N, Y is CR1 and V is CR2 (ring system (2) above).
In a further especially preferred embodiment X is N, Y is CR1 and V is N (ring system (6) above).
In a preferred embodiment R2 represents hydrogen or C^ alkoxy.
In a more preferred embodiment R2 represents hydrogen or methoxy.
In a most preferred embodiment R2 represents hydrogen.
In a preferred embodiment p is 1 or 2.
In a preferred embodiment 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 NR6, wherein R6 is methyl or hydrogen, preferably hydrogen; or M represents a C5 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 NR6.
In a more preferred embodiment M represents a C2 alkylene group; or M represents a C5 alkylene group.
In a further more preferred embodiment M represents a CZ 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 C5 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).
In a further more preferred embodiment M represents a -CH2- group.
In a most preferred embodiment M represents a -CH2CH2CH20- group; or M represents a -CH2CH2CH2CH20- group.
In a further preferred embodiment R6 represents methyl or hydrogen, more preferably hydrogen.
In a further preferred embodiment Z represents a group S(0)mNR8R9, NR6S(0)mR10 or S(0)mR10; wherein m is 1 or 2, more preferably 2; R8 and R9 are independently methyl or hydrogen, more preferably both are hydrogen; R10 is methyl; R6 is methyl or hydrogen, more preferably hydrogen.
In a more preferred embodiment Q represents a CH3S02(CH2)2.3NH, CH3SO(CH2)2. 3NH, CH3S02(CH2)2.3N(CH3), CH3SO(CH2)2.3N(CH3), CH3S02NH(CH2)2.3NH or CH3S02NH(CH2)2.3N(CH3) group.
In an especially preferred embodiment Q represents a group CH3S02CH2CH2NH.
In a further especially preferred embodiment Q represents a group CH3S02CH2CH2N(CH3).
In a further preferred embodiment Z represents a group CONR8R9; wherein R8 and R9 are independently methyl or hydrogen, more preferably both are hydrogen.
In another preferred embodiment Z represents a group C02R7; wherein R7 is methyl or hydrogen.
In an especially preferred embodiment Q represents NH2COCH2NH or NH2COCH2N(CH3). In a further preferred embodiment Q represents a group of formula
Figure imgf000012_0001
wherein R6 represents methyl or hydrogen, more preferably hydrogen; m is 2; and R10 is methyl.
In a further preferred embodiment R11 is NR8R9, wherein R8 and R9 are independently methyl or hydrogen, more preferably both are hydrogen.
In a further preferred embodiment R11 is OR10, wherein R10 is tert-butyl.
In an especially preferred embodiment R1 is CH3SO2CH2CH2NHCH2.
In a further especially preferred embodiment R1 is selected from the group comprising H02CCH2NHCH2, NH2COCH2NHCH2 or NH2COCH2N(CH3) CH2.
In a further especially preferred embodiment R1 is selected from the group comprising CH3SO2CH2CH2N(CH3)CH2 or HO2CCH2N(CH3)CH2.
In a further especially preferred embodiment R1 is selected from the group comprising CH3S02CH2CH2NHCH2CH2CH20 or
CH3S02CH2CH2N(CH3)CH2CH2CH20.
In a further especially preferred embodiment R1 is selected from the group comprising CH3S02CH2CH2NHCH2CH2CH2CH20 or CH3S02CH2CH2N(CH3)CH2CH2 CH2CH2O.
In a most preferred embodiment R1 is CH3SO2CH2CH2NHCH2CH2 CH2CH2O.
In a further especially preferred embodiment R1 is a group of formula
Figure imgf000013_0001
In a further especially preferred embodiment R1 is a group of formula
Figure imgf000013_0002
ln a further preferred embodiment n is 2.
In a further preferred embodiment, when Q represents a group of formula
Figure imgf000013_0003
In a further especially preferred embodiment the group Q is a thiomorpholine-1- oxide-4-yl group.
In a preferred embodiment 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 R3 group and optionally substituted by up to three independently selected R4 groups.
In a more preferred embodiment U represents a phenyl, indolyl or 1 H-indazolyl group substituted by an R3 group and optionally substituted by up to three, preferably one or two, independently selected R4 groups. In an especially preferred embodiment U represents a phenyl or indazolyl group substituted by an R3 group and optionally substituted by up to three, preferably one or two, independently selected R4 groups.
The R3 and R4 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 R3 and R4 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.
In a more preferred embodiment, where U represents a phenyl group the group R3 is in the para- position relative to the bond from U to the linking NH group.
In a preferred embodiment R3 represents benzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
In a further preferred embodiment R3 represents benzyl, halo-, dihalo- and trihalobenzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
In a further preferred embodiment R3 represents a group of formula
Figure imgf000014_0001
, wherein 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.
In a more preferred embodiment R3 represents benzyloxy, fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl.
In an especially preferred embodiment R3 represents fluorobenzyloxy (especially 3- fluorobenzyloxy). In another especially preferred embodiment R3 represents fluorobenzyl (especially 3- fluorobenzyl.
In a further preferred embodiment the ring U is not substituted by an R4 group; in an especially preferred embodiment U is phenyl or indazolyl unsubstituted by an R4 group.
In a further preferred embodiment U is substituted by an R4 group, preferably halo, more preferably chloro.
In an especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents benzyloxyphenyl, fluorobenzyloxyphenyl, benzenesulphonylphenyl, benzylindazolyl or phenoxyphenyl.
In an especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents benzyloxyphenyl, fluorobenzyloxyphenyl, fluorobenzyloxy(chlorophenyl), benzenesulphonylphenyl, benzylindazolyl or phenoxyphenyl.
In a more especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents benzyloxyphenyl, 3-fluorobenzyloxyphenyl, benzenesulphonylphenyl or benzylindazolyl.
In a further more especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents fluorobenzylindazolyl (especially 3- fluorobenzylindazolyl).
In another more especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents benzyloxyphenyl or benzylindazolyl.
In a further more especially preferred embodiment the group U together with the substituent(s) R3 and R4 represents 3-fluorobenzyloxyphenyl, 3-fluorobenzyiindazolyl or benzenesulphonylphenyl. In a most especially preferred embodiment U together with the substituent(s) R3 and R4 represents 3-fluorobenzylindazolyl.
In a most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR2, wherein R2 is hydrogen or methoxy; Y is CR1 wherein R1 is a CH3S02CH2CH2NHCH2, NH2COCH2NHCH2, NH2COCH2N(CH3)CH2, HO2CCH2NHCH2, prolinamido-methyl or proline(t-butyl- ester)-methyl group; U is phenyl or indazolyl; R3 is benzyl or benzyloxy; and R4 is not present.
In a further most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR2, wherein R2 is hydrogen or methoxy; Y is CR1 wherein R1 is CH3S02CH2CH2NHCH2CH2CH2O, CH3S02CH2CH2N(CH3)CH2CH2CH20, CH3S02CH2CH2NHCH2CH2CH2CH2O or CH3S02CH2CH2N(CH3)CH2CH2CH2CH2O; U is phenyl or indazolyl; R3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R4 is not present or is halo (especially chloro).
In a most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR2, wherein R2 is hydrogen or methoxy; V is CR1 wherein R1 is a CH3S02CH2CH2NHCH2, NH2COCH2NHCH2, NH2COCH2N(CH3)CH2, H02CCH2NHCH2, prolinamido-methyl or proline(t-butyl- ester)-methyl group; U is phenyl or indazolyl; R3 is benzyl or benzyloxy; and R4 is not present.
In a further most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR2, wherein R2 is hydrogen or methoxy; V is CR1 wherein R1 is CH3S02CH2CH2NHCH2CH2CH2O, CH3S02CH2CH2N(CH3)CH2CH2CH20, CH3S02CH2CH2NHCH2CH2CH2CH2O or CH3S02CH2CH2N(CH3)CH2CH2CH2CH20; U is phenyl or indazolyl; R3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R4 is not present or is halo (especially chloro).
In a further most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; V is N; Y is CR1 wherein R1 is a CH3S02CH2CH2NHCH2) NH2COCH2NHCH2, NH2COCH2N(CH3)CH2,
H02CCH2NHCH2, prolinamido-methyl or proline(t-butyl-ester)-methyl group; U is phenyl or indazolyl; R3 is benzyl or benzyloxy; and R4 is not present.
In a further most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; V is N; Y is CR1 wherein R1 is CH3S02CH2CH2NHCH2CH2CH2O, CH3S02CH2CH2N(CH3)CH2CH2CH20,
CH3S02CH2CH2NHCH2CH2CH2CH20 or CH3S02CH2CH2N(CH3)CH2CH2CH2CH20; U is phenyl or indazolyl; R3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R4 is not present or is halo (especially chloro).
Preferred compounds of the present invention include:
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(methanesulphonyl)ethylaminomethyl)-quinazolin-4- yl)amine hydrochloride; 2-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetic acid;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetamide;
2-(Λ/- 4-(1-Benzyl-1H-indazol-5-ylamino)quinazolin-6-yl)methyl)-/V-methylamino)- acetamide;
(2R)-1 -(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yimethyl)pyrrolidine-2- carboxylic acid -butyl ester;
(2S)-1-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-ylmethyl)pyrrolidine-2- carboxamide;
4-(4'-Benzyloxyanilino)-6-(4'-(2"-methanesulphonylethyl)aminobutoxy)quinazoline;
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(4-{[2-(methanesulphonyl)ethyi]amino} butoxy)-4-quinazolinamine;
N-[1-(3-Fluorobenzyl)-1 H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)-4-quinazolinamine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-quinazolin-4- yl) amine; 6-(4-{[2-(Methanesulphonyl)ethyl]amino}butoxy)-N-[4-(benzenesulphonyl)phenyl]-4- quinazolinamine;
N-[4-(Benzyloxy)phenyl]-6-(3-{methyl[2-(methanesulphonyl)ethyl]amino}propoxy)-4- quinazolinamine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. Especially preferred compounds of the present invention include:
N-[1-(3-Fluorobenzyl)-1 H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)-4-quinazolinamine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
Other preferred compounds of the present invention include the following compounds (in groups denoted hereafter as Lists 1 and 2)
List 1
4-(1-Benzyl-1 H-indazol-5-ylamino)-7-(2-(methanesulphonyl)ethylaminomethyl)- quinazoline;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-7-yl)methylamino)acetic acid; 2-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-7-yl)methylamino)acetamide;
2-(Λ/-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-7-yl)methyl)-Λ/-methylamino)- acetamide;
(2R)-1-(4-(1-Benzyl-1H-indazol-5-ylamino)quinazolin-7-ylmethyl)pyrrolidine-2- carboxylic acid f-butyl ester; (2S)-1 -(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-7-ylmethyl)pyrrolidine-2- carboxamide;
List 2
4-(1-Benzyl-1H-indazol-5-ylamino)-6-(2-(methanesulphonyl)ethylaminomethyl)- pyrido[3,4-d]pyrimidine;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-yl)methylamino)acetic acid;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-yl)methylamino)- acetamide; 2-(Λ/-(4-(1 -Benzyl-1 H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-yl)methyl)-Λ/- methylamino)acetamide;
(2R)-1 -(4-(1 -Benzyl-1 H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxylic acid f-butyl ester;
(2S)-1-(4-(1-Benzyl-1 H-indazol-5-ylamino)pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxamide; List 3
4-(4'-Benzyloxyanilino)-7-(4'-(2"-methanesulphonylethyl)aminobutoxy)quinazoline; N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-7-(4-{[2-(methanesulphonyl)ethyl]amino} butoxy)-4-quinazolinamine; N-[1 -(3-Fluorobenzyl)-1 H-indazol-5-yl]-7-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)-4-quinazolinamine;
7-(4-{[2-(Methyl)ethyl]amino}butoxy)-N-[4-(benzenesulphonyl)phenyl]-4-quinazolin- amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino)-propoxy)-quinazolin-4- yl)amine;
N-[4-(Benzyloxy)phenyl]-7-(3-{methyl[2-(methanesulphonyl)ethyl]amino}propoxy)-4- quinazolinamine;
List 4 4-(4'-Benzyloxyanilino)-6-(4'-(2"-methanesulphonylethyl)aminobutoxy)pyrido[3,4- djpyrimidine;
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(4-{[2-(methanesulphonyl)ethyl]amino} butoxy)- pyrido[3,4-d]pyrimidin-6-ylamine;
N-[1-(3-Fluorobenzyl)-1 H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)- pyrido[3,4-djpyrimidin-6-ylamine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-pyrido[3,4- d]pyrimidin-6-yl)amine;
6-(4-{[2-(Methanesulphonyl)ethyl]amino}butoxy)-N-[4-(benzenesulphonyl)phenyl]- pyrido[3,4-d]pyrimidin-6-ylamine; N-[4-(Benzyloxy)phenyl]-6-(3-{methyl[2-(methanesulphonyl)ethyi]amino}propoxy)- pyrido[3,4-d]pyrimidin-6-yl)amine;
and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
It is considered that the compounds specified in lists 1 and 3 above in which R1 is in the 7-position are of particular interest in the context of lck and/or ZAP-70 activity.
Other preferred compounds of the present invention include the following compounds (in groups denoted hereafter as Lists 5 to 157) List 5
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-7-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulρhonyl-ethylamino)-butyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propylamino)-7- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)-7-methoxy- quinazolin-4-yl)amine;
List 6
(4-Benzyioxyphenyl)-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-7-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-7-methoxy- quinazolin-4-yl)amine;
List 7
(4-Benzyloxyphenyl)-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-7-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-7-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)-7- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)-7- methoxyquinazolin-4-yl)amine;
List 8
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-quinazolin-4-yl)- amine; (4-Benzyloxyphenyl)-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-quinazolin- 4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-quinazolin-4- yl)amine;
List 9
(4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-quinazolin- 4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)- quinazplin-4-yl)amine;
List 10
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonylethylamino)-ethoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonylethylamino)-butyl)-quinazolin-4-yl)- amine; (4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonylethylamino)-propyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonylethylamino)-ethyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonylethylamino)-propylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonylethylamino)-ethylamino)-quinazolin-
4-yl)amine;
List 11 (1 -Benzyl- 1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-7- methoxy-quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(3 2-methanesulphonyl-ethylamino)-propylamino)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl- 1 H-indazol-5-yl)-(6-(2-i 2-methanesulphonyl-ethylamino)-ethylamino)-7- methoxyquinazolin-4-yl)amine;
List 12
(1-Benzyl-1 H-indazol-5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl- 1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazo 5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylaminό)-7- methoxyquinazolin-4-yl)amine;
List 13
(1 -Benzyl- 1 H-indazol-5-yl)-(6-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-7- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)-7- methoxyquinazolin-4-yl)amine;
List 14 (1-Benzyl-1H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-quinazolin- 4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-quinazolin-
4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)- quinazolin-4-yl)amine;
List 15
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1 -oxo-1. λ.4-thiomorphoiin-4-yl)-propoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-quinazolin-
4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butyl)-quinazolin-4- yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-quinazolin-
4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(2-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-ethyl)-quinazolin-4- yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine; List 16
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yi)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine
List 17
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino propoxy)-6-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyi-ethylamino ■ethoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyioxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino ■butyI)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino -propyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethylamino ■ethyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino ■propylamino)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethylamino ■ethylamino)-6-methoxy- quinazolin-4-yl)amine;
List 18
(4-Benzyloxyphenyl)-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-6-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-6-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-6-methoxy- quinazolin-4-yl)amine;
List 19
(4-Benzyloxyphenyl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorphoiin-4-yl)-butyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-6-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorphoiin-4-yl)-propylamino)-6- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)-6- methoxyquinazolin-4-yl)amine;
List 20
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino)-propoxy)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino)-butyl)-quinazolin-4-yl)- amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino)-propyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethylamino)-propylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethylamino)-quinazolin- 4-yl)amine;
List 21 (4-Benzyloxyphenyl)-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-quinazolin-4-yl)- amine; (4-Benzyloxyphenyl)-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-quinazolin-
4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-quinazolin-4- yl)amine;
List 22
(4-Benzyloxyphenyl)-(7-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-quinazolin- 4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-quinazoiin-4- yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(4-Benzyioxyphenyl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine;
List 23
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(2-methanesulphonyl-ethylamino)-propoxy)-6- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(2-methanesulphonyl-ethylamino)-butyl)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(2-methanesulphonyl-ethylamino)-propyl)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(2-methanesulphonyl-ethylamino)-propylamino)-6- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethylamino)-6- methoxyquinazolin-4-yl)amine;
List 24
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-6- methoxyquinazoiin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-6-methoxy- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-6-methoxy- quinazolin-4-yl)amine; (1 -Benzyl- 1 H-indazol-5-yl)-(7-(3 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-6-methoxy- quinazolin-4-yl)amine;
(1 -Benzyl- 1 H-indazol-5-yl)-(7-(2 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-6-methoxy- quinazolin-4-yl)amine;
(1 -Benzyl- 1 H-indazol-5-yl)-(7-(3-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-6- methoxyquinazolin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-6- methoxyquinazolin-4-yl)amine;
List 25
(1-Benzyl-1 H-indazol -5-yl)-(7-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-6- methoxyquinazolin-4- yl)amine;
(1-Benzyl-1 H-indazol -5-yl)-(7-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-6- methoxyquinazolin-4- yl)amine;
(1-Benzyl-1 H-indazol -5-yl)-(7-(4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-6- methoxyquinazolin-4- yl)amine;
(1 -Benzyl- 1 H-indazol -5-yl)-(7-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-6- methoxyquinazolin-4 yl)amine;
(1 -Benzyl-1 H-indazol _5-y |)-(7-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-6- methoxyquinazolin-4- yl)amine;
(1 -Benzyl-1 H-indazol -5-yl)-(7-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)-6- methoxyquinazoiin-4- yl)amine;
(1 -Benzyl-1 H-indazol -5-yl)-(7-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)-6- methoxyquinazolin-4- yl)amine;
List 26
(1 -Benzyl-1 H-indazol-5-yl)-(7-(3 2-methanesulphonyl-ethylamino)-propoxy)- quinazoIin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(2-ι 2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(4 2-methanesulphonyl-ethylamino)-butyl)-quinazolin-
4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3 2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl)-quinazolin- 4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(2-methanesulphonyl-ethylamino)-propylamino)- quinazolin-4-yl)amine; (1 -Benzyl- 1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethylamino)- quinazolin-4-yl)amine;
List 27
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-quinazolin-
4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-quinazolin-4- yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-quinazolin-
4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-quinazolin-4- yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(1 -oxo-1.λ.4-thiomorphoiin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine;
List 28 (1 -Benzyl-1 H-indazol-5-yl)-(7-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)- quinazoiin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine; (1-Benzyl-1H-indazol-5-yl)-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
(1 -Benzyl- 1 H-indazol-5-yl)-(7-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethylammo)- quinazolin-4-yl)amine;
List 29
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-pyrido[3,4- d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propylamino)-pyrido-
[3,4-d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)-pyrido[3,4- d]pyrimidin-4-yl)amine;
List 30
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-ethoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1 -oxo-1. λ.4-thiomorphoiin-4-yl)-propylamino)-pyrido[3,4- d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(1-oxo-1.λ.4-thiomorphoiin-4-yl)-ethylamino)-pyrido[3,4- d]pyrimidin-4-yl)amine;
List 31 (4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-pyrido[3,4- d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
List 32
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-pyrido-
[3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-pyrido-
[3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-pyrido-
[3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine; List 33
(1-Benzyl-1 H-indazol-5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)-pyrido- [3,4-d]pyrimidin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(3-i 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-pyrido[3,4- d]pyrimidin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(2-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-pyrido[3,4- d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(3-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine (1-Benzyl-1 H-indazol-5-yl)-(6-(2-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyiamino)-pyrido- [3,4-d]pyrimidin-4-yl)amine;
List 34
(1-Benzyl-1 H-indazol-5-yl)-(6-(3 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)-pyrido-
[3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(2-ι 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-pyrido- [3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-pyrido- [3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(3 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-pyrido- [3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(2 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-pyrido- [3,4-d]pyrimidin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(6-(3 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine (1-Benzyl-1 H-indazol-5-yl)-(6-(2 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
List 35
4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-7-(2-(methanesulphonyl)ethylamino- methyl)quinazoline; 2-(4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-7-yl)methylamino)acetic acid;
2-(4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-7-yl)methylamino)- acetamide; (2R)-1-(4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-7-ylmethyl)- pyrrolidine-2-carboxylic acid -butyl ester;
(2S)-1 -(4-(1 -(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-7-ylmethyl)- pyrrolidine-2-carboxamide;
List 36
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-6-(2-(methanesulphonyl)ethylamino- methyl)-pyrido[3,4-d]pyrimidine;
2-(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)methyl- amino)acetic acid; 2-(Λ/-(4-(3-Fluorobenzyl-1 H-indazol-5-yl amino)-pyrido[3,4-d]pyrimidin-6-yl)methyl)- Λ/-methylamino)acetamide;
(2R)-1-(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxylic acid f-butyl ester;
(2S)-1-(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxamide;
List 37
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)- propoxy)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)- 7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)- 7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 38 (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl- amino)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl- amino)-7-methoxyquinazolin-4-yl)amine;
List 39
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-
7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-ι 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-
7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl- amino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl- amino)-7-methoxyquinazoiin-4-yl)amine;
List 40
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3-(2-methanesulphonyl-ethylamino)- propoxy)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(2- 2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(4- 2-methanesulphonyl-ethylamino)-butyl)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(3- 2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(2-ι 2-methanesulphonyl-ethylamino)-ethyl)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(3- 2-methanesulphonyl-ethylamino)-propyl- amino)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(2- 2-methanesulphonyl-ethylamino)-ethyl- amino)-quinazolin-4-yl)amine;
List 41 (4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(4- 1 -oxo-1. λ.4-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(3- 1 -oxo-1.λ.4-thiomorphoIin-4-yl)-propyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(2- 1 -oxo-1. λ.4-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl -(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl- amino)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl- amino)-quinazolin-4-yl)amine;
List 42
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propoxy)-quinazoiin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl (6-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(6-(4 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(3 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine; (4-(3-Fiuorobenzyl-1 H-indazol-5-yl)-(6-(3-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl- amino)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl- amino)-quinazolin-4-yl)amine;
List 43
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3-ι 2-methanesulphonyl-ethylamino)- propoxy)-6-methoxyquinazolin-4-yl)amine (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2 2-methanesulphonyl-ethylamino)-ethoxy)- 6-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(4-ι 2-methanesulphonyl-ethylamino)-butyl)-6- methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(3- 2-methanesulphonyl-ethylamino)-propyl)- 6-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(2- 2-methanesulphonyl-ethylamino)-ethyl)-6- methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(3- 2-methanesulphonyl-ethylamino)-propyl- amino)-6-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 2-methanesulphonyl-ethylamino)-ethyl- amino)-6-methoxyquinazolin-4-yl)amine;
List 44
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(2-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-6- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(4 1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-6- methoxyquinazoiin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(3 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-6- methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-6- methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(3 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl- amino)-6-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl- amino)-6-methoxyquinazolin-4-yl)amine;
List 45
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(4-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-
6-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-
6-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl- amino)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl- amino)-6-methoxyquinazolin-4-yl)amine;
List 46
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3- 2-methanesulphonyl-ethylamino)- propoxy)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(4- 2-methanesulphonyl-ethylamino)-butyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3- 2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 2-methanesulphonyl-ethylamino)-ethyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(3- 2-methanesulphonyl-ethylamino)-propyl- amino)-quinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl- amino)-quinazolin-4-yl)amine;
List 47
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl (7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(7-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl- amino)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl -(7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl- amino)-quinazolin-4-yl)amine;
List 48
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propoxy)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2-ι 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(4-< 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1H-indazol-5-yl)-(7-(2-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(3-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(7-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine; List 49
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3 2-methanesulphonyl-ethylamino)- propoxy)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-ι 2-methanesulphonyl-ethylamino)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-ι 2-methanesulphonyl-ethylamino)- butyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 2-methanesulphonyl-ethylamino)- propyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 2-methanesulphonyl-ethylamino)- ethyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 2-methanesulphonyl-ethylamino)- propylamino)-7-methoxypyrido[3,4-d]pyrimidine (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 2-methanesulphonyl-ethylamino)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidine;
List 50
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluoιobenzyl-1 H-indazol-5-ylamino)-(6-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 1-0X0-1.λ.4-thiomorpholin-4-yl)- propyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 1-0X0-1.λ.4-thiomorpholin-4-yl)- ethyl)-7-methoxypyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidine;
List 51
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-ι 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-7-methoxypyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidine;
List 52
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3 2-methanesulphonyl-ethylamino)- propoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(2 2-methanesulphonyl-ethylamino)- ethoxy)-pyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4 2-methanesulphonyl-ethylamino)- butyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(3 2-methanesulphonyl-ethylamino)- propyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2 2-methanesulphonyl-ethylamino)- ethyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3 2-methanesulphonyl-ethylamino)- propylamino)-py do[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2- 2-methanesulphonyl-ethylamino)- ethylamino)-pyrido[3,4-d]pyrimidine;
List 53
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4 1 -oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3 1-0X0-1.λ.4-thiomorpholin-4-yl)- propyl)-pyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1H-indazol-5-ylamino) 6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-pyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino) 6-(3-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-pyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-ι 6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-pyrido[3,4-d]pyrimidine;
List 54
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6- (3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl propoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6 (2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl ethoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6-ι (4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl butyl)-pyrido[3,4-d]pyrimidine; (4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6 (3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl propyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6 (2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl ethyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6 (3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl propylamino)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)- 6 (2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl ethylamino)-pyrido[3,4-d]pyrimidine;
List 55
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-quinazolin-4-yl)amine; List 56
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-(7-(2-(methanesulphonyl)ethylamino- methyl)-quinazoline;
2-(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilinoquinazolin-7-yl)methylamino)acetic acid;
2-(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilinoquinazolin-7-yl)methylamino)acetamide;
(2R)-1-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino)-quinazolin-7-ylmethyl)pyrrolidine-
2-carboxylic acid f-butyl ester;
(2S)-1-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino quinazolin-7-ylmethyl)pyrrolidine-
2-carboxamide;
List 57
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-6-(2-(methanesulphonyl)-ethylamino- methyl)-pyrido[3,4-d]pyrimidine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-pyrido[3,4-d]pyrimidin-6-yl)methyl-amino)- acetic acid;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-pyrido[3,4-d]pyrimidin-6-yl)methylamino)- acetamide;
(2R)-1-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilinopyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxylic acid f-butyl ester; (2S)-1-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxamide;
List 58
(4-(3-ChIoro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butyl)-7-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesuIphonyl-ethylamino)- ethyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-7-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 59
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1-OXO-1.λ.4-thiomorpholin-4-yl)- propyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 60
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-( 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-( 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-( 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-( 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl -(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 61
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)- propoxy)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2 1-0X0-1.λ.4-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4 1-0X0-1.λ.4-thiomorpholin-4-yl)- butyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2 1-0X0-1.λ.4-thiomorpholin-4-yl)- ethyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine;
List 62 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine;
List 63
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 2-methanesulphonyl-ethylamino)- ethoxy)-quinazolin~4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4- 2-methanesulphonyl-ethylamino)- butyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 2-methanesulphonyl-ethylamino)- propyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 2-methanesulphonyl-ethylamino)- ethyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 2-methanesulphonyl-ethylamino)- propylamino)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 2-methanesulphonyl-ethylamino)- ethylamino)-quinazolin-4-yl)amine;
List 64 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3- 2-methanesulphonyl-ethylamino)- propoxy)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2- 2-methanesulphonyl-ethylamino)- ethoxy)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4- 2-methanesulphonyl-ethylamino)- butyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3- 2-methanesulphonyl-ethylamino)- propyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxyjphenyl-(7-(2- 2-methanesulphonyl-ethylamino)- ethyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3- 2-methanesulphonyl-ethylamino)- propylamino)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2- 2-methanesulphonyl-ethylamino)- ethylamino)-6-methoxyquinazolin-4-yl)amine;
List 65 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2- 1-0X0-1.λ.4-thiomorpholin-4-yl)- ethoxy)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4- 1-0X0-1.λ.4-thiomorpholin-4-yl)- butyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propyl)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fIuorobenzyl)oxy]phenyl-(7-(2-(1 -oxo-1. λ.4-thiomorpholin-4-yl)- ethylamino)-6-methoxyquinazolin-4-yl)amine;
List 66 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-6-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-6-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl -(7-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-6-methoxyquinazolin-4-yl)amine;
List 67
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)- propoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyi)oxy]phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine;
List 68 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1 1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(1 1 -dioxo-1.λ.6-thiomorphoiin-4-yl)- butyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1 1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(1 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(1 1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine;
List 69 (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethylamino)- ethoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethylamino)- butyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethylamino)- propyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethylamino)- ethyl)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethylamino)- propylamino)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-quinazolin-4-yl)amine;
List 70
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fIuorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
List 71
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)- propyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
List 72 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl -(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
List 73 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1-OXO-1.λ.4-thiomorpholin-4-yl)- propoxy)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethoxy)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- butyl)-pyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)- propylamino)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)- ethylamino)-pyrido[3,4-d]pyrimidin-4-yl)amine;
List 74
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethoxy)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fiuorobenzyl)oxy]phenyl-(6-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-pyrido[3,4-d]pyrimidin-4-yl)amine;
List 75 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethoxy)-pyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butyl)-pyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propyl)-pyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethyl)-pyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-pyrido[3,4-d]pyrimidin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-pyrido[3,4-d]ρyrimidin-4-yl)amine;
List 76 N-[4-(Benzenesulphonyl)aniiino]-7-(2-(methanesulphonyl)ethylaminomethyl)- quinazoline;
2- {N-[4-(Benzenesulphonyl)anilino]} quinazolin-7-yl)methylamino)acetic acid;
2-( N-[4-(Benzenesulphonyl)anilino] quinazolin-7-yl)methylamino)acetamide;
(2R)-1-(4-(N-[4-(Benzenesulphonyl)phenyl])quinazolin-7-ylmethyl)pyrrolidine-2- carboxylic acid f-butyl ester;
(2S)-1-(4-(N-[4-(Benzenesulphonyl)phenyl])quinazolin-7-ylmethyl)pyrroiidine-2- carboxamide;
List 77 N-[4-(Benzenesulphonyl)anilino]-6-(2-(methanesulphonyl)ethylaminomethyl)- pyrido[3.4-d]pyrimidine;
2-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-6-yl)methylamino)acetic acid;
2-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-6-yl)methylamino)- acetamide;
(2R)-1-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxylic acid f-butyl ester;
(2S)-1-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-6-ylmethyl)- pyrrolidine-2-carboxamide;
List 78 N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-7-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)-
7-methoxyquinazolin-4-yl)amine;
List 79
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)-
7-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)ρhenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-7- methoxyquinazolin-4-yl)amine;
List 80
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-7-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 81
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)pheny]l-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)ρhenyl]-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine;
List 82 N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-quinazolin-4-yl)amine;
List 83
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine;
N-[4-(BenzenesuIphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(2-methanesulphonyl-ethylamino)- propylamino)-quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)- ethylamino)-quinazolin-4-yl)amine;
List 84
N-[4-(Benzenesulphonyl)phenyl-(7-(3-(2-methanesulphonyl-ethylamino)-propoxy)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-7-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-6- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(7-(4-(2-methanesulphonyl-ethylamino)-butyl)-6- methoxyquinazolin-4-yI)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(3-(2-methanesulphonyl-ethylamino)-propyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(3-(2-methanesulphonyl-ethylamino)- propylamino)-6-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(2-methanesulphonyl-ethylamino)-ethylamino)- 6-methoxyquinazolin-4-yl)amine; List 85
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-6- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(7-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- 6-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-6- methoxyquinazolin-4-yl)amine;
List 86
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-6- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-6- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-6-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(7-(2-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-6-methoxyquinazolin-4-yl)amine;
List 87 N-[4-(Benzenesulphonyl)phenyl]-(7-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)pheny]l-(7-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(7-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl 7-(2- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl 7-(3- 1 -oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl 7-(2-ι 1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)- quinazolin-4-yl)amine;
List 88
N-[4-(Benzenesulphonyl)phenyl 7-(3- 1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(2- 1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(4- 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl 7-(3- 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl' 7-(2- 1-dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(3- 1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl- amino)-quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(2- 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl- amino)-quinazolin-4-yl)amine;
List 89 N-[4-(Benzenesulphonyl)phenyl 7-(2- 2-methanesulphonyl-ethylamino)-ethoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(4-ι 2-methanesulphonyl-ethylamino)-butyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(3- 2-methanesulphonyl-ethylamino)-propyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(2- 2-methanesulphonyl-ethylamino)-ethyl)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl 7-(3- 2-methanesulphonyl-ethylamino)-propyl- amino)-quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(7-(2-(2-methanesulphonyl-ethylamino)-ethyl- amino)-quinazolin-4-yl)amine;
List 90 N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(2-methanesulphonyl-ethylamino)-propyl- amino)-7-methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(2-methanesulphonyl-ethylamino)-ethylamino)- 7-methoxypyrido[3,4-d]pyrimidin-4yl)amine;
List 91
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-propyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- 7-methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
List 92 N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)-7- methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- propylamino)-7-methoxypyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidin-4yl)amine;
List 93 N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethoxy)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)pheny]l-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1-oxo-1.λ.4-thiomorpholin-4-yl)-ethyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1-oxo-1.λ.4-thiomorpholin-4-yl)-propylamino)- pyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-ethylamino)- pyrido[3,4-d]pyrimidin-4yl)amine;
List 94
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propoxy)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethoxy)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butyl)- pyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl)- pyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-propyl- amino)-pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-ethyl- amino)-pyrido[3,4-d]pyrimidin-4yl)amine;
List 95
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)-ethoxy)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(2-methanesulphonyl-ethylamino)-butyl)- pyrido[3,4-d]pyrimidin-4yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(2-methanesulphonyl-ethylamino)-propyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl)- pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(3-(2-methanesulphonyl-ethylamino)-propyl- amino)-pyrido[3,4-d]pyrimidin-4yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(2-(2-methanesulphonyl-ethylamino)-ethyl- amino)-pyrido[3,4-d]pyrimidin-4yl)amine;
List 96 (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-quinazolin-4- yl)amine; (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)-quinazolin-4- yl)amine;
List 97 (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butoxy)-7- methoxyquinazolin-4-yl)amine;
(1 -Benzyl- 1 H-indazol-5-yl)-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorρholin-4-yl)-butoxy)-quinazolin- 4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)- quinazolin-4-yl)amine;
List 98
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino)-butoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-6-methoxy- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino)-butoxy)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-quinazolin-4-yl)- amine;
(4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-quinazolin-4- yl)amine;
List 99
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(2-methanesulphonyl-ethylamino)-butoxy)-6- methoxyquinazolin-4-yl)amine; (1-Benzyl-1H-indazol-5-yl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-6-methoxy- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-6- methoxyquinazolin-4-yl)amine; (1 -Benzyl-1 H-indazol-5-yl)-(7-(4-(2-methanesulphonyl-ethylamino)-butoxy)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butoxy)-quinazolin- 4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)- quinazolin-4-yl)amine;
List 100
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)- pyrido[3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butoxy)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)- pyrido[3,4-d]pyrimidin-4-yl)amine;
List 101
4-(1-(3-Fluorobenzyl-1H-indazol-5-yl)amino)-6-(2-methanesulphonylethylamino)- butoxy)-quinazoline;
4-(1-(3-Fluorobenzyl-1H-indazol-5-yl)amino)-6-(2-methanesulphonylethylamino)- butoxy)-pyrido[3,4-djpyhmidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorphoiin-4-yl)-butoxy)-7- methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butoxy)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)- quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butoxy)-quinazolin-4-yl)amine;
List 102
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-(6-(4-methanesulphonylethylamino)- butoxy)-pyrido[3,4-d]pyrimidine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonylethylamino)- butoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)- butoxy)-7-methoxyquinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butoxy)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-( 1-0x0-1.λ.4-thiomorpholin-4-yl)- butoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butoxy)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butoxy)-quinazolin-4-yl)amine;
List 103 N-[4-(Benzenesulphonyl)anilino]-6-(2-methanesulphonylsulphonylethylaminobutoxy)- quinazoline;
N-[4-(Benzenesulphonyl)anilino]-6-(2-methanesulphonylsulphonylethylaminobutoxy)- pyrido[3,4-d]pyrimidine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)-7- methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butoxy)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butoxy quinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(2-methanesulphonyl-ethylamino)-butoxy)- quinazolin-4-yl)amine;
List 104
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-7-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)-7- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butylamino)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)-quinazolin- 4-yl)amine;
List 105
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)-7- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)-7- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine; List 106
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino)-butylamino)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1-oxo-1.λ.4-thiomorphoiin-4-yl)-butylamino)-6-methoxy- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)-6- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethylamino)-butylamino)-quinazolin- 4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-quinazolin-4- yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
List 107
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(2-methanesulphonyl-ethylamino)-butylamino)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-6- methoxyquinazolin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)-6- methoxyquinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(2-methanesulphonyi-ethylamino)-butylamino)- quinazolin-4-yl)amine;
(1 -Benzyl-1 H-indazol-5-yl)-(7-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(7-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
List 108 (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-pyrido[3,4- d]pyrimidin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)-pyrido- [3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
(1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1. λ.4-thiomorpholin-4-yl)-butylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine; (1-Benzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)-butylamino)- pyrido[3,4-d]pyrimidin-4-yl)amine;
List 109
4-(1-(3-Fluorobenzyl-1 H-indazol-5-yl)amino)-6-(2-(methanesulphonyl)ethylamino)- butylamino)-quinazoline;
4-(1-(3-Fluorobenzyl-1H-indazol-5-yl)amino)-6-(2-(methanesulphonyl)ethylamino)- butylamino)-pyrido[3,4-d]pyrimidine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)- butylamino)-7-methoxyquinazolin-4-yl)amine; (4-(3-Fluorobenzyl-1H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 -oxo-1.λ.4-thiomorpholin-4-yl)- butylamino)-quinazolin-4-yl)amine;
(4-(3-Fluorobenzyl-1 H-indazol-5-yl)-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yi)- butylamino)-quinazolin-4-yl)amine;
List 110
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butylamino)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-(6-(2-(methanesulphonyl)ethylamino) butylamino)-pyrido[3,4-d]pyrimidine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)- butylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1 ,1-dioxo-1.λ.6-thiomorpholin-4-yl)- butylamino)-7-methoxyquinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)- butylamino)-quinazolin-4-yl)amine; (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butyiamino)-quinazolin-4-yl)amine;
(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethylamino)- butylamino)-quinazolin-4-yl)amine;
List 111
N-[4-(Benzenesulphonyl)anilino]-6-(4-(2-(methanesulphonyl)ethylamino)butylamino)- quinazoline;
N-[4-(Benzenesulphonyl)anilino]-(6-(4-(2-(methanesulphonyl)ethylamino)butylamino) -pyrido[3,4-d]pyrimidine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(2-methanesulphonyl-ethylamino)-butylamino)- 7-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)-7- methoxyquinazolin-4-yl)amine; N-[4-(Benzenesulphonyl)phenyl-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butylamino)-7-methoxyquinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1-oxo-1.λ.4-thiomorpholin-4-yl)-butylamino)- quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(1 , 1 -dioxo-1.λ.6-thiomorpholin-4-yl)- butylamino)-quinazolin-4-yl)amine;
N-[4-(Benzenesulphonyl)phenyl]-(6-(4-(2-methanesulphonyl-ethylamino)- butylamino)-quinazolin-4-yl)amine;
List 112 (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)-butoxy)-7- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)-ethoxy)-7- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)-butyl)-7- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyi)amino)-propyl)-7- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)-ethyl)-7- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)butylamino) -7-methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)propylamino) -7-methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethylamino)- 7-methoxyquinazolin-4-yl)amine;
List 113
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butoxy)- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propoxy)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethoxy)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl N-methyl)amino)-butyl)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl-ι N-methyl)amino)-propyl)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethyl)- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)butylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)propylamino) quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl N-methyl)amino)ethylamino) quinazolin-4-yl)amine;
List 114
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butoxy)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propoxy)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethoxy)-6- methoxyquinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butyl)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propyl)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethyl)-6- methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)butylamino) -6-methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)propylamino) -6-methoxyquinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethylamino)- 6-methoxyquinazoiin-4-yl)amine;
List 115
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butoxy)- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propoxy)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethoxy)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butyl)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propyl)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl-ι N-methyl)amino)-ethyl)- quinazolin-4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)butylamino)- quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)propylamino) quinazolin-4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)ethylamino) quinazolin-4-yl)amine;
List 116
(4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)-butoxy)-7- methoxypyrido[3,4-d]pyrimidin-4-yl)amine; (4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl-ι N-methyl amino)-propoxy)-7- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl N-methyl amino)-ethoxy)-7- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl-ι N-methyl amino)-butyl)-7- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propyl)-7- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl N-methyl amino)-ethyl)-7- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyioxyphenyl)-(6-(4-(2-methanesulphonyl-ethyl N-methyl amino)butylamino) -7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)propylamino) -7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethylamino)- 7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
List 117
(4-Benzyloxyphenyl)-(6-(4- 2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(3- 2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(2- 2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(4- 2-methanesulphonyl-ethyl- N-methyl amino)-butyl)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(3-i 2-methanesulphonyl-ethyl- N-methyl amino)-propyl)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(2-< 2-methanesulphonyl-ethyl- N-methyl amino)-ethyl)- pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(4-ι 2-methanesulphonyl-ethyl- N-methyl amino)butylamino)- pyrido[3,4-d]pyhmidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(3-ι 2-methanesulphonyl-ethyl- N-methyl amino)propylamino) pyrido[3,4-d]pyrimidin -4-yl amine; (4-Benzyloxyphenyl)-(6-(2- 2-methanesulphonyl-ethyl- N-methyl amino)ethylamino) pyτido[3,4-d]pyrimidin -4-yl)amine;
List 118
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl N-methyl)amino)-butoxy)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propoxy)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethoxy)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butyl)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propyl)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethyl)-6- methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)butylamino) -6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)propylamino) -6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethylamino)- 6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
List 119
(4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butoxy)- pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propoxy)- pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethoxy)- pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)-butyl)- pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)-propyl)- pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)-ethyl)- pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzyloxyphenyl)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)butylamino)- pyrido[3,4-d]pyrimidin -4-y.)amine;
(4-Benzyloxyphenyl)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)propylamino) pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzyloxyphenyl)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)ethylamino) pyrido[3,4-d]pyrimidin -4-yl)amine;
List 120
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)-7-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)-7-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)-7-methoxyquinazoline; 4-(1 -Benzyl- 1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butyl)-7-methoxyquinazoline;
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propyl)-7-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethyl)-7-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)butylamino)-7-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)propylamino)-7-methoxyquinazoline; 4-(1 -Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethylamino)-7-methoxyquinazoline;
List 121
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)- quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)-quinazoIine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)- quinazoline; 4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl N-methyl amino)-butyl)-quinazoline;
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-ι N-methyl amino)-propyl)-quinazoline; 4-(1 -Benzyl- 1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-ι N-methyl amino)-ethyl)-quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-ι N-methyl amino)butylamino)-quinazoline;
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl N-methyl amino)propylamino)quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-ι N-methyl amino)ethylamino)quinazoline;
List 122 4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)-6-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)-6-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)-6-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butyl)-6-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propyl)-6-methoxyquinazoline; 4-(1 -Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethyl)-6-methoxyquinazoline;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl amino)butylamino)-6-methoxyquinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl amino)propylamino)-6-methoxyquinazoline;
4-(1-Benzy.-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethylamino)-6-methoxyquinazoline;
List 123 4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butoxy)-quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propoxy)-quinazoline; 4-(1 -Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethoxy)-quinazoline;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butyl)-quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propyl)-quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethyl)-quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)butylamino)-quinazoline; 4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)propylamino)quinazoline;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)ethylamino)quinazoline;
List 124
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butoxy)-7-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propoxy)-7-methoxypyrido[3,4-d]pyrimidine; 4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethoxy)-7-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)butylamino)-7-methoxypyrido[3,4-d]pyrimidine; 4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)propylamino)-7-methoxypyrido[3,4-d]pyhmidine; 4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethylamino)-7-methoxypyrido[3,4-d]pyrimidine;
List 125
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butyl)-pyrido[3.4-d]pyrimidine; 4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propyl)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethyl)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl amino)butylamino)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl amino)propylamino)pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl amino)ethylamino)pyrido[3,4-d]pyrimidine;
List 126
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl amino)-butoxy)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl amino)-propoxy)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl amino)-ethoxy)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(4-(2-methanesuiphonyl-ethyl- N-methyl amino)-butyl)-6-methoxypyrido[3,4-d]pyrimidine; 4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propyl)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethyl)-6-methoxypyrido[3,4-d]pyrimidine; 4-(1 -Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)butylamino)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)propylamino)-6-methoxypyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethylamino)-6-methoxypyrido[3,4-d]pyrimidine;
List 127
4-(1-Benzyl-1 H-indazol-5-yiamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butoxy)-pyrido[3,4-d]pyrimidine; 4-(1 -Benzyl- 1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)-propoxy)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethoxy)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)-butyl)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulρhonyl-ethyl-(N-methyl amino)-propyl)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)-ethyl)-pyrido[3,4-d]pyrimidine; 4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl amino)butylamino)-pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl amino)propylamino)pyrido[3,4-d]pyrimidine;
4-(1-Benzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl amino)ethylamino)pyrido[3,4-d]pyrimidine;
List 128
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-7-methoxyquinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-7-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-7-methoxyquinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-7-methoxyquinazoline;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-7-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-7-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-7-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-7-methoxyquinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-7-methoxyquinazoline;
List 129
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)- quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)- quinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-quinazoline;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)quinazoline; 4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)quinazoline;
List 130 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-6-methoxyquinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-6-methoxyquinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-6-methoxyquinazoline;
List 131 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-quinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-quinazoline; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)quinazoline;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)quinazoline;
List 132
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-7-methoxypyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-7-methoxypyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-7-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-7-methoxypyrido[3,4-d]pyrimidine;
List 133
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-pyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-pyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)- pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)pyhdo[3,4-d]pyrimidine;
List 134
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-6-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-6-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-6-methoxypyhdo[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-6-methoxypyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-6-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-6-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-6-methoxypyhdo[3,4-d]pyhmidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-6-methoxypyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-6-methoxypyrido[3,4-d]pyrimidine; List 135
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)- pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-pyrido[3,4-d]pyrimidine; 4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)pyrido[3,4-d]pyrimidine;
4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)pyrido[3,4-d]pyrimidine;
List 136
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-7-methoxyquinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-7-methoxyquinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyi)amino)propylamino)-7-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-7-methoxyquinazolin-4-yl)amine;
List 137
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)- quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-quinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)- quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)quinazolin-4-yl)amine;
List 138
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-6-methoxyquinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-6-methoxyquinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-6-methoxyquinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-6-methoxyquinazolin-4-yl)amine;
List 139
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-quinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-quinazolin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)quinazolin-4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)quinazolin-4-yl)amine;
List 140
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yI)amine;
List 141
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(6-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine;
List 142 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-6-methoxypyrido[3,4-d]py midin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]ρhenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethylamino)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
List 143 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)-butyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)-propyl)-pyrido[3,4-d]pyrimidin -4-yl)amine; 4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)-ethyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(4-(2-methanesulphonyl-ethyl-(N- methyl)amino)butylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(3-(2-methanesulphonyl-ethyl-(N- methyl)amino)propylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
4-(3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl-(7-(2-(2-methanesulphonyl-ethyl-(N- methyl)amino)ethylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
List 144
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butoxy)-7-methoxyquinazolin-4-yi)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-7-methoxyquinazolin-4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethoxy)-7-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butyl)-7-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-7-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethyl)-7-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butylamino)-7-methoxyquinazolin-4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propylamino)-7-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)-7-methoxyquinazolin~4-yl)amine;
List 145
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butoxy)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-quinazolin-4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethoxy)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- buty.)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-ι N-methyl)amino)- propyl)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl N-methyl)amino)- ethyl)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl-ι N-methyl)amino)- butylamino)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-ι N-methyl)amino)- propylamino)quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)quinazolin-4-yl)amine;
List 146
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butoxy)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyi-ethyl- N-methyl)amino)- ethoxy)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butyl)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethyl)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butylamino)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propylamino)-6-methoxyquinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)-6-methoxyquinazolin-4-yl)amine; List 147
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl N-methyl)amino)- butoxy)-quinazoiin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl-> N-methyl)amino)- ethoxy)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butyl)-quinazolin-4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyi)-(7-(2-(2-methanesulphonyl-ethyl-ι N-methyl)amino)- ethyl)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butylamino)-quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propylamino)quinazolin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)quinazolin-4-yl)amine;
List 148
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butoxy)-7-methoxypyrido[3,4-d]pyrimidin-4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl-ι N-methyl)amino)- ethoxy)-7-methoxypyrido[3,4-d]py midin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethyl)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)- propylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)- ethylamino)-7-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
List 149
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)- butoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)- propoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)- ethoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)- butyl)-pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)- propyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)- ethyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)- butylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)- propylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(6-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)- ethylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
List 150
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)- butoxy)-6-methoxypyrido[3,4-d]pyhmidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl-(N-methyl)amino)- propoxy)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl-(N-methyl)amino)- ethoxy)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl-(N-methyl)amino)- butyl)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethyl)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N- methyl)amino)butylamino)-6-methoxypyrido[3,4-d]pyrimidin -4 yl)amine; (4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N- methyl)amino)propylamino)-6-methoxypyrido[3,4-d]pyrimidin -4 -yl)amine; (4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)-6-methoxypyrido[3,4-d]pyrimidin -4-yl)amine;
List 151
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethoxy)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butyi)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propyl)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethyl)-pyrido[3,4-d]pyrimidin -4-yl)amine; (4-Benzenesulphonylphenyl)-(7-(4-(2-methanesulphonyl-ethyl- N-methyl)amino)- butylamino)-pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(3-(2-methanesulphonyl-ethyl- N-methyl)amino)- propylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
(4-Benzenesulphonylphenyl)-(7-(2-(2-methanesulphonyl-ethyl- N-methyl)amino)- ethylamino)pyrido[3,4-d]pyrimidin -4-yl)amine;
List 152
2-(Λ/- N-(4-Benzyloxyphenyl)quinazolin-6-yl)methyl)-Λ/-methylamino)acetamide;
2-(Λ/- N-[4-(Benzenesulphonyl)phenyl])quinazolin-6-yl)methyl)-Λ/-methylamino)- acetamide; 2-(Λ/- (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilinoquinazolin-6-yl)methyl)-/V-methyl- amino)acetamide;
2-(Λ/-(4-(1-(1-Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl)methyl)-Λ/-methylamino)- acetamide; 2-(Λ/-(4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl)methyl)-Λ/-methyl- amino)acetamide;
List 153
2-(N-[4-(Benzyloxy)anilino])pyrido[3,4-d]pyrimidin-6-yl)methyl)-Λ/-methylamino)- acetamide;
2-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-6-yl)methyl)-Λ/-methyl- amino)acetamide;
2-(Λ/-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-pyrido[3,4-d]pyrimidin-6-yl)methyl)- Λ/-methylamino)acetamide; 2-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)methylamino)- acetamide;
2-(4-(3-Fluorobenzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)methyl- amino)acetamide;
List 154
2-(Λ/-f N-(4-Benzyloxyphenyl)quinazolin-7-yl)methyl)-Λ/-methylamino)acetamide;
2-(Λ/- N-[4-(Benzenesulphonyl)phenyl])quinazolin-7-yl)methyl)-Λ/-methylamino)- acetamide;
2-(Λ/- (4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilinoquinazolin-7-yl)methyl)-Λ/-methyl- amino)acetamide;
2-(Λ/- 4-(1-(1-Benzyl-1 H-indazol-5-ylamino)-quinazolin-7-yl)methyl)-Λ/-methyl- amino)acetamide;
2-(/V- 4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-quinazolin-7-yl)methyl)-Λ/- methylamino)acetamide;
List 155
2-(N-[4-(Benzyloxy)anilino])pyrido[3,4-d]ρyrimidin-7-yl)methyl)-Λ/-methylamino)- acetamide;
2-(N-[4-(Benzenesulphonyl)anilino])pyrido[3,4-d]pyrimidin-7-yl)methyl)-Λ/-methyl- amino)acetamide; 2-(Λ/-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-pyrido[3,4-d]pyrimidin-7-yl)methyl)- Λ/-methylamino)acetamide;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-7-yl)methylamino)- acetamide; 2-(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-7-yl)methyl- amino)acetamide;
List 156
2-(Λ/-(N-(4-Benzyloxyphenyl)-7-methoxyquinazolin-6-yl)methyl)-Λ/-methylamino)- acetamide;
2-(Λ/-(N-[4-(Benzenesulphonyl)phenyl])-7-methoxyquinazolin-6-yl)methyl)-/V- methylamino)acetamide;
2-(Λ/-('(4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-7-methoxyquinazolin-6-yl)methyl)- Λ/-methylamino)acetamide; 2-(Λ/-(4-(1-(1-Benzyl-1H-indazol-5-ylamino)-7-methoxyquinazolin-6-yl)methyl)-/V- methylamino)acetamide;
2-(Λ/- 4-(1-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-7-methoxyquinazolin-6-yl)methyl)- Λ/-methylamino)acetamide;
List 157
2-(N-[4-(Benzyloxy)anilino])-7-methoxypyrido[3,4-d]pyrimidin-6-yl)methyl)-Λ/-methyl- amino)acetamide;
2-( N-[4-(Benzenesulρhonyi)anilino])-7-methoxypyrido[3,4-d]pyrimidin-6-yl)methyl)-Λ/- methylamino)acetamide; 2-(Λ/-((4-(3-Chloro-4-[(3-fluorobenzyl)oxy]anilino-7-methoxypyrido[3,4-d]pyrimidin-6- yl)methyl)-Λ/-methylamino)acetamide;
2-(4-(1-Benzyl-1 H-indazol-5-ylamino)-7-methoxypyrido[3,4-d]pyrimidin-6-yl)methyl- amino)acetamide;
2-(4-(3-Fluorobenzyl-1 H-indazol-5-ylamino)-7-methoxypyrido[3,4-d]pyrimidin-6- yl)methylamino)acetamide;
and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. It is considered that the compounds specified in lists 17 to 28, 35, 43 - 48, 56, 64 - 69, 76, 84 - 89, 99, 106, 107, 114, 115, 118, 119, 122, 123, 126, 127, 130, 131,' 134, 135, 138, 138, 142, 143, 146, 147, 150, 151 , 154 and 155 above in which R1' is in the 7-position are of particular interest in the context of lck and/or ZAP-70 activity.
Certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms or may exhibit cis-trans isomerism). The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are included within the scope of the present invention. Likewise, it is understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.
Salts of the compounds of the present invention may comprise acid addition salts derived from a nitrogen in the compound of formula (I). The therapeutic activity resides in the moiety derived from the compound of the invention as defined herein and the identity of the other component is of less importance although for therapeutic and prophylactic purposes it is, preferably, pharmaceutically acceptable to the patient. Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example β-toluenesulphonic, acids.
According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) as defined above which comprises the steps: (a) the reaction of a compound of formula (II)
Figure imgf000092_0001
wherein X is as defined above; Y' is C-M-L' and V is N; or Y' is N and V' is C-M-L'; or Y' is C-M-L' and V is CR2; or Y' is CR2 and V is C-M-L'; wherein R2 and M are as defined above, and L and L' are suitable leaving groups, with a compound of formula (III)
UNH2 (III) wherein U is as defined above, to prepare a compound of formula (IV)
Figure imgf000093_0001
and subsequently (b) reaction with appropriate reagent(s) to substitute the group Q by replacement of the leaving group L'; and, if desired, (c) subsequently converting the compound of formula (I) thereby obtained into another compound of formula (I) by means of appropriate reagents.
Alternatively, the compound of formula (II) as defined above is reacted with the appropriate reagents to substitute the group Q by replacement of the leaving group L' and then the product thereby obtained (of formula (V) below) is reacted with the compound of formula (III) as defined above, followed, if desired, by conversion of the compound of formula (I) thereby obtained into another compound of formula (I).
In a variant of this alternative the compound of formula (V)
Figure imgf000093_0002
wherein X, Y, V and L are as defined above, may be prepared by the reaction of a compound of formula (VI)
Figure imgf000094_0001
wherein V and Y' are as defined above, with appropriate reagents to substitute the group Q for the leaving group L' to prepare a compound of formula (VII)
Figure imgf000094_0002
and subsequent reaction to incorporate the leaving group L. For example, a chloro leaving group can be incorporated by reaction of a corresponding 3,4- dihydropyrimidone with carbon tetrachloride/triphenylphosphine in an appropriate solvent.
The group Q may, therefore, be substituted onto the side chain attached to the basic ring system by replacement of a suitable leaving group L' carried by the side chain in the appropriate position on the ring.
According to a further aspect of the present invention there is provided a process for the preparation of a compound of formula (I) as defined above which comprises the steps:
(a) reacting a compound of formula (IV) as defined above with appropriate reagent(s) to prepare a compound of formula (VIII)
Figure imgf000094_0003
wherein X and U are as defined above; Y" is CT and V" is N; or Y" is N and V" is CT; or Y" is CT and V" is CR2; or Y" is CR2 and V" is CT; wherein R2 is as defined above and T is an appropriately functionalised group; and (b) subsequently converting the group T into the group R1 by means of appropriate reagent(s); and, if desired, (c) subsequently converting the compound of formula (I) thereby obtained into another compound of formula (I) by means of appropriate reagents.
Such processes are particularly suitable for the preparation of compounds of formula (I) wherein M represents a C^-alkylene group.
Analogous processes would also be suitable for the preparation of compounds of formula (I) wherein M represents a C5-alkylene group.
In such cases preferably the group T would carry a terminal formyl group (CHO).
Where T represents a formyl group the compound may be suitably prepared from the corresponding iodo substituted compound, for example by reaction with sodium formate under suitable conditions and with appropriate additional reagents (for example in a suitable solvent, such as DMF, together with a palladium catalyst, such as b.s(triphenylphosphine) palladium(ll)chloride, and triphenylphosphine); this will involve carbon monoxide as the reacting species.
Where T represents a OHC-CH2 group the compound may be prepared by a suitable Wittig reaction of the compound wherein T represents OHC, for example with methoxymethyltriphenylphosphonium chloride. The initial unsaturated ether from this reaction will rearrange under acid conditions to the homologous aldehyde.
A similar process could be repeated a number of times as necessary to build a longer chain length, i.e. to prepare a compound wherein T represents a OHC-(CH2)2. 3 group. Alternatively, the compound wherein T represents a OHC-CH2CH2 group may be prepared by a suitable Wittig reaction of the compound wherein T represents OHC with (1 ,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide, followed by reduction of the resulting double bond and deprotection to give the saturated compound; this will also require a careful choice of reduction conditions so as not to affect the desired terminal aldehyde and any other sensitive groups in the molecule. Therefore a suitable process may comprise reaction of a compound of formula (VIII) in which T carries a terminal formyl substituent (i.e. is a -CHO group or a -(C alkylene)-CHO group) (of formula (Villa)) with a compound of formula QH. The reaction preferably involves a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride.
As an alternative process an appropriate iodo-substituted compound may be reacted with suitable compounds containing a terminal double or triple bond in a palladium catalysed reaction. Such a reaction scheme would result in the introduction of an appropriate side chain, for example carrying a terminal aldehyde, or a protected aldehyde or indeed already carrying the group Q, in its alkene form which could then be reduced to the saturated version.
Compounds of formula (I) in which M contains an additional heteroatom may be prepared by analogous methods. For example, where M contains a nitrogen atom adjacent the basic ring sytem the compounds may be prepared from the appropriate amino-substituted compound. This may be readily reacted with an aldehyde by a reductive amination reaction. Thus it might be appropriate to use a monoprotected dialdehyde, react the free aldehyde with the amino group on the basic ring system, then deprotect the now terminal aldehyde prior to the final reductive amination with the compound of formula QH. Similarly, where M contains an oxygen or sulphur atom adjacent the basic ring system the compounds may be prepared from the appropriate hydroxy- or thiol-substituted compounds respectively. Such compounds, if deprotonated, will react with a relevant compound carrying a suitable leaving group (such as bromo or tosylate), to build on a side chain containing a protected terminal aldehyde.
According to a further alternative synthesis of compounds of formula (I) wherein M contains an oxgyen or sulphur atom adjacent the basic ring system, these may be prepared from the appropriate hydroxy- or thiol-substituted compounds of formula (VIII) (prepared, for example, by deprotection of the corresponding acetoxy- or thioacetyl-substituted compounds via General Procedure D), which may be deprotonated and reacted with a relevant N-protected amine carrying a suitable leaving group (such as bromo or tosylate), to build on a side-chain containing a protected tertiary amine. The N-protection may then readily be removed by hydrolysis methods well-known to those skilled in the art.
Scheme 1 , for example, outlines the synthesis of derivatives of formula (I) carrying a group QM, wherein M contains an oxygen atom adjacent the basic ring system and Q is an N-protected Z-(CH2)P-NR6- group in which R6 represents hydrogen.
Scheme 1
Figure imgf000097_0001
(IX) (X) (XI)
(Vlllb)
deprotection
Figure imgf000097_0002
Figure imgf000097_0003
Figure imgf000097_0004
(I)
wherein V, V", X, Y, U, Z, L and p are as defined above. P' is preferably a CF3CO group and deprotection (by MeOH, NaOH) is illustrated in General Procedure E; L is preferably bromo.
As a further alternative process, the compounds of formula (I) may be prepared by first alkylating the hydroxy- or thio-substituted intermediates of formula (VIII) with a relevant alkylating agent containing a suitable leaving group (such as a haloalcohol) according to General Procedure C; followed by reaction of the resulting alkylated- bicyclic species (Vlllc) with a suitable amine as illustrated in General Procedure F. An example of such a process is outlined in Scheme 2 below.
Scheme 2
Figure imgf000098_0001
(XIII) (Vlllb) (Vlllc) (XIV)
85°C, solvent
Figure imgf000098_0002
(i)
wherein V, V", X, Y, U, Q, L and p are as defined above.
Analogous processes to those described in Schemes 1 and 2 above may be used to prepare compounds of formula (I) which carry R1 in the 7-position of the basic ring system, for example, via compounds of formula (Vllld) and formula (Vllle).
Figure imgf000098_0003
(Vllld) (Vllle)
For compounds of formula (I) in which M contains a heteroatom which is not adjacent the basic ring system combinations of techniques similar to those described above would be used to prepare a compound of formula (II), (IV), (VI) or (VIII) which carries either a terminal OHC group or a suitable leaving group L' in the side chain prior to reaction with a reagent to introduce the group Q, for example with a compound of formula QH. Care will need to be taken in utilising reductive aminations if the substrate has a nitrogen atom in the M group; this would have to be a tertiary N atom or would need to be appropriately protected to prevent it from taking part in the reductive amination itself.
Appropriate processes for preparing all of the relevant starting materials and intermediate compounds of formulae (II), (IV), (VI), (VIII), (IX), (X), (χi), (χn)t (Xm) and (XIV) will thus be well-known to the person skilled in the art. Further possibilities are referred to in WO97/30034, WO97/30035 and W097/22596.
Alternatively, for the preparation of those compounds of formula (I) in which Q contains an S(0)m functionality another suitable process may comprise oxidation of a compound (of formula (Vlllf)) containing a corresponding thio functionality. For example, to prepare a compound of formula (I) in which Q is a substituent of formula CH3SO2CH2CH2NH one could oxidise the compound bearing the corresponding substituent CH3SCH2CH2NH. Suitable methods for the oxidation to the desired compound of formula (I) will be well known to the person skilled in the art but include, for example, reaction with an organic peroxide, such as peracetic acid or metachlorobenzoic acid, or reaction with an inorganic oxidising agent, such as OXONE®. The preparation of a sulphoxide compound of formula (I) from the corresponding thio compound requires careful conditions to control the oxidation state of the product; in general one uses only one equivalent of the relevant oxidising agent and the temperature of the reaction is kept low.
The compound of formula (Vlllf) as defined above may be prepared by analogous reactions to those described above used to prepare the compounds of formula (I). For example, one could use similar methods to prepare a compound carrying a side chain of formula CH3SCH2CH2NH2-M-.
A sulphoxide compound of formula (I) may, of course, be further oxidised to a sulphone compound of formula (I) by analogous methods.
Alternatively, an analogous scheme to those described above could be used wherein the substitution of the group R1 onto the basic ring system occurs prior to the coupling reaction with the compound of formula (III). In general, the group R2 will be present as a substituent in the basic ring system prior to the introduction of the group R1 or the group NHU. Where R2 is other than hydrogen it may in certain circumstances be necessary to protect the group prior to performing the reaction steps to introduce the R1 and NHU substituents. Suitable protecting groups, methods for their introduction and methods for their removal would be well known to the person skilled in the art. For a description of protecting groups and their use see T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", 2nd edn., John Wiley & Sons, New York, 1991. Particular mention should be made of the situation where R2 is hydroxy; suitable protecting groups to ensure non-interference with the subsequent reaction steps include the 2- methoxyethoxymethyl ether (MEM) group or a bulky silyl protecting group such as tert-butyldiphenyisilyl (TBDPS).
Suitable leaving groups for L and L' will be well known to those skilled in the art and include, for example, halo such as fluoro, chloro, bromo and iodo; sulphonyloxy groups such as methanesulphonyloxy and toluene-p-sulphonyloxy; alkoxy groups; and triflate.
The coupling reaction referred to above with the compound of formula (III) is conveniently carried out in the presence of a suitable inert solvent, for example a C<|_4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone, acetonitrile or DMSO at a non-extreme temperature, for example from 0 to 150°C, suitably 10 to 120°C, preferably 50 to 100°C.
Optionally, the reaction is carried out in the presence of a base. Examples of suitable bases include an organic amine such as triethylamine, or an alkaline earth metal carbonate, hydride or hydroxide, such as sodium or potassium carbonate, hydride or hydroxide.
The compound of formula (I) may be obtained from this process in the form of a salt with the acid HL, wherein L is as hereinbefore defined, or as the free base by treating the salt with a base as hereinbefore defined. The compounds of formulae (II) and (III) as defined above, the reagents to substitute the group R\ and the reagent(s) to convert the group T into the group R are either readily available or can be readily synthesised by those skilled in the art using conventional methods of organic synthesis.
As indicated above, the compound of formula (I) prepared may be converted to another compound of formula (I) by chemical transformation of the appropriate substituent or substituents using appropriate chemical methods (see for example, J.March "Advanced Organic Chemistry", Edition III, Wiley Interscience, 1985).
For example, a compound containing an alkylthio group may be oxidised to the corresponding sulphinyi or sulphonyl compound by use of an organic peroxide (e.g. benzoyi peroxide) or suitable inorganic oxidant (eg OXONE ®).
A compound containing a nitro substituent may be reduced to the corresponding amino-compound, e.g. by use of hydrogen and an appropriate catalyst (if there are no other susceptible groups), by use of Raney Nickel and hydrazine hydrate or by use of iron/acetic acid.
Amino substituents may be acylated by use of an acid chloride or an anhydride under appropriate conditions. Equally an amide group may be cleaved to the amino compound by treatment with, for example, dilute aqueous base.
An amino substituent may also be converted to a dimethylamino substituent by reaction with formic acid and sodium cyanoborohydride. Similarly, reaction of a primary or secondary amino group with another suitable aldehyde under reducing conditions will lead to the corresponding substituted amine.
All of the above-mentioned chemical transformations may also be used to convert any relevant intermediate compound to another intermediate compound prior to the final reaction to prepare a compound of formula (I); this would thus include their use to convert one compound of formula (III) to a further compound of formula (III) prior to any subsequent reaction. Various intermediate compounds used in the above-mentioned processes, including but not limited to certain of the compounds of formulae (II), (III), (IV), (V), (VI), (VII), (VIII), (XII) and (XIV) as illustrated above, are novel and thus represent a further aspect of the present invention.
In particular, a further aspect of the present invention is intermediate compounds of formulae (Villa) defined above.
In particular, a yet further aspect of the present invention is intermediate compounds of formula (XIV) as defined above.
The compounds of formula (I) and salts thereof have anticancer activity as demonstrated hereinafter by their inhibition of the protein tyrosine kinase c-erbB-2, c-erbB-4, and/or EGF-r enzymes and their effect on selected cell lines whose growth is dependent on c-erbB-2 or EGF-r tyrosine kinase activity.
The present invention thus also provides compounds of formula (I) and pharmaceutically acceptable salts or solvates thereof for use in medical therapy, and particularly in the treatment of disorders mediated by aberrant protein tyrosine kinase activity such as human malignancies and the other disorders mentioned above. The compounds of the present invention are especially useful for the treatment of disorders caused by aberrant c-erbB-2 and/or EGF-r such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers and psoriasis.
A further aspect of the invention provides a method of treatment of a human or animal subject suffering from a disorder mediated by aberrant protein tyrosine kinase activity, including susceptible malignancies, which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in therapy. A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of cancer and malignant tumours.
A further aspect of the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for the treatment of psoriasis.
Whilst it is possible for the compounds, salts or solvates of the present invention to be administered as the new chemical, it is preferred to present them in the form of a pharmaceutical formulation.
According to a further feature of the present invention there is provided a pharmaceutical formulation comprising at least one compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain for example 0.5mg to 1g, preferably 70mg to 700mg, more preferably 5mg to 100mg of a compound of the formula (I) depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.
Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations are preferably applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas.
Pharmaceutical formulations adapted for nasal administration wherein the carrier is a solid include a coarse powder having a particle size for example in the range 20 to
500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient.
Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists which may be generated by means of various types of metered dose pressurised aerosols, nebulizers or insufflators.
Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The animal requiring treatment with a compound, salt or solvate of the present invention is usually a mammal, such as a human being.
A therapeutically effective amount of a compound, salt or solvate of the present invention will depend upon a number of factors including, for example, the age and weight of the animal, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the present invention for the treatment of neoplastic growth, for example colon or breast carcinoma, will generally be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day and more usually in the range of 1 to 10 mg/kg body weight per day. Thus, for a 70kg adult mammal, the actual amount per day would usually be from 70 to 700 mg and this amount may be given in a single dose per day or more usually in a number (such as two, three, four, five or six) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt or solvate of the present invention may be determined as a proportion of the effective amount of the compound p_er se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
The compounds of the present invention and their salts and solvates may be employed alone or in combination with other therapeutic agents for the treatment of the above-mentioned conditions. In particular, in anti-cancer therapy, combination with other chemotherapeutic, hormonal or antibody agents is envisaged. Combination therapies according to the present invention thus comprise the administration of at least one compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one other pharmaceutically active agent. The compound(s) of formula (I) and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of formula (I) and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
Certain embodiments of the present invention will now be illustrated by way of example only. The physical data given for the compounds exemplified is consistent with the assigned structure of those compounds.
1H NMR spectra were obtained at 500MHz on a Bruker AMX500 spectrophotometer, on a Bruker spectrophotometer at 300Mz, or on a Bruker AC250 or Bruker AM250 spectrophotometer at 250MHz. J values are given in Hz. Mass spectra were obtained on one of the following machines: VG Micromass Platform (electrospray positive or negative), HP5989A Engine (thermospray positive) or Finnigan-MAT LCQ (ion trap) mass spectrometer. Analytical thin layer chromatography (tic) was used to verify the purity of some intermediates which could not be isolated or which were too unstable for full characterisation, and to follow the progress of reactions. Unless otherwise stated, this was done using silica gel (Merck Silica Gel 60 F254). Unless otherwise stated, column chromatography for the purification of some compounds used Merck Silica gel 60 (Art. 1.09385, 230-400 mesh), and the stated solvent system under pressure.
Petrol refers to petroleum ether, either the fraction boiling at 40-60°C, or at 60-80°C. Ether refers to diethylether. DMSO refers to dimethylsulphoxide. THF refers to tetrahydrofuran. TEA refers to triethylamine. HPLC refers to high pressure liquid chromatography.
Useful preparative techniques are described in WO96/09294, WO97/03069, W097/13771 , W095/19774, WO96/40142 and WO97/30034; also described in these publications are appropriate intermediate compounds other than those detailed below.
Preparation processes specified in the prior art or in the experimental details below for compounds with a particular basic ring system (1) to (6) above may be suitably adapted for others of these basic ring systems.
General Procedures
(A) Reaction of an amine with a bicyclic species containing a 4-chloropyrimidine or 4-chloropyridine ring
The optionally substituted bicyclic species and the specified amine were mixed in an appropriate solvent (typically acetonitriie unless otherwise specified, although ethanol, 2-propanol or DMSO may also be used), and heated to reflux. When the reaction was complete (as judged by tic), the reaction mixture was allowed to cool. The resulting suspension was diluted, e.g. with acetone, and the solid collected by filtration, washing e.g. with excess acetone, and dried at 60°C in vacuo, giving the product as the hydrochloride salt. If the free base was required (e.g ' for further reaction), this was obtained by treatment with a base e.g. triethylamine; purification by chromatography was then performed if required.
(B) Reaction of an aldehyde with an amine by reductive amination
An aldehyde and the required primary or secondary amine were stirred together in a suitable solvent (such as dichloromethane) containing glacial acetic acid ( 4A molecular sieves may also be present) for ca. 1 h. A suitable reducing agent, such as sodium (triacetoxy)borohydride was then added and stirring continued under nitrogen until the reaction was complete (as judged by hplc or tic). The resulting mixture was washed with an aqueous basic solution (e.g. sodium or potassium carbonate) and extracted with a suitable solvent, e.g. dichloromethane. The dried organic phase was evaporated and the residue purified either by column chromatography or by Bond But™ cartridge. If desired, the isolated material was converted into the hydrochloride salt, e.g. by treatment with ethereal hydrogen chloride.
(C) Reaction of an alkylating agent with 4-substituted-6-hydroxy-bicyclic species
To a solution of the optionally substituted 6-hydroxybicyclic species in a suitable solvent (such as DMF) was added a strong base, for example NaHMDS, dropwise and the mixture was stirred for 20 minutes at room temperature under nitrogen. The solution containing the formed anion was then added to a solution of the optionally substituted alkylating agent, for example an alkyl bromide in a suitable solvent (typically DMF), slowly over a period of 40 minutes. The resulting mixture was allowed to stir under nitrogen at room temperature for 1 h and then concentrated in vacuo. The residue was dissolved in a suitable solvent , e.g. ethyl acetate and diluted with water. The aqueous layer was extracted with a suitable solvent , e.g. ethyl acetate and the combined extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. Filtration through Celite™ and removal of volatiles in vacuo gave the crude material which was purified by column chromatography.
(D) Hydrolysis of Acetic Esters An aqueous basic solution, e.g., ammonium hydroxide solution was added to a solution of the relevant acetic ester in a suitable solvent (such as methanol) and the mixture was heated at 90° C for 3 h. The reaction mixture was then cooled to room temperature and filtered. The white solid was washed with an organic solvent, such as diethyl ether.
(E) Hydrolysis of trifluoroacetic amides
The optionally substituted trifluoroacetic amide was dissolved in a suitable solvent mixture, such as methanol / NaOH and the resulting mixture stirred at room temperature for 1 h. The reaction mixture was concentrated to one-third volume under reduced pressure and then diluted with an appropriate solvent, e.g. dichloromethane. The aqueous layer was extracted with a suitable solvent , e.g. methylene chloride and the combined organic layers were washed with water and brine, and dried over anhydrous potassium carbonate. The solution was filtered through Celite™ and concentrated in vacuo to yield the desired product.
(F) Reaction of an amine with an optionally substituted 6-(3-halo C^ alkoxy)bicyclic species A mixture of a substituted 6-(3-halo C<|_4 alkoxy)bicyclic species (0.1 mmol) and the appropriate amine (0.3 mmol) in DMF (1.5 mL) was heated to 85 °C for 14 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and diluted with methylene chloride (10 mL) and water (5 mL). The aqueous layer was extracted with methylene chloride (3 x 5 mL) and the combined organic layers were washed with water and brine, and dried over anhydrous potassium carbonate. Filtration through Celite™ and concentration in vacuo gave the crude material which was purified by column chromatography (silica gel, 1%TEA/ EtOAc) to yield the desired product.
Synthesis of Intermediates
Λ/-5-[Λ/-tett-Butoxycarbonyl)amino]-2-chloropyridine
A stirred solution of 6-chloronicotinic acid (47.3g), diphenylphosphoryl azide (89.6g) and triethylamine (46ml) in t-butanol (240ml) were heated under reflux under nitrogen for 2.5 h. The solution was cooled and concentrated in vacuo. The syrupy residue was poured into 3 litres of a rapidly stirred solution of 0.33N aqueous sodium carbonate. The precipitate was stirred for 1 h and filtered. The solid was washed with water and dried in vacuo at 70°C to give the title compound (62g) as a pale brown solid; m.p. 144-146°C; δH [2H6J-DMSO 8.25(1 H.d), 7.95 (1 H, bd), 7.25 (1H, d), 6.65(1 H, bs), 1.51 (9H,s); m/z (M + 1)+ 229.
This material may subsequently be carried forward to the appropriately substituted pyridopyrimidine intermediate according to the procedures as described in W095/19774, J. Med. Chem., 1996, 39, pp 1823-1835, and J. Chem. Soc, Perkin Trans. 1 , 1996, pp 2221-2226. Specific compounds made by such procedures include 6-chloro-pyrido[3,4-d]pyrimidin-4-one and 4,6-dichloro-pyrido[3,4-d]- pyrimidine.
4-Chloro-6-bromoquinazoline and 4-chloro-6-iodoquinazoiine were prepared as described in WO 96/09294.
1 -Benzyl-5-nitro-1 H-indole
Dry dimethylsulphox.de (20 ml) was added to potassium hydroxide (4.2 g, 0.074 mol) (crushed pellets) and the mixture was stirred under nitrogen for 5 mins. 5- Nitroindole (commercially available) (3.0 g, 0.019 mol) was then added and the red mixture stirred for 30 min at room temperature. The mixture was then cooled to -10 °C, benzyl bromide (4.4 ml, 0.037 mol) was slowly added and the mixture stirred and allowed to warm to room temperature over a period of 40 mins. Water (50 ml) was then added and the mixture was extracted with diethyl ether (2 x 200 ml). The extracts were washed with water (4 x 50 ml), dried over sodium sulphate and evaporated to leave an oily solid. The excess benzyl bromide was removed by dissolving the whole in diethyl ether (50 ml), diluting this solution with 40-60 petrol (50 ml) and then gradually removing the diethyl ether in vacuo to leave a yellow solid suspended in the petrol. The solid was filtered, washed with copious amounts of 40- 60 petrol and dried to give 1-benzyl-5-nitroindole (2.4 g, 51 %) as a yellow solid m p 102-104 °C; δH [2H6]-DMSO 8.53 (1 H, s, 4-H), 8.00 (1 H, d, J 9, 6-H), 7.78 (1 H,' s, 2- H), 7.68 (1 H, d, J 9, 7-H), 7.36-7.20 (5H, m, 2'-H, 3'-H, 4'-H, 5'-H, 6'-H) 6 81 (1 H s 3-H), 5.52 (2H, s, CH2).
5-Amino-1-benzyl-1 H-indole A solution of 1-benzyl-5-nitroindole (0.51 g, 0.02 mol) in a mixture of ethyl acetate (25 ml) and methanol (25 ml) was carefully added to 10% palladium on charcoal (45 mg). The resulting suspension was stirred at room temperature under an atmosphere of hydrogen. When the reaction was complete (indicated by tic or calculated uptake of hydrogen) the suspension was filtered through a pad of Hyflo™, and the filtrate evaporated to dryness to give 5-amino-1-benzylindole (0.40 g, 91%) as an off-white solid; m.p. 66-68 °C; δH [2Hβ]-DMSO 7.30-7.12 (6H, m, 2-H, 2"-H, 3"-H, 4"-H, 5"-H, 6"-H), 7.08 (1 H, d, J 8, 7-H), 6.70 (1H, s, 4-H), 6.49 (1 H, d J 8 6- H), 6.18 (1 H, s, 3-H), 5.28 (2H, s, CH2), 4.38 (2H, bs, NH2).
2-Benzyl-5-nitro-1 H-benzimidazole
A mixture of 4-nitro-o-phenylene diamine (1.54g) and phenylacetic acid (2.04g) in 5N aqueous HCI (16ml) were heated at 110 °C under nitrogen for 22 h. The mixture was cooled to room temperature and the accumulated black solid collected by filtration. This crude residue was then adsorbed onto silica and chromatographed to give the title compound (0.84g) as a purple foam; δH CDCI3 9.70 (1 H, bs), 8.15 (1 H, d), 7.30 (7H, m), 4.30 (2H,s); m/z (M + 1 )+ 254.
5-Amino-2-benzyl-1 H-benzimidazole The title compound was prepared from 5-nitro-2-benzylbenzimidazole by an analogous reduction method to that described above for 5-amino-1-benzyl-1 H- indole; m/z (M + 1)+ 224. Also note the published method (J. Het. Chem., 23, 1109- 13, (1986)).
1-Λ/-Benzyl-5-nitro-1 H-indazole and 2-Λ/-Benzyl-5-nitro-1 H-indazole
A stirred mixture of 5-nitroindazole (50g), potassium carbonate (46.6g, 1.1 equiv.) and benzyl bromide (57.6g, 1.1 equiv) in Λ/,Λ/-dimethylformamide (500 ml) was heated at 75°C for a period of 4 h. The reaction was then cooled and water (500ml) was gradually added to precipitate the product which was filtered off and washed with water (50ml) and dried in the air at ambient temperature. The weight of pale yellow solid thus obtained was 72.3g (93%), m.p. 95-97°C; HPLC (Partisil 5, dichloromethane, 4ml/min, 250nm) gave an isomer ratio (1-Λ/-benzyl : 2-Λ/-benzyl) of 63:37 (RT-1 V 3.4min, RT-2N 6.6min). To a filtered solution of the mixed regioisomers (100g) in acetone (470ml) at room temperature was added, gradually with stirring, water (156ml) and the mixture was stirred for 1 h. The resultant yellow crystalline solid was filtered off and dried in the air at ambient temperature to give 36.4g (34%) of material; m.p.124-126°C; HPLC showed an isomer ratio (1-Λ/-benzyl : 2-Λ/-benzyl) of 96:4; δH (CDCI3) 5.58 (2H,s,CH2), 7.12-7.15(2H) & 7.22-7.29(3H)- (phenyl), 7.33(1 H,dt, J 1Hz & 9Hz, H-7), 8.15(1H,dd, J 2Hz & 9Hz,H-6), 8.19(1H,d, J 1 Hz,H-3), 8.67 (1 H,dd, J 1 & 2Hz, H-4).
Also note the published method in FR 5600, 8 January 1968.
5-Amino-1 -Λ/-benzyl-1 H-indazole 1-Benzyl-5-nitroindazole (400g) was suspended in ethanoi (5 litre) and hydrogenated in the presence of 5% platinum on carbon catalyst (20g) operating at 1 bar pressure and 50-60°C. When hydrogen uptake was complete the reactor contents were heated to 70°C, discharged and filtered while still hot and the filtrate concentrated to ~4 litre which caused some crystallisation. Water (4 litre) was then gradually added with stirring and the mixture was stirred at 5°C overnight. The resultant crystals were filtered off and air-dried at ambient temperature to give 305g (86%) of material, m.p.150-152°C; HPLC (Supelcosil ABZ +, gradient 0.05% trifluoroacetic acid in water/0.05% trifluoroacetic acid in acetonitrile,1.5ml/min, 220nm) showed <1% of the corresponding 2-Λ/-isomer (RT-1 / 6.03min, RT-2Λ/ 5.29min); δH (CDCI3) 3.3-3.8(2H,broad s,NH2), 5.47 (2H,s,CH2), 6.74(1 H,dd,J 2 & 9Hz,H-6), 6.87(1 H,dd,J 1 & 2Hz,H-4), 7.06- 7.11(3H) & 7.17-7.25(3H)-(phenyl & H- 7), 7.77(1 H,d,J 1 Hz,H-3).
Also note the published method in FR 5600, 8 January 1968.
1-Benzyl-3-methyl-5-nitro-1 H-indazole
2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236, 1995) (0.24g) was treated with triethylamine (0.73ml)and benzyl hydrazine dihydrochloride (0.255g) in ethanoi (20ml) at reflux under N2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16g) was collected by filtration; m/z (M+1)+ 268.
1 -Benzyl-3-methyl-1 H-indazol-5-ylamine
1-Benzyl-3-methyl-5-nitroindazole (0.15g) in THF (15ml) was treated with platinum on carbon (0.05g, 5%) under an atmosphere of hydrogen at room temperature. When hydrogen uptake was complete, the mixture was filtered and concentrated in vacuo to give the title compound; m/z (M+1)+ 268.
Further amino-indazole intermediates The relevant nitro-substituted 1 H-indazole was treated with a base such as potassium carbonate or sodium hydroxide in a suitable solvent, such as acetone or acetonitrile. The appropriate aryl halide or heteroaryl halide was added and the reaction mixture heated or stirred at room temperature overnight. Subsequent concentration in vacuo and chromatography on silica gave the desired 1 -substituted nitro-1H-indazoles. Hydrogenation was carried out by analogy with the preparation of 5-amino-1-benzyl-1 H-indole described above.
Amines prepared by such methods include:-
5-Amino-1-benzyl-1 H-indazole; m/z (M+1)+ 224 5-Amino-1 -(2-fluorobenzyl)-1 H-indazole; m/z (M+1 )+ 242
5-Amino-1-(3-fluorobenzyl)-1 H-indazole; m/z (M+1)+ 242
5-Amino-1-(4-fluorobenzyl)-1 H-indazole; m/z (M+1)+ 242
5-Amino-1-(2-pyridylmethyl)-1 H-indazole; m/z (M+1)+ 225
5-Amino-1-(3-pyridylmethyl)-1 H-indazole; m/z (M+1)+ 225 5-Amino-1 -(4-pyridylmethyl)-1 H-indazole; m/z (M+1 )+ 225
5-Amino-1 -(2, 3-difluorobenzyl)-1 H-indazole; m/z (M+1)+ 260
5-Amino-1 -(3, 5-difluorobenzyl)-1 H-indazole; m/z (M+1)+ 260.
1-Benzenesulphonylindol-5-yl-amine was prepared according to the published method (J. Org. Chem., 55, 1379-90, (1990)).
3-Benzenesulphoriylindol-6-yl-amine
3-Benzenesulphonyl-6-nitroindole (K. Wojciechowski and M Makosza, Tet. Lett., 25 (42), p4793, 1984) was hydrogenated by analogy with the procedures above to give the title compound; δH [2H6]DMSO 11.64 (1 H,s), 7.94 (2H,m), 7.81 (1 H,s), 7.57 (3H,m), 7.49(1 H,d), 6.60(1 H,s), 6.55 (1 H,dd), 5.40 (2H,s).
4-Benzyloxyaniline is commercially available as the hydrochloride salt; this is treated with aqueous sodium carbonate solution, and the mixture extracted with ethyl acetate; the organic solution is dried (MgSO and concentrated to give the free base as a brown solid, used without further purification.
Other substituted anilines were in general prepared by analogous methods to those outlined in WO 96/09294 and/or as follows:
Step 1: Preparation of the precursor nitro-compounds
4-Nitrophenol (or an appropriate substituted analogue, such as 3-chloro-4- nitrophenol) was treated with a base such as potassium carbonate or sodium hydroxide in an appropriate solvent, such as acetone or acetonitrile. The appropriate aryl or heteroaryl halide was added and the reaction mixture heated or stirred at room temperature overnight.
Purification A: Most of the acetonitrile was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with further dichloromethane (x 2), and the combined dichloromethane layers were concentrated in vacuo.
Purification B: removal of insoluble material by filtration, followed by concentration of the reaction mixture in vacuo, and chromatography on silica.
Step 2: Reduction to the corresponding aniline
The precursor nitro compound was reduced by catalytic hydrogenation at atmospheric pressure using 5%Pt/carbon, in a suitable solvent (eg ethanoi, THF, or mixtures thereof to promote solubility). When reduction was complete, the mixture was filtered through Harborlite™, washing with excess solvent, and the resulting solution concentrated in vacuo to give the desired aniline. In some cases, the anilines were acidified with HCI (e.g. in a solution in dioxane) to give the corresponding hydrochloride salt.
Anilines prepared by such methods include: 4-(2-Fluorobenzyloxy)aniline; m/z (M+1)+ 218
4-(3-Fluorobenzyloxy)aniline; m/z (M+1)+ 218
4-(4-Fluorobenzyloxy)aniline; m/z (M+1)+ 218
3-Chloro-4-(2-fluorobenzyloxy)aniline; m/z (M+1)+ 252
3-Chloro-4-(3-fluorobenzyloxy)aniline; m/z (M+1)+ 252 3-Chloro-4-(4-fIuorobenzyioxy)aniline; m/z (M+1)+ 252 4-(Pyridyl-2-methoxy)aniline; m/z (M+1)+201 4-(Pyridyl-4-methoxy)aniline; m/z (M+1)+201 4-(Pyridyl-3-methoxy)aniline; m/z (M+1)+201 4-Benzyloxy-3-chloroaniline; m/z (M+1)+ 234 and, in appropriate cases, their hydrochloride salts.
4-Benzenesulphonylaniline was prepared by the published method (Helv. Chim. Acta., 1983, 66(4), p 1046.
(1-Benzyl-1H-indazol-5-yl)-(6-chloropyridof3,4-dlpyrimidin-4-yl)-amine hydrochloride Prepared according to Procedure A from 1-benzyl-1 H-indazol-5-ylamine (1 equiv) and 4,6-dichloropyrido[3,4-d]pyrimidine (1 - 1.3 equivs); δH [2H6.-DMSO 9.08 (1 H,s), 8.92 (1 H,s), 8.82 (1H,s), 8.23 (1 H,d), 8.19 (1 H,s), 7.80 (1H,d), 7.70 (1 H,dd), 7.38-7.22 (5H,m), 5.69 (2H,s); m/z 387 (M + 1)+.
(1-Benzyl-1 H-indol-5-yl)-(6-chloro-pyridor3,4-d]pyrimidin-4-yl)-amine hydrochloride Prepared according to Procedure A from 1-benzyl-1H-indol-5-ylamine (1 equiv) and 4,6-dich.oro-pyrido[3,4-d]pyrimidine (1 - 1.3 equivs); δH ^HgjDMSO 11.45(1H,s),
9.08(1 H,s), 8.95(1 H,s), 8.80(1 H,s), 7.98(1 H,d), 7.60(2H,m), 7.30(6H,m), 6.60(1 H,d), 5.48(2H,s); m/z 386 (M+1+).
(2-Benzyl-1 H-benzimidazol-5-yl)-(6-chloro-pyridof3,4-d]pyrimidin-4-yl)-amine Prepared according to Procedure A from 5-amino-2-benzyl-1 H-benzimidazole (1 equiv) and 4,6-dichloro-pyrido[3,4-d]pyrimidine (1 - 1.3 equivs); δH [2H6.-DMSO 9.13(1 H,s), 8.93(1 H,s), 8.84(1 H,s), 8.60(1 H,s), 8.05(1 H,dd), 7.88(2H,d), 7.50(6H, m), 4.61 (2H,s); m/z 387 (M + 1)+.
(4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine Prepared according to Procedure A from 4-benzyloxyaniline (1 equiv) and 4,6- dichloro-pyrido[3,4-c pyrimidine (1 - 1.3 equiv); δH (CDCI3) 9.11 (1 H,s), 8.78 (1 H,s), 7.75 (1H,d), 7.56 (2H,dd), 7.40 (5H,m), 7.15 (2H,d), 5.10 (2H,s); m/z 409 (M + 1)+.
(4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine hydrochloride 4-Chloro-6-bromoquinazoline (0.25g, LOmmol) and 4-benzyloxyaniline (0.25g, 1.3mmol) were mixed in 2-propanol (6ml) and heated at reflux for 10 mins (Procedure A). The solution was allowed to cool at room temperature and the 2- propanol removed in vacuo. The resulting solid was triturated with acetone to give the product as a yellow solid (0.39g, 88%); δH [2H6]-DMSO 11.60 (1 H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1 H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1 H, d, 8-H), 7.65 (2H, d, 2'-H 6'-H), 7.50-7.25 (5H, m, Ph-H), 7.10 (2H, d, 3'-H, 5'-H), 5.15 (2H, s, CH2); m/z 405/407 (M+).
(4-Benzyloxyphenyl)-(6-(3-bromopropoxy)quinazolin-4-yl amine Prepared according to Procedure C from 4-benzyloxyphenyl-6-hydroxyquinazolin-4- yl amine (1 equiv) and 3-bromopropanol (1 equiv); δH (DMSO) 9.57 (s, 1 H), 8.38 (s, 1 H), 7.91 (d, 1 H), 7.62-7.68 (m, 3H), 7.43-7.47 (m, 2H), 7.37 (m, 2H), 7.30 (m, 1 H), 7.02 (d, 2H), 5.09 (s, 2H), 4.23 (m, 2H), 3.71 (m, 2H), 2.32 (m, 2H); MS m/z 466 (M+1)+.
(4-Benzyloxyphenyl)-(6-iodoquinazolin-4-yl)-amine hydrochloride
4-Chloro-6-iodoquinazoline (8g) was treated with 4-benzyloxyaniline (5.5g) in acetonitrile (500ml) at reflux under N2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13g); δH [2H6]-DMSO 11.45 (1 H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1 H, s, 2-H), 8.36 (1 H, d, 7-H), 7.69 (1 H, d, 8-H), 7.63 (2H, d,' 2'-H, 6'-H), 7.52-7.29 (5H, m, Ph-H), 7.14 (2H, d, 3'-H, 5'-H), 5.18 (2H, s, CH2); m/z 454 (M+1)+.
4-Benzyloxyphenyl-(6-acetoxyquinazolin-4-yl)amine
Prepared according to Procedure A from 4-chloro-6-acetoxy-quinazoline (1 equiv) and 4-benzyloxyaniline (1 equiv). δH (DMSO-d6) 11.36 (s, 1 H), 8.90 (s, 1 H), 8.64 (s, 1 H), 7.92-8.02 (m, 2H), 7.65 (d, 2H), 7.37-7.52 (m, 5H), 7.15 (d, 2H),'5.19 (s, 2H)! 2.42 (s, 3H); MS m/z 386 (M+1)+.
4-Benzyloxyphenyl-(6-hydroxyquinazolin-4yl)amine Prepared according to Procedure D from 4-benzyloxyphenyl-(6-acetoxyquinazolin-4- yl)amine. δH (DMSO-d6) 10.04 (s, 1 H), 9.43 (s, 1 H), 8.39 (s, 1 H), 7.71-7.77 (m, 4H), 7.66 (d, 1 H), 7.33-7.51 (m, 6H), 7.05 (s, 2H), 5.14 (s, 2H); MS /z 344 (M+1)\ '
4-(3-Fluorobenzyloxy)-3-chlorophenyl-(6-acetoxyquinazolin-4-yl)amine Prepared according to Procedure A from 4-chloro-6-acetoxy-quinazoline (1 equiv) and 4-(3-fluorobenzyloxy)-3-chloroaniline (1 - 1.3 equivs). δH (DMSO-d6) 11.18 (bs, 1 H), 8.89 (s, 1 H), 8.52 (s, 1H), 7.87-7.94 (m, 3H), 7.60-7.62 (m, 1H), 7.42-7.48 (m, 1H), 7.27-7.33 (m, 4H), 7.14-7.19 (m, 1H), 5.27 (s, 2H), 2.40 (s, 3H); MS m/z 438 (M+1)+.
4-(3-Fluorobenzyloxy)-3-chlorophenyl-(6-hydroxyquinazolin-4-yl)amine Prepared according to Procedure D from 4-(3-fluorobenzyloxy)-3-chlorophenyl- (6- acetoxyquinazolin-4-yl)amine. δH (DMSO-d6) 10.10 (bs, 1 H), 9.51 (s, 1H), 8.46 (s, 1 H), 8.08 (d, 1 H), 7.76-7.79 (m, 3H), 7.42-7.53 (m, 2H), 7.18-7.36 (m, 4H), 5.27 (s, 2H); MS t7?/z 385 (M+1)+.
(1-Benzyl-1 H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine
6-Bromo-4-chloroquinazoline (5.0g) was reacted with 5-amino-1-benzyl-1 H-indazole (5.0g) in acetonitrile (100ml) at 100°C according to Procedure A. The resulting precipitate was treated with triethylamine in ethyl acetate and water to give the title compound as a yellow solid, (7.37g); δH [2Hβ] -DMSO 9.93(1 H,s), 8.82 (1H,d), 8.52(1 H,s), 8.19(1H,s), 8.09(1 H,s), 7.92(1 H,dd), 7.65(3H,m), 7.25(5H,m), 5.62(2H,s).
(1-Benzyl-1 H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine hydrochloride 4-Chloro-6-iodoquinazoline (5.8g) was treated with 5-amino-1-benzyl-1 H-indazole (3.90g) in acetonitrile (500ml) at reflux under N2 for 18 hours (Procedure A). Subsequent cooling and filtration gave the title compound (8.26g); m/z 478 (M+1)+.
4-Benzyloxyphenyl-(6-hydroxy-7-methoxyquinazolin-4yl)amine hydrochloride Prepared according to Procedure A from 4-chloro-6-acetoxy-7-methoxyquinazoline (prepared as described in WO96/33980) (1 equiv) and 4-benzyloxyaniline (1 equiv). MS m/z 374 (M+1)+.
(1-Benzyl-1H-indazol-5-yl)-(6-hydroxy-7-methoxyquinazolin-4-yl)-amine hydrochloride
Prepared according to Procedure A from 4-chloro-6-acetoxy-7-methoxyquinazoline (prepared as described in WO96/33980) (1 equiv) and 1-benzyl-1 H-indazol-5-yl- amine (1 equiv); MS 398 m/z (M+1)+. (4-(4-Benzenesulphonyl)-phenyl)-(6-hvdroxy-7-methoxyquinazolin-4-yl)-amine hydrochloride
Prepared according to Procedure A from 4-chloro-6-acetoxy-7-methoxyquinazoline (prepared as described in WO96/33980) (1 equiv) and 4-benzeneaniline (1 equiv);
Figure imgf000118_0001
1-(3-Fluorobenzyl)-1 H-indazol-5yl)-(6-acetoxyquinazolin-4-yl)amine Prepared according to Procedure A from 4-chloro-6-acetoxy-quinazoline (1 equiv) and 1-(3-fluorobenzyl)-1 H-indazol-5yl amine (1 equiv). δH (DMSO-d6) 11.65 (s, 1H), 8.95 (s, 1 H), 8.74 (d, 1 H), 8.30 (s, 1 H), 8.16 (s, 1 H), 7.93-8.09 (m, 2H), 7.92 (d, 1 H), 7.71 (m, 1 H), 7.41-7.48 (m, 1 H), 7.13-7.21 (m, 2H), 5.80 (s, 2H), 2.47(s, 3H); MS m/z 427 (M+1)+.
1-(3-Fluorobenzyl)-1 H-indazol-5yl)-(6-hydroxyquinazolin-4-yl)amine
Prepared according to Procedure D from 1-(3-fluorobenzyl)-1 H-indazol-5-yl) -(6- acetoxy-quinazolin-4-yl)amine. δH (DMSO-d6) 10.06 (s, 1 H), 9.59 (s, 1 H), 8.42 (s, 1 H), 8.28 (s, 1 H), 8.17 (s, 1 H), 7.67-7.81 (m, 4H), 7.38-7.44 (m, 2H), 7.06-7.12 (m, 3H), 5.72 (s, 2H); MS m/z 385 (M+1)+.
7-lodoquinazolin-4-one
7-Aminoquinazolin-4-one (R. Dempsy and E. Skito, Biochemistry, 30, 1991 , 8480) (1.61g) was suspended in 6N HCI (20ml) and cooled in an ice bath. A solution of sodium nitrite (0.75g) in water (10ml) was added dropwise over 15 minutes. After a further 10 minutes, a solution of potassium iodide (1.66g) in water (5ml) was added dropwise. The mixture was warmed to 20°C and after 3 hours partitioned between ethyl acetate and sodium thiosulphate. The organic phase was dried and concentrated in vacuo to give the title compound (0.485g); m/z 271(M+1+).
4-Chloro-7-iodoquinazoline
7-lodoquinazolin-4-one (0.46g) was treated with phosphorous oxychloride (5ml) at reflux under nitrogen for 2 hours. The mixture was cooled, evaporated and partitioned between saturated aqueous sodium carbonate and ethyl acetate. The organic phase was dried and concentrated in vacuo to give the title compound (0.43g); m/z 291 (M+1+). 4-Chloro-6-acetoxyquinazoline
Prepared in a similar manner to 4-chloro-7-iodo-quinazoline using 4,6-dihydroxy- quinazoline (Drug Des. Discovery (1992), 9(2), 167-76). δH (DMSO-d6) 9.15 (s, 1H) 8.21 (d, 1 H), 8.09 (d, 1H), 7.99 (m, 1H), 2.39 (s, 3H).; MS m/z 223 (M+1)+.
(1 -Benzyl-1 H-indazol-5-yl)-(7-iodoquinazolin-4-yl)amine hvdrochloririfi 4-Chloro-7-iodoquinazoline (0.42g) was treated with 1-benzyl-1H-indazol-5-ylamine (0.323g) in acetonitrile (20ml) at reflux under nitrogen for 18 h (Procedure A). The mixture was cooled and filtered to give the title compound (0.57g); m/z (M+1 +) 478.
(6-Chloropyridor3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)amine 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1g) and 4-(4-fluorobenzyloxy)aniline (1.08g) in acetonitrile (70ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.83g); m/z 381 (M+1)+.
(6-Chloropyrido[3,4-d1pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyhaminfi 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1g) and 4-(3-fluorobenzyloxy)aniline (1.08g) in acetonitrile (70ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.86g); m/z 381 (M+1)+.
4-(4-(4-Benzenesulphonyl)-phenyl)-6-iodo-quinazolineamine
4-Chloro-6-iodoquinazoline (1g) and 4-(benzene)-aniline (800mg) in acetonitrile (5ml) were reacted together as in Procedure A. The product was obtained by filtration as a yellow solid (1.5g); t77/z 488 (M+1).
4-(4-Benzenesulphonyl-phenyl)-(6-acetoxyquinazolin-4yl)amine Prepared according to Procedure A from 4-chloro-6-acetoxy-quinazoline (1 equiv) and 4-(benzenesulphonyl)-aniiine (1 equiv). δH (DMSO-d6) 10.80 (bs, 1 H), 8.84 (s, 1 H), 8.47 (s, 1 H), 7.91-8.18 (m, 5H), 7.83 (m, 1 H), 7.59-7.69 (m, 2H),' 2.35 (s, 3H)| MS m/z (M+1)+ 419.
4-(4-Benzenesulphonylphenyl)-(6-hydroxyquinazolin-4ynaminfi Prepared according to Procedure D from 4-(4-benzenesulphonylphenyl)-(6- acetoxyquinazolin-4yl)amine. δH NMR (DMSO-d6) 10.25 (s, 1 H), 9.93 (s, 1H), 8.56 (s, 1 H), 8.22 (d, 2H), 7.97 (m, 3H), 7.62-7.84 (m, 7H); MS m/z (M+1)+ 377.'
(1 -H-lndazol-5-yl)-(6-iodoquinazolin-4-yl)amine hydrochloride 6-lodo-4-chloroquinazoline (4.87g) was reacted with 5-amino-1 -H-indazole (2.68g) in acetonitrile according to Procedure A. The precipitate was collected by filtration, washed with excess acetonitrile and dried in vacuo to give the title compound as a brown solid (7.1 g); t?7/z 388 (M+1+).
4-(1-Benzyl-1 H-indazol-5-ylamino)quinazoline-6-carbaldehyde (1-Benzyl-1 H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine was prepared from its hydrochloride salt by treatment aqueous sodium bicarbonate and extraction with ethyl acetate. A mixture of the resulting material (0.478g), sodium formate (0.10g), bis(triphenylphosphine)palladium(ll)chloride (0.14g) and triphenylphosphine (0.006g) in DMF (5ml) was stirred at 110°C under an atmosphere of carbon monoxide for 3 h. After cooling the reaction mixture was treated with 5% aqueous sodium hydroxide solution and extracted with ether. The combined extracts were washed with water, dried (MgS04), and concentrated in vacuo. Trituration with ether gave the aldehyde product as a yellow solid (0.123g); δH [2H6]-DMSO 10.35 (1 H, s), 10.14 (1 H, s), 9.22 (1 H, s), 8.63 (1 H, s), 8.27 (1H, dd), 8.21 (1 H, d), 8.17 (1 H, s), 7.89 (1 H, d), 7.68-7.80 (2H, m), 7.22-7.38 (5H, m), 5.69 (2H, s); m/z 380 (M+1)+.
Λ/-Methyl-Λ/-(2-methanesulphonyl-ethyl)amine hydrochloride Methylvinyl sulphone (2.1g, 19.78mmol) and methylamine (33% solution in IMS, 40ml, excess) were mixed and heated at reflux under a nitrogen atmosphere for 6 hours. After standing overnight at room temperature, the mixture was concentrated in vacuo to give a yellow oil, which was treated with ethereal HCI to give a sticky solid. Trituration with absolute ethanoi gave the title compound as a white solid which was collected by filtration and dried at 60°C in vacuo (1.01g, 5.82mmol, 29%); δH [2H6JDMSO 9.27 (2H,bs), 3.59 (2H,dd), 3.31 (2H,dd), 2.57 (3H,s).
N-Methyl-N-(2-methylethyl)amine Prepared according to Procedure E from N-methyl-N-(2- methylethyl)trifluoroacetamide . δH (DMSO-d6) 3.36 (bs, 1 H); 3.21 (t, 2H); 3.02 (s, 3H); 2.86 (t, 2H); 2.29 (s, 3H); MS m/z 138 (M+1 ).
Λ/-[2-(Methanesulphonamido)ethyl]acetamide
Λ/-Acetylethylenediamine (10.2g, lOOmmol) and triethylamine (15ml, 10.9g, 108mmol) were dissolved in dichloromethane (300ml) and the solution cooled to 0°C. Methane chloride (8ml, 11.8g, 103mmol) was dissolved in dichloromethane (10ml) and added dropwise, and stirring was continued at 0°C for 3h. The dichloromethane was removed in vacuo, and the residue was suspended in a mixture of ether and acetone, removing the insoluble material by filtration. The filtrate was concentrated in vacuo to give the title compound as a pale brown gum (14.5g, 88.3mmol, 88%); δH [2H6JDMSO 7.93 (1 H,bt), 7.05 (1 H,t), 3.11 (2H,t), 2.97 (2H,t), 2.89 (3H,s), 2.09 (3H,s).
Λ/-(4-Bromobutyl)-2,2,2-trifluoro-Λ/-r2-(methanesulphonylethyl)acetamide To a solution of 2,2,2-trifluoro-Λ/-[2-(methanesulphonylethyl) acetamide (WO98/02434) (1 mmol) in DMF (2 mL) was added NaHMDS (1.0 M in THF, 1 mL) slowly and the yellow solution was stirred at room temperature for 30 minutes. The solution containing the resulting anion was added to a solution of 1 ,4-dibromobutane (4 mmol) in DMF (10 mL) and the mixture was stirred at room temperature under nitrogen for 72 h. The reaction mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (15 mL) and saturated aqueous NaHC03 (10 mL). Ethyl acetate (3X) was used to extract the aqueous layer and the combined organic layers were washed with water and brine, and dried over anhydrous magnesium sulfate. Filtration through Celite™-silica gel and concentration in vacuo gave the crude material which was purified by column chromatography (35% EtOac/hexanes) to yield white solids. 1H NMR NMR (DMSO-d6) 3.81 (m, 2H), 3.58 (m, 3H), 3.49 (m, 3H), 3.08 (s, 3H), 1.69-1.82 (m, 4H); electrospray MS m/z 376 (M+Na)+.
Λ/-Methyl-2,2,2-trifluoro-Λ/-[2-(methanesulphonylethyl) acetamide Prepared in a similar manner to Λ/-(4-bromobutyl)-2,2,2-trifluoro-Λ/-[2- (methanesulphonylethyl)acetamide utilizing 2,2,2-trifluoro-Λ/-[2-
(methanesulphonyiethyl)acetamide and methyl iodide. δH (DMSO-d6) 3.83 (t, 2H); 3.49 (t, 2H); 3.16 (2, 3H); 3.06 (s, 3H); electrospray MS m/z 256 (M+Na). 2-(Methanesulphonamido)ethylamine hydrochloride
Λ/-[2-(Methanesulphonamido)ethyl]acetamide (14.5g, 88.3mmol) and concentrated hydrochloric acid (100ml) were dissolved in water (100ml) and heated to reflux for a total of 3 hours. After cooling, the water was removed in vacuo, and the residue was left for several days at room temperature until crystallisation was underway. Trituration with a mixture of ethanoi and ether gave the title compound as a white solid which was dried in vacuo at 60°C (7.5g, 42.9mmol, 49%); δH [2H6]DMSO 8.22 (2H,bs), 7.42 (1 H,t), 3.23 (2H,q), 2.87 (3H,s), 2.85-2.95 (2H,m).
2-Phthalimidoethylsulphonamide
2-Phthalimidoethyl chloride (prepared as described in J. Am. Chem. Soc, 69, 1393- 1401 , (1947)) (10.0g, 36.5mmol) was added to cone, aqueous ammonia solution (O.88OM0I, 120ml), cooled to 0°C. The mixture was stirred at 0°C for 30 min and then at room temperature for 2 hours. Concentration in vacuo, followed by trituration with water gave 2-phthalimidoethylsulphonamide as a white solid (3.70g, 14.6mmol, 40%); δH [2H6]DMSO 7.80-7.92 (4H,m), 7.03 (2H,bs), 3.96 (2H,dd), 3.30-3.38 (2H,m, obscured by water).
2-Aminoethylsulphonamide hydrochloride
2-Phthalimidoethy.sulphonamide (3.68g, 14.5mmol) was suspended in ethanoi (50ml) and hydrazine hydrate (0.70g, 71.5mmol) was added. The mixture was heated to reflux for 4 hours. The mixture was partially concentrated in vacuo, diluted with water, acidified to pH 1 with 2N HCI, and filtered. The filtrate was concentrated /'t7 vacuo to give a white solid. Treatment with more 2N HCI, followed by trituration with a mixture of ethanoi and acetone gave the title compound as a white solid (1.0g, 6.23mmol, 43%); δH D20 3.60-3.69 (2H,m), 3.50-3.58 (2H,m).
N-{4-[(4-{3-Chloro-4-[(3-fluorobenzyl)oxy]anilino}-6-quinazolinyl)oxy]butyl}-2,2,2- trifluoro-N-[2-(methanesulphonyl)ethyl]acetamide
Prepared according to Procedure C from 4-[4-(3-chloro-(3-fluorobenzyloxy)phenyl)- (6-hydroxyquinazolin-4yl)amine (1 equiv) and 4-bromo-[N-[2-(methanesulphonyl)- ethyl]]-N-trifluoromethylcarbonylbutylamine (1 equiv). δH (DMSO) 9.55 (s, 1 H), 8.45 (s, 1H), 7.96 (s, 1 H), 7.85 (s, 1 H), 7.69 (d, 2H), 7.43-7.47 (m, 2H), 7.24-7.31 (m, 2H), 7.15 (m, 1H), 5.22 (s, 2H), 4.15 (m, 2H), 3.77 (m, 2H), 3.44-3.52 (m, 4H), 3.02 (s, 3H), 1.80 (m, 4H); MS m/z 669 (M+1 )+.
N-f4-({4-[4-(Benzyloxy)anilino1-6-quinazolinyl)oxy)butyll-2,2,2-trifluoro-N-r2-(methyl sulphonyQethyllacetamide
Prepared according to Procedure C from 4-[4-(benzyloxy)phenyl)-(6- hydroxyquinazolin-4-yl)amine (1 equiv) and 4-bromo-[N-[2-(methanesulphonyl)- ethyl]]-N-trifluoromethylcarbonylbutylamine (1 equiv). δH (DMSO) 9.58 (s, 1 H), 8.37 (s, 1 H), 7.89 (s, 1 H), 7.62-7.67 (m, 3H), 7.28-7.45 (m, 7H), 7.02 (d, 1 H), 5.09 (s, 2H), 4.14 (m, 2H), 3.78 (m, 2H), 3.44-3.56 (m, 4H), 3.03 (s, 3H), 1.79 (m, 4H); MS m/z (M+1)+ 617.
2,2,2-Trifluoro-N-{4-[(4-{[1-(3-fluorobenzyl)-1 H-indazol-5-yl]amino}-6- quinazolinyl)oxy]butyl}-N-[2-(methanesulphonyl)ethynacetamide Prepared according to Procedure C from 4-[1-(3-fluorobenzyl)-1 H-indazol-5-yl]-(6- hydroxyquinazolin-4yl)amine (1 equiv) and Λ/-(4-bromobutyl)-2,2,2-trifluoro-Λ/-[2- (methanesulphonylethyl)acetamide (1 equiv). δH (DMSO) 9.66 (s, 1 H), 8.40 (s, 1 H), 8.14 (d, 2H), 7.91 (d, 1 H), 7.63-7.72 (m, 3H), 7.46 (m, 1 H), 7.33 (m, 1 H); 5.67 (m, 2H), 4.16 (m, 2H), 3.78 (m, 2H), 3.44-3.57 (m, 4H), 3.03 (s, 3H), 1.80 (m, 4H); MS m/z 659 (M+1 )+.
2,2,2-Trifluoro-N-[2-(methanesulphonyl)ethyl1-N-[4-({4-[4-(benzenesuiphonyl)anilino1- 6-quinazolinyl}oxy)butyl]acetamide
Prepared according to Procedure C from 4-(4-benzenesulphonyl)phenyl)-(6- hydroxyquinazolin-4yl)amine (1 equiv) and Λ/-(4-bromobutyl)-2,2,2-trifluoro-Λ/-[2- (methanesulphonylethyl)acetamide (1 equiv). δH (DMSO) 9.95 (s, 1H), 8.61 (s, 1H), 8.18 (d, 2H), 7.96-8.02 (m, 5H), 7.81 (d, 1 H), 7.57-7.23 (4 H, m), 4.22 (m, 2H), 3.83 (m, 2H), 3.49-3.57 94 H, m), 3.08 93 H, s), 1.85 (4 H, m); MS m/z 650 (M+1)+.
Intermediates of formula (XII) described in Scheme 1 , in particular those in which P' represents a trifluoromethylcarbonyl group are of interest. Those specifically mentioned in the Intermediate section have been shown to exhibit c-erbB-2 activity. Such compounds thus represent a further aspect of the present invention. Examples
Example 1
Figure imgf000124_0001
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(methanesulphonyl)ethylaminomethyl)-quinazolin-4- y amine hydrochloride
4-(1-Benzyl-1 H-indazol-5-yiamino)quinazoline-6-carbaldehyde (0.10g) was reacted with 2-(methanesulphonyl)ethylamine (2 equiv.) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/dichloromethane, followed by acidification with HCI/dioxane, gave the product as a yellow solid (0.053g); δH [ H6] -DMSO 9.95 (2H, br), 9.18 (1H,s), 8.89 (1 H,s), 8.28 (1H,d), 8.22 (1H,s), 8.14 (1 H,s), 7.98 (1 H,d), 7.83 (1 H,d), 7.70 (1 H,d), 7.21-7.38 (5H,m), 5.71 (2H,s), 4.41 (2H,s), 3.30-3.75 (4H,m), 3.15 (3H,s); m/z 487 (M+1)+.
Example 2
Figure imgf000124_0002
2-(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetic acid
4-(1-Benzyl-1 H-indazol-5-ylamino)quinazoline-6-carbaldehyde (0.1 Og) was reacted with 2-aminoacetic acid (0.065g) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/dichloromethane, gave the crude product. This was suspended in methanol, treated with 2N aq. NaOH solution at room temperature for 3 hours, and the mixture neutralised with sat. aq.NH4CI solution. The resulting solution was extracted with ether, and the organic layer concentrated in vacuo to give the product as a yellow solid (0.027g); δH [2HQ] - DMSO 10.14 (br), 8.67 (1 H,s), 8.53 (1 H,s), 8.23 (1 H,s), 8.12 (1 H,s), 7.91 (1 H, d), 7.68-7.80 (2H,m), 7.21-7.38 (6H,m), 5.68 (2H,s), 4.14 (2H,s), 3.30 (2H,s); m/z 439 (M+1)+.
Example 3
Figure imgf000125_0001
2-(4-(1-Benzyl-1H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetamide 4-(1-Benzyl-1H-indazol-5-ylamino)quinazoline-6-carbaldehyde (0.1 Og) was reacted with glycinamide hydrochloride (2 equiv.) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/ethyl acetate, gave the product as a yellow solid (0.01 Og); δH [2H6J -DMSO 9.87 (1H,s), 8.47-8.57 (2H,m), 8.22
(1H,s), 8.13 (1 H,s), 7.88 (1 H,d), 7.65-7.79 (2H,m), 7.20-7.38 (7H,m), 5.68 (2H,s), 3.89 (2H,s), 3.10 (2H,s); m/z 438 (M+1)+.
Example 4
Figure imgf000125_0002
2-(Λ/-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yl)methyl)-Λ/-methylamino)- acetamide 4-(1-Benzyl-1 H-indazol-5-ylamino)quinazoline-6-carbaldehyde (0.1 Og) was reacted with sarcosinamide (2 equiv.) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/ethyl acetate, gave the product as a yellow solid (0.030g); δH [2H6] -DMSO 9.92 (1 H,s), 8.55 (1 H,s), 8.50 (1 H,s), 8.21 (1 H,s),
8.14 (1 H,s), 7.90 (1 H,d), 7.63-7.77 (3H,m), 7.18-7.45 (7H,m), 5.68 (2H,s), 3.75 (2H,s), 3.39 (3H,s), 2.98 (2H,s); m/z 452 (M+1)\
Example 5
Figure imgf000126_0001
(2R)-1 -(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-6-ylmethyl)pyrrolidine-2- carboxylic acid f-butyl ester
4-(1-Benzyl-1 H-indazol-5-ylamino)quinazoline-6-carbaldehyde (0.066g) was reacted with D-proline f-butyl ester hydrochloride (0.072g) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/ethyl acetate, gave the product as a yellow solid (0.030g); δH [2H6] -DMSO 9.20 (1 H,br), 8.84 (1 H,s), 8.14-8.20 (2H,m), 8.09 (1 H,s), 7.97 (1H,d), 7.80 (1 H,d), 7.63-7.70 (1 H,m), 7.21-7.35 (6H,m), 5.68 (2H,s), 4.50 (2H,s), 4.09-4.12 (1 H,m), 3.25-3.50 (2H, m, obscured by water), 1.85-2.05 (4H,m), 1.32 (9H,s); m/z 535 (M+1)+.
Example 6
Figure imgf000126_0002
(2S)-1-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-ylmethyl)pyrrolidine-2- carboxamide
4-(1-Benzyl-1 H-indazol-5-ylamino)quinazoline-6-carbaldehyde (0.066g) was reacted with L-prolineamide (2 equiv.) according to Procedure B. Purification using a Bond Elut™ cartridge, eluting with methanol/ethyl acetate, gave the product as a yellow solid (0.040g); δH [2H6] -DMSO 9.95 (1 H,br), 8.48-8.53 (2H,m), 8.17 (1 H,s), 8.13 (1 H,s), 7.88 (1 H,d), 7.64-7.76 (3H,m), 7.13-7.44 (7H,m), 5.67 (2H,s), 3.96-4.05 (2H,m), 3.44-3.52 (1 H,m), 2.76-3.06 (2H,m), 1.60-1.85 (4H,m); m/z 478 (M+1)+.
Example 7
Figure imgf000127_0001
4-(4'-Benzyloxyanilino)-6-(4'-(2"-methanesulphonylethyl)aminobutoxy)quinazoline Prepared according to Procedure E from N-[4-({4-[4-(benzyloxy)anilino]-6- quinazolinyl}oxy)butyl]-2,2,2-trifluoro-N-[2-(methanesulphonyl)ethyl]acetamide. δH (DMSO) 9.55 (s, 1 H), 8.44 (s, 1H), 7.92 (d, 1 H), 7.68-7.74 (m, 3H), 7.35-7.52 (m, 6H), 7.09 (d, 2H), 5.16 (s, 2H), 4.18 (m, 2H), 3.32 (m, 2H), 3.11 (s, 3H), 2.96 (m, 3H), 2.64 (m, 2H), 1.88 (m, 2H), 1.64 (m, 2H); MS m/z 521 (M+1)\
Example 8
Figure imgf000127_0002
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(4-{f2-(methanesulphonyl)ethyl1amino) butoxy)-4-quinazolinamine
Prepared according to Procedure E from N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}- quinazolinoxybutyl-2,2,2-trifluoro-N-[2-(methanesulphonyl)ethyl]acetamide. δH
(DMSO) 9.54 (s, 1 H), 8.44 (s, 1 H), 7.96 (d, 1 H), 7.84 (d, 1 H), 7.67-7.71 (m, 2H), 7.41-7.48 (m, 2H), 7.24-7.31 (m, 3H), 7.15 (m, 1 H), 5.22 (s, 2H), 4.12 (m, 2H), 3.17 (m, 2H), 2.98 (s, 3H), 2.90 (m, 2H), 2.58 (m, 2H), 1.81 (m, 2H), 1.58 (m, 2H); MS m/z 573 (M+1)+.
Example 9
Figure imgf000127_0003
N-f1-(3-Fluorobenzyl)-1 H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethylj-amino}- butoxy)-4-quinazolinamine
Prepared according to Procedure E from 2,2,2-trifluoro-N-{4-[(4-{[1-(3-fluorobenzyl)- 1 H-indazol-5-yl]amino}-6-quinazolinyl)oxy]butyl}-N-[2-(methanesulphonyl)ethyl]- acetamide. δH (DMSO) 9.65 (s, 1 H), 8.39 (s, 1 H), 8.12-8.16 (d, 2H), 7.89 (s, 1H), 7.64-7.72 (m, 3H), 7.45 (m, 1 H), 7.31-7.36 (m, 1 H), 7.01-7.09 (m, 3H), 4.13 (2 H, t), 3.19 (s, 2H), 2.98 (s, 3H), 2.90 (2 H, t), 2.58 92 H, t), 1.82 (m, 2H), 1.58 (2 H, t); MS m/z 563 (M+1)+.
Example 10
Figure imgf000128_0001
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-quinazolin-4- yl) amine
Prepared according to Procedure F from (4-benzyloxyphenyl)-(6-(3-bomopropoxy)- quinazoline (0.1 mmol) and 2-(methanesulphonyl)ethylamine (0.3mmol). δH (DMSO) 9.54 (s, 1 H), 8.37 (s, 1 H), 7.87 (s, 1 H), 7.62-7.66 (m, 3H), 7.28-7.45 (m, 7H), 7.02 (d, 2H), 5.09 (s, 2H), 4.17 (m, 2H), 3.20 (m, 2H), 2.97 (s, 3H), 2.92 (m, 2H), 2.70 (m, 2H), 1.91 (m, 2H); MS m/z 507(M+1)+.
Example 11
Figure imgf000128_0002
6-(4-{f2-(Methyl)ethynamino}butoxy)-N-[4-(benzenesulphonyl)phenyn-4- quinazolinamine
Prepared according to Procedure E from 2,2,2-trifluoro-N-[2-(methyl)ethyl]-N-[4-({4- [4-(benzenesulphonyl)anilino]-6-quinazolinyl}oxy)butyl]acetamide. δH (DMSO) 9.86
(s, 1 H), 8.55 (s, 1 H), 8.13 (d, 1 H), 7.89-7.96 (m, 5H), 7.74 (d, 1 H), 7.58-7.67 (m, 3H), 7.52 (d, 2H), 4.13 (2 H, t), 3.18 (2 H, t), 2.97 (s, 3H), 2.88 (2 H, t), 2.56 (2 H, t), 1.81 (m, 2H), 1.57 (m, 2H); MS m/z 555 (M+1)+.
Example 12
Figure imgf000129_0001
N-r4-(Benzyloxy)phenyl]-6-(3-{methyl[2-(methanesulphonyl)ethyllamino)propoxy)-4- quinazolinamine Prepared according to Procedure F from N-[4-(benzyloxy)phenyl]-6-(3- bromopιopoxy)-4-quinazoline (0.1 mmol) and N-methyl-2-(methanesulphonyl)ethyl- amine (0.3mmol). δH (DMSO) 9.50 (s, 1 H), 8.37 (s, 1 H), 7.86 (d, 1 H), 7.61-7.67 (m, 3H), 7.30-7.45 (6 H, m), 7.02 (d, 2H),5.09 (s, 2H), 4.13 (2 H, t), 3.29 (m, 2H), 2.96 (s, 3H), 2.75 (m, 2H), 2.53 (m, 2H), 2.20 (s, 3H), 1.93 (m, 2H); MS m/z 521(M+1)+.
Further examples
The compounds in Lists 1 to 157 above and their hydrochloride salts, if appropriate, are prepared by analogous techniques using the appropriate starting materials.
Biological Data
Compounds of the present invention were tested for protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays.
Substrate Phosphorylation Assay The substrate phosphorylation assays use baculovirus expressed, recombinant constructs of the intracellular domains of c-erbB-2 and c-erbB-4 that are constitutively active and EGFr isolated from solubilised A431 cell membranes. The method measures the ability of the isolated enzymes to catalyse the transfer of the γ-phosphate from ATP onto tyrosine residues in a biotinylated synthetic peptide (Biotin-GluGluGluGluTyrPheGluLeuVal). Substrate phosphorylation was detected following either of the following two procedures: a.) c-ErbB-2, c-ErbB4 or EGFr were incubated for 30 minutes, at room temperature, with 10mM MnCI2, 10μM ATP, 5 μM peptide, and test compound (diluted from a 5mM stock in DMSO, final DMSO concentration is 2%) in 40mM HEPES buffer, pH 7.4. The reaction was stopped by the addition of EDTA (final concentration 0.15mM) and a sample was transferred to a streptavid in-coated 96-well plate. The plate was washed and the level of phosphotyrosine on the peptide was determined using a Europium-labelled antiphosphotyrosine antibody and quantified with a time-resolved fluorescence technique, b.) ErbB2 was incubated for 50 minutes at room temperature with 15 mM MnCI2, 2 μM ATP, 0.25 μCi [γ-33P] ATP/well, 5 μM peptide substrate, and test compound (diluted from a 10mM stock in DMSO, final DMSO concentration is 2%) in 50 mM MOPS pH 7.2. The reaction was terminated by the addition of 200 μl of PBS containing 2.5 mg/ml streptavid in-coated SPA beads (Amersham Inc.), 50 μM ATP, 10 mM EDTA and 0.1 %TX-100. The microtitre plates were sealed and SPA beads were allowed to settle for at least six hours. The SPA signal was measured using a Packard Topcount 96-well plate scintillation counter (Packard Instrument Co., Meriden, CT).
The results are shown in Table 1 as the IC50 values.
Table 1
Figure imgf000130_0001
Figure imgf000131_0001
Cellular assays: Methylene Blue Growth Inhibition Assay
Human breast (BT474), head and neck (HN5) and gastric tumor (N87) cell lines were cultured in low glucose DMEM (Life Technologies 12320-032) containing 10% fetal bovine serum (FBS) at 37°C in a humidified 10% C02, 90% air incubator. The SV40 transformed human mammary epithelial cell line HB4a was transfected with either human H-ras cDNA (HB4a r4.2) or the human c-erbB2 cDNA (HB4a c5.2). The HB4a clones were cultured in RPMI containing 10% FBS, insulin (5 μg/ml), hydrocortisone (5 μg/ml), supplemented with the selection agent hygromycin B (50μg/ml). Cells were harvested using trypsin/EDTA, counted using a haemocytometer, and plated in 100 ml of the appropriate media, at the following densities, in a 96-well tissue culture plate (Falcon 3075): BT474 10,000 cells/well, HN5 3,000 cells/well, N87 10,000 cells/well, HB4a c5.2 3,000 cells/well, HB4a r4.2 3,000 cells/well. The next day, compounds were diluted in DMEM containing 100 mg/ml gentamicin, at twice the final required concentration, from 10mM stock solutions in DMSO. 100ml/well of these dilutions were added to the 100ml of media currently on the cell plates. Medium containing 0.6% DMSO was added to control wells. Compounds diluted in DMEM were added to all cell lines, including the HB4a r4.2 and HB4a c5.2 cell lines. The final concentration of DMSO in all wells was 0.3%. Cells were incubated at 37°C, 10% C02 for 3 days. Medium was removed by aspiration. Cell biomass was estimated by staining cells with 100μl per well methylene blue (Sigma M9140, 0.5% in 50:50 ethano water), and incubation at room temperature for at least 30 minutes. Stain was removed, and the plates rinsed under a gentle stream of water, and air-dried. To release stain from the cells 100μl of solubilisation solution was added (1% N-lauroyl sarcosine, Sodium salt, Sigma L5125, in PBS), and plates were shaken gently for about 30 minutes. Optical density at 620 nM was measured on a microplate reader. Percent inhibition of cell growth was calculated relative to vehicle treated control wells. Concentration of compound that inhibits 50% of cell growth (IC50) was interpolated using nonlinear regression (Levenberg-Marquardt) and the equation, y = Vmax*(1-(x/(K+x))) + Y2, where "K" was equal to the IC50.
Activity against a range of naturally occurring EGFr or c-erbB-2 over-expressing human tumour cell lines (BT474-breast, HN%-head and neck, and N87-gastric) is assessed with selected compounds by the same methodology. The results are shown in Table 2 below as the IC50 values.
Table 2
Figure imgf000132_0001
Figure imgf000132_0002

Claims

Claims:
1. A compound of formula (I)
Figure imgf000133_0001
or a salt or solvate thereof;
wherein X is N or CH;
Y is CR1 and V is N; or Y is N and V is CR1; or Y is CR1 and V is CR2; or Y is CR2 and V is CR1;
R1 represents a group Q-M-, wherein M is 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 NR6; or wherein M is a C5 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 NR6;
Q represents a group of formula Z-(CH2)P-NR6, wherein p is 1 to 4 and Z is selected from the group comprising NR6S(0)--,R10, S(0)mNR8R9, CONR8R9, NR6COR7, S(0)mR10 and C02R7;
or Q represents a group of formula
Figure imgf000133_0002
or Q represents a group of formula
Figure imgf000134_0001
wherein R11 represents NR8R9 or OR10;
or Q represents a group of formula
Figure imgf000134_0002
wherein R6, R7, R8 and R9 each independently represent H or C^ alkyl, and R10 represents C^ alkyl; m is 1 or 2; and n is 1 or 2;
R2 is selected from the group comprising hydrogen, halo, hydroxy, C^ alkyl, C^ alkoxy, C^ alkylamino and di[C^ alkyl]amino;
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 R3 group and optionally substituted by up to three independently selected R4 groups;
R3 is selected from a group comprising benzyl, halo-, dihalo- and trihalobenzyi, benzoyi, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
or R3 represents a group of formula
Figure imgf000134_0003
wherein each R5 is independently selected from halogen, C^ alkyl and C^ alkoxy; and n is 0 to 3;
each R4 is independently hydroxy, halogen, C^ alkyl, C2„ alkenyl, C2 alkynyl, C^ alkoxy, amino, C^ alkylamino, di[C^ alkyljamino, C^ alkylthio, C^ alkylsulphinyl, C^ alkylsulphonyl, C1J( alkylcarbonyl, carboxy, carbamoyi, C alkoxycarbonyl, C^ alkanoylamino, N-(C alkyl)carbamoyl, N,N-di(ClJ( alkyl)carbamoyl, cyano, nitro and trifluoromethyl.
2. A compound as claimed in claim 1 wherein R2 is hydrogen or C1 -4 alkoxy.
3. A compound as claimed in claims 1 and 2 wherein M represents a -CH2-, - CH2CH2CH20- group; or M represents a -CH2CH2CH2CH20- group.
4. A compound as claimed in any of claims 1 to 3 wherein Z represents a group S(0)mNR8R9, NR6S(0)mR10 or S(0)mR10; wherein m is 1 or 2; R8 and R9 are independently methyl or hydrogen; R10 is methyl; R6 is methyl or hydrogen, or wherein Z represents a group CONR8R9 or C02R7;wherein R7 is methyl or hydrogen.
5. A compound as claimed in any of claims 1 to 4 wherein Q represents a CH3S02(CH2)2.3NH, CH3SO(CH2)2.3NH, CH3S02(CH2)2.3N(CH3), CH3SO(CH2)2.3N(CH3), CH3S02NH(CH2)2.3NH or CH3S02NH(CH2)2.3N(CH3) group; or wherein Q represents H02C(CH2)2.3NH, H02C (CH2)2.3N(CH3), NH2CO(CH2)2.3NH, NH2CO(CH2)2.3N(CH3),
Figure imgf000135_0001
A compound as claimed in any of claims 1 to 5 wherein R1 is selected from the group comprising CH3S02CH2CH2NHCH2;
Figure imgf000136_0001
H02CCH2NHCH2, NH2COCH2NHCH2 or NH2COCH2N(CH3)CH2;
CH3S02CH2CH2N(CH3)CH2 or H02CCH2N(CH3)CH2; CH3S02CH2CH2NHCH2CH2CH20 or CH3S02CH2CH2N(CH3)CH2CH2CH20;
CH3S02CH2CH2NHCH2CH2 CH2CH20 or CH3S02CH2CH2N(CH3)CH2CH2 CH2CH20.
7. A compound as claimed in any of claims 1 to 6 wherein U represents a phenyl or 1H-indazolyl group substituted by an R3 group and optionally substituted by up to three independently selected R4 groups.
8. A compound as claimed in any one of claims 1 to 7 wherein R3 represents benzyloxy, fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl; or R3 represents fluorobenzyl (especially 3-fluorobenzyl).
9. A compound as claimed in any of claims 1 to 8 wherein the group U together with the substituent(s) R3 and R4 represents benzyloxyphenyl, fluorobenzyloxyphenyl, benzenesulphonylphenyl, benzylindazolyl or phenoxyphenyl; or wherein the group U together with the substituent(s) R3 and R4 represents fluorobenzyloxy(chlorophenyl) or fluorobenzylindazolyl.
10. A compound of formula (I) or a salt or solvate thereof as claimed in any of claims 1 to 9 wherein X is N; V is CR2, wherein R2 is hydrogen or methoxy; Y is CR1 wherein R1 is a CH3S02CH2CH2NHCH2, NH2COCH2NHCH2, NH2COCH2N(CH3)CH2, H02CCH2NHCH2, prolinamido-methyl or proline(t-butyl-ester)-methyl group; U is phenyl or indazolyl; R3 is benzyl or benzyloxy; and R4 is not present.
11. A compound of formula (I) or a salt or solvate thereof as claimed in any of claims 1 to 9 wherein X is N; V is CR2, wherein R2 is hydrogen or methoxy; Y is CR1 wherein R1 is CH3S02CH2CH2NHCH2CH2CH20,
CH3S02CH2CH2N(CH3)CH2CH2CH20, CH3S02CH2CH2NHCH2CH2CH2CH20 or CH3S02CH2CH2N(CH3)CH2CH2CH2CH20; U is phenyl or indazolyl; R3 is benzyl, fluorobenzyl, benzenesulphonyl, benzyloxy or fluorobenzyloxy; and R4 is not present or is halo (especially chloro).
12. A compound as claimed in claim 1 selected from:
(1-Benzyl-1 H-indazol-5-yl)-(6-(2-(methanesulphonyl)ethylaminomethyl)-quinazolin-4- yl)amine hydrochloride;
2-(4-(1 -Benzyl- 1 H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetic acid;
2-(4-(1-Benzyl-1H-indazol-5-ylamino)quinazolin-6-yl)methylamino)acetamide; 2-(Λ/-(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-6-yl)methyl)-/V- methylamino)acetamide;
(2R)-1 -(4-(1 -Benzyl-1 H-indazol-5-ylamino)quinazolin-6-ylmethyl)pyrrolidine-2- carboxylic acid f-butyl ester;
(2S)-1-(4-(1-Benzyl-1 H-indazol-5-ylamino)quinazolin-6-ylmethyl)pyrrolidine-2- carboxamide;
4-(4'-Benzyloxyanilino)-6-(4'-(2"-methanesulphonylethyl)aminobutoxy) quinazoline;
N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-(4-{[2-(methanesulphonyl)ethyl]amino} butoxy)-4-quinazolinamine; N-[1 -(3-Fluorobenzyl)-1 H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)-4-quinazolinamine;
(4-Benzyloxyphenyl)-(6-(3-(2-methanesulphonyl-ethylamino)-propoxy)-quinazolin-4- yl) amine;
6-(4-{[2-(Methanesulphonyl)ethyl]amino}butoxy)-N-[4-(benzenesulphonyl)phenyl]-4- quinazolinamine;
N-[4-(Benzyloxy)phenyl]-6-(3-{methyl[2-(methanesulphonyl)ethyl]amino}propoxy)-4- quinazolinamine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
13. A compound as claimed in claim 12 selected from:
N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-(4-{[2-(methanesulphonyl)ethyl]amino}- butoxy)-4-quinazolinamine; and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof.
14. A process for the preparation of a compound of formula (I) as defined in claim
1 which comprises the steps:
(a) the reaction of a compound of formula (II)
Figure imgf000138_0001
wherein X is as defined above; Y' is C-M-L' and V is N; or Y' is N and V is C-M-L'; or Y' is C-M-L' and V is CR2; or Y' is CR2 and V is C-M-L'; wherein R2 and M are as defined above, and L and L' are suitable leaving groups, with a compound of formula (III)
UNH2 (III) wherein U is as defined above, to prepare a compound of formula (IV)
Figure imgf000138_0002
and subsequently (b) reaction with appropriate reagent(s) to substitute the group Q by replacement of the leaving group L'; and, if desired, (c) subsequently converting the compound of formula (I) thereby obtained into another compound of formula (I) by means of appropriate reagents.
15. A process for the preparation of a compound of formula (I) as defined in claim 1 in which the compound of formula (II) as defined in claim 14 is reacted with the appropriate reagents to substitute the group Q by replacement of the leaving group L' and then the product thereby obtained of formula (V)
Figure imgf000139_0001
is reacted with the compound of formula (III) as defined above, followed, if desired, by conversion of the compound of formula (I) thereby obtained into another compound of formula (I).
16. A process as claimed in claim 15 wherein the compound of formula (V)
Figure imgf000139_0002
wherein X, Y, V, U and L are as defined above, may be prepared by the reaction of a compound of formula (VI)
Figure imgf000139_0003
wherein V and Y' are as defined above, with appropriate reagents to substitute the group Q for the leaving group L' to prepare a compound of formula (VII)
Figure imgf000139_0004
and subsequent reaction to incorporate the leaving group L.
17. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises the steps:
(a) reacting a compound of formula (IV) as defined above with appropriate reagent(s) to prepare a compound of formula (VIII)
Figure imgf000140_0001
wherein X and U are as defined above;
Y" is CT and V" is N; or Y" is N and V" is CT; or Y" is CT and V is CR2; or Y" is CR2 and V" is CT; wherein R2 is as defined above and T is an appropriately functionalised group; and (b) subsequently converting the group T into the group R1 by means of appropriate reagent(s); and, if desired, (c) subsequently converting the compound of formula (I) thereby obtained into another compound of formula (I) by means of appropriate reagents.
18. A pharmaceutical formulation comprising at least one compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
19. A pharmaceutical formulation as claimed in claim 18 in unit dosage form and containing a compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof in an amount of from 70 to 700 mg.
20. A compound of formula (I) as claimed in in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof for use in therapy.
21. The use of a compound of formula (I) as claimed in in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for the treatment of a disorder mediated by abberant protein tyrosine kinase activity.
22. The use of a compound of formula (I) as claimed in claim 21 in the preparation of a medicament for the treatment of cancer and malignant tumours.
23. The use of a compound of formula (I) as claimed in claim 21 in the preparation of a medicament for the treatment of psoriasis.
24. A method of treatment of a human or animal subject suffering from a disorder mediated by abberant protein tyrosine kinase activity which comprises administering to said subject an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof.
25. A method of treatment of a human or animal subject suffering cancer and malignant tumours which comprises administering to said subject an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof.
26. A method of treatment of a human or animal subject suffering from psoriasis which comprises administering to said subject an effective amount of a compound of formula (I) as claimed in any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof.
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