[go: up one dir, main page]

US20030176451A1 - Heterocyclic compounds - Google Patents

Heterocyclic compounds Download PDF

Info

Publication number
US20030176451A1
US20030176451A1 US10/342,810 US34281003A US2003176451A1 US 20030176451 A1 US20030176451 A1 US 20030176451A1 US 34281003 A US34281003 A US 34281003A US 2003176451 A1 US2003176451 A1 US 2003176451A1
Authority
US
United States
Prior art keywords
phenyl
amine
methanesulphonyl
methyl
ethylamino
Prior art date
Legal status (The legal status 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 status listed.)
Abandoned
Application number
US10/342,810
Inventor
Malcolm Carter
George Cockerill
Stephen Guntrip
Karen Lackey
Kathryn Smith
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=10825153&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20030176451(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Individual filed Critical Individual
Priority to US10/342,810 priority Critical patent/US20030176451A1/en
Publication of US20030176451A1 publication Critical patent/US20030176451A1/en
Priority to US11/050,033 priority patent/US7109333B2/en
Assigned to SMITHKLINE BEECHAM (CORK) LIMITED reassignment SMITHKLINE BEECHAM (CORK) LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SMITHKLINE BEECHAM CORPORATION
Priority to US11/532,926 priority patent/US20070015775A1/en
Assigned to SMITHKLINE BEECHAM CORPORATION reassignment SMITHKLINE BEECHAM CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SMITHKLINE BEECHAM (CORK) LIMITED
Priority to US11/752,582 priority patent/US20070238875A1/en
Priority to US12/691,784 priority patent/US8513262B2/en
Priority to US13/943,049 priority patent/US8912205B2/en
Priority to US14/536,896 priority patent/US9199973B2/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LEO OSPREY LIMITED
Assigned to GLAXOSMITHKLINE LLC reassignment GLAXOSMITHKLINE LLC ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SMITHKLINE BEECHAM CORPORATION
Assigned to LEO OSPREY LIMITED reassignment LEO OSPREY LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GLAXOSMITHKLINE LLC
Priority to US14/887,434 priority patent/US20160051551A1/en
Priority to US15/226,949 priority patent/US20160339027A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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.I, 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 kinases such as EGFr, c-erbB-2, c-erbB-4, c-met, tie-2, PDGFr, c-src, lck, Zap70, and fyn.
  • protein tyrosine kinases such as EGFr, c-erbB-2, c-erbB-4, c-met, 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 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-R receptor kinases hence allowing treatment of a broader range of tumours.
  • the present invention also includes compounds which are active against lck and/or zap70 receptor kinases; these may also be active against c-erbB-2 and/or EGF-R receptor kinases.
  • the compounds may be selective towards lck and/or zap70 in comparison to c-erbB-2 and/or EGF-R.
  • 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.
  • Y is CR 1 and V is N;
  • Y is CR 1 and V is CR 2 ;
  • Y is CR 2 and V is CR 1 ;
  • R 1 represents a group CH 3 SO 2 CH 2 CH 2 NHCH 2 —Ar—, wherein Ar is selected from phenyl, furan, thiophene, pyrrole and thiazole, each of which may optionally be substituted by one or two halo, C 1-4 alkyl or C 1-4 alkoxy groups;
  • R 2 is selected from the group comprising hydrogen, halo, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino and di[C 1-4 alkyl]amino;
  • U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group, substituted by an R 3 group and optionally substituted by at least one independently selected R 4 group;
  • R 3 is selected from a group comprising benzyl, halo-, dihalo- and trihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
  • R 3 represents trihalomethylbenzyl or trihalomethylbenzyloxy
  • R 3 represents a group of formula
  • each R 5 is independently selected from halogen, C 1-4 alkyl and C 1-4 alkoxy; and n is 0 to 3;
  • each R 4 is independently hydroxy, halogen, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, di[C 1-4 alkyl]amino, C 1-4 alkylthio, C 1-4 alkylsulphinyl, C 1-4 alkylsulphonyl, C 1-4 alkylcarbonyl, carboxy, carbamoyl, C 1-4 alkoxycarbonyl, C 1-4 alkanoylamino, N-(C 1-4 alkyl)carbamoyl, N,N-di(C 1-4 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 7-position are of particular interest in the context of lck and/or zap70 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 activity whereas the compounds in which R 1 is in the 7-position are of particular interest in the context of lck and/or zap70 activity.
  • Ring systems (1), (2), (5) and (6) are preferred; ring systems (2) and (6) are more preferred.
  • Ring system (1) is also 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.
  • halo is, for example, fluoro, chloro, bromo or iodo; preferably it is fluoro, chloro or bromo, more preferably fluoro or chloro;
  • C 1-4 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 1-4 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 1-14 alkylamino is, for example, methylamino, ethylamino or propylamino; preferably it is methylamino;
  • di[C 1-4 alkyl]amino is, for example, dimethylamino, diethylamino, N-methyl-N-ethylamino or dipropylamino; preferably it is dimethylamino;
  • C 1-4 alkylthio is, for example, methylthio, ethylthio, propylthio or isopropylthio, preferably methylthio;
  • C 1-4 alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl or isopropylsulphinyl, preferably methylsulphinyl;
  • C 1-4 alkylsulphonyl is, for example, methanesulphonyl, ethylsulphonyl, propylsulphonyl or isopropylsulphonyl, preferably methanesulphonyl;
  • C 1-4 alkylcarbonyl is, for example methylcarbonyl, ethylcarbonyl or propylcarbonyl;
  • C 1-4 alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl;
  • C 1-4 alkanoylamino (where the number of carbon atoms includes the CO functionality) is, for example, formamido, acetamido, propionamido or butyramido;
  • N-(C 1-4 alkyl)carbamoyl is, for example, N-methylcarbamoyl or N-ethylcarbamoyl;
  • N,N-di(C 1-4 alkyl)carbamoyl is, for example, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl or N,N-diethylcarbamoyl.
  • X is N
  • Y is CR 1
  • V is CR 2 (ring system (2) above).
  • X is N
  • Y is CR 2
  • V is CR 1 (ring system (2) above).
  • X is N
  • Y is CR 1
  • V is N (ring system (6) above).
  • R 2 represents hydrogen or C 1-4 alkoxy.
  • R 2 represents hydrogen or methoxy.
  • R 2 represents halo; more preferred R 2 is fluoro.
  • the group Ar is substituted by one halo, C 1-4 alkyl or C 1-4 alkoxy group.
  • the group Ar is substituted by a C 1-4 alkyl group.
  • the group Ar does not carry any optional substituents.
  • Ar represents furan, phenyl or thiazole, each of which may optionally be substituted as indicated above.
  • Ar represents furan or thiazole, each of which may optionally be substituted as indicated above.
  • Ar represents unsubstituted furan or thiazole.
  • the side chain CH 3 SO 2 CH 2 CH 2 NHCH 2 may be linked to any suitable position of the group Ar.
  • the group R 1 may be linked to the carbon atom carrying it from any suitable position of the group Ar.
  • 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 bicyclic ring system, but these groups are preferably bound to the ring which is not bound to the bridging NH group in such a case.
  • U represents a phenyl, indolyl, or 1H-indazolyl group substituted by an R 3 group and optionally substituted by at least one independently selected R 4 group.
  • U represents a phenyl or 1H-indazolyl group substituted by an R 3 group and optionally substituted by at least one independently selected R 4 group.
  • R 3 represents benzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
  • R 3 represents trihalomethylbenzyloxy.
  • 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 bromobenzyloxy (especially 3-bromobenzyloxy) and trifluoromethylbenzyloxy.
  • 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.
  • the ring U is substituted by an R 4 group selected from halo or C 1-4 alkoxy; especially chloro, fluoro or methoxy.
  • the ring U is substituted by an R 4 group wherein R 4 represents halo, especially 3-fluoro.
  • U together with R 4 represents methoxyphenyl, fluorophenyl, trifluoromethylphenyl or chlorophenyl.
  • U together with R 4 represents methoxyphenyl or fluorophenyl.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl, (fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl, benzylindazolyl or phenoxyphenyl.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl, (3-fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl or benzylindazolyl.
  • the group U together with the substituent(s) R 3 and R 4 represents (3-bromobenzyloxy)phenyl, (3-trifluoromethylbenzyloxy)phenyl, or (3-fluorobenzyloxy)-3-methoxyphenyl.
  • the group U together with the substituent(s) R 3 and R 4 represents 3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl, benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl, (3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.
  • the group U together with the substituent(s) R 3 and R 4 represents benzyloxyphenyl or (3-fluorobenzyloxy)phenyl.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); Y is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R 3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); Y is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); Y is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R 3 is benzyl or fluorobenzyl; 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, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R 3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R 3 is benzyl or fluorobenzyl; and R 4 is not present.
  • a compound of formula(1) or a salt or solvate thereof wherein X is N, Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is phenoxy; 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 as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R 3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R 3 is benzyl or fluorobenzyl; and R 4 is not present.
  • a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R 3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is benzyloxy, fluorobenzyloxy, phenoxy or benzenesulphonyl; and R 4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R 3 is benzyl or fluorobenzyl; and R 4 is not present.
  • a compound of formula(1) or a salt or solvate thereof wherein X is CH, Y is CR 2 , wherein R 2 is hydrogen, halo (especially fluoro) or C 1-4 alkoxy (especially methoxy); V is CR 1 wherein R 1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R 3 is phenoxy; and R 4 is not present.
  • Preferred compounds of the present invention include:
  • Particularly preferred compounds of the present invention include:
  • 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 p-toluenesulphonic, acids.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids
  • organic acids such as tartaric, acetic, trifluoroacetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic and arylsulphonic, for example p-toluenesulphonic, acids.
  • Y′ is CL′ and V′ is N;
  • the compound of formula (II) as defined above is reacted with the appropriate reagents to substitute the group R 1 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).
  • 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 R 1 may, therefore, be substituted onto the basic ring system by replacement of a suitable leaving group. This may, for example, be carried out by reaction of the corresponding aryl or heteroaryl stannane derivative with the corresponding compound of formula (IV) carrying the leaving group L′ in the appropriate position on the ring.
  • Y′′ is CR 2 and V′′ is CT; wherein R 2 is as defined above and T is an appropriately functionalised group;
  • the group T would represent a group Ar as defined above carrying a formyl group (CHO).
  • T represents a group Ar carrying a formyl group
  • the compound (of formula (VIIIa)) may be suitably prepared from the corresponding dioxolanyl substituted compound (of formula (VIIIb)), for example by acid hydrolysis.
  • the dioxolanyl substituted compound may be prepared by reaction of a compound of formula (IV) with an appropriate reagent to substitute the relevant leaving group with the substituent carrying the dioxolanyl ring.
  • This reagent could, for example, be an appropriate heteroaryl stannane derivative.
  • a suitable process may comprise reaction of a compound of formula (VIIIa) in which T is a group Ar carrying a formyl substituent (i.e. a —CHO group) with a compound of formula CH 3 SO 2 CH 2 CH 2 NH 2 .
  • the reaction preferably involves a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride.
  • another suitable process may comprise oxidation of a compound of formula (VIIIc) in which T is a group Ar carrying a substituent of formula CH 3 SCH 2 CH 2 NHCH 2 or CH 3 SOCH 2 CH 2 NHCH 2 .
  • 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 compound of formula (VIIIc) in which T is a group Ar carrying a substituent of formula CH 3 SCH 2 CH 2 NHCH 2 or CH 3 SOCH 2 CH 2 NHCH 2 may be prepared by an analogous reaction to that described above, namely reaction of a compound of formula (VIIIa) in which T is a group Ar carrying a formyl substituent (i.e. a —CHO group) with a compound of formula CH 3 SCH 2 CH 2 NH 2 or CH 3 SOCH 2 CH 2 NH 2 respectively.
  • the group T is converted into the group R 1 by a de novo synthesis of a substituted heterocyclic system using appropriate agents.
  • a de novo synthesis of a substituted heterocyclic system using appropriate agents.
  • Such a process would involve standard synthetic methodology known to the person skilled in the art for building up the heterocylic ring system.
  • T could represent a haloketone group as shown in the compound of formula (IX) in scheme 1 below which, when coupled with an appropriate N-protected thioamide [compound of formula (XI) in scheme 2], would result in the formation of an N-protected amino-substituted thiazole system of formula (X).
  • Scheme 1 outlines, for example, the synthesis of derivatives carrying a substituted thiazole ring as an R 1 substituent:
  • halo is as previously defined (preferably iodo)
  • P′ in the compound of formula (XI) is a suitable protecting group, such as trifluorocarbonyl.
  • the group R 2 will be present as a substituent in the basic ring system prior to the introduction of the group R 1 or the group NHU.
  • R 2 is other than hydrogen it may in certain circumstances be necessary to protect the group prior to performing the reaction steps to introduce the R 1 and NHU substituents.
  • 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-butyldiphenylsilyl (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 1-4 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.
  • a suitable inert solvent for example a C 1-4 alkanol, such as isopropanol, a halogenated hydrocarbon, an ether, an aromatic hydrocarbon or a dipolar aprotic solvent such as acetone, acetonitrile or DMSO
  • a non-extreme temperature for example from 0 to 150° C., suitably 10 to 120° C., preferably 50 to 100° C.
  • the reaction is carried out in the presence of a base.
  • 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 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).
  • a compound containing an alkylthio group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (e.g. benzoyl peroxide) or suitable inorganic oxidant (eg OXONE ®).
  • an organic peroxide e.g. benzoyl peroxide
  • suitable inorganic oxidant e.g 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.
  • Another further aspect of the present invention is intermediate compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) 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. Certain compounds of formula (I) are also demonstrated hereinafter to inhibit lck and/or zap70 protein tyrosine kinase enzymes and are expected to have activity in disease conditions in which T cells are hyperactive.
  • 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 and/or lck activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, psoriasis and rheumatoid arthritis.
  • 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.
  • 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 rheumatoid arthritis.
  • 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.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain for example 0.5 mg to 1 g, preferably 70 mg to 700 mg, more preferably 5 mg to 100 mg 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.
  • compositions 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).
  • compositions 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.
  • compositions 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.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.
  • the formulations are preferably applied as a topical ointment or cream.
  • the active ingredient may be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions 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.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles and mouth washes.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • compositions 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.
  • compositions 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.
  • compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.
  • compositions 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.
  • 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
  • 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.
  • 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 per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above.
  • 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.
  • Analytical thin layer chromatography 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 progess 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 dimethylsulphoxide
  • THF refers to tetrahydrofuran.
  • HPLC refers to high pressure liquid chromatography.
  • NMM refers to N-methylmorpholine
  • a suitable leaving group such as chloro, bromo, iodo or triflate
  • a suitable palladium catalyst such as bis(triphenylphosphine)palladium (II) chloride or 1,
  • the compound containing the 1,3-dioxolan-2-yl group was suspended in an appropriate solvent, e.g. THF and treated with hydrochloric acid, either as an aqueous solution (e.g. 2N) or as a solution in dioxane (e.g. 4 molar) and stirred at ambient temperature until the reaction was judged complete (e.g. by tic or LC/MS analysis). Generally the mixture was diluted with water, and the resulting precipitate was collected by filtration, washed with water and dried to give the aldehyde.
  • an appropriate solvent e.g. THF
  • hydrochloric acid either as an aqueous solution (e.g. 2N) or as a solution in dioxane (e.g. 4 molar)
  • a suitable palladium catalyst such as bis(triphenylphosphine) palladium (II) chloride or tetrakis(triphenylphosphine) palladium (0) was heated at reflux in an appropriate solvent (typically ace
  • a bicyclic pyrimidine vinyl ether such as the product of general procedure F-1) and 1 equivalent of a bromination reagent, such as N-bromosuccinimide or bromine, were stirred at 0° C. in a suitable solvent (typically 10% aqueous THF or dichloromethane) until the reaction was complete.
  • a suitable solvent typically 10% aqueous THF or dichloromethane
  • the resulting mixture was dried over anhydrous magnesium sulfate and concentrated, or in the case of bromine the solid was filtered, to provide the corresponding ⁇ -bromoketone.
  • This material may subsequently be carried forward to the appropriately substituted pyridopyrimidine intermediate according to the procedures as described in WO95/19774, 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.
  • Amines prepared by such methods include:
  • Step 1 Preparation of the Precursor Nitro-Compounds
  • 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 ethanol, THF, or mixtures thereof to promote solubility).
  • a suitable solvent eg ethanol, THF, or mixtures thereof to promote solubility.
  • the mixture was filtered through HarborliteTM, washing with excess solvent, and the resulting solution concentrated in vacuo to give the desired aniline.
  • the anilines were acidified with HCl (e.g. in a solution in dioxane) to give the corresponding hydrochloride salt.
  • Anilines prepared by such methods include:
  • the reaction was filtered and the residue washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature for a further hour.
  • the dioxane was removed under vacuum, the reaction diluted with water and the solid which precipitated was collected by filtration, and washed with water, iso-hexane and acetone. This precipitate was converted to the free base by partitioning into a mixture of triethylamine, ethyl acetate and water.
  • the organic phase was washed with water, dried (magnesium sulphate) and the solvent removed under vacuum.
  • the cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO 4 , filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%).
  • the cooled reaction mixture was partitioned between 30 ml of water and 40 ml of ethyl acetate.
  • the organic solution was washed with 30 ml of brine, dried with Na 2 SO 4 and concentrated in vacuo.
  • the residue was chromatographed on silica gel with hexanes/ethyl acetate (1:1 to 0:1). The resulting solution was concentrated to near dryness and the resulting solid suspended in ether and filtered to give 0.232 g of product as a pale yellow solid.
  • the cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO 4 , filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added to facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellow solid 287 mg (59%).
  • the product was purified on Bond ElutTM cartridge, eluting sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate.
  • the ketal (0.385 g, 0.824 mmol) was stirred at room temperature in a mixture of THF (10 ml) and 1N HCl (10 ml) for 2 hr.
  • the suspension was basified with 2N NaOH (5 ml) and the THF was removed.
  • the aqueous suspension was filtered and washed with water to give the product as a yellow solid (0.346 g);m/z 424.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Obesity (AREA)
  • Vascular Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Indole Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)

Abstract

A process for the preparation of a compound of formula (I)
Figure US20030176451A1-20030918-C00001
comprising the steps:
(a) reacting a compound of formula (II)
Figure US20030176451A1-20030918-C00002
wherein L and L′ are suitable leaving groups, with a compound of formula (III)
UNH2  (III)
to prepare a compound of formula (IV)
Figure US20030176451A1-20030918-C00003
and subsequently (b) substituting the group R1 by replacement of the leaving group L′.

Description

  • 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. [0001]
  • 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.I, 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. [0002]
  • 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. [0003]
  • Aberrant protein tyrosine kinase activity has also been implicated in a variety of other disorders: psoriasis, (Dvir et al, J. Cell. Biol; 1991, 113, 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). [0004]
  • 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. [0005]
  • 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. [0006]
  • 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. [0007]
  • 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-met, 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. [0008]
  • 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. [0009]
  • 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. [0010]
  • 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 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-R receptor kinases hence allowing treatment of a broader range of tumours. [0011]
  • The present invention also includes compounds which are active against lck and/or zap70 receptor kinases; these may also be active against c-erbB-2 and/or EGF-R receptor kinases. The compounds may be selective towards lck and/or zap70 in comparison to c-erbB-2 and/or EGF-R. [0012]
  • 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. [0013]
  • Accordingly, the present invention provides a compound of formula (I) [0014]
    Figure US20030176451A1-20030918-C00004
  • or a salt or solvate thereof; [0015]
  • wherein X is N or CH; [0016]
  • Y is CR[0017] 1 and V is N;
  • or Y is N and V is CR[0018] 1;
  • or Y is CR[0019] 1 and V is CR2;
  • or Y is CR[0020] 2 and V is CR1;
  • R[0021] 1 represents a group CH3SO2CH2CH2NHCH2—Ar—, wherein Ar is selected from phenyl, furan, thiophene, pyrrole and thiazole, each of which may optionally be substituted by one or two halo, C1-4 alkyl or C1-4 alkoxy groups;
  • R[0022] 2 is selected from the group comprising hydrogen, halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino and di[C1-4 alkyl]amino;
  • U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group, substituted by an R[0023] 3 group and optionally substituted by at least one independently selected R4 group;
  • R[0024] 3 is selected from a group comprising benzyl, halo-, dihalo- and trihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
  • or R[0025] 3 represents trihalomethylbenzyl or trihalomethylbenzyloxy;
  • or R[0026] 3 represents a group of formula
    Figure US20030176451A1-20030918-C00005
  • wherein each R[0027] 5 is independently selected from halogen, C1-4 alkyl and C1-4 alkoxy; and n is 0 to 3;
  • each R[0028] 4 is independently hydroxy, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, amino, C1-4 alkylamino, di[C1-4 alkyl]amino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbonyl, carboxy, carbamoyl, C1-4 alkoxycarbonyl, C1-4 alkanoylamino, N-(C1-4 alkyl)carbamoyl, N,N-di(C1-4 alkyl)carbamoyl, cyano, nitro and trifluoromethyl;
  • with the proviso that the following compounds are excluded: [0029]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine; [0030]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl-amine; [0031]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)furan-2-yl)-quinazolin-4-yl-amine; [0032]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)furan-2-yl)-quinazolin-4-yl-amine; [0033]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-1-methyl-pyrrol-2-yl)-quinazolin-4-yl-amine; [0034]
  • and their hydrochloride salts. [0035]
  • Solvates of the compounds of formula (I) are also included within the scope of the present invention. [0036]
  • 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: [0037]
    Figure US20030176451A1-20030918-C00006
  • It will be seen that for compounds containing the basic ring system (1) the group R[0038] 1 may be at the 6- or 7-position; the compounds in which R1 is in the 7-position are of particular interest in the context of lck and/or zap70 activity.
  • It will be seen that for compounds containing the basic ring system (2) the group R[0039] 1 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 activity whereas the compounds in which R1 is in the 7-position are of particular interest in the context of lck and/or zap70 activity.
  • Ring systems (1), (2), (5) and (6) are preferred; ring systems (2) and (6) are more preferred. [0040]
  • Ring system (1) is also more preferred. [0041]
  • 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. [0042]
  • Suitable values for the various groups listed above within the definitions for R[0043] 1, 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; [0044]
  • C[0045] 1-4 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[0046] 2-4 alkenyl is, for example, ethenyl, prop-1-enyl or prop-2-enyl; preferably it is ethenyl;
  • C[0047] 2-4 alkynyl is, for example, ethynyl, prop-1-ynyl or prop-2-ynyl; preferably it is ethynyl;
  • C[0048] 1-4 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[0049] 1-14 alkylamino is, for example, methylamino, ethylamino or propylamino; preferably it is methylamino;
  • di[C[0050] 1-4 alkyl]amino is, for example, dimethylamino, diethylamino, N-methyl-N-ethylamino or dipropylamino; preferably it is dimethylamino;
  • C[0051] 1-4 alkylthio is, for example, methylthio, ethylthio, propylthio or isopropylthio, preferably methylthio;
  • C[0052] 1-4 alkylsulphinyl is, for example, methylsulphinyl, ethylsulphinyl, propylsulphinyl or isopropylsulphinyl, preferably methylsulphinyl;
  • C[0053] 1-4 alkylsulphonyl is, for example, methanesulphonyl, ethylsulphonyl, propylsulphonyl or isopropylsulphonyl, preferably methanesulphonyl;
  • C[0054] 1-4 alkylcarbonyl is, for example methylcarbonyl, ethylcarbonyl or propylcarbonyl;
  • C[0055] 1-4 alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl;
  • C[0056] 1-4 alkanoylamino (where the number of carbon atoms includes the CO functionality) is, for example, formamido, acetamido, propionamido or butyramido;
  • N-(C[0057] 1-4 alkyl)carbamoyl is, for example, N-methylcarbamoyl or N-ethylcarbamoyl;
  • N,N-di(C[0058] 1-4 alkyl)carbamoyl is, for example, N,N-dimethylcarbamoyl, N-methyl-N-ethylcarbamoyl or N,N-diethylcarbamoyl.
  • In an especially preferred embodiment X is N, Y is CR[0059] 1 and V is CR2 (ring system (2) above).
  • In a further especially preferred embodiment X is N, Y is CR[0060] 2 and V is CR1 (ring system (2) above).
  • In a further especially preferred embodiment X is N, Y is CR[0061] 1 and V is N (ring system (6) above).
  • In a preferred embodiment R[0062] 2 represents hydrogen or C1-4 alkoxy.
  • In a more preferred embodiment R[0063] 2 represents hydrogen or methoxy.
  • In a further preferred embodiment R[0064] 2 represents halo; more preferred R2 is fluoro.
  • In a preferred embodiment the group Ar is substituted by one halo, C[0065] 1-4 alkyl or C1-4 alkoxy group.
  • In a more preferred embodiment the group Ar is substituted by a C[0066] 1-4 alkyl group.
  • In a further more preferred embodiment the group Ar does not carry any optional substituents. [0067]
  • In a further more preferred embodiment Ar represents furan, phenyl or thiazole, each of which may optionally be substituted as indicated above. [0068]
  • In a further more preferred embodiment Ar represents furan or thiazole, each of which may optionally be substituted as indicated above. [0069]
  • In a most preferred embodiment Ar represents unsubstituted furan or thiazole. [0070]
  • The side chain CH[0071] 3SO2CH2CH2NHCH2 may be linked to any suitable position of the group Ar. Similarly, the group R1 may be linked to the carbon atom carrying it from any suitable position of the group Ar.
  • In a preferred embodiment, when Ar represents furan the side chain CH[0072] 3SO2CH2CH2NHCH2 is in the 4-position of the furan ring and the link to the carbon atom carrying the group R1 is from the 2-position of the furan ring.
  • In another preferred embodiment, when Ar represents furan the side chain CH[0073] 3SO2CH2CH2NHCH2 is in the 3-position of the furan ring and the link to the carbon atom carrying the group R1 is from the 2-position of the furan ring.
  • In a most preferred embodiment, when Ar represents furan the side chain CH[0074] 3SO2CH2CH2NHCH2 is in the 5-position of the furan ring and the link to the carbon atom carrying the group R1 is from the 2-position of the furan ring.
  • In a further most preferred embodiment, when Ar represents thiazole the side chain CH[0075] 3SO2CH2CH2NHCH2 is in the 2-position of the thiazole ring and the link to the carbon atom carrying the group R1 is from the 4-position of the thiazole ring.
  • The R[0076] 3 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 bicyclic 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 preferred embodiment U represents a phenyl, indolyl, or 1H-indazolyl group substituted by an R[0077] 3 group and optionally substituted by at least one independently selected R4 group.
  • In a more preferred embodiment U represents a phenyl or 1H-indazolyl group substituted by an R[0078] 3 group and optionally substituted by at least one independently selected R4 group.
  • In a more preferred embodiment, where U represents a phenyl group the group R[0079] 3 is in the para-position relative to the bond from U to the linking NH group.
  • In a further more preferred embodiment, where U represents a 1H-indazolyl group the group R[0080] 3 is in the 1-position of the indazolyl group.
  • In a preferred embodiment R[0081] 3 represents benzyl, pyridylmethyl, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl.
  • In a further preferred embodiment R[0082] 3 represents trihalomethylbenzyloxy.
  • In a further preferred embodiment R[0083] 3 represents a group of formula
    Figure US20030176451A1-20030918-C00007
  • 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. [0084]
  • In a more preferred embodiment R[0085] 3 represents benzyloxy, fluorobenzyloxy (especially 3-fluorobenzyloxy), benzyl, phenoxy and benzenesulphonyl.
  • In a further more preferred embodiment R[0086] 3 represents bromobenzyloxy (especially 3-bromobenzyloxy) and trifluoromethylbenzyloxy.
  • In a further preferred embodiment the ring U is not substituted by an R[0087] 4 group; in an especially preferred embodiment U is phenyl or indazolyl unsubstituted by an R4 group.
  • In a further preferred embodiment the ring U is substituted by an R[0088] 4 group selected from halo or C1-4 alkoxy; especially chloro, fluoro or methoxy.
  • In a more preferred embodiment the ring U is substituted by an R[0089] 4 group wherein R4 represents halo, especially 3-fluoro.
  • In an especially preferred embodiment U together with R[0090] 4 represents methoxyphenyl, fluorophenyl, trifluoromethylphenyl or chlorophenyl.
  • In a more especially preferred embodiment U together with R[0091] 4 represents methoxyphenyl or fluorophenyl.
  • In an especially preferred embodiment the group U together with the substituent(s) R[0092] 3 and R4 represents benzyloxyphenyl, (fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl, benzylindazolyl or phenoxyphenyl.
  • In a more especially preferred embodiment the group U together with the substituent(s) R[0093] 3 and R4 represents benzyloxyphenyl, (3-fluorobenzyloxy)phenyl, (benzenesulphonyl)phenyl or benzylindazolyl.
  • In another more especially preferred embodiment the group U together with the substituent(s) R[0094] 3 and R4 represents (3-bromobenzyloxy)phenyl, (3-trifluoromethylbenzyloxy)phenyl, or (3-fluorobenzyloxy)-3-methoxyphenyl.
  • In another more especially preferred embodiment the group U together with the substituent(s) R[0095] 3 and R4 represents 3-fluorobenzyloxy-3-chlorophenyl, benzyloxy-3-chlorophenyl, benzyloxy-3-trifluoromethylphenyl, (benzyloxy)-3-fluorophenyl, (3-fluorobenzyloxy)-3-fluorophenyl or (3-fluorobenzyl)indazolyl.
  • In a most especially preferred embodiment the group U together with the substituent(s) R[0096] 3 and R4 represents benzyloxyphenyl or (3-fluorobenzyloxy)phenyl.
  • In a preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; V is CR[0097] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); Y is CR1 wherein R1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 CR[0098] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); Y is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 CR[0099] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); Y is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R3 is benzyl or fluorobenzyl; and R4 is not present.
  • In a further more preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is N; Y is CR[0100] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 CR[0101] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • 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 CR[0102] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R3 is benzyl or fluorobenzyl; and R4 is not present.
  • In a most especially preferred embodiment there is provided a compound of formula(1) or a salt or solvate thereof wherein X is N, Y is CR[0103] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is phenoxy; and R4 is not present.
  • In another more 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 CR[0104] 1 wherein R1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • In another 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 CR[0105] 1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is benzyloxy, fluorobenzyloxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • In another 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 CR[0106] 1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R3 is benzyl or fluorobenzyl; and R4 is not present.
  • In yet another preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR[0107] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted phenyl, furan or thiazole; U is phenyl or indazole; R3 is benzyl, fluorobenzyl, benzyloxy, fluorobenzyloxy, bromobenzyloxy, trifluoromethylbenzyloxy, phenoxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • In yet another most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR[0108] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is benzyloxy, fluorobenzyloxy, phenoxy or benzenesulphonyl; and R4 is not present or is halo (especially chloro or fluoro), or methoxy.
  • In yet another most preferred embodiment there is provided a compound of formula (I) or a salt or solvate thereof wherein X is CH; Y is CR[0109] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is indazole; R3 is benzyl or fluorobenzyl; and R4 is not present.
  • In a most especially preferred embodiment there is provided a compound of formula(1) or a salt or solvate thereof wherein X is CH, Y is CR[0110] 2, wherein R2 is hydrogen, halo (especially fluoro) or C1-4 alkoxy (especially methoxy); V is CR1 wherein R1 is as defined above in which Ar is unsubstituted furan or thiazole; U is phenyl; R3 is phenoxy; and R4 is not present.
  • Preferred compounds of the present invention include: [0111]
  • 4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0112]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0113]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0114]
  • (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0115]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0116]
  • (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0117]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0118]
  • N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0119]
  • N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0120]
  • N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0121]
  • N-[4-(Benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0122]
  • N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0123]
  • N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0124]
  • N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0125]
  • N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0126]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0127]
  • 6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine; [0128]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0129]
  • N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0130]
  • N-[4-(Benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0131]
  • N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0132]
  • 6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine; [0133]
  • 6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine; [0134]
  • 6-[2-({[2-(Methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine [0135]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0136]
  • N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0137]
  • N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0138]
  • N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0139]
  • N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0140]
  • 6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4-benzenesulphonyl)phenyl-4-quinazolinamine; [0141]
  • N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0142]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0143]
  • N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0144]
  • N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine; [0145]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof. [0146]
  • Other preferred compounds of the present invention include: [0147]
  • (4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine; [0148]
  • (4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine; [0149]
  • (4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)quinolin-4-yl)amine; [0150]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof. [0151]
  • Other preferred compounds of the present invention include the following (in groups denoted hereafter as Lists 1 to 48): [0152]
  • List 1 [0153]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0154]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0155]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0156]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0157]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0158]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0159]
  • List 2 [0160]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0161]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0162]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0163]
  • (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0164]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0165]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0166]
  • List 3 [0167]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0168]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0169]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0170]
  • (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0171]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0172]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0173]
  • List 4 [0174]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0175]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0176]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0177]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0178]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0179]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0180]
  • List 5 [0181]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0182]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0183]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0184]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0185]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0186]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0187]
  • List 6 [0188]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0189]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0190]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0191]
  • (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0192]
  • (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)pyrido[3,4-d]pyrimidin-4-yl)-amine; [0193]
  • List 7 [0194]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0195]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0196]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0197]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0198]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0199]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)pyrido[3,4-d]pyrimidin-4-yl)-amine; [0200]
  • List 8 [0201]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0202]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0203]
  • List 9 [0204]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)furan-2-yl)-quinazolin-4-yl)-amine; [0205]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0206]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0207]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0208]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0209]
  • List 10 [0210]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-4-yl)-quinazolin-4-yl)-amine; [0211]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0212]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0213]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0214]
  • List 11 [0215]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-5-yl)-quinazolin-4-yl)-amine; [0216]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0217]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0218]
  • (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0219]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0220]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0221]
  • List 12 [0222]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-quinazolin-4-yl)-amine; [0223]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0224]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0225]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0226]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0227]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0228]
  • List 13 [0229]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-quinazolin-4-yl)-amine; [0230]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0231]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0232]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0233]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0234]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0235]
  • List 14 [0236]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)phenyl)-quinazolin-4-yl)-amine; [0237]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0238]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0239]
  • (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0240]
  • (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-quinazolin-4-yl)-amine; [0241]
  • (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)quinazolin-4-yl)-amine; [0242]
  • List 15 [0243]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)phenyl)-quinazolin-4-yl)-amine; [0244]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0245]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0246]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0247]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-quinazolin-4-yl)-amine; [0248]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)quinazolin-4-yl)-amine; [0249]
  • List 16 [0250]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0251]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0252]
  • (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0253]
  • (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0254]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0255]
  • List 17 [0256]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)furan-2-yl)-quinazolin-4-yl)-amine; [0257]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0258]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0259]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0260]
  • 5 (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0261]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0262]
  • List 18 [0263]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-4-yl)-quinazolin-4-yl)-amine; [0264]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0265]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0266]
  • (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0267]
  • (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0268]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0269]
  • List 19 [0270]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)thiazol-5-yl)-quinazolin-4-yl)-amine; [0271]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0272]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0273]
  • (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0274]
  • (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0275]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0276]
  • List 20 [0277]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-quinazolin-4-yl)-amine; [0278]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0279]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0280]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0281]
  • (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0282]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0283]
  • List 21 [0284]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)thiazol-2-yl)-quinazolin-4-yl)-amine; [0285]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0286]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0287]
  • (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0288]
  • (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0289]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0290]
  • List 22 [0291]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)phenyl)-quinazolin-4-yl)-amine; [0292]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0293]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0294]
  • (4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0295]
  • (4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-quinazolin-4-yl)-amine; [0296]
  • (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)quinazolin-4-yl)-amine; [0297]
  • List 23 [0298]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)phenyl)-quinazolin-4-yl)-amine; [0299]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0300]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0301]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0302]
  • (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)phenyl)-quinazolin-4-yl)-amine; [0303]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)quinazolin-4-yl)-amine; [0304]
  • List 24 [0305]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0306]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0307]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0308]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0309]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0310]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0311]
  • List 25 [0312]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0313]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0314]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0315]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0316]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0317]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0318]
  • List 26 [0319]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0320]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0321]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0322]
  • (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0323]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0324]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0325]
  • List 27 [0326]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0327]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0328]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0329]
  • (4-Benzenesulphonyl-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0330]
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0331]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0332]
  • List 28 [0333]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0334]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0335]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0336]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0337]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0338]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0339]
  • List 29 [0340]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0341]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0342]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0343]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0344]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0345]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0346]
  • List 30 [0347]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0348]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0349]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0350]
  • (4-Benzenesulphonyl-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0351]
  • (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0352]
  • (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0353]
  • List 31 [0354]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0355]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0356]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0357]
  • (4-Benzenesulphonyl-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0358]
  • (4-Benzyloxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0359]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyridin-4-yl)-amine; [0360]
  • List 32 [0361]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0362]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0363]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0364]
  • (4-Phenoxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0365]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0366]
  • (4-Phenoxy-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0367]
  • (4-Phenoxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0368]
  • (4-Phenoxy-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0369]
  • List 33 [0370]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0371]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0372]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0373]
  • (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0374]
  • (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0375]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0376]
  • List 34 [0377]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0378]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0379]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0380]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0381]
  • (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0382]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino) methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0383]
  • List 35 [0384]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0385]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0386]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0387]
  • (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0388]
  • (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0389]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0390]
  • List 36 [0391]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0392]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0393]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0394]
  • (4-Benzenesulphonyl-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0395]
  • (4-Benzyloxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0396]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0397]
  • List 37 [0398]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0399]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0400]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0401]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0402]
  • (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0403]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0404]
  • List 38 [0405]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0406]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0407]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0408]
  • (4-Benzenesulphonyl-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0409]
  • (4-Benzyloxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0410]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0411]
  • List 39 [0412]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0413]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0414]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0415]
  • (4-Benzenesulphonyl-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0416]
  • (4-Benzyloxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0417]
  • (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0418]
  • List 40 [0419]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0420]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0421]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0422]
  • (4-Benzenesulphonyl-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0423]
  • (4-Benzyloxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0424]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-quinolin-4-yl)-amine; [0425]
  • List 41 [0426]
  • (4-Benzyloxy-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0427]
  • (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0428]
  • (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0429]
  • (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0430]
  • (4-Benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0431]
  • (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0432]
  • (4-Benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0433]
  • (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0434]
  • (4-Benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0435]
  • (4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0436]
  • List 42 [0437]
  • (4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0438]
  • 35 (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0439]
  • (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0440]
  • (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0441]
  • (4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0442]
  • (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0443]
  • (4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0444]
  • (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0445]
  • (4-Benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0446]
  • (4-(3-Fluoro-benzyloxy-3-fluorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0447]
  • List 43 [0448]
  • (4-Benzyloxy-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine [0449]
  • (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0450]
  • (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0451]
  • (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0452]
  • (4-Benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0453]
  • (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0454]
  • (4-Benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0455]
  • (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0456]
  • List 44 [0457]
  • (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0458]
  • (4-Benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0459]
  • (4-(3-Fluoro-benzyloxy-3-bromophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0460]
  • (4-Benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0461]
  • (4-(3-Fluoro-benzyloxy-3-iodophenyl)-(6-(5-((2methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine. [0462]
  • List 45 [0463]
  • N-[4-(Benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0464]
  • N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0465]
  • N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0466]
  • N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0467]
  • N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0468]
  • N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0469]
  • N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0470]
  • N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0471]
  • N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0472]
  • N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0473]
  • N-[1-(3-Fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0474]
  • List 46 [0475]
  • N-[4-(Benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0476]
  • N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0477]
  • N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino)methyl)-2-furyl]-4-quinazolinamine [0478]
  • N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0479]
  • N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0480]
  • N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0481]
  • N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0482]
  • N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0483]
  • N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0484]
  • N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0485]
  • N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0486]
  • List 47 [0487]
  • N-[4-(benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0488]
  • N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0489]
  • N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0490]
  • N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4yl]-4-quinazolinamine; [0491]
  • N-[4-Benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0492]
  • N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino)methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0493]
  • N-[4-Benzyloxy-3-iodophenyl]-7-methoxy-6-[2-(([2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0494]
  • N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0495]
  • N-[4-Benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0496]
  • N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0497]
  • N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-methoxy-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0498]
  • List 48 [0499]
  • N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0500]
  • N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0501]
  • N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0502]
  • N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0503]
  • N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0504]
  • N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0505]
  • N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-[2-(([2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0506]
  • N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0507]
  • N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0508]
  • N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0509]
  • N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0510]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. [0511]
  • Particularly preferred compounds of the present invention include: [0512]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0513]
  • (4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-fu ran-2-yl)-quinazolin-4-yl)-amine; [0514]
  • N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0515]
  • N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0516]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0517]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0518]
  • N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0519]
  • 6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine; [0520]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0521]
  • N-(1-Benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [0522]
  • N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine; [0523]
  • N-(3-Chloro-4-benzyloxyphenyl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine; [0524]
  • N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0525]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; [0526]
  • N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine; [0527]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. [0528]
  • Further particularly preferred compounds of the present invention include: [0529]
  • (4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine; [0530]
  • (4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine; [0531]
  • (4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)amine; [0532]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. [0533]
  • Other particularly preferred compounds of the present invention include: [0534]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0535]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinazolin-4-yl)-amine; [0536]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [0537]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinazolin-4-yl)-amine; [0538]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0539]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinazolin-4-yl)-amine; [0540]
  • (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0541]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinazolin-4-yl)-amine; [0542]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0543]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-quinolin-4-yl)-amine; [0544]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0545]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0546]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0547]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0548]
  • (4-Phenoxy-phenyl)-(7-(3-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0549]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-phenyl)-quinolin-4-yl)-amine; [0550]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. [0551]
  • Other most particularly preferred compounds of the present invention include: [0552]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)-quinolin-4-yl)-amine; [0553]
  • (4-Phenoxy-phenyl)-(7-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-5-yl)-quinolin-4-yl)-amine; [0554]
  • (4-Phenoxy-phenyl)-(7-(4-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl) amine; [0555]
  • (4-Phenoxy-phenyl)-(7-(5-((2-methanesulphonyl-ethylamino)methyl)-thiazol-2-yl)-quinolin-4-yl)-amine; [0556]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts or solvates thereof. [0557]
  • 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. [0558]
  • 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 p-toluenesulphonic, acids. [0559]
  • 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: [0560]
  • (a) the reaction of a compound of formula (II) [0561]
    Figure US20030176451A1-20030918-C00008
  • wherein X is as defined above; [0562]
  • Y′ is CL′ and V′ is N; [0563]
  • or Y′ is N and V′ is CL′; [0564]
  • or Y′ is CL′ and V′ is CR[0565] 2;
  • or Y′ is CR[0566] 2 and V′ is CL′;
  • wherein R[0567] 2 is 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) [0568]
    Figure US20030176451A1-20030918-C00009
  • and subsequently (b) reaction with appropriate reagent(s) to substitute the group R[0569] 1 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 R[0570] 1 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) [0571]
    Figure US20030176451A1-20030918-C00010
  • wherein X, Y, V, U and L are as defined above, may be prepared by the reaction of a compound of formula (VI) [0572]
    Figure US20030176451A1-20030918-C00011
  • wherein V′ and Y′ are as defined above, with appropriate reagents to substitute the group R[0573] 1 for the leaving group L′ to prepare a compound of formula (VII)
    Figure US20030176451A1-20030918-C00012
  • 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. [0574]
  • The group R[0575] 1 may, therefore, be substituted onto the basic ring system by replacement of a suitable leaving group. This may, for example, be carried out by reaction of the corresponding aryl or heteroaryl stannane derivative with the corresponding compound of formula (IV) carrying the leaving group L′ 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: [0576]
  • (a) reacting a compound of formula (IV) as defined above with appropriate reagent(s) to prepare a compound of formula (VIII) [0577]
    Figure US20030176451A1-20030918-C00013
  • wherein X and U are as defined above; [0578]
  • Y″ is CT and V″ is N; [0579]
  • or Y″ is N and V″ is CT; [0580]
  • or Y″ is CT and V″ is CR[0581] 2;
  • or Y″ is CR[0582] 2 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 R[0583] 1 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.
  • In one alternative, the group T would represent a group Ar as defined above carrying a formyl group (CHO). [0584]
  • Where T represents a group Ar carrying a formyl group the compound (of formula (VIIIa)) may be suitably prepared from the corresponding dioxolanyl substituted compound (of formula (VIIIb)), for example by acid hydrolysis. The dioxolanyl substituted compound may be prepared by reaction of a compound of formula (IV) with an appropriate reagent to substitute the relevant leaving group with the substituent carrying the dioxolanyl ring. This reagent could, for example, be an appropriate heteroaryl stannane derivative. [0585]
  • Therefore a suitable process may comprise reaction of a compound of formula (VIIIa) in which T is a group Ar carrying a formyl substituent (i.e. a —CHO group) with a compound of formula CH[0586] 3SO2CH2CH2NH2. The reaction preferably involves a reductive amination by means of an appropriate reducing agent, for example sodium triacetoxyborohydride.
  • Alternatively, another suitable process may comprise oxidation of a compound of formula (VIIIc) in which T is a group Ar carrying a substituent of formula CH[0587] 3SCH2CH2NHCH2 or CH3SOCH2CH2NHCH2. 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 compound of formula (VIIIc) in which T is a group Ar carrying a substituent of formula CH3SCH2CH2NHCH2 or CH3SOCH2CH2NHCH2 may be prepared by an analogous reaction to that described above, namely reaction of a compound of formula (VIIIa) in which T is a group Ar carrying a formyl substituent (i.e. a —CHO group) with a compound of formula CH3SCH2CH2NH2 or CH3SOCH2CH2NH2 respectively.
  • Alternatively, an analogous scheme to those described above could be used wherein the substitution of the group R[0588] 1 onto the basic ring system occurs prior to the coupling reaction with the compound of formula (III).
  • According to a further alternative process the group T is converted into the group R[0589] 1 by a de novo synthesis of a substituted heterocyclic system using appropriate agents. Such a process would involve standard synthetic methodology known to the person skilled in the art for building up the heterocylic ring system.
  • For example, T could represent a haloketone group as shown in the compound of formula (IX) in scheme 1 below which, when coupled with an appropriate N-protected thioamide [compound of formula (XI) in scheme 2], would result in the formation of an N-protected amino-substituted thiazole system of formula (X). [0590]
  • Scheme 1 outlines, for example, the synthesis of derivatives carrying a substituted thiazole ring as an R[0591] 1 substituent:
    Figure US20030176451A1-20030918-C00014
  • wherein halo is as previously defined (preferably iodo), and P′ in the compound of formula (XI) is a suitable protecting group, such as trifluorocarbonyl. [0592]
  • An analogous process may be used to prepare compounds of formula(I) which carry R[0593] 1 in the 7-position of the basic ring system from a starting compound of formula(IVb)
    Figure US20030176451A1-20030918-C00015
  • via intermediates of formulae (Xb) and (XIb) which are respectively analogous to those of formulae (Xa) and (XIb). [0594]
  • An appropriately substituted thioamide coupling reagent, suitable for preparation of a thiazole ring system, may be prepared according to Scheme 2: [0595]
    Figure US20030176451A1-20030918-C00016
  • Wherein in scheme 2 the trifluorocarbonyl protecting group in the compounds of formula (XIV), (XV) and (XVIa) is equivalent to the group P′ in scheme 1. [0596]
  • Alternatively, an analogous scheme to those described above could be used wherein the substitution of the group R[0597] 1 onto the basic ring system occurs prior to the coupling reaction with the compound of formula(III).
  • Other substituted thioamides are prepared using analogous processes to that shown above. [0598]
  • In general, the group R[0599] 2 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. 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-butyldiphenylsilyl (TBDPS).
  • 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. [0600]
  • 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. [0601]
  • 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[0602] 1-4 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. [0603]
  • 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. [0604]
  • The compounds of formulae (II) and (III) as defined above, the reagents to substitute the group R[0605] 1, and the reagent(s) to convert the group T into the group R1 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). [0606]
  • For example, a compound containing an alkylthio group may be oxidised to the corresponding sulphinyl or sulphonyl compound by use of an organic peroxide (e.g. benzoyl peroxide) or suitable inorganic oxidant (eg OXONE ®). [0607]
  • 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. [0608]
  • 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. [0609]
  • 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. [0610]
  • 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. [0611]
  • 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) and (VIII) as illustrated above, are novel and thus represent a further aspect of the present invention. [0612]
  • In particular, a further aspect of the present invention is intermediate compounds of formulae (VIIIa) and (VIIIb) defined above, with the exception of the following compounds: [0613]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0614]
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde; [0615]
  • 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde; [0616]
  • (4-Benzyloxy-phenyl)-(6-(5-[1,3-dioxolan-2-yl]-fu ran-2-yl)-quinazolin-4-yl)-amine; [0617]
  • 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde; [0618]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine; [0619]
  • 5-(4-(1-Benzyl-1 H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehyde; [0620]
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-1-methyl-pyrrole-2-carbaldehyde; [0621]
  • (1-Benzyl-1H-indazol-5-yl)-(7-(5-[1,3-dioxolan-2-yl]-furan-2-yl)-quinazolin-4-yl)-amine; [0622]
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl)-furan-2-carbaldehyde. [0623]
  • In particular, a yet further aspect of the present invention is intermediate compounds of formula (VIIIc) as defined above; [0624]
  • with the proviso that the following compound is excluded: [0625]
  • (4-Benzyloxy-phenyl)-(6-(5-((2-methanesulphinyl-ethylamino)-methyl)-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine. [0626]
  • In particular, another further aspect of the present invention is intermediate compounds of formulae (X), (XI), (XII), (XIII), (XIV), (XV) and (XVI) as defined above. [0627]
  • 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. Certain compounds of formula (I) are also demonstrated hereinafter to inhibit lck and/or zap70 protein tyrosine kinase enzymes and are expected to have activity in disease conditions in which T cells are hyperactive. [0628]
  • 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 and/or lck activity such as breast, ovarian, gastric, pancreatic, non-small cell lung, bladder, head and neck cancers, psoriasis and rheumatoid arthritis. [0629]
  • 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. [0630]
  • 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. [0631]
  • 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. [0632]
  • 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. [0633]
  • 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 rheumatoid arthritis. [0634]
  • 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. [0635]
  • 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. [0636]
  • 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 0.5 mg to 1 g, preferably 70 mg to 700 mg, more preferably 5 mg to 100 mg 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. [0637]
  • 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). [0638]
  • 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. [0639]
  • 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). [0640]
  • Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. [0641]
  • 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. [0642]
  • 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. [0643]
  • Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles and mouth washes. [0644]
  • Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas. [0645]
  • 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. [0646]
  • 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. [0647]
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations. [0648]
  • 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. [0649]
  • 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. [0650]
  • 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. [0651]
  • The animal requiring treatment with a compound, salt or solvate of the present invention is usually a mammal, such as a human being. [0652]
  • 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 70 kg 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 per se. It is envisaged that similar dosages would be appropriate for treatment of the other conditions referred to above. [0653]
  • 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. [0654]
  • 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. [0655]
  • [0656] 1H NMR spectra were obtained at 500 MHz on a Bruker AMX500 spectrophotometer, on a Bruker spectrophotometer at 300 MHz, on a Bruker AC250 or Bruker AM250 spectrophotometer at 250 MHz and on a Varian Unity Plus NMR spectrophotometer at 300 or 400 MHz. 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 progess 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. [0657]
  • Ether refers to diethylether. [0658]
  • DMSO refers to dimethylsulphoxide. [0659]
  • THF refers to tetrahydrofuran. [0660]
  • HPLC refers to high pressure liquid chromatography. [0661]
  • NMM refers to N-methylmorpholine [0662]
  • Useful preparative techniques are described in WO96/09294, WO97/03069, WO97/13771, WO95/19774, WO96/40142 and WO97/30034; also described in these publications are appropriate intermediate compounds other than those detailed below. [0663]
  • 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. [0664]
  • General Procedures [0665]
  • (A) Reaction of an Amine with a Bicyclic Species Containing a 4-chloropyrimidine or 4-chloropyridine Ring [0666]
  • The optionally substituted bicyclic species and the specified amine were mixed in an appropriate solvent (typically acetonitrile 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. [0667]
  • (B) Reaction of a Product from Procedure (A) with a Heteroaryl Tin Reagent [0668]
  • A stirred mixture of the product from Procedure (A), (containing a suitable leaving group such as chloro, bromo, iodo or triflate), a heteroaryl stannane and a suitable palladium catalyst, such as bis(triphenylphosphine)palladium (II) chloride or 1,4-bis(diphenylphosphino)butane palladium (II) chloride (prepared as described in C. E. Housecroft et. al., Inorg. Chem., (1991), 30(1), 125-130), together with other appropriate additives (such as diisopropylethylamine or lithium chloride), were heated at reflux in dry dioxane or another suitable solvent (e.g. DMF) under nitrogen until the reaction was complete. The resulting mixture was generally purified by chromatography on silica. [0669]
  • (C) Removal of a 1,3-dioxolan-2-yl Protecting Group to Liberate an Aldehyde [0670]
  • The compound containing the 1,3-dioxolan-2-yl group was suspended in an appropriate solvent, e.g. THF and treated with hydrochloric acid, either as an aqueous solution (e.g. 2N) or as a solution in dioxane (e.g. 4 molar) and stirred at ambient temperature until the reaction was judged complete (e.g. by tic or LC/MS analysis). Generally the mixture was diluted with water, and the resulting precipitate was collected by filtration, washed with water and dried to give the aldehyde. [0671]
  • (D) Reaction of an Aldehyde with an Amine by Reductive Amination [0672]
  • An aldehyde (such as the product of General Procedure C) 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 Elut™ cartridge. If desired, the isolated material was then converted into the hydrochloride salt e.g. by treatment with ethereal hydrogen chloride. [0673]
  • (E) Reaction Sequence to Prepare Appropriately Substituted Thioamides E-1 Reaction of an Aminosulfide with Chloroacetonitrile [0674]
  • To a stirred mixture of an aminosulfide and a suitable base such as sodium bicarbonate or sodium carbonate in an appropriate solvent (typically acetonitrile, although DMF or dioxane can be used) was added chloroacetonitrile dropwise. The resulting mixture was heated to reflux until the reaction was complete. The solid was filtered and the filtrate was concentrated to provide the corresponding aminonitrile. [0675]
  • E-2 Trifluoroacetamide Protection of an Aminonitrile [0676]
  • A solution of the aminonitrile (such as the product of general procedure A) and an amine base, such as triethylamine or NMM in a suitable solvent (e.g. dichloromethane), was cooled to 0° C. and trifluoroacetic anhydride was added dropwise. The resulting mixture was stirred at room temperature until the reaction was complete. Water was added and the mixture was extracted with a suitable solvent (e.g. dichloromethane), the organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by column chromatography to provide the corresponding trifluoroacetamide. [0677]
  • E-3 Oxidation of a Cyanosulfide [0678]
  • To a stirred solution of a sulfide (such as the product of general procedure El) in a suitable solvent (typically methanol/water (2:1), although dichloromethane can be used) cooled to 0° C. was added an oxidizing agent (typically oxone, although MCPBA can be used). The resulting mixture was stirred at room temperature until the reaction was complete. The reaction was concentrated to remove any organic solvents, diluted with water, and extracted with an appropriate solvent (e.g. dichloromethane). The organic layer was dried and concentrated to provide the corresponding cyanosulfone. [0679]
  • E-4 Preparation of Thioamides [0680]
  • To a solution of a cyanosulfone (such as the product of general procedure E-3) and an organic base (e.g. triethylamine) in THF was added hydrogen sulfide gas. The resulting mixture was stirred at room temperature until the reaction was complete. The mixture was concentrated and triturated with hexane to provide thioamide. [0681]
  • (F) Reaction Sequence to Prepare an Optionally Substituted Thiazole [0682]
  • F-1 Reaction of a Vinyistannane with a Product from Procedure (A) [0683]
  • A stirred mixture of the optionally substituted bicyclic 4-anilinopyrimidine species, tributyl(1-ethoxyvinyl)stannane (1 to 5 molar equivalents), and a suitable palladium catalyst (0.03 to 0.1 molar equivalents), such as bis(triphenylphosphine) palladium (II) chloride or tetrakis(triphenylphosphine) palladium (0) was heated at reflux in an appropriate solvent (typically acetonitrile, although DMF or dioxane can be used) until the reaction was complete. The resulting mixture was concentrated and generally purified by trituration with diethyl ether to provide the corresponding bicyclic pyrimidine vinyl ether. [0684]
  • F-2 Reaction of a Product from Procedure (F-1) with a Bromination Reagent [0685]
  • A bicyclic pyrimidine vinyl ether (such as the product of general procedure F-1) and 1 equivalent of a bromination reagent, such as N-bromosuccinimide or bromine, were stirred at 0° C. in a suitable solvent (typically 10% aqueous THF or dichloromethane) until the reaction was complete. The resulting mixture was dried over anhydrous magnesium sulfate and concentrated, or in the case of bromine the solid was filtered, to provide the corresponding α-bromoketone. [0686]
  • F-3 Reaction of a Product from Procedure (F-2) with a Product from Procedure (E-4) [0687]
  • A stirred mixture of an α-bromoketone (such as the product of general procedure F-2) and thioamide from Procedure E-4 in a 1:1 molar ratio was heated to 70-100° C. in an appropriate solvent (typically DMF, although acetonitrile and THF can be used) until the reaction was complete. The resulting mixture was washed with an aqueous basic solution (e.g. sodium carbonate) and extracted with a suitable solvent, e.g. ethyl acetate. The dried organic layer was concentrated and the residue was purified by column chromatography to provide the corresponding trifluoroacetamide aminothiazole. [0688]
  • F-4 Removal of a Trifluoroacetamide Protecting Group to Liberate an Aminothiazole [0689]
  • A mixture of a trifluoroacetamide protected aminothiazole (such as the product of general procedure F-3) in 2M NaOH/methanol (1:1) was stirred at room temperature until the reaction was complete. The mixture was concentrated, poured into water and extracted with an appropriate solvent e.g. 10% MeOH/dichloromethane. The dried organic layer was concentrated, then dissolved in ethyl acetate/MeOH (1:1) and treated with 4M HCl/dioxane. The resulting solid was filtered to provide the corresponding amine hydrochloride salt. [0690]
  • Synthesis of Intermediates [0691]
  • N-5-[N-tert-Butoxycarbonyl)amino]-2-chloropyridine [0692]
  • A stirred solution of 6-chloronicotinic acid (47.3 g), diphenylphosphoryl azide (89.6 g) and triethylamine (46 ml) in t-butanol (240 ml) were heated under reflux under nitrogen for 2.5 hours. 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 one hour and filtered. The solid was washed with water and dried in vacuo at 70° C. to give the title compound (62 g) as a pale brown solid; m.p. 144-146° C.; δH [[0693] 2H6]-DMSO 8.25(1H, d), 7.95 (1H, bd), 7.25 (1H, d), 6.65(1H, 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 WO95/19774, 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. [0694]
  • 2-Amino-4-fluoro-5-iodo-benzoic Acid [0695]
  • To a vigorously stirred solution of dichloromethane (700 ml), methanol (320 ml), and 2-amino-4-fluoro-benzoic acid (33.35 grams, 215 mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles) followed by portion addition of benzyltrimethyl ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours. The mixture was filtered to remove the insolubles. The remaining solid residue was washed with 200 ml of dichloromethane. The filtrate was concentrated and redissolved in a one to one mixture of ethyl acetate (1 litre) and a 0.2 N solution of sodium hydroxide (1 litre), added-to a 2 litre separatory funnel and extracted. The organic layer was washed with an additional 200 ml of water. The aqueous layers were combined and acidified with 2N hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with water and dried under vacuum at 60° C. to yield 46.5 grams (77%) of the title compound. [0696] 1H NMR (400 MHz, DMSO-d6) δ: 8.04(d, 1H), 7.1 (s, broad, 2H), 6.63(d, 1H). ESI-MS m/z 280 (M−1).
  • 4-Fluoro-5-iodo-isatoic Anhydride [0697]
  • Anhydrous dioxane (0.5 litres), 2-amino-4-fluoro-5-iodo-benzoic acid (46 grams, 164 mmoles), and trichloromethylchloroformate (97.4 grams, 492 mmoles) were added to a one litre one neck flask equipped with a magnetic stir bar and reflux condenser. The solution was placed under anhydrous nitrogen, stirred and heated to reflux for 16 hours. The reaction mixture was allowed to cool and was poured into one litre of hexanes. The solid was collected by suction filtration, washed with an additional 0.5 litres of hexanes, and dried under vacuum at room temperature to yield 45.5 grams (90%) of the title compound. [0698] 1H NMR (400 MHz, DMSO-d6) δ: 11.86(s, 1H), 8.24(d, 1H), 6.84(d, 1H). ESI-MS m/z 308 (M+1).
  • 4-Chloro-6-bromoquinazoline and 4-Chloro-6-iodoquinazoline were Prepared as Described in WO 96/09294. [0699]
  • 4-Hydroxy-6-iodo-7-fluoroquinazoline [0700]
  • Dimethylformamide (0.5 litres), 4-fluoro-5-iodo-isatoic anhydride (45 grams, 147 mmoles), and formamidine acetate (45.92 grams, 441 mmoles), were combined in a one litre one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated at 110° C. for 6 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to one third its original volume on the rotary evaporator. The resulting mixture was poured onto 3 litres of ice water. The resulting precipitated solid was collected by suction filtration. The solid was washed with an additional one litre of distilled water. The resulting solid was dried under vacuum at 70° C. to yield 38.9 grams (91%) of the title compound. [0701] 1H NMR (400 MHz, DMSO-d6) δ: 12.43(s, 1H), 8.46(d, 1H), 8.12(s, 1H), 7.49(d, 1H). ESI-MS m/z 291(M+1).
  • 4-Chloro-6-iodo-7-fluoro-quinazoline Hydrochloride [0702]
  • Thionyl chloride (0.6 litres), 4-hydroxy-6-iodo-7-fluoro-quinazoline (36 grams, 124 mmoles), and dimethylformamide (6 ml) were combined in a one litre one-neck flask fitted with a magnetic stir bar. The mixture was placed under anhydrous nitrogen and heated to a gentle reflux for 24 hours. The mixture was allowed to cool, followed by concentrating the reaction mixture to a thick yellowish residue. To this residue was added dichloromethane (0.1 litre) and toluene (0.1 litre). The mixture was concentrated to dryness. This procedure was repeated two additional times. To the resulting solid was added 0.5 litres of dry dichloromethane and the mixture was stirred for one hour. The mixture was filtered and the remaining solids were washed with minimal dichloromethane. The dichoromethane filtrates were combined, concentrated to a solid, and dried under vacuum at room temperature to yield 28.6 grams (67%) of the title compound. [0703] 1H NMR (400 MHz, CDCl3-d1) δ: 9.03(s, 1H), 8.76(d, 1H), 7.69(d, 1H). ESI-MS m/z 309(M+1).
  • 2-Bromo-4-(1,3-dioxolan-2-yl) Thiazole [0704]
  • 2-Bromothiazole-4-carbaldehyde (6.56 g, 34.17 mmol) [A. T. Ung, S. G. Pyne/Tetrahedron: Asymmetry 9 (1998) 1395-1407]and ethylene glycol (5.72 ml, 102.5 mmol) were heated under reflux in toluene (50 ml),with a Dean and Stark trap fitted, for 18 hr. The product was concentrated and purified by column chromatography (15% ethyl acetate/hexane) to give the product as a yellow solid (6.03 g); m/z 236,238. [0705]
  • 4-(1,3-Dioxolan-2-yl)-5-(tributylstannyl)Thiazole [0706]
  • 2-Bromo-4-(1,3-dioxolan-2-yl) thiazole (6.4 g, 27.14 mmol) was stirred at −780 C in dry THF (38 ml).1.6M n butyl lithium in hexane (18.6 ml, 29.78 mmol) was added dropwise under nitrogen. After 30 min at this temperature, tributyl tin chloride (7.35 ml, 27.14 mmol) was added dropwise. The reaction was allowed to warm to 0° and water (20 ml) was added. The product was extracted into ether (3×100 ml). The combined organic extracts were dried (MgSO[0707] 4) and evaporated. The residue was triturated with isohexane (3×100 ml) and the mother liquors were decanted, combined and concentrated to give a brown oil (11.88 g); m/z 444-450.
  • 1-N-Benzyl-5-nitro-1H-indazole and 2-N-Benzyl-5-nitro-1H-indazole [0708]
  • A stirred mixture of 5-nitroindazole (50 g), potassium carbonate (46.6 g, 1.1 equiv.) and benzyl bromide (57.6 g, 1.1 equiv) in N,N-dimethylformamide (500 ml) was heated at 75° C. for a period of 4 hours. The reaction was then cooled and water (500 ml) was gradually added to precipitate the product which was filtered off and washed with water (50 ml) and dried in the air at ambient temperature. The weight of pale yellow solid thus obtained was 72.3 g (93%), m.p. 95-97° C.; HPLC (Partisil 5, dichloromethane, 4 ml/min, 250 nm) gave an isomer ratio (1-N-benzyl: 2-N-benzyl) of 63:37 (RT-1N 3.4 min, RT-2N 6.6 min). To a filtered solution of the mixed regioisomers (100 g) in acetone (470 ml) at room temperature was added, gradually with stirring, water (156 ml) and the mixture was stirred for one hour. The resultant yellow crystalline solid was filtered off and dried in the air at ambient temperature to give 36.4 g (34%) of material; m.p.124-126° C.; HPLC showed an isomer ratio (1-N-benzyl 2-N-benzyl) of 96:4; □□ (CDCl[0709] 3) 5.58 (2H,s,CH2), 7.12-7.15(2H) & 7.22-7.29(3H)-(phenyl), 7.33 (1H,dt, J=1 Hz & 9 Hz, H-7), 8.15(1H,dd, J=2 Hz & 9 Hz,H-6), 8.19(1H,d,J=1 Hz,H-3), 8.67 (1H,dd,J=1 Hz & 2 Hz, H-4).
  • Also note the published method in FR 5600, Jan. 8, 1968. [0710]
  • 5-Amino-1-N-benzyl-1H-indazole [0711]
  • 1-Benzyl-5-nitroindazole (400 g) was suspended in ethanol (5 litre) and hydrogenated in the presence of 5% platinum on carbon catalyst (20 g) 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 305 g (86%) of material, m.p.150-152° C.; HPLC (Supelcosil ABZ+, gradient 0.05% trifluoroacetic acid in water/0.05% trifluoroacetic acid in acetonitrile, 1.5 ml/min, 220 nm) showed <1% of the corresponding 2-N-isomer (RT-1 N 6.03 min, RT-2N 5.29 min); □□ (CDCl[0712] 3) 3.3-3.8(2H,broad s,NH2), 5.47 (2H,s,CH2), 6.74 (1H,dd,J=2 Hz & 9 Hz,H-6), 6.87 (1H,dd,J=1 Hz & 2 Hz,H-4), 7.06-7.11(3H) & 7.17-7.25 (3H)-(phenyl & H-7), 7.77 (1H,d,J=1 Hz,H-3).
  • Also note the published method in FR 5600, Jan. 8, 1968. [0713]
  • 1-Benzyl-3-methyl-5-nitro-1H-indazole [0714]
  • 2-Fluoro-5-nitroacetophenone (H. Sato et al, Bioorganic and Medicinal Chemistry Letters, 5(3), 233-236,1995) (0.24 g) was treated with triethylamine (0.73 ml)and benzyl hydrazine dihydrochloride (0.255 g) in ethanol (20 ml) at reflux under N[0715] 2 for 8 days. The mixture was cooled and the solid 1-benzyl-3-methyl-5-nitroindazole (0.16 g) was collected by filtration; m/z (M+1)+268.
  • 1-Benzyl-3-methyl-1H-indazol-5-ylamine [0716]
  • 1-Benzyl-3-methyl-5-nitroindazole (0.15 g) in THF (15 ml) was treated with platinum on carbon (0.05 g, 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)[0717] +268.
  • Further Amino-Indazole Intermediates [0718]
  • The relevant nitro-substituted 1H-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-1H-indole described above. [0719]
  • Amines prepared by such methods include: [0720]
  • 5-Amino-1-benzyl-1H-indazole; m/z (M+1)[0721] +224
  • 5-Amino-1-(2-fluorobenzyl)-1H-indazole; m/z (M+1)[0722] +242
  • 5-Amino-1-(3-fluorobenzyl)-1H-indazole; m/z (M+1)[0723] +242
  • 5-Amino-1-(4-fluorobenzyl)-1H-indazole; m/z (M+1)[0724] +242
  • 5-Amino-1-(2-pyridylmethyl)-1H-indazole; m/z (M+1)[0725] +225
  • 5-Amino-1-(3-pyridylmethyl)-1H-indazole; m/z (M+1)[0726] +225
  • 5-Amino-1-(4-pyridylmethyl)-1H-indazole; m/z (M+1)[0727] +225
  • 5-Amino-1-(2,3-difluorobenzyl)-1H-indazole; m/z (M+1)[0728] +260
  • 5-Amino-1-(3,5-difluorobenzyl)-1H-indazole; m/z (M+1)[0729] +260.
  • 1-Benzenesulphonylindol-5-yl-amine was Prepared According to the Published Method (J. Org. Chem., 55,1379-90, (1990)). [0730]
  • 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[0731] 4) 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: [0732]
  • Step 1: Preparation of the Precursor Nitro-Compounds [0733]
  • 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. [0734]
  • 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 (×2), and the combined dichloromethane layers were concentrated in vacuo. [0735]
  • Purification B: removal of insoluble material by filtration, followed by concentration of the reaction mixture in vacuo, and chromatography on silica. [0736]
  • Step 2: Reduction to the Corresponding Aniline [0737]
  • The precursor nitro compound was reduced by catalytic hydrogenation at atmospheric pressure using 5% Pt/carbon, in a suitable solvent (eg ethanol, 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 HCl (e.g. in a solution in dioxane) to give the corresponding hydrochloride salt. [0738]
  • Anilines prepared by such methods include: [0739]
  • 4-(2-Fluorobenzyloxy)aniline; m/z (M+1)[0740] +218
  • 4-(3-Fluorobenzyloxy)aniline; m/z (M+1)[0741] +218
  • 4-(4-Fluorobenzyloxy)aniline; m/z (M+1)[0742] +218
  • 3-Chloro-4-(2-fluorobenzyloxy)aniline; m/z (M+1)[0743] +252
  • 3-Chloro-4-(3-fluorobenzyloxy)aniline; m/z (M+1)[0744] +252
  • 3-Chloro-4-(4-fluorobenzyloxy)aniline; m/z (M+1)[0745] +252
  • 4-Benzyloxy-3-chloroaniline; m/z (M+1)[0746] +234
  • and, in appropriate cases, their hydrochloride salts. 4-Benzenesulphonylaniline was prepared by the published method (Helv. Chim. Acta., 1983, 66(4), p1046. [0747]
  • [0748] 4-Benzyloxy-3-trifluoromethyl-nitrobenzene
  • 60% NaH dispersion (1.4 g, 33.5 mmol) in mineral oil was washed with hexanes and then suspended in DMF (10 ml). To this NaH suspension in DMF, added benzyl alcohol (2.8 ml, 26.3 mmol) with water bath to keep the temperature below 30° C. The reaction mixture was stirred until the evolution of the hydrogen gas ceased. To a solution of 2-fluoro-5-nitrobenzotrifluoride (5.0 g, 23.9 mmol) in DMF (20 ml) was added the benzyl alkoxide solution slowly at 0° C. Upon the completion of the addition, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 200 ml ice water, stirred until the yellow solid was formed. Filtered and the solid was washed with water and then trituated with pentane. 5.9 g yellow solid was collected (yield: 83%). ESI-MS m/z 298 (M+H)[0749] +
  • 4-Benzyloxy-3-trifluoromethyl-aniline [0750]
  • Raney Ni suspension (about 200 mg Ni) was stirred with methanol. The supernate was decanted. This was repeated twice and then fresh methanol was added. To this suspension of Ni in methanol, was added 2-O-benzyl-5-nitrotrifluoride (375 mg, 1.26 mmol). With the water bath to keep the temperature below 30 ° C., the hydrazine hydrate (189 mg, 3.79 mmol) was slowly added. Upon the completion of addition, the reaction mixture was stirred at room temperature for 10 minutes and then 45° C. until evolution of nitrogen gas ceased. Filtered through Celite® and the filtrate was concentrated under reduced pressure. 336 mg thick yellow syrup was obtained (yield: 100%). ESI-MS m/z 268 (M+H)[0751] +.
  • 4-(Tributylstannyl)thiazole-2-carbaldehyde [0752]
  • 4-Bromo-2-(tributylstannyl)thiazole (T. R. Kelly and F. Lang, [0753] Tetrahedron Lett., 36, 9293, (1995)) (15.0 g) was dissolved in THF (150 ml) under a nitrogen atmosphere, cooled to −85□C and treated with t-BuLi (1.7M, in pentane, 43 ml). The mixture was stirred at −85□C for 30 min, and then N-formylmorpholine (8.4 g) was added by syringe. After further stirring at −85□C for 10 min the mixture was allowed to warm to room temperature. Water (200 ml) was added and the mixture was extracted with diethyl ether (4×100 ml). The combined ethereal extracts were washed with water, dried (NaSO4), and concentrated in vacuo. Chromatography on silica, eluting with 10%ether/i-hexane, gave the title compound as a yellow oil; □□[2H6]DMSO 10.03 (1H,s), 8.29 (1H,s), 1.55(6H,q), 1.21-1.37 (6H,m), 1.09-1.20 (6H,m), 0.85 (9H,t).
  • (1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amine Hydrochloride [0754]
  • Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [[0755] 2H6]-DMSO 9.08 (1H,s), 8.92 (1H,s), 8.82 (1H,s), 8.23 (1H,d), 8.19 (1H,s), 7.80 (1H,d), 7.70 (1H,dd), 7.38-7.22 (5H,m), 5.69 (2H,s); m/z (M+1)+387.
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1.3-dioxolan-2-yl]-furan-2-yl)-pyrido[3,4-d]-pyrimidin-4-yl)-amine [0756]
  • (1-Benzyl-1H-indazol-5-yl)-(6-chloropyrido[3,4-d]pyrimidin-4-yl)-amine (4.28 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem Soc., Chem. Commun., (1988), p560) (10 g) and 1,4-bis(diphenylphosphino)butane palladium (II) chloride (1 g) were heated at reflux in dioxane (150 ml) for 24 hr (Procedure B). The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound as a yellow solid; □□[[0757] 2H6]-DMSO 10.46 (1H, s), 9.17 (1H, s), 8.74 (1H, s), 8.52 (1H, s), 8.23 (1H, s), 8.18 (1H, s), 7.80-7.68 (2H, m), 7.41-7.22 (5H, m), 7.17 (1H, d), 6.80 (1H, d), 6.06 (1H, s), 5.71 (2H, s), 4.20-3.96 (4H, m).
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde [0758]
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-[1,3-dioxolanyl]-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (3.03 g) and 2N HCl (50 ml) were stirred in THF (50 ml) for 16 hr. The resulting precipitate was filtered and washed with water to give the hydrochloride salt of the product; δH [[0759] 2H6]DMSO 11.70 (1H,s), 9.74 (1H,s) 9.30 (1H,s), 9.27 (1H,s), 8.85 (1H,s), 8.23 (1H,s), 8.18 (1H,s), 7.68-7.87 (3H,m), 7.55 (1H,d), 7.22-7.38 (5H,m), 5.71 (2H,s). Subsequent neutralisation with triethylamine in ethanol/water gave the title compound; δH [2H6]-DMSO 9.64(1H,s), 9.19 (1H,s), 9.09(1H,s), 8.72(1H,s), 8.12(2H,m), 7.71 (2H,m), 7.63(1H,dd), 7.43(1H,d), 7.20(5H,m), 5.62(2H,s).
  • (4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine [0760]
  • Prepared according to Procedure A from 4-benzyloxyaniline and 4,6-dichloro-pyrido[3,4-d]pyrimidine; □□ (CDCl[0761] 3) 9.11 (1H,s), 8.78 (1H,s), 7.75 (1H,d), 7.56 (2H,dd), 7.40 (5H,m), 7.15 (2H,d), 5.10 (2H,s); m/z (M+1)+409.
  • 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde [0762]
  • (4-Benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (4.0 g, 11.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (J. Chem. Soc., Chem. Commun., (1988), 560) (6.0 g, 14.0 mmol) were reacted together in a procedure analogous to Procedure B above for 20 hrs. The reaction mixture was allowed to cool, 1N HCl (50 ml) added and stirred at room temperature for 15 minutes. The reaction was filtered and the residue washed with dioxane (20 ml) and 2N HCl (20 ml). The combined filtrate and washings were stirred at room temperature for a further hour. The dioxane was removed under vacuum, the reaction diluted with water and the solid which precipitated was collected by filtration, and washed with water, iso-hexane and acetone. This precipitate was converted to the free base by partitioning into a mixture of triethylamine, ethyl acetate and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent removed under vacuum. The residue was triturated with iso-hexane/ethyl acetate to give the product (2.41 g, 52%) as a yellow solid; □□ [[0763] 2H6]-DMSO 10.60 (1H, b, NH), 9.83 (1H, s, CHO), 9.30 (1H, s, 2-H), 9.08 (1H, s, 5-H or 8-H), 8.76 (1H, s, 5-H or 8-H), 7.89 (1H, d, furan-H), 7.82 (2H, d, 2′-H, 6′-H), 7.65-7.42 (6H, m, 5×Ph-H, furan-H), 7.21 (2H, d, 3′-H, 5′-H), 5.26 (2H, s, OCH2); m/z (M+1)+423.
  • (4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine [0764]
  • Reaction of (4-benzyloxyphenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)amine (5.44 g, 15.0 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (10.4 g, 24.2 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic amount) in dioxane (150 ml) according to Procedure B, followed by purification by silica gel chromatography (eluted with 50-100% EtOAc/i-hexane), allowed the isolation of the dioxolane product (3.45 g, 7.40 mmol, 49%); □□ [[0765] 2H6]DMSO 10.28 (1H,s), 9.13 (1H,s), 8.69 (1H,s), 8.61 (1H,s), 7.71 (2H,d), 7.31-7.52 (5H,m), 7.14 (1H,d), 7.09 (2H,d), 6.77 (1H,d), 6.03 (1H,s), 5.15 (2H,s), 3.95-4.19 (4H,m).
  • This could then be converted to 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (identical to that described above) using Procedure C. [0766]
  • (4-Phenoxyphenyl)-(7-iodoquinolin-4-yl)amine [0767]
  • 4-Chloro-7-iodoquinoline (10 g, 34 mmol) [Semenov, V. P.; Studenikov, A. N. Synthesis of 7-iodo-4-aminoquinoline derivatives. Khim. Geterotsikl. Soedin. (1980), Issue 7, 972-5] and 4-phenoxyaniline (6.38 g, 34 mmol) in butanol (75 ml) were heated at gentle reflux (120° C.) overnight (18 hrs). On cooling the resultant precipitate was collected by filtration and washed with acetonitrile (2×50 ml). The resultant solid was suspended in chloroform (500 ml) and 2N sodium carbonate solution (300 ml) and heated at 75° C. for 45 mins. On cooling the resultant precipitate was collected by filtration, washed with water (2×50 ml) and dried to yield the product as a pale brown solid. (9.95 g, 66%) δH [[0768] 2H6] DMSO 8.35(3H,m), 8.20(1H,s), 8.10(1H,d), 7.85(1H,s), 7.35(4H,m), 7.15(4H,d), 6.75(1H,d).
  • (4-Benzyloxyphenyl)-(6-bromoquinazolin-4-yl)-amine Hydrochloride [0769]
  • 4-Chloro-6-bromoquinazoline (0.25 g, 1.0 mmol) and 4-benzyloxyaniline (0.25 g, 1.3 mmol) were mixed in 2-propanol (6 ml) 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 (0.39 g, 88%); δH [[0770] 2H6]-DMSO 11.60 (1H, b, NH), 9.21 (1H, s, 5-H), 8.86 (1H, s, 2-H), 8.20 (1H, d, 7-H), 7.90 (1H, 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-iodoquinazolin-4-yl)-amine Hydrochloride [0771]
  • 4-Chloro-6-iodoquinazoline (8 g) was treated with 4-benzyloxyaniline (5.5 g) in acetonitrile (500 ml) at reflux under N[0772] 2 for 18 hours. Subsequent cooling and filtration gave the title compound (13.13 g); δH [2H6]-DMSO 11.45 (1H, b, NH), 9.22 (1H, s, 5-H), 8.89 (1H, s, 2-H), 8.36 (1H, d, 7-H), 7.69 (1H, 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 (M+1)+454.
  • (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0773]
  • Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml) and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110° C. (oil bath temperature) for 16 hours. The mixture was cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. δH (400 MHz, DMSO-d[0774] 6): 11.2(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H), 7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
  • (1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0775]
  • Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-iodo-7-fluoroquinazoline. δH (400 MHz, DMSO-d[0776] 6): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H), 8.18(s, 1H), 8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H), 7.29(m, 2H), 7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).
  • (4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0777]
  • Prepared according to Procedure A from 4-(benzenesulphonyl)phenylamine and 4-chloro-6-iodo-7-fluoroquinazoline. [0778] 1H NMR (400 MHz, DMSO-d6) δ: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61 (m, 2H). ESI-MS m/z 504(M−1).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)amine [0779]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-3-chlorophenyl)amine and 4-chloro-6-iodo-quinazoline. [0780] 1H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506 (M+1).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)amine [0781]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-3-fluorophenyl)amine and 4-chloro-6-iodo-quinazoline. [0782] 1H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d, 1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z 490 (M+1).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)Amine [0783]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-3-methoxyphenyl)amine and 4-chloro-6-iodo-quinazoline. [0784] 1H NMR 400 MHz (DMSO-d6) 11.29 (bs, 1H0; 9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H); 7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80 (s, 3H); MS m/z 502 (M+1)
  • 6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)Amine [0785]
  • Prepared according to Procedure A from 4-benzyloxy)-3-fluorophenylamine and 4-chloro-6-iodo-quinazoline. [0786] 1H NMR (DMSO-d6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H); 7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H); 7.24 (m, 1H); 5.18 (s, 2H); MS m/z 472 (M+1)
  • 6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0787]
  • Prepared according to Procedure A from (4-(3-bromobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. [0788] 1H NMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H); 7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H); 5.17 (s, 2H).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0789]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. [0790] 1H NMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H); 7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m, 1H); 7.03 (d, 2H); 5.13 (s, 2H); MS m/z 472 (M+1)
  • 6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0791]
  • Prepared according to Procedure A from (4-(3-trifluoromethylbenzyloxy)-phenyl)amine and 4-chloro-6-iodo-quinazoline. [0792] 1H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).
  • 6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)Amine [0793]
  • The mixture of 4-chloro-6-iodo-quinazoline (366 mg, 1.26 mmol) and 4-O-benzyl-3-trifluoroaniline (405 mg, 1.26 mmol) in isopropanol (12 ml) was heated to reflux for 3.5 hours. Filtered, washed with isopropanol and dried. 535 mg yellow solid was afforded. (yield: 76%). ESI-MS m/z 522 (M+H)[0794] +.
  • (4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine [0795]
  • Synthesized according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO[0796] 4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellowish solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1(s, 1H), 8.85(d, 1H), 8.45(s, 1H), 7.6(m, 3H), 7.44(d, 2H), 7.38(m, 2H), 7.31 (m, 1H), 7.03(m, 2H), 6.94(m, 1H), 6.74(d, 1H), 6.01(s, 1H), 5.1(s, 2H), 4.10(m, 2H), 3.96(m, 2H). ESI-MS m/z 482(M−1).
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine [0797]
  • Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ[0798] 1H NMR (400 MHz, DMSO-d6) δ 10.27(s, 1H), 8.89(d, 1H), 8.46(s, 1H), 8.1(d, 2H), 7.69(d, 1H), 7.61(m, 2H), 7.26(m, 5H), 6.96(m, 1H), 6.74(d, 1H), 6.01 (s, 1H), 5.65(s, 2H), 4.09(m, 2H), 3.96(m, 2H). ESI-MS m/z 506(M−1).
  • (4-Benzenesulphonyl)phenyl-(6-(5-(1,3-dioxolan-2-yl)-fu ran-2-yl)-7-fluoro-quinazolin-4-yl)-amine [0799]
  • Prepared according to Procedure B from (4-benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ[0800] 1H NMR (400 MHz, DMSO-d6) 10.49(s, 1H), 8.88(d, 1H), 8.63(s, 1H), 8.1 (d, 2H), 7.95(m, 4H), 7.65(m, 4H), 6.97(m, 1H), 6.75(d, 1H), 6.01 (s, 1H), 4.09(m, 2H), 3.97(m, 2H). ESI-MS m/z 516(M−1).
  • (4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine [0801]
  • Prepared according to Procedure B from (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.5 g, 3.7 mmol) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (1.9 g, 4.42 mmol) dissolved in dioxan (30 ml) and heated at reflux under nitrogen for 6 hr. The solvent was removed from the cooled reaction under vacuum, and the residual oil was triturated with iso-hexane/ethyl acetate to give the product (1.07 g, 62%) as a pale yellow solid; δH [[0802] 2H6]-DMSO 9.96 (1H, b, NH), 8.80 (1H, s, 5-H), 8.51 (1H, s, 2-H), 8.18 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (2H, d, 2′-H, 6′-H), 7.58-7.30 (5H, m, 5×Ph-H), 7.10 (3H, m, 3′-H, 5′-H, furan 3-H), 6.78 (1H, d, furan 4-H), 6.12 (1H, s, CH02), 5.18 (2H, s, PhCH2), 4.22-3.94 (4H, m, 2×CH2); m/z 466 (M+1)+.
  • (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine [0803]
  • Prepared according to Procedure B using 6-Iodo-(4-benzyloxy-3-trifluoromethyl-phenyl)-quinazolin-4-yl)amine (480 mg, 0.92 mmol), and 5-tributyltin-(1,3-dioxolan-2-yl)-furan (731 mg, 1.38 mmol) in dioxane (10 ml). The resulting product was a yellow solid (0.47 g, 95.8% yield). ESI-MS m/z 534 (M+H)[0804] +.
  • 5-(4-(4-Benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde [0805]
  • Prepared according to Procedure C using (4-Benzyloxy-3-trifluoromethylphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (470 mg, 0.88 mmol) solution in THF (5 ml) followed by the addition of 2N HCl (20 ml) at room temperature. The resulting mixture was stirred for 30 minutes. Water was added (15 ml) then filtered. The yellow solid was washed with water and small amount of ether and dried in vacuo (0.39 g, 84% yield). ESI-MS m/z 490 (M+H)[0806] +.
  • (4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine [0807]
  • Prepared according to Procedure B from a solution of (4-benzyloxyphenyl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amine (0.30 g, 0.59 mmol), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (0.37 g, 0.86 mmol), lithium chloride (78 mg, 1.8 mmol), and dichloro-bis(triphenylphosphine)palladium (90 mg, 0.13 mmol) in 2 ml of DMF under nitrogen was stirred at 85-90° C. for 50 minutes. The cooled reaction mixture was partitioned between 30 ml of water and 40 ml of ethyl acetate. The organic solution was washed with 30 ml of brine, dried with Na[0808] 2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with hexanes/ethyl acetate (1:1 to 0:1). The resulting solution was concentrated to near dryness and the resulting solid suspended in ether and filtered to give 0.232 g of product as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 9.90(s, 1H), 8.71 (s, 1H), 8.40(s, 1H), 7.60(d, 2H), 7.44(d, 2H), 7.37(t, 2H), 7.30(t, 1H), 7.24(s, 1H), 7.00(m, 3H), 6.67(d, 1H), 5.99(s, 1H), 5.09(s, 2H), 4.10(m, 2H), 4.02(s, 3H), 3.95(m, 2H). ESI-MS m/z 496(M+1).
  • (4-Benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine [0809]
  • Prepared according to Procedure B from a solution of (4-benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine hydrochloride (508 mg, 1 mmole), 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan (645 mg, 1.5 mmole), diisopropylethyl amine (650 mg, 5 mmole), and dichlorobis(triphenylphosphine) palladium (140 mg, 0.2 mmole) in 6 ml of DMF under nitrogen was stirred at 100° C. (oil bath temperature) for 4 hours. The cooled reaction mixture was extracted with water (100 ml) and ethyl acetate (100 ml). The organic phase was washed with brine (100 ml). The aqueous layers were combined and washed with additional ethyl acetate (100 ml). The organic layers were combined, dried with MgSO[0810] 4, filtered and concentrated to a residue. The residue was chromatographed on silica gel with a methanol-chloroform mixture. Fractions were collected, combined, and concentrated. The resultant solid was suspended in dichloromethane (10 ml) and diethyl ether was added to facilitate precipitation. The solid was filtered and dried under vacuum at room temperature to yield a yellow solid 287 mg (59%). 1H NMR (400 MHz, DMSO-d6) δ: 10.1 (s, 1H), 8.85 (d, 1H), 8.45 (s, 1H), 7.6 (m, 3H), 7.44 (d, 2H), 7.38 (m, 2H), 7.31 (m, 1H), 7.03 (m, 2H), 6.94 (m, 1H), 6.74 (d, 1H), 6.01 (s, 1H), 5.1 (s, 2H), 4.10 (m, 2H), 3.96 (m, 2H). ESI-MS m/z 482(M−1).
  • (4-Benzyloxyphenyl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0811]
  • Prepared according to Procedure A from 4-chloro-6-iodo-7-fluoro-quinazoline hydrochloride (4.02 grams, 11.65 mmoles), anhydrous dioxane (70 ml), dichloromethane (20 ml), and 4-benzyloxyaniline hydrochloride (2.83 grams, 12 mmoles). The mixture was stirred and heated to 110° C. (oil bath temperature) for 16 hours, cooled to room temperature and filtered to remove the precipitated solids. The solids were washed with cold anhydrous dioxane (100 ml) followed by cold anhydrous diethyl ether. The yellowish solid was collected and dried under vacuum at room temperature to yield 4.68 grams (79%) of the title compound. δH NMR (400 MHz, DMSO-d[0812] 6): 11.2(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 7.64(d, 1H), 7.58(d, 2H), 7.44(d, 2H), 7.38(m, 2H), 7.31 (m, 1H), 7.09(d, 2H), 5.14(s, 2H) ESI-MS m/z 472(M+1).
  • (1-Benzyl-1H-indazol-5-yl)-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0813]
  • Prepared according to Procedure A from 1-benzyl-1H-indazol-5-ylamine and 4-chloro-6-iodo-7-fluoroquinazoline. 8H NMR (400 MHz, DMSO-d[0814] 6): 11.55(s, 1H), 9.41 (d, 1H), 8.8(s, 1H), 8.18(s, 1H), 8.05(d, 1H), 7.78(d, 1H), 7.69(d, 1H), 7.61 (m, 1H), 7.29(m, 2H), 7.23(m, 3H), 5.67(s, 2H). ESI-MS m/z 496(M+1).
  • (4-Benzenesulphonyl)phenyl-(6-iodo-7-fluoro-quinazolin-4-yl)-amine Hydrochloride [0815]
  • Prepared according to Procedure A from 4-benzenesulphonyl)phenylamine and 4-chloro-6-iodo-7-fluoroquinazoline. δHNMR (400 MHz, DMSO-d[0816] 6) δ: 10.89(s, 1H), 9.3(d, 1H), 8.79(s, 1H), 8.07(d, 2H), 8.0(d, 2H), 7.94(d, 2H), 7.67(m, 2H), 7.61 (m, 2H). ESI-MS m/z 504(M−1).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-chlorophenyl)-quinazolin-4yl)Amine [0817]
  • Prepared according to Procedure A from 4-(3-fluorobenzyloxy)-3-chlorophenyl)-amine and 4-chloro-6-iodoquinazoline. [0818] 1H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H); 8.58 (s, 1H); 8.09 (d, 1H); 8.00 (d, 1H); 7.61 (d, 1H); 7.52 (d, 1H); 7.44 (m, 1H); 7.20-7.33 (m, 3H); 7.15 (m, 1H); 5.21 (s, 2H); MS m/z 506 (M+1)
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-fluorophenyl)-quinazolin-4yl)Amine [0819]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and 4-chloro-6-iodoquinazoline. [0820] 1H NMR (DMSO-d6) 9.83 (s, 1H); 8.92 (s, 1H); 8.57 (s, 1H); 8.08 (d, 1H); 7.85 (d, 1H); 7.53 (d, 1H); 7.50 (d, 1H); 7.43 (m, 1H); 7.30-7.20 (m, 3H); 7.15 (m, 1H); 5.20 (s, 2H); MS m/z 490 (M+1)
  • 6-Iodo-(4-(3-fluorobenzyloxy)-3-methoxyphenyl)-quinazolin-4yl)Amine [0821]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-3-fluorophenyl)-amine and 4-chloro-6-iodoquinazoline. [0822] 1H NMR 400 MHz (DMSO-d6) 11.29 (bs, 1H0; 9.14 (s, 1H); 8.87 (s, 1H); 8.32 (d, 1H); 7.62 (d, 1H); 7.42 (m, 1H); 7.34 (d, 1H); 7.29-7.22 (m, 3H); 7.18-7.08 (m, 2H); 5.15 (s, 2H); 3.80 (s, 3H); MS m/z 502 (M+1)
  • 6-Iodo-(4-benzyloxy-3-fluorophenyl)-quinazolin-4-yl)Amine [0823]
  • Prepared according to Procedure A from (4-benzyloxy-3-fluorophenyl)-amine and 4-chloro-6-iodoquinazoline. [0824] 1H NMR (DMSO-d6) 9.82 (s, 1H); 8.93 (s, 1H); 8.57 (s, 1H); 8.09 (d, 1H); 7.84 (d, 1H); 7.51 (m, 2H); 7.44 (d, 2H); 7.37 (m, 2H); 7.33 (m, 1H); 7.24 (m, 1H); 5.18 (s, 2H), MS m/z 472 (M+1)
  • 6-Iodo-(4-(3-bromobenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0825]
  • Prepared according to Procedure A from (4-(3-bromobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. [0826] 1H NMR (DMSO-d6) 9.84 (s, 1H); 8.98 (s, 1H); 8.57 (s, 1H); 8.13 (m, 2H); 7.71 (d, 2H); 7.56 (d, 2H); 7.50 (m, 1H); 7.41 (m, 1H); 7.08 (d, 2H); 5.17 (s, 2H).
  • 6-Iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0827]
  • Prepared according to Procedure A from (4-(3-fluorobenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. [0828] 1H NMR (DMSO-d6) 9.77 (s, 1H); 8.92 (s, 1H); 8.50 (s, 1H); 8.06 (d, 1H); 7.66 (d, 2H); 7.50 (d, 1H); 7.42 (m, 1H); 7.30-7.25 (m, 2H); 7.14 (m, 1H); 7.03 (d, 2H); 5.13 (s, 2H), MS m/z 472 (M+1)
  • 6-Iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)-quinazolin-4-yl)Amine [0829]
  • Prepared according to Procedure A from (4-(3-trifluoromethylbenzyloxy)-phenyl)-amine and 4-chloro-6-iodoquinazoline. [0830] 1H NMR (DMSO-d6) 9.2 (bs, 1H); 8.91 (s, 1H); 8.37 (d, 1H); 7.89-7.72 (m, 8H); 7.19 (d, 2H); 5.30 (s, 2H).
  • 4-(4-(4-Phenoxyphenylamino)-quinolin-7-yl) Thiazole-2-carbaldehyde [0831]
  • Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (2 g, 4.56 mmol), 4-(tributylstannyl)thiazole-2-carbaldehyde (1.84 g, 4.56 mmol) and dichlorobis(triphenylphosphine)palladium (II) (0.74 g, 20 mol %) heated at reflux overnight (18 hrs) in dioxane (50 ml). The cooled solution was filtered through a plug of Celite®, concentrated and triturated with iso-hexane (3×20 ml). The resultant solid was purified via flash column chromatography on silica gel, eluting with 5% methanol in chloroform. The purified product was isolated as a yellow solid (0.85 g, 44%). δH [[0832] 2H6] DMSO 10.10(1H,s), 9.30(1,bs), 8.90(1Hs), 8.50(2H, s&d), 8.45(1H,d), 8.20(1H,d), 7.40(5H, bm), 7.10(4H, 2d), 6.80(1H,d).
  • 5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl) thiazole-4-carbaldehyde [0833]
  • Prepared according to Procedure B from (4-phenoxyphenyl)-(7-iodoquinolin-4-yl)amine (0.876 g, 2 mmol), 4-(1,3-dioxolan-2-yl)-5-tributylstannylthiazole (2.1 mmol), bis (triphenylphosphine) palladium (II) chloride (0.105 g, 0.15 mmol, 7.5 mol %) and silver oxide (0.463 g, 2 mmol) heated under reflux under nitrogen for 18 hr. The reaction mixture was then filtered through Harborlite® and the filtrate was concentrated. The product was purified on Bond Elut™ cartridge, eluting sequentially with dichloromethane, chloroform, diethyl ether and ethyl acetate. The ketal (0.385 g, 0.824 mmol) was stirred at room temperature in a mixture of THF (10 ml) and 1N HCl (10 ml) for 2 hr. The suspension was basified with 2N NaOH (5 ml) and the THF was removed. The aqueous suspension was filtered and washed with water to give the product as a yellow solid (0.346 g);m/z 424. [0834]
  • 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde [0835]
  • Prepared according to Procedure C from 4-(4-benzyloxy-phenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (1.0 g, 2.1 mmol). The precipitate which formed was collected by filtration and washed with acetone, then partitioned between ethyl acetate, triethylamine and water. The organic phase was washed with water, dried (magnesium sulphate) and the solvent was removed under vacuum. Trituration with isohexane/ethyl acetate gave the product as an orange solid (610 mg, 69%); δH [[0836] 2H6]-DMSO 10.05 (1H, b, NH), 9.62 (1H, s, CHO), 8.95 (1H, s, 5-H), 8.48 (1H, s, 2-H), 8.24 (1H, d, 7-H), 7.80 (1H, d, 8-H), 7.70 (1H, d, furan 4-H), 7.59 (2H, d, 2′-H, 6′-H), 7.48-7.25 (6H, m, 5×Ph-H, furan 3-H), 7.02 (2H, m, 3′-H, 5′-H), 5.09 (2H, s, CH2); m/z 422 (M+1)+.
  • 5-(4-(4-Benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-fu ran-2-carbaldehyde Hydrochloride [0837]
  • Prepared according to Procedure C from (4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-pyrido[3,4-d]pyrimidin-4-yl)-amine(0.301 g, 0.60 mmol). After stirring 45 minutes, the resulting suspension was filtered and washed with ether to give 0.26 g of product as a yellow solid. [0838] 1H NMR (400 MHz, DMSO-d6) δ: 11.67(br s, 1H), 9.68(s, 1H), 9.14(s, 1H), 8.78(s, 1H), 7.73(d, 1H), 7.52(d, 2H), 7.44(m, 3H), 7.39(m, 3H), 7.32(m, 1H), 7.11(d, 2H), 5.14(s, 2H), 4.12(s, 3H). ESI-MS m/z 452(M+1).
  • 6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)Phenyl-amine [0839]
  • Prepared according to Procedure B from 4-(4-benzenesulphonyl)phenyl-7-methoxy-quinazolin-4-yl-amine and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)furan. δ[0840] 1H NMR (400 MHz, DMSO-d6) 10.36(s, 1H), 8.74(s, 1H), 8.58(s, 1H), 8.10(d, 2H), 7.93(m, 4H), 7.62(m, 3H), 7.32(s, 1H), 7.04(d, 1H), 6.68(d, 1H), 5.99(s, 1H), 4.09(m, 2H), 4.04(s, 3H), 3.95(m, 2H). ESI-MS m/z 530(M+1).
  • 5-(4-(4-Phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde [0841]
  • (4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)amine (1.4 g) was treated with 1 M aqueous hydrochloric acid-tetrahydrofuran (60 ml, 1:1) in accordance with procedure C. Addition of 1M aqueous sodium hydroxide solution to pH 10 followed by extraction with ethyl acetate, drying (magnesium sulfate) and concentration to dryness afforded a yellow solid (1.2 g); δH [[0842] 2H6] DMSO 9.70 (1H, s), 9.10 (1H, s), 8.51 (2H, m), 8.35 (1H, s), 8.02 (1H, d), 7.73 (1H, d), 7.57 (1H, d), 7.42 (4H, m), 7.22-7.04 (5H, m), 6.88 (1H, d); m/z 407 (M+1)+.
  • 5-(7-Methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)-furan-2-carbaldehyde Hydrochloride [0843]
  • Prepared according to Procedure C from 6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine. 61H NMR (400 MHz, DMSO-d[0844] 6) 11.54(br s, 1H), 9.68(s, 1H), 9.13(s, 1H), 8.83(s, 1H), 7.95-8.06(m, 6H), 7.72(d, 1H), 7.68(m, 1H), 7.62(m, 2H), 7.46(s, 1H), 7.39(d, 1H), 4.12(s, 3H). ESI-MS m/z 486(M+1).
  • 5-(4-(4-Benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carboxaldehyde Hydrochloride [0845]
  • Prepared according to Procedure C from a stirred solution of (4-benzyloxyphenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine (0.51 grams, 1.1 mmol) in 20 ml of THF was added 5 ml of 1 N HCl. After stirring for 90 minutes, the resultant suspension was filtered and washed with diethyl ether (200 ml) to yield, after drying under vacuum, a yellow solid (0.32 grams, 61% yield). δ[0846] 1H NMR (400 MHz, DMSO-d6) 11.52(s, 1H), 9.70(s, 1H), 9.25(d, 1H),8.76(s, 1H), 7.76(m, 2H), 7.55(d, 2H), 7.45(d, 2H), 7.33(m, 4H), 7.11(d, 2H), 5.14(s, 2H). ESI-MS m/z 440(M+1).
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde Hydrochloride [0847]
  • Prepared according to Procedure C from (1-benzyl-1H-indazol-5-ylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl)-amine. δ[0848] 1H NMR (400 MHz, DMSO-d6) 11.68(s, 1H),9.71 (s, 1H), 9.28(d, 1H), 8.74(s, 1H), 8.12(s, 1H), 8.02(s, 1H), 7.78(m, 3H), 7.58(m, 2H), 7.3(m, 5H), 5.65(s, 2H). ESI-MS m/z 462(M−1).
  • 5-(4-(4-Benzenesulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-fu ran-2-carbaldehyde Hydrochloride [0849]
  • Prepared according to Procedure C from 6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-fluoro-quinazolin-4-yl-(4-benzenesulphonyl)phenyl-amine. [0850] 1H NMR (400 MHz, DMSO-d6) δ: 10.96(s, 1H), 9.7(s, 1H), 9.16(d, 1H), 8.72(s, 1H), 8.07(d, 2H), 7.96(m, 4H), 7.75(m, 2H), 7.64(m, 3H), 7.29(m, 1H. ESI-MS m/z 472(M−1).
  • 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde Hydrochloride [0851]
  • Prepared according to Procedure C from 4-(4-benzyloxyphenylamino)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (6.70 g, 14.4 mmol). The resulting precipitate was collected by filtration and washed with water to give the hydrochloride salt as a yellow solid (6.50 g, 14.1 mmol, 98%); δH [[0852] 2H6]DMSO 12.15 (1H,s), 9.69 (1H,s) 9.58 (1H,s), 8.88 (1H,s), 8.50 (1H,dd), 8.02 (1H,d), 7.77 (1H,d), 7.62-7.74 (3H,m), 7.31-7.52 (5H,m), 7.15 (2H,d), 5.17 (2H,s).
  • (4-Phenoxyphenyl)-(7-(5-(1,3-dioxolan-2-yl)furan-2-yl)-quinolin-4-yl)Amine [0853]
  • (4-Phenoxyphenyl)-(7-iodo-quinolin-4-yl)amine (2 g) was treated with 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (2.16 g) and tetrakis (triphenylphosphine) palladium (0) (0.26 g) in dimethylacetamide (20 ml) in accordance with Procedure B. Purification via column chromatography, eluting with ethyl acetate, followed by trituration with diethylether afforded a yellow solid (1.4 g); δH [[0854] 2H6] DMSO 9.10 (1H, s), 8.45 (2H, m), 8.13 (1H, s), 7.96 (1H, d), 7.41 (4H, m), 7.22 (1H, d), 7.20-7.03 (5H, m), 6.83 (1H, d), 6.75 (1H, d), 6.02 (1H, s), 4.13 (2H, m), 4.01 (2H, m); m/z 451 (M+1)+.
  • (1-Benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine [0855]
  • Prepared according to Procedure A from 6-bromo-4-chloroquinazoline (5.0 g) and 5-amino-1-benzyl-1H-indazole (5.0 g) in acetonitrile (100 ml) at 100° C. The resulting precipitate was treated with triethylamine in ethyl acetate and water to give the title compound as a yellow solid, (7.37 g); δH [[0856] 2H6]-DMSO 9.93(1H,s), 8.82 (1H,d), 8.52(1H,s), 8.19(1H,s), 8.09(1H,s), 7.92(1H,dd), 7.65(3H,m), 7.25(5H,m), 5.62(2H,s).
  • (1-Benzyl-1H-indazol-5-yl)-(6-iodoquinazolin-4-yl)-amine Hydrochloride [0857]
  • Prepared according to Procedure A from 4-chloro-6-iodoquinazoline (5.8 g) was treated with 5-amino-1-benzyl-1H-indazole (3.90 g) in acetonitrile (500 ml) at reflux under N[0858] 2 for 18 hours. Subsequent cooling and filtration gave the title compound (8.26 g); m/z (M+1)+478.
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine [0859]
  • Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(6-bromoquinazolin-4-yl)-amine (4.3 g), 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan (J. Chem. Soc., Chem Commun., (1988), 560) (10 g) and 1,4-bis(diphenylphosphino) palladium (II) chloride (1 g) in dioxane. The solvent was removed in vacuo and the residue chromatographed on silica. Subsequent trituration gave the title compound δH [[0860] 2H6]-DMSO 10.13 (1H, s), 8.85 (1H, s), 8.54 (1H, s), 8.20 (3H, m), 7.80 (3H, m), 7.30 (5H, m), 7.13 (1H, d), 6.79 (1H, d), 6.04 (1H, s), 5.71 (2H, s), 4.15 (4H, m).
  • (1-Benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine [0861]
  • Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-7-methoxy-6-trifluoromethanesulphonyl-quinazolin-4-yl)-amine and 2-(tributylstannyl)-5-(1,3-dioxolan-2-yl)-furan. [0862] 1H NMR (400 MHz, DMSO-d6) δ: 10.07(s, 1H), 8.75(s, 1H), 8.42(s, 1H), 8.09(s, 2H), 7.64(m, 2H), 7.2-7.3(m, 6H), 7.01 (d, 1H), 6.68(d, 1H), 5.99(s, 1H), 5.64(s, 2H), 4.09(m, 2H), 4.03(s, 3H), 3.94(m, 2H). ESI-MS m/z 520(M+1).
  • 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-yl)-furan-2-carbaldehyde Hydrochloride [0863]
  • Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-quinazolin-4-yl)-amine (2.0 g). The resulting precipitate was filtered, washed with water and dried at 60° C. in vacuo to give the product as a yellow solid (1.80 g, 3.73 g, 91%); δH [[0864] 2H6]-DMSO 12.30 (1H, s), 9.79 (1H, s), 9.62 (1H, s), 8.85 (1H, s), 8.62 (1H, m), 8.31 (1H, s), 8.19 (1H, m), 8.10 (1H, d), 7.90 (2H, m), 7.78 (2H, m), 7.40 (5H, m), 5.80 (2H, s).
  • 5-(4-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-quinazolin-6-yl)-furan-2-carbaldehyde Hydrochloride [0865]
  • Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-7-methoxy-quinazolin-4-yl)-amine. δH NMR (400 MHz, DMSO-d[0866] 6): 11.94(br s, 1H), 9.68(s, 1H), 9.20(s, 1H), 8.79(s, 1H), 8.19(s, 1H), 7.97(d, 1H), 7.81(d, 1H), 7.74(d, 1H), 7.57(m, 1H), 7.44(s, 1H), 7.41(d, 1H), 7.30(m, 2H), 7.24(m, 3H), 5.68(s, 2H), 4.13(s, 3H). ESI-MS m/z 476(M+1).
  • 7-Iodoquinazolin-4-one [0867]
  • 7-Amino-quinazolin-4-one (R. Dempsy and E. Skito, Biochemistry, 30, 1991, 8480) (1.61 g) was suspended in 6N HCl (20 ml) and cooled in an ice bath. A solution of sodium nitrite (0.75 g) in water (10 ml) was added dropwise over 15 minutes. After a further 10 minutes, a solution of potassium iodide (1.66 g) in water (5 ml) 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 (0.485 g); m/z (M+1+) 271. [0868]
  • 4-Chloro-7-iodoquinazoline [0869]
  • 7-Iodoquinazolin-4-one (0.46 g) was treated with phosphorous oxychloride (5 ml) 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 (0.43 g); m/z (M+1+) 291. [0870]
  • (1-Benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine Hydrochloride [0871]
  • Prepared according to Procedure A from 4-Chloro-7-iodoquinazoline (0.42 g) and 1-benzyl-1H-indazol-5-ylamine (0.323 g) in acetonitrile (20 ml) at reflux under nitrogen for 18 hours. The mixture was cooled and filtered to give the title compound (0.57 g); m/z (M+1+) 478. [0872]
  • (1-Benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)-furan-2-yl)quinazolin-4-yl]Amine Hydrochloride [0873]
  • Prepared according to Procedure B from (1-benzyl-1H-indazol-5-yl)-(7-iodoquinazolin-4-yl)-amine hydrochloride and 5-(1,3-dioxolan-2-yl)-2-(tri-n-butylstannyl)furan; tlc Rf, 0.25 (100% EtOAc on silica); m/z (M+1+) 490. [0874]
  • 5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde [0875]
  • Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-amine hydrochloride (0.27 g) stirred in THF:2N HCl (2:1, 15 ml) at 20° C. for 1 hour. Filtration gave 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde, which was not further characterised. [0876]
  • (4-Benzyloxy-phenyl)-(6-((5-(2-methylthio-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine Dihydrochloride [0877]
  • 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde (100 mg) and (methylthio)ethylamine (80 mg) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using column chromatography, followed by conversion to the hydrochloride salt gave a yellow solid (61 mg). m/z 497 (M+1)[0878] +.
  • (6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine [0879]
  • 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.83 g); m/z 381 (M+1)[0880] +.
  • (6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine [0881]
  • (6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine (1.82 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) in dioxan (40 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through celite and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid (1.21 g); m/z 485 (M+1)[0882] +.
  • 5-(4-(4-(4-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde [0883]
  • (6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine (500 mg) was treated with acid as in Procedure C. The product was collected by filtration as a red solid (330 mg); m/z 441 (M+1)[0884] +.
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine [0885]
  • 5-(4-(4-(4-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (110 mg) and (methylthio)ethylamine (0.06 ml) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge gave a yellow oil (52 mg); m/z 516 (M+1)[0886] +.
  • (6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine [0887]
  • 4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(3-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.86 g); m/z 381 (M+1)[0888] +.
  • (6-(5-(1,3-Dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine [0889]
  • (6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine (1.85 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.82 g) in dioxan (40 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through Celite® and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid (1.74 g); m/z 485 (M+1)[0890] +.
  • 5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-3-carbaldehyde [0891]
  • (6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine (1 g) and 5-(tributylstannyl)-furan-3-carbaldehyde (J. Org. Chem. (1992), 57(11), 3126-31) (1.84 g) in dioxan (35 ml) were reacted together as in Procedure B. The solvent was evaporated and the residue suspended in dichloromethane. The mixture was filtered through Celite® and then evaporated. The residue was triturated with hexane giving a beige solid (1 g); m/z 441 (M+1)[0892] +.
  • 5-(4-(4-(3-Fluorobenzyloxy)-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde [0893]
  • (6-(5-(1,3-Dioxolan-2-yl)-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-(4-(3-fluorobenzyloxy)-phenyl)-amine (500 mg) was treated with acid as in Procedure C. The product was collected by filtration as a beige solid (251 mg); m/z 441 (M+1)[0894] +.
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine [0895]
  • (5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (125 mg) and (methylthio)ethylamine (0.08 ml) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge gave a yellow oil (80 mg); m/z 516 (M+1)[0896] +.
  • (4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine [0897]
  • Prepared according to Procedure A from 4-benzenesulphonylaniline ([0898] Helv. Chim. Acta., 1983, 66 (4), 1046) and 4,6-dichloropyrido[3,4-a]pyrimidine; □□ [2H6]-DMSO 9.09 (1H,s), 8.80-8.88 (2H,m), 8.19 (2H,d), 7.94-8.09 (4H,m), 7.53-7.20 (3H,m); m/z (M+1)+397.
  • (4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine [0899]
  • (4-Benzenesulphonyl-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (3.67 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (6.9 g) were reacted together in dioxan (100 ml) as in Procedure B. Purification by column chromatography gave a cream solid (2.59 g); □□ [[0900] 2H6]DMSO 10.6 (1H,s) 9.26 (1H,s) 8.82 (1H,s) 8.78 (1H,s) 8.25 (2H,d) 8.0-8.3 (4H, d+m) 7.65-7.8 (3H,m) 7.21 (1H,d) 6.82 (1H,d) 6.09 (1H,s) 4.0-4.2 (4H,m); m/z 501 (M+1)+.
  • 5-(4-(4-Benzenesulphonyl-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)furan-2-carbaldehyde Hydrochloride [0901]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-(1,3-dioxolan-2-yl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (2.59 g) was treated with acid in tetrahydrofuran (70 ml) as in Procedure C. The compound was obtained as a yellow solid after filtration (1.57 g); □□ [[0902] 2H6]DMSO 9.7 (1H,s) 9.26 (1H,s) 9.11 (1H,s) 8.82 (1H,s) 8.19 (1H,s) 8.15 (1H,s) 7.95-8.03 (4H,m) 7.75 (1H,d) 7.58-7.7 (3H,m) 7.49 (1H,s); m/z 457 (M+1)+.
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride [0903]
  • 5-(4-((4-Benzenesulphonyl-phenyl)amino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde (250 mg) and (methylthio)ethylamine (185 mg)) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge, gave a yellow solid (245 mg), 70 mg of which was converted to the hydrochloride salt, (yellow solid, 68 mg); m/z 532 (M+1)[0904] +.
  • (4-Benzyloxy-phenyl)-(6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine [0905]
  • (4-Benzyloxy-phenyl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (1.4 g) and 3-(1,3-dioxolan-2-yl)-phenyl-tributylstannane (3.08 g) [A. Lee and W—C. Dai, Tetrahedron (1997), 53(3), 859-868] in dioxan (30 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through celite and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid. This material was further purified by column chromatography, giving a brown foam (252 mg); m/z 477 (M+1)[0906] +.
  • 3-(4-((4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde [0907]
  • (4-(4-Benzyloxy-phenyl)-6-(3-(1,3-dioxolan-2-yl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (250 mg) was treated with acid as in Procedure C. The product was isolated by filtration as a brown solid (115 mg); m/z 433 (M+1)[0908] +.
  • 4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde [0909]
  • (4-Benzyloxy-phenyl)-(6-iodo-quinazolin-4-yl)-amine (2 g) and 4-(tributylstannyl)-thiazol-2-carbaldehyde (3.28 g) in dioxan (25 m[) were reacted together as in Procedure B. The mixture was evaporated and the residue purified using column chromatography, giving a yellow solid (849 mg); m/z 439 (M+1)[0910] +.
  • Other suitable intermediates prepared by analogous methods to those described above are: [0911]
  • (4-Benzyloxy-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0912]
  • (4-(3-Fluoro-benzyloxy)-3-chlorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0913]
  • (4-Benzyloxy-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0914]
  • (4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0915]
  • (4-Benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0916]
  • (4-(3-Fluoro-benzyloxy-3-bromophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0917]
  • (4-Benzyloxy-3-iodophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0918]
  • (4-(3-Fluoro-benzyloxy-3-iodophenyl)-6-(chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0919]
  • (4-Benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0920]
  • (4-(3-Fluoro-benzyloxy-3-fluorophenyl)-6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine; [0921]
  • 5-((4-Benzyloxy-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu ran-2-carbaldehyde; [0922]
  • 5-((4-(3-Fluoro-benzyloxy)-3-chlorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde; [0923]
  • 5-((4-Benzyloxy-3-trifluoromethylphenylamino)-pyrido[3,4-d] 6-yl)-furan-2-carbaldehyde; [0924]
  • 5-((4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu ran-2-carbaldehyde; [0925]
  • 5-((4-Benzyloxy-3-bromophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu ran-2-carbaldehyde; [0926]
  • 5-((4-(3-Fluoro-benzyloxy-3-bromophenylamino)-pyrido[3,4-d]6-yl)-furan-2-carbaldehyde; [0927]
  • 5-((4-Benzyloxy-3-iodophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-fu ran-2-carbaldehyde; [0928]
  • 5-((4-(3-Fluoro-benzyloxy-3-iodophenylamino)-pyrido[3,4-d] 6-yl)-furan-2-carbaldehyde; [0929]
  • 5-((4-Benzyloxy-3-fluorophenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carboxaldehyde; [0930]
  • 5-((4-(3-Fluoro-benzyloxy-3-fluorophenylamino)-pyrido[3,4-d] 6-yl)-furan-2-carbaldehyde; [0931]
  • N-[4-(benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0932]
  • N-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-6-chloro-4-quinazolinamine [0933]
  • N-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine [0934]
  • N-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0935]
  • N-[4-Benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0936]
  • N-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0937]
  • N-[4-Benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0938]
  • N-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0939]
  • N-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0940]
  • N-[4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-6-chloro-4-quinazolinamine; [0941]
  • N-[1-(3-fluorobenzyl-1H-indazol-5-yl]-7-fluoro-6-chloro-4-quinazolinamine; [0942]
  • 5-(4-[4-(Benzyloxy)-3-chlorophenylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0943]
  • 5-(4-[4-(3-Fluoro-benzyloxy)-3-chlorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0944]
  • 5-(4-[4-Benzyloxy-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0945]
  • 5-(4-[4-(3-Fluoro-benzyloxy)-3-trifluoromethylphenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0946]
  • 5-(4-[4-Benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0947]
  • 5-(4-[4-(3-Fluoro-benzyloxy-3-bromophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0948]
  • 5-(4-[4-Benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0949]
  • 5-[4-(3-Fluoro-benzyloxy-3-iodophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0950]
  • 5-[4-Benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde [0951]
  • 5-(4-(3-Fluoro-benzyloxy-3-fluorophenyl]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde; [0952]
  • 5-(4-[1-(3-Fluorobenzyl-1H-indazol-5-ylamino]-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde;[0953]
    • EXAMPLES Example 1
  • [0954]
    Figure US20030176451A1-20030918-C00017
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride [0955]
  • (4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (52 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (99 mg) at room temperature for 2 days. The mixture was then partitioned between aqueous sodium carbonate solution and dichloromethane. The dried organic phase was evaporated and the residue purified by Bond Elut™ cartridge, followed by conversion to the hydrochloride salt, giving a yellow solid (31 mg); δH [[0956] 2H6]DMSO 9.9 (1H,bs) 9.25 (1H,s) 8.8 (1H,s) 7.9 (2H,d) 7.5-7.6 (2H,m) 7.1-7.3 (5H,m) 6.9 (1H,d) 5.2 (2H,s) 4.5 (2H,s) 3.6-3.8 (4H,m) 3.2 (3H,s);-m/z 548 (M+1)+.
    • Example 2
  • [0957]
    Figure US20030176451A1-20030918-C00018
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride [0958]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(2-(methylthio)-ethylaminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (80 mg) in methanol (9 ml) and water (3 ml) was treated with Oxone™ (153 mg) at room temperature for 2 days. The mixture was then partitioned between aqueous sodium carbonate solution and dichloromethane. The dried organic phase was evaporated and the residue purified by Bond Elut™ cartridge, followed by conversion to the hydrochloride salt, giving a yellow solid (69 mg); δH [[0959] 2H6]DMSO 9.8 (1H,bs) 9.4 (1H,s) 9.3 (1H,s) 8.7 (1H,s) 7.8 (2H,d) 7.3-7.4 (2H,m) 7.0-7.3 (5H,m) 6.8 (1H,d) 5.3 (2H,s) 4.4 (2H,s) 3.5-3.7 (4H,m) 3.1 (3H,s); m/z 548 (M+1)+.
    • Example 3
  • [0960]
    Figure US20030176451A1-20030918-C00019
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride [0961]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-((2-methylthio-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine (162 mg) in methanol (20 ml) and water (10 ml) was treated with Oxone™ (345 mg) at room temperature for 18 h. The mixture was then evaporated and the residue purified by Bond Elut™ cartridge, followed by conversion to the hydrochloride salt, giving a yellow solid (55 mg); δH [[0962] 2H6]DMSO 9.8 (1H,bs) 9.3 (1H,s) 9.2 (1H,s) 8.8 (1H,s) 8.3 (2H,d) 7.9-8.0 (4H,m) 7.6-7.7 (3H,m) 7.2 (1H,d) 6.8 (1H,d) 4.4 (2H,s) 3.3-3.7 (4H,m) 3.1 (3H,s); m/z 564 (M+1)+.
    • Example 4
  • [0963]
    Figure US20030176451A1-20030918-C00020
  • (4-Benzyloxy-phenyl)-(6-(3-((2-methanesulphonyl-ethylamino)-methyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride. [0964]
  • 3-((4-(4-Benzyloxy-phenyl)-amino)-pyrido[3,4-d]pyrimidin-6-yl)-benzaldehyde (106 mg) and 2-methanesulphonyl-ethylamine (111 mg) in dichloromethane (5 ml) were reacted together as in Procedure D. Purification using column chromatography, followed by conversion to the hydrochloride salt, gave a yellow solid (66 mg); δH [[0965] 2H6]DMSO 9.6 (2H,bs) 9.3 (1H,s) 9.2 (1H,s) 8.65 (1H,s) 8.55 (1H,s) 8.3 (1H,m) 7.7-7.8 (2H,m) 7.6 (2H,m) 7.25-7.45 (4H,m) 7.0 (2H,d) 5.1 (2H,s) 4.3 (2H,s) 3.2-3.8 (4H,m) 3.1 (3H,s). m/z 540 (M+1)+.
    • Example 5
  • [0966]
    Figure US20030176451A1-20030918-C00021
  • (4-Benzyloxyphenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-quinazolin-4-yl)-amine Dihydrochloride [0967]
  • 5-((4-(4-Benzyloxyphenyl)-amino)-quinazolin-6-yl)-furan-2-carbaldehyde (200 mg) and 2-methanesulphonyl-ethylamine (215 mg) in dichloromethane (10 ml) were reacted together as in Procedure D. Purification using column chromatography, followed by conversion to the hydrochloride salt, gave a yellow solid (121 mg); δH [[0968] 2H6]DMSO 9.7 (1H,s) 8.9 (1H,s) 8.4 (1H,d) 8.0 (1H,d) 7.75 (2H,d) 7.3-7.5 (7H,m) 7.1 (2H,d) 6.85 (1H,d) 5.2 (2H,s) 4.4 (2H,s) 3.2-3.7 (4H,m) 3.1 (3H,s); m/z 529(M+1)+.
    • Example 6
  • [0969]
    Figure US20030176451A1-20030918-C00022
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(4-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine Dihydrochloride [0970]
  • 5-(4-(4-(3-Fluorobenzyloxy)-phenyl)-pyrido[3,4-d]pyrimidin-6-yl)-furan-3-carbaldehyde (300 mg) and 2-methanesulphonyl-ethylamine (335 mg) in dichloromethane (15 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge, followed by conversion to the hydrochloride salt, gave a yellow solid (110 mg); δH [[0971] 2H6]DMSO 9.8 (2H,br) 9.3 (1H,s) 9.0 (1H,s) 8.8 (1H,s) 8.2 (1H,s) 8.0 (1H,s) 7.1-7.8 (7H,m) 7.0 (1H,s) 5.2 (2H,s) 4.1-4.3 (4H,brm) 3.3-3.5 (2H,bs) (hidden under H2O peak) 3.2 (3H,s); m/z 548(M+1)+.
    • Example 7
  • [0972]
    Figure US20030176451A1-20030918-C00023
  • (4-Benzyloxy-phenyl)-(6-(2-((2-methanesulphonyl-ethylamino)-methyl)-thiazol-4-yl)-quinazolin-4-yl)-amine Dihydrochloride [0973]
  • 4-(4-(4-Benzyloxy-phenyl)-amino)-quinazolin-6-yl)-thiazol-2-carbaldehyde (70 mg) and 2-methanesulphonyl-ethylamine (79 mg) in dichloromethane (10 ml) were reacted together as in Procedure D. Purification using a Bond Elut™ cartridge, followed by conversion to the hydrochloride salt, gave a yellow solid (59 mg); δH [[0974] 2H6]DMSO 12.3 (1H,s) 10.0 (1H,s) 8.95 (1H,s) 8.8 (1H,s) 8.75 (1H,d) 7.4-7.6 (6H,m) 7.2 (2H,d) 5.25 (2H,s) 4.8 (2H,s) 3.6-3.8 (4H,m) 3.2 (3H,s); m/z 546(M+1)+.
    • Example 8
  • [0975]
    Figure US20030176451A1-20030918-C00024
  • N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0976]
  • Prepared according to Procedure D from 5-(4-{4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [0977] 1H NMR 400 MHz (DMSO-d6) 9.40 (s,1H); 8.67 (s,1H);
  • 8.30 (d,1H); 7.86 (d,1H); 7.75 (d,2H); 7.43 (m,1H); 7.30-7.21 (m,3H); 7.15 (m,1H); 7.07 (d,2H); 6.80 (d,1H); 5.15 (s,2H); 4.40 (s,2H); 3.65 (m,2H); 3.40 (m,2H); 3.11 (s,3H); MS m/z 547 (M+1). [0978]
    • Example 9
  • [0979]
    Figure US20030176451A1-20030918-C00025
  • N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0980]
  • Prepared according to Procedure D from 5-(4-{3-methoxy-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [0981] 1H NMR 400 MHz (DMSO-d6) 9.22 (s,1H); 8.78 (s,1H); 8.31 (d,1H); 7.88 (d,1H); 7.50-7.08 (m,8H); 6.84 (d,1H); 5.13 (s,2H); 4.42 (s,2H); 3.80 (s,3H); 3.60 (m,2H); 3.40 (m, 2H, obscured by water peak); 3.10 (s,3H); MS m/z 577 (M+1).
    • Example 10
  • [0982]
    Figure US20030176451A1-20030918-C00026
  • N-[4-(benzyloxy)phenyl]-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0983]
  • Prepared in a similar manner to Procedure D from 5-(4-(4-benzyloxy-phenylamino)-7-methoxy-quinazolin-6-yl)-fu ran-2-carbaldehyde hydrochloride(78 mg, 0.16 mmol), 2-methanesulphonylethylamine(33 mg, 0.27 mmol), acetic acid(15 mg, 0.25 mmol) and triethylamine(18 mg, 0.18 mmol) in 3 ml of 1,2-dichloroethane added to sodium triacetoxyborohydride(102 mg, 0.48 mmol) portionwise over a two day period. The reaction mixture was stirred four days and then partitioned between 10 ml of 0.5M NaHCO[0984] 3 solution and 50 ml of ethyl acetate. The organic solution was dried with Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel with methanol/methylene chloride(1:49 to 2:48). The resulting solid was crystallized from a small volume of ethyl acetate, suspended in ether and filtered to give 43 mg of product as a pale yellow solid. δ1H NMR (400 MHz, DMSO-d6) 9.78(s, 1H), 8.73(s, 1H), 8.42(s, 1H), 6.64(d, 2H), 7.47(m, 2H), 7.40(m, 2H), 7.33(m, 1H), 7.25(s, 1H), 7.04(d, 2H), 6.98(d, 1H), 6.46(d, 1H), 5.12(s, 2H), 4.04(s, 3H), 3.86(s, 2H), 3.28(t, 2H), 3.01 (s, 3H), 2.99(t, 2H). ESI-MS m/z 559(M+1).
    • Example 11
  • [0985]
    Figure US20030176451A1-20030918-C00027
  • N-[4-(benzyloxy)phenyl]-6-[4-({[2-methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [0986]
  • Prepared according to Procedure D from 5-(4-{4-benzyloxyanilino}-6-quinazolinyl)-furan-3-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [0987] 1HNMR 400 MHz, d6DMSO 9.51 (bs,2H), 9.11 (s, 1H), 8.79 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.60 (d, 2H), 7.5-7.3 (m, 5H), 7.11 (d, 2H), 5.14 (s, 2H), 4.14 (bs, 2H), 3.6-3.5 (m, 3H), 3.12 (s, 3H); MS m/z 529 (M+1).
    • Example 12
  • [0988]
    Figure US20030176451A1-20030918-C00028
  • N-{4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [0989]
  • Prepared according to Procedure F from 6-iodo-(4-(3-fluorobenzyloxy)-3-methoxypheny)quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [0990] 1H NMR 400 MHz (CD3OD) 9.40 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H); 8.38 (s, 1H); 7.89 (d, 1H); 7.50 (s, 1H); 7.40 (t, 1H); 7.34 (m, 1H); 7.27 (d, 1H); 7.22 (d, 1H); 7.08 (d, 1H); 7.03 (t, 1H); 5.19 (s, 2H); 4.81 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 594 (M+1)+, 592 (m−1)−.
    • Example 13
  • [0991]
    Figure US20030176451A1-20030918-C00029
  • N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine. [0992]
  • Prepared according to Procedure F from 6-iodo-(4-(3-bromobenzyloxy)-phenyl)quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [0993] 1H NMR 400 MHz (CD3OD) 9.40 (s, 1H); 8.78 (d, 1H); 8.74 (d, 1H); 8.34 (s, 1H); 7.88 (d, 1H); 7.65 (d, 2H); 7.62 (s, 1H); 7.48 (d, 1H); 7.30 (d, 1H); 7.30 (m, 1H); 7.12 (d, 2H); 5.16 (s, 2H); 4.80 (s, 2H); 3.85 (m, 2H); 3.75 (m, 2H); 3.10 (s, 3H); MS m/z 624, 626 (M+1)+, 622, 624 (m−1)−.
    • Example 14
  • [0994]
    Figure US20030176451A1-20030918-C00030
  • N-{4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [0995]
  • Prepared according to Procedure F from 6-iodo-(4-(3-fluorobenzyloxy)-phenyl)-quinazolin-4-ylamine and (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [0996] 1H NMR 400 MHz (CD3OD) 9.44 (s, 1H); 8.79 (s, 1H); 8.76 (d, 1H); 8.37 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.53 (d, 1H); 7.46 (d, 2H); 7.38 (m, 2H); 7.32 (d, 1H); 7.24 (d, 1H); 5.21 (s, 2H); 4.82 (s, 2H); 3.85 (m, 2H); 3.77 (m, 2H); 3.11 (s, 3H); MS m/z 564 (M+1)+, 562 (m−1)−.
    • Example 15
  • [0997]
    Figure US20030176451A1-20030918-C00031
  • N-[4-(benzyloxy)-3-fluorophenyl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [0998]
  • Prepared according to Procedure F from 6-iodo-(4-benzyloxy)-3-fluorophenyl)quinazolin-4-ylamine and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [0999] 1H NMR 400 MHz (CD3OD) 9.41 (s, 1H); 8.77 (d, 1H); 8.75 (s, 1H); 8.36 (s, 1H); 7.90 (d, 1H); 7.71 (d, 2H); 7.60 (m, 1H); 7.40 (m, 1H); 7.23 (m, 1H); 7.11 (d, 2H); 7.03 (m, 1H); 5.17 (s, 2H); 4.81 (s, 2H); 3.85 (m, 2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 564 (M+1)+, 562 (m−1)−.
    • Example 16
  • [1000]
    Figure US20030176451A1-20030918-C00032
  • N-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1001]
  • Prepared according to Procedure D from 5-(4-{4-(1-benzyl-1H-indazol-5-yl)-7-methoxy-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ [1002] 1H NMR (400 MHz, DMSO-d6) 9.94(s, 1H), 8.76(s, 1H), 8.43(s, 1H), 8.13(d, 1H), 8.12(s, 1H), 7.70(d, 1H), 7.66(m, 1H), 7.31 (m, 2H), 7.25(m, 4H), 7.00(d, 1H), 6.46(d, 1H), 5.67(s, 2H), 4.05(s, 3H), 3.85(s, 2H), 3.27(t, 2H), 3.00(s, 3H), 2.98(t, 2H); ESI-MS m/z 583(M+1).
    • Example 17
  • [1003]
    Figure US20030176451A1-20030918-C00033
  • 6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-(4-{[3-(trifluoromethyl) benzyl]oxy}phenyl)-4-quinazolinamine [1004]
  • Prepared according to Procedure D from 5-(4-{4-(3-trifluoromethylbenzyloxy)anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1005] 1H NMR 300 MHz (DMSO-d6) 11.63 (bs, 1H); 9.88 (bs, 1H); 9.59 (bs, 1H); 8.88 (s, 1H); 8.43 (d, 1H); 7.97 (d, 1H); 7.90-7.67 (m, 6H); 7.34 (d, 1H); 7.19 (d, 2H); 6.89 (d, 1H); 5.30 (s, 2H); 4.45 (s, 2H); 3.78 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.19 (s, 3H); MS m/z 597 (M+1).
    • Example 18
  • [1006]
    Figure US20030176451A1-20030918-C00034
  • N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1007]
  • Prepared according to Procedure D from 5-(4-{3-fluoro-4-(3-fluorobenzyloxy)anilino}-6-quinazolinyl)-fu ran-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1008] 1H NMR 400 MHz (DMSO-d6) 9.61 (bs, 2H); 9.28 (bs, 1H); 8.80 (s, 1H); 8.34 (d, 1H); 7.87 (m, 2H); 7.59 (d, 1H); 7.44 (m, 1H); 7.2-7.38 (m, 4H); 7.18 (m, 1H); 6.83 (s, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.60 (m, 2H); 3.45 (m, 2H, obscured by water peak); 3.16 (s, 3H); MS m/z 565 (M+1).
    • Example 19
  • [1009]
    Figure US20030176451A1-20030918-C00035
  • N-{4-[(3-bromobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1010]
  • Prepared according to Procedure D from 5-(4-{3-bromo-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1011] 1H NMR 400 MHz (DMSO-d6) 11.78 (bs, 1H); 9.65 (bs, 1H); 9.39 (bs, 1H); 8.78 (s, 1H); 8.37 (d, 1H); 7.90 (d, 1H); 7.66 (m, 3H); 7.53 (d, 1H); 7.42 (d, 1H); 7.38 (m, 1H); 7.22 (s, 1H); 7.18 (d, 2); 6.82 (d, 1H); 5.18 (s, 2H); 4.41 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H, obscured by water peak); 3.10 (s, 3H); MS m/z 606, 608 (M+1).
    • Example 20
  • [1012]
    Figure US20030176451A1-20030918-C00036
  • N-[4-(benzyloxy)phenyl]-6-[3-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1013]
  • Prepared according to Procedure D from 5-(4-(4-benzyloxyanilino)-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine(1 equiv). [1014] 1HNMR 400 MHz,(d6DMSO) 9.46(brs,1H), 8.94 (s,1H), 8.7 (s,1H), 8.16 (d,1H), 7.96 (s,1H), 7.88 (d,1H), 7.67 (d,2H), 7.5-7.2 (m,5H), 7.07 (d,2H), 6.93 (s,1H), 5.12 (s, 2H), 4.38 (brs,2H), 3.59 (m,2H), 3.46 (brs,2H), 3.09 (s,3H); MS m/z 529 (M+1)
    • Example 21
  • [1015]
    Figure US20030176451A1-20030918-C00037
  • N-[1-(3-fluorobenzyl)-1H-indazol-5-yl]-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [1016]
  • Prepared according to Procedure F from 6-iodo-(4-(3-fluorobenzyl)-1H-indazol-5-yl)quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [1017] 1H NMR (d4 MeOH) d 9.44 (s, 1H), 8.76 (m, 2H), 8.36 (s, 1H), 8.18 (s, 1H), 8.15, (s, 1H), 7.92 (d, 1H), 7.75 (m, 2H), 7.34 (m, 1H), 7.04 (m, 2H), 6.92 (d, 1H), 5.71 (s, 2H), 4.80 (s, 2H), 3.82 (m, 2H), 3.74 (m, 2H), 3.08 (s, 3H); MS m/z 588 (M+H+)
    • Example 22
  • [1018]
    Figure US20030176451A1-20030918-C00038
  • 6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine [1019]
  • Prepared according to Procedure D from 5-(4-{4-(benzenesulphonyl)phenyl}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1020] 1H NMR (DMSO-d6) 10.27 (s, 1H), 8.78 (s, 1H), 8.65 (s, 1H), 8.18-8.22 (m, 3H), 7.97-8.01 (m, 4H), 7.86 (d, 1H), 7.62-7.72 (m, 3H), 7.10 (d, 1H), 6.51 (d, 1H), 3.84 (s, 1H), 3.28 (t, 2H), 3.03 (s, 3H), 2.99 (t, 2H); m/z (M+1)+563.
    • Example 23
  • [1021]
    Figure US20030176451A1-20030918-C00039
  • 6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine [1022]
  • Prepared according to Procedure F from 6-iodo-(4-(benzenesulphonyl)-phenyl)-quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [1023] 1H NMR 400 MHz (DMSO-d6) 9.80 (s, 1H); 8.87 (s, 1H); 8.65 (s, 1H); 8.64 (s, 1H); 8.17 (s, 1H); 8.03 (s, 1H); 7.98 (m, 2H); 7.66 (m, 5H); 4.73 (s, 2H); 3.68 (m, 2H); 3.55 (m, 2H); 3.12 (s, 3H); MS m/z 580 (M+1)+, 578 (m−1)−.
    • Example 24
  • [1024]
    Figure US20030176451A1-20030918-C00040
  • 6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine [1025]
  • Prepared according to Procedure F from 6-iodo-(4-(3-trifluoromethylbenzyloxy)-phenyl)quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [1026] 1H NMR 400 MHz (CD3OD) 9.40 (s, 1H); 8.75 (d, 1H); 8.73 (s, 1H); 8.35 (s, 1H); 7.89 (d, 1H); 7.77 (s, 1H); 7.73 (m, 1H); 7.61 (m, 3H); 7.52 (m, 1H); 7.14 (d, 2H); 5.24 (s, 2H); 4.82 (s, 2H); 3.85 (m, 2H); 3.76 (m, 2H); 3.10 (s, 3H); MS m/z 614 (M+1)+, 612 (m−1)−.
    • Example 25
  • [1027]
    Figure US20030176451A1-20030918-C00041
  • N-{3-fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [1028]
  • Prepared according to Procedure F from 6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). [1029] 1H NMR 400 MHz (CD3OD) 9.28 (s, 1H); 8.78 (s, 1H); 8.74 (d, 1H); 8.31 (s, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.63 (m, 1H); 7.54 (m, 1H); 7.49 (m, 1H); 7.37 (m, 1H); 7.25 (m, 2H); 7.05 (m, 1H); 5.24 (s, 2H); 4.77 (s, 2H); 3.81 (m, 2H); 3.72 (m, 2H); 3.10 (s, 3H); MS m/z 582 (M+1)+, 580 (m−1)−
    • Example 26
  • [1030]
    Figure US20030176451A1-20030918-C00042
  • N-(1-benzyl-1H-indazol-5-yl)-6-[2-({[2-(methanesulphonyl)ethyl]amino}methyl)-1,3-thiazol-4-yl]-4-quinazolinamine [1031]
  • Prepared according to Procedure F from 6-iodo-4-(1-benzyl-1H-indazol-5-yl)-quinazolin-4-ylamine (1 equiv), 2-ethoxyvinyl-tributylstannane (1 equiv), N-bromosuccinimide (1 equiv) and N-(trifluoroacetyl)-N-(methanesulphonylethyl)-aminomethylthioamide (1 equiv). δ[1032] 1H NMR (d4 MeOH) 9.37 (s, 1H), 8.74 (m, 2H), 8.33 (s, 1H), 8.17 (s, 1H), 8.14, (s, 1H), 7.90 (d, 1H), 7.70 (m, 2H), 7.22 (m, 5H), 5.69 (s, 2H), 4.78 (s, 2H), 3.81 (m, 2H), 3.74 (m, 2H), 3.09 (s, 3H); MS m/z 570 (M+H+).
    • Example 27
  • [1033]
    Figure US20030176451A1-20030918-C00043
  • N-(3-Fluoro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine [1034]
  • Prepared according to Procedure D from 5-(4-{3-fluoro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1035] 1H NMR 400 MHz (DMSO-d6) 8.83 (s,1H); 8.35 (d,1H); 7.89 (d,1H); 7.83 (d,1H); 7.59 (d,1H); 7.48-7.31 (m,7H); 7.26 (s,1H); 6.83 (d,1H); 5.21 (s,2H); 4.42 (s,2H); 3.60 (m,2H); 3.44 (m, 2H, obscured by water peak); 3.12 (s,3H); MS m/z 547 (M+H+).
    • Example 28
  • [1036]
    Figure US20030176451A1-20030918-C00044
  • N-(3-Chloro-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine [1037]
  • Prepared according to Procedure D from 5-(4-{3-chloro-4-benzyloxyanilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1038] 1H NMR 400 MHz (DMSO-d6) 9.71 (bs, 2H); 9.45 (bs, 1H); 8.86 (s, 1H); 8.36 (d, 1H); 7.98 (d, 1H); 7.90 (d, 1H); 7.74 (d, 1H); 7.49-7.44 (m, 2H); 7.40 (m, 2H); 7.35-7.30 (m, 2H); 7.28 (d, 1H); 6.83 (d, 1H); 5.25 (s, 2H); 4.42 (s, 2H); 3.62 (m, 2H); 3.44 (m, 2H); 3.12 (s, 3H); MS m/z 563 (M+H+).
    • Example 29
  • [1039]
    Figure US20030176451A1-20030918-C00045
  • N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1040]
  • Prepared according to Procedure D from 5-(4-{3-chloro-4-(3-fluorobenzyloxy)-anilino}-6-quinazolinyl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1041] 1H NMR 400 MHz (DMSO-d6) 9.60 (bs, 1H); 9.32 (bs, 1H); 8.82 (bs, 1H); 8.34 (d, 1H); 8.0 (s, 1H); 7.88 (d, 1H); 7.74 (d, 1H); 7.45 (m, 1H); 7.34-7.23 (m, 4H); 7.17 (m, 1H); 6.83 (d, 1H); 5.27 (s, 2H); 4.42 (s, 2H); 3.59 (m, 2H); 3.40 (m, 2H, obscured by waterpeak); 3.12 (s, 3H); MS m/z 581 (M+H+).
    • Example 30
  • [1042]
    Figure US20030176451A1-20030918-C00046
  • (4-Phenoxyphenyl)-(7-(2-(2-methanesulphonyl)ethylaminomethyl)thiazol-4-yl)-quinolin-4-yl)amine [1043]
  • A suspension of (4-(4-(4-phenoxy)anilino)-quinolin-7-yl)thiazole-2-carbaldehyde (0.05 g, 0.14 mmol), sodium triacetoxyborohydride (0.12 g, 0.56 mmol), methanesulphonylethylamine (0.15 g, 1.2 mmol) and powdered 3 Å molecular sieves in dichloromethane (6 ml) and glacial acetic acid (1 ml) was stirred at room temperature (21° C.) overnight (18 hrs) according to Procedure D. The crude reaction mixture was filtered through a SPE column (SCX resin, 5 g, 25 ml), sequentially washed with methanol (2×10 ml) and 10% ammonia in methanol (3×10 ml) and the product isolated as a pale yellow gum. Trituration with water (5 ml) and drying of the resultant solid over phosphorus pentoxide at 60° C. under vacuum for 5 hrs yielded the purified product as a pale yellow solid (0.031 g, 49%); δH [[1044] 2H6] DMSO 8.80(1H,s), 8.25(3H,m), 8.10(1H,s), 7.90(1H,d), 7.20(4H,2d), 6.85(5H,m), 6.60(1H,d), 3.95(2H,d), 2.90(7H,m); m/z 531 (M+1)+.
    • Example 31
  • [1045]
    Figure US20030176451A1-20030918-C00047
  • (4-Phenoxyphenyl)-(7-(4-(2-methanesulphonyl)ethylaminomethyl)thiazol-5-yl)-quinolin-4-yl)amine [1046]
  • 4-(4-Phenoxyanilino) 7-(4-formyl thiazol-5-yl) quinoline(50 mg, 0.118 mmol), methanesulphonylethylamine (50 mg) and molecular seives (4A, 2 large spatula tips) were stirred in a mixture of dichloromethane (6 ml) and acetic acid (1 ml) at room temperature for 2 hr (Procedure D). Sodium triacetoxyborohydride (0.12 g, 0.567 mmol) was then added and the reaction was stirred at room temp for 18 hr. The reaction mixture was added to a 5 g SCX cartridge and washed with methanol, the product was eluted with 10% methanolic ammonia. The product was triturated with water to give a beige solid (39.7 mg); δH [[1047] 2H6] DMSO 9.32 (1H,s), 9.22 (1H,s), 8.64 (2H, m), 8.19 (1H, s), 7.87 (1H,d), 7.56 (4H, m), 7.27 (6H, m), 7.02 (1H, d), 4.07 (2H, s), 3.42 (2H,t), 3.14 (5H,m);m/z 531.
    • Example 32
  • [1048]
    Figure US20030176451A1-20030918-C00048
  • (4-Phenoxyphenyl)-(7-(5-(2-(methanesulphonyl)ethylaminomethyl)furan-2-yl)-quinolin-4-yl)Amine [1049]
  • 5-(4-(4-phenoxyphenylamino)-quinolin-7-yl)furan-2-carbaldehyde (0.05 g) was reacted with 2-(methanesulphonyl)ethylamine (0.075 g) according to procedure D. Acidification with acetic acid (0.5 ml) followed by purification using a ion-exchange (SCX) Bond Elut™ cartridge, eluting with methanol-ammonia (9:1), concentration and trituration with diethylether afforded an off-white solid; δH [[1050] 2H6] DMSO 8.44 (1H, d), 8.41 (1H, d), 8.11 (1H, s), 7.85 (1H, d), 7.44-7.35 (4H, m), 7.18-7.03 (6H, m), 6.79 (1H, d), 6.47 (1H, d), 3.82 (2H, s), 3.01 (2H, t); m/z 514 (M+1)+.
    • Example 33
  • [1051]
    Figure US20030176451A1-20030918-C00049
  • 6-[5-({[2-(Methanesulphonyl)ethyl]amino}methyl)-2-furyl]-7-methoxy-N-(4-benzenesulphonyl)phenyl-4-quinazolinamine [1052]
  • Prepared according to Procedure D from 5-(7-methoxy-4-(4-benzenesulphonyl)phenylamino-quinazolin-6-yl)furan-2-carbaldehyde hydrochloride (0.6 equiv) and 2-methanesulphonyl (1 equiv). δ[1053] 1H NMR (400 MHz, DMSO-d6) 10.23 (s, 1H), 8.76(s, 1H), 8.59 (s, 1H), 8.14 (d, 2H), 7.96 (m, 4H), 7.59-7.71 (m, 3H), 7.33 (s, 1H), 7.03 (d, 1H), 6.47 (d, 1H), 4.06 (s, 3H), 3.86 (s, 2H), 3.27 (t, 2H), 3.00 (s, 3H), 2.98 (t, 2H). ESI-MS m/z 593(M+1).
    • Example 34
  • [1054]
    Figure US20030176451A1-20030918-C00050
  • N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1055]
  • Prepared according to Procedure D from a mixture of 5-(4-(4-benzyloxy-phenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.13 grams) in 1,2-dichloroethane (3 ml), diisopropylethylamine (65 mg), acetic acid (45 mg), 2-methanesulphonylethylamine (0.125 grams), and sodium triacetoxyborohydride (0.27 grams). The mixture was stirred for 18 hours. The reaction mixture was quenched with methanol (3 ml) and poured into a separatory funnel containing aqueous saturated sodium hydrogen carbonate (100 ml) and ethyl acetate (100 ml). The mixture was extracted. The organic layer was washed with water. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was treated with ethyl acetate/hexanes and collected by filtration (0.083 g, 61% yield). δ[1056] 1H NMR (400 MHz, DMSO-d6) 9.98(s, 1H), 8.83(d, 1H), 8.44(s, 1H), 7.58(m, 3H), 7.44(m, 2H), 7.37(m, 2H), 7.31 (m, 1H), 7.03(d, 1H), 6.91(m, 1H), 6.5(d, 1H), 5.1(s, 2H), 3.84(s, 1H), 3.25(m, 2H), 2.99(s, 3H), 2.96(m, 2H). ESI-MS m/z 545(M−1).
    • Example 35
  • [1057]
    Figure US20030176451A1-20030918-C00051
  • N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1058]
  • Prepared according to Procedure D from 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ[1059] 1H NMR (400 MHz, DMSO-d6) 10.16(s, 1H), 8.91(d, 1H), 8.46(s, 1H), 8.11(s, 2H), 7.65(m, 3H), 7.26(m, 5H), 6.93(m, 1H), 6.54(d, 2H), 5.65(s, 2H), 3.89(s, 2H), 3.28(m, 2H), 2.99(m, 5H). ESI-MS m/z 569(M−1).
    • Example 36
  • [1060]
    Figure US20030176451A1-20030918-C00052
  • N-[4-(Phenylsulphonyl)phenyl]-7-fluoro-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine [1061]
  • Prepared according to Procedure D from 5-(4-(4-Phenylsulphonylphenylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). [1062] 1H NMR (400 MHz, DMSO-d6) δ: 10.38(s, 1H), 8.87(d, 1H), 8.62(s, 1H), 8.11 (d, 2H), 7.95(m, 4H), 7.63(m, 4H), 6.94(m, 1H), 6.51 (d, 1H), 3.84(s, 2H), 3.25(m, 2H), 2.98(s, 3H), 2.95(m, 2H). ESI-MS m/z 579(M−1).
    • Example 37
  • [1063]
    Figure US20030176451A1-20030918-C00053
  • N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-4-furyl]-4-quinazolinamine [1064]
  • The mixture of 5-(4-(4-benzyloxy-3-trifluoromethylphenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde (211 mg, 0.40 mmol), 2-methanesulphonyl-ethylamine (99 mg, 2.0 mmol), acetic acid (0.5 ml) in dichloromethane (15 ml) was stirred at room temperature for 1.5 hours then was heated to reflux for 1 hour. The mixture was cooled to 0° C. with ice bath. Sodium cyanoborohydride (50 mg, 0.8 mmol) was added at 0° C. The reaction mixture then was stirred at room temperature for 1 hour. Diluted with ethyl acetate (50 ml), then quenched with saturated sodium bicarbonate solution slowly. Extracted with ethyl acetate and the combined organic extracts were washed with brine, dried over MgSO[1065] 4 and concentrated in vacuo. Purification of the resulting residue was accomplished using flash chromatography on silica gel with 2% methanol in ethyl acetate which afforded a yellow solid (0.10 g, 43% yield). H1 NMR (400 MHz, DMSO).δ10.0 (s, 1H), 8.7 (s, 1H), 8.5 (s,1H), 8.1 (d, 1H), 8.1 (s, 2H), 7.8 (d, 1H), 7.4 (m, 5H), 7.3 (m,1H), 7.0 (d, 1H), 6.5 (d,1H), 5.3 (s,2H), 3.8 (s,2H), 3.2 (m, 2H), 3.0 (s, 3H), 2.9 (m, 2H). ESI-MS m/z 597 (M+H)+.
    • Further Examples
  • The compounds in Lists 1 to 48 above and their hydrochloride salts, if appropriate, are prepared by analogous techniques using the appropriate starting materials. [1066]
  • Biological Data [1067]
  • Compounds of the present invention were tested for protein tyrosine kinase inhibitory activity in substrate phosphorylation assays and cell proliferation assays. [1068]
  • Substrate Phosphorylation Assay [1069]
  • 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 g-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 10 mM MnCl[1070] 2, 10 mM ATP, 5 mM peptide, and test compound (diluted from a 5 mM stock in DMSO, final DMSO concentration is 2%) in 40 mM HEPES buffer, pH 7.4. The reaction was stopped by the addition of EDTA (final concentration 0.15 mM) and a sample was transferred to a streptavidin-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 MnCl2, 2 mM ATP, 0.25 mCi [γ-33P] ATP/well, 5 mM peptide substrate, and test compound (diluted from a 10 mM stock in DMSO, final DMSO concentration is 2%) in 50 mM MOPS pH 7.2. The reaction was terminated by the addition of 200 ml of PBS containing 2.5 mg/ml streptavidin-coated SPA beads (Amersham Inc.), 50 mM 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, Conn.).
  • The results are shown in Tables 1 A (examples 1 to 7) and 1 B (examples 8 to 29 and 33 to 37) as the IC[1071] 50 values.
    TABLE 1A
    Substrate Phosphorylation
    Example erbB2 - assay (b) EGF-r - assay (a)
    1 +++ +++
    2 +++ +++
    3 +++ +++
    4 ++ +++
    5 +++ +++
    6 ++
    7 +++ +++
  • [1072]
    TABLE 1B
    Substrate
    Phosphorylation
    Example erbB2 - assay (b)
    8 +++
    9 +++
    10 +++
    11 +++
    12 ++
    13 ++
    14 +++
    15 +++
    16 +++
    17 +++
    18 +++
    19 +++
    21 +++
    22 +++
    23 +++
    24 +++
    25 +++
    26 +++
    27 +++
    28 +++
    29 +++
    33 +++
    34 +++
    35 +++
    36 +++
    37 +++
    IC50 values Symbol
    <0.10 μM +++
    0.10 -1.0 μM ++
    1.0-10.0 μM +
    >10.0 μM −
    Not determined ND
  • Cellular Assays: Methylene Blue Growth Inhibition Assay [1073]
  • 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% CO[1074] 2, 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 (50 μg/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 10 mM stock solutions in DMSO. 100 ml/well of these dilutions were added to the 100 ml 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% CO2 for 3 days. Medium was removed by aspiration. Cell biomass was estimated by staining cells with 100 μl per well methylene blue (Sigma M9140, 0.5% in 50:50 ethanol: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 100 μl of solubilization 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.
  • Table 2 illustrates the inhibitory activity of compounds of the present invention as IC[1075] 50 values in μM against a range of tumor cell lines.
    TABLE 2
    Cell Proliferation
    HB4a HB4a
    Example erbB2 ras B1474 HN5 N87
    1 +++ + +++ +++ +++
    2 +++ + +++ +++ +++
    3 +++ + +++ +++ +++
    4 +++ − +++ +++ +++
    5 +++ − +++ +++ +++
    6 +++ − +++ +++ +++
    7 +++ ++ +++ +++ +++
    8 +++ ++ +++ +++ +++
    9 +++ ++ +++ +++ +++
    10 +++ ++ +++ +++ +++
    11 +++ − +++ +++ +++
    12 +++ − +++ ++ +++
    13 ++ − ++ + ++
    14 +++ − +++ +++ +++
    15 +++ − +++ +++ +++
    16 +++ ++ +++ +++ +++
    17 ++ ++ +++ ++ ++
    18 +++ ++ +++ +++ +++
    19 +++ − +++ +++ +++
    20 +++ − +++ ++ +++
    21 +++ ++ +++ +++ +++
    22 +++ + +++ +++ +++
    23 +++ + +++ +++ ++
    24 ++ − ++ +++ ++
    25 +++ − +++ +++ +++
    26 +++ ++ +++ +++ +++
    27 +++ ++ +++ +++ +++
    28 +++ + +++ +++ +++
    29 +++ − +++ +++ +++
    33 +++ ++ +++ +++ +++
    34 +++ − +++ +++ +++
    35 +++ + +++ +++ +++
    36 ++ − ++ ++ ++
    37 +++ + +++ +++ +++
    IC50 value Symbol
    <5 μM +++
    5-25 μM ++
    25-50 μM +
    >50 μM −
    Not determined ND
  • Major Metabolites: [1076]
  • Liver S-9 homogenates (5 mg/mL protein concentration) from prepared pooled male Sprague Dawley rat livers and pooled human livers (XenoTech, LLC, Kansas City, Kans.) were incubated in 96-well polypropylene plates with representative examples selected from examples 1 to 40 (10 μM) in a total volume of 0.5 mL. Stock solutions of these compounds were prepared in DMSO at a concentration of 1 mM to maintain a <1% final DMSO concentration for each reaction. Enzymatic incubations contained cofactors (5.71 mM NADPH, 7.14 mM glucose-6-phosphate, 7.14 mM UDPGA, 47.1 mM potassium chloride, and 11.4 mM magnesium chloride in 0.1 M potassium phosphate buffer, pH 7.4). Control samples were aspirated from the reaction samples at time zero and placed immediately into 2 volumes of ice-chilled acetonitrile. Sample reaction plates were incubated for 60 min in a shaker incubator maintained at 37° C. supplied with O[1077] 2. Reactions were terminated by addition of 2 volumes of ice-chilled acetonitrile. All samples were vortexed and centrifuged at 2000×g for 10 min. The supernatant was removed and analyzed by LC-MS. The metabolite identification work was done by using reversed-phase HPLC coupled with ion-trap mass spectroscopy.
  • For example: [1078]
    Figure US20030176451A1-20030918-C00054
  • N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine [1079]
    Figure US20030176451A1-20030918-C00055
  • Prepared according to Procedure D and identified as a major metabolite of N-[4-(benzyloxy)phenyl]-6-[4-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine in [1080] 1HNMR 300 MHz, CDCl3 8.69(s,1H), 8.11 (s,1H), 8.02 (d,1H), 7.88 (d, 1H), 7.61 (d,2H), 7.5-7.2 (m,7H), 7.05 (d,2H), 6.83 (s,1H), 5.10 (s,2H), 3.82 (s,2H); MS m/z 423 (M+1).
  • Thus, particular compounds of interest as metabolites (either as isolated compounds or compounds in vivo) are compounds of formula (XVII): [1081]
    Figure US20030176451A1-20030918-C00056
  • in which Ar, Y, V, X and U are as defined above; all possible preferments for these groups as defined above are applicable. [1082]
  • Compounds of formula (XII) of special interest include: [1083]
  • 4-(4-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [1084]
  • (4-(3-Fluorobenzyloxy)-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [1085]
  • (4-Benzenesulphonyl-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [1086]
  • (4-Benzyloxy-phenyl)-(6-(3-(aminomethyl)phenyl-pyrido[3,4-d]pyrimidin-4-yl)-amine; [1087]
  • (4-Benzyloxy-phenyl)-(6-(5-(aminomethyl)-furan-2-yl)-quinazolin-4-yl)-amine; [1088]
  • (4-(3-Fluorobenzyloxy-phenyl)-(6-(4-(aminomethyl)-fu ran-2-yl)-pyrido[3,4-d]pyrimidin-4-yl)-amine; [1089]
  • (4-Benzyloxy-phenyl)-(6-(2-(aminomethyl)-thiazol-4-yl)-quinazolin-4-yl)-amine; [1090]
  • N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1091]
  • N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1092]
  • N-[4-(Benzyloxy)phenyl]-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1093]
  • N-[4-(Benzyloxy)phenyl]-6-[4-(aminomethyl)-2-furyl]-4-quinazolinamine; [1094]
  • N-{4-[(3-Fluorobenzyl)oxy]-3-methoxyphenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1095]
  • N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1096]
  • N-{4-[(3-Fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1097]
  • N-[4-(Benzyloxy)-3-fluorophenyl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1098]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-methoxy-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1099]
  • 6-[5-(aminomethyl)-2-furyl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine; [1100]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1101]
  • N-{4-[(3-Bromobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1102]
  • N-[4-(Benzyloxy)phenyl]-6-[3-(aminomethyl)-2-furyl]-4-quinazolinamine; [1103]
  • N-[1-(3-Fluorobenzyl)-1H-indazol-5-yl]-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1104]
  • 6-[5-(Aminomethyl)-2-furyl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine; [1105]
  • 6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-[4-(benzenesulphonyl)phenyl]-4-quinazolinamine; [1106]
  • 6-[2-(Aminomethyl)-1,3-thiazol-4-yl]-N-(4-{[3-(trifluoromethyl)benzyl]oxy}phenyl)-4-quinazolinamine [1107]
  • N-{3-Fluoro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1108]
  • N-(1-Benzyl-1H-indazol-5-yl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1109]
  • N-(3-Fluoro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1110]
  • N-(3-Chloro-4-benzyloxyphenyl)-6-[2-(aminomethyl)-1,3-thiazol-4-yl]-4-quinazolinamine; [1111]
  • N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1112]
  • (4-Phenoxyphenyl)-(7-(2-(aminomethyl)-thiazol-4-yl)-quinolin-4-yl)amine; [1113]
  • (4-Phenoxyphenyl)-(7-(4-(aminomethyl)-thiazol-5-yl)-quinolin-4-yl)amine; [1114]
  • (4-Phenoxyphenyl)-(7-(5-(aminomethyl)-furan-2-yl)-quinolin-4-yl)amine; [1115]
  • 6-[5-(Aminomethyl)-2-furyl]-7-methoxy-N-(4-phenylsulphonyl)phenyl-4-quinazolinamine; [1116]
  • N-[4-(Benzyloxy)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1117]
  • N-(1-Benzyl-1H-indazol-5-yl)-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1118]
  • N-[4-(Benzenesulphonyl)phenyl]-7-fluoro-6-[5-(aminomethyl)-2-furyl]-4-quinazolinamine; [1119]
  • N-(3-Trifluoromethyl-4-benzyloxyphenyl)-6-[5-(aminomethyl)-4-furyl]-4-quinazolinamine; [1120]
  • and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof. [1121]

Claims (6)

1. A process for the preparation of a compound of formula (I)
Figure US20030176451A1-20030918-C00057
wherein;
Y is CR1 and V is N;
or Y is CR1 and V is CR2;
R1 represents a group CH3SO2CH2CH2NHCH2—Ar—, wherein Ar is selected from furan or thiazole, each of which may optionally be substituted by one or two halo, C1-4 alkyl or C1-4 alkoxy groups;
R2 is selected from the group consisting of hydrogen, halo, hydroxy, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylamino and di(C1-4 alkyl)amino;
U represents a phenyl, pyridyl, 3H-imidazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl, 1H-indazolyl, 2,3-dihydro-1H-indazolyl, 1H-benzimidazolyl, 2,3-dihydro-1H-benzimidazolyl or 1H-benzotriazolyl group, substituted by an R3 group and optionally substituted by at least one independently selected R4 group;
R3 is selected from a group consisting of benzyl, halo-, dihalo- and trihalobenzyl, benzoyl, pyridylmethyl, pyridylmethoxy, phenoxy, benzyloxy, halo-, dihalo- and trihalobenzyloxy and benzenesulphonyl;
or R3 represents a group of formula
Figure US20030176451A1-20030918-C00058
wherein each R5 is independently selected from halogen, C1-4 alkyl and C1-4 alkoxy; and n is 0 to 3;
each R4 is independently hydroxy, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, amino, C1-4 alkylamino, di(C1-4 alkyl)amino, C1-4 alkylthio, C1-4 alkylsulphinyl, C1-4 alkylsulphonyl, C1-4 alkylcarbonyl, carboxy, carbamoyl, C1-4 alkoxycarbonyl, C1-4 alkanoylamino, N-(C1-4 alkyl)carbamoyl, N,N-di(C1-4 alkyl)carbamoyl, cyano, nitro and trifluoromethyl;
comprising the steps:
Figure US20030176451A1-20030918-C00059
wherein Y′ is CL′ and V′ is N;
or Y′ is CL′ and V′ is CR2;
wherein L and L′ are suitable leaving groups,
with a compound of formula (III)
UNH2  (III)
to prepare a compound of formula (IV)
Figure US20030176451A1-20030918-C00060
and subsequently (b) substituting the group R1 by replacement of the leaving group L′.
2. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises the steps:
Figure US20030176451A1-20030918-C00061
wherein U is as defined in claim 1;
Y″ is CT and V″ is N;
or Y″ is CT and V″ is CR2;
wherein R is as defined in claim 1 and T is a group Ar substituted with formyl, CH3SCH2CH2NHCH2—; or CH3SOCH2CH2NHCH2—;
and (b) subsequently converting the group T into the group R1.
3. The process of claim 2, wherein the Group T is converted into the group R1 by reductive amination.
4. The process of claim 2, wherein the Group T is converted into the group R1 by oxidation.
5. The process of claim 1, further comprising converting the compound of formula (I) thereby obtained into another compound of formula (I), wherein said conversion is effected by akylthio group oxidation, nitro group reduction, amino group acylation, or amino group substitution.
6. The process of claim 2, further comprising converting the compound of formula (I) thereby obtained into another compound of formula (I), wherein said conversion is effected by akylthio group oxidation, nitro group reduction, amino group acylation, or amino group substitution.
US10/342,810 1998-01-12 2003-01-15 Heterocyclic compounds Abandoned US20030176451A1 (en)

Priority Applications (9)

Application Number Priority Date Filing Date Title
US10/342,810 US20030176451A1 (en) 1998-01-12 2003-01-15 Heterocyclic compounds
US11/050,033 US7109333B2 (en) 1998-01-12 2005-02-03 Heterocyclic compounds
US11/532,926 US20070015775A1 (en) 1998-01-12 2006-09-19 Heterocyclic compounds
US11/752,582 US20070238875A1 (en) 1998-01-12 2007-05-23 Heterocyclic compounds
US12/691,784 US8513262B2 (en) 1998-01-12 2010-01-22 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US13/943,049 US8912205B2 (en) 1998-01-12 2013-07-16 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/536,896 US9199973B2 (en) 1998-01-12 2014-11-10 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/887,434 US20160051551A1 (en) 1998-01-12 2015-10-20 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US15/226,949 US20160339027A1 (en) 1998-01-12 2016-08-03 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GBGB9800569.7A GB9800569D0 (en) 1998-01-12 1998-01-12 Heterocyclic compounds
GB9800569.7 1998-01-12
US09/582,746 US6727256B1 (en) 1998-01-12 1999-01-08 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US10/342,810 US20030176451A1 (en) 1998-01-12 2003-01-15 Heterocyclic compounds

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
US09/582,746 Continuation US6727256B1 (en) 1998-01-12 1999-01-08 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US09582746 Continuation 1999-01-08
PCT/EP1999/000048 Continuation WO1999035146A1 (en) 1998-01-12 1999-01-08 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US11/050,033 Continuation US7109333B2 (en) 1998-01-12 2005-02-03 Heterocyclic compounds
US11/752,582 Continuation US20070238875A1 (en) 1998-01-12 2007-05-23 Heterocyclic compounds

Publications (1)

Publication Number Publication Date
US20030176451A1 true US20030176451A1 (en) 2003-09-18

Family

ID=10825153

Family Applications (11)

Application Number Title Priority Date Filing Date
US09/582,746 Expired - Lifetime US6727256B1 (en) 1998-01-12 1999-01-08 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US10/071,358 Expired - Lifetime US6713485B2 (en) 1998-01-12 2002-02-08 Heterocyclic compounds
US10/342,810 Abandoned US20030176451A1 (en) 1998-01-12 2003-01-15 Heterocyclic compounds
US11/050,033 Expired - Lifetime US7109333B2 (en) 1998-01-12 2005-02-03 Heterocyclic compounds
US11/532,926 Abandoned US20070015775A1 (en) 1998-01-12 2006-09-19 Heterocyclic compounds
US11/752,582 Abandoned US20070238875A1 (en) 1998-01-12 2007-05-23 Heterocyclic compounds
US12/691,784 Expired - Fee Related US8513262B2 (en) 1998-01-12 2010-01-22 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US13/943,049 Expired - Fee Related US8912205B2 (en) 1998-01-12 2013-07-16 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/536,896 Expired - Fee Related US9199973B2 (en) 1998-01-12 2014-11-10 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/887,434 Abandoned US20160051551A1 (en) 1998-01-12 2015-10-20 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US15/226,949 Abandoned US20160339027A1 (en) 1998-01-12 2016-08-03 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Family Applications Before (2)

Application Number Title Priority Date Filing Date
US09/582,746 Expired - Lifetime US6727256B1 (en) 1998-01-12 1999-01-08 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US10/071,358 Expired - Lifetime US6713485B2 (en) 1998-01-12 2002-02-08 Heterocyclic compounds

Family Applications After (8)

Application Number Title Priority Date Filing Date
US11/050,033 Expired - Lifetime US7109333B2 (en) 1998-01-12 2005-02-03 Heterocyclic compounds
US11/532,926 Abandoned US20070015775A1 (en) 1998-01-12 2006-09-19 Heterocyclic compounds
US11/752,582 Abandoned US20070238875A1 (en) 1998-01-12 2007-05-23 Heterocyclic compounds
US12/691,784 Expired - Fee Related US8513262B2 (en) 1998-01-12 2010-01-22 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US13/943,049 Expired - Fee Related US8912205B2 (en) 1998-01-12 2013-07-16 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/536,896 Expired - Fee Related US9199973B2 (en) 1998-01-12 2014-11-10 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US14/887,434 Abandoned US20160051551A1 (en) 1998-01-12 2015-10-20 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US15/226,949 Abandoned US20160339027A1 (en) 1998-01-12 2016-08-03 Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Country Status (47)

Country Link
US (11) US6727256B1 (en)
EP (3) EP1047694B1 (en)
JP (2) JP3390741B2 (en)
KR (1) KR100569776B1 (en)
CN (1) CN1134438C (en)
AP (1) AP1446A (en)
AR (2) AR015507A1 (en)
AT (3) ATE322491T1 (en)
AU (2) AU749549C (en)
BG (1) BG64825B1 (en)
BR (1) BR9906904B1 (en)
CA (1) CA2317589C (en)
CO (1) CO4820390A1 (en)
CY (3) CY1105618T1 (en)
CZ (1) CZ298047B6 (en)
DE (4) DE69918528T2 (en)
DK (3) DK1047694T3 (en)
EA (1) EA002455B1 (en)
EE (1) EE04616B1 (en)
EG (1) EG24743A (en)
ES (3) ES2319119T3 (en)
FR (1) FR08C0038I2 (en)
GB (1) GB9800569D0 (en)
GE (1) GEP20022678B (en)
HR (2) HRP20000469B1 (en)
HU (1) HU227593B1 (en)
IL (2) IL137041A0 (en)
IS (1) IS2276B (en)
LU (1) LU91475I2 (en)
MA (1) MA26596A1 (en)
ME (1) ME00757B (en)
MY (1) MY124055A (en)
NL (1) NL300360I2 (en)
NO (2) NO316176B1 (en)
NZ (1) NZ505456A (en)
OA (1) OA11444A (en)
PE (1) PE20000230A1 (en)
PL (1) PL192746B1 (en)
PT (3) PT1460072E (en)
RS (1) RS49779B (en)
SI (3) SI1047694T1 (en)
SK (1) SK285405B6 (en)
TR (1) TR200002015T2 (en)
TW (1) TW477788B (en)
UA (1) UA66827C2 (en)
WO (1) WO1999035146A1 (en)
ZA (1) ZA99172B (en)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060009460A1 (en) * 2004-06-04 2006-01-12 Dickson John K Jr Quinoline- and isoquinoline-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
US7173136B2 (en) 2002-11-02 2007-02-06 Astrazeneca Ab 3-Cyano-quinoline derivatives
US20070054928A1 (en) * 2003-09-26 2007-03-08 Exelixis, Inc. c-Met modulators and methods of use
US20090318373A1 (en) * 2002-07-15 2009-12-24 Rice Kenneth D Receptor-type kinase modulators and methods of use
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US8927558B2 (en) 2011-05-20 2015-01-06 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Methods for detecting and reducing impurities of Lapatinib and salts thereof
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators

Families Citing this family (424)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6294532B1 (en) 1997-08-22 2001-09-25 Zeneca Limited Oxindolylquinazoline derivatives as angiogenesis inhibitors
RS49779B (en) * 1998-01-12 2008-06-05 Glaxo Group Limited, Byciclic heteroaromatic compounds as protein tyrosine kinase inhibitors
US7262201B1 (en) 1998-10-08 2007-08-28 Astrazeneca Ab Quinazoline derivatives
GB2345486A (en) * 1999-01-11 2000-07-12 Glaxo Group Ltd Heteroaromatic protein tyrosine kinase inhibitors
DK1553097T3 (en) 1999-02-10 2010-12-13 Astrazeneca Ab Quinazoline derivative as angiogenesis inhibitor and intermediates thereto
GB9910579D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
GB9910580D0 (en) 1999-05-08 1999-07-07 Zeneca Ltd Chemical compounds
YU90901A (en) 1999-06-21 2004-07-15 Boehringer Ingelheim Pharma Gmbh. & Co.Kg. Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
US6933299B1 (en) 1999-07-09 2005-08-23 Smithkline Beecham Corporation Anilinoquinazolines as protein tyrosine kinase inhibitors
WO2001004111A1 (en) * 1999-07-09 2001-01-18 Glaxo Group Limited Anilinoquinazolines as protein tyrosine kinase inhibitors
JP4870304B2 (en) 1999-09-21 2012-02-08 アストラゼネカ アクチボラグ Quinazoline derivatives and their use as pharmaceuticals
UA74803C2 (en) 1999-11-11 2006-02-15 Осі Фармасьютікалз, Інк. A stable polymorph of n-(3-ethynylphenyl)-6,7-bis(2-methoxyetoxy)-4-quinazolinamine hydrochloride, a method for producing thereof (variants) and pharmaceutical use
JP2003520855A (en) * 2000-01-28 2003-07-08 アストラゼネカ アクチボラグ Chemical compound
GB0002952D0 (en) * 2000-02-09 2000-03-29 Pharma Mar Sa Process for producing kahalalide F compounds
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
AR035851A1 (en) * 2000-03-28 2004-07-21 Wyeth Corp 3-CIANOQUINOLINS, 3-CIANO-1,6-NAFTIRIDINES AND 3-CIANO-1,7-NAFTIRIDINS AS INHIBITORS OF PROTEIN KINASES
CA2409139A1 (en) 2000-05-02 2001-11-08 Array Biopharma, Inc. Process for the reduction of cyano-substituted sulfones to aminoalkylene-substituted sulfones
JP4044839B2 (en) 2000-06-22 2008-02-06 ファイザー・プロダクツ・インク Substituted bicyclic derivatives for treating abnormal cell proliferation
ES2305081T3 (en) 2000-06-28 2008-11-01 Astrazeneca Ab SUBSTITUTED QUINOZOLINE DERIVATIVES AND ITS USE AS INHIBITORS.
EP1792902A1 (en) * 2000-06-30 2007-06-06 Glaxo Group Limited Processes for preparation of 5-(6-quinazolinyl)-furan-2-carbaldehydes
EP1294715B1 (en) * 2000-06-30 2007-02-14 Glaxo Group Limited Quinazoline ditosylate salt compounds
CN1315822C (en) 2000-08-09 2007-05-16 阿斯特拉曾尼卡有限公司 Quinoline derivatives having VEGF inhibiting activity
JP2004509876A (en) 2000-09-20 2004-04-02 メルク　パテント　ゲゼルシャフト　ミット　ベシュレンクテル　ハフトング 4-amino-quinazoline
ATE399766T1 (en) 2000-10-20 2008-07-15 Eisai R&D Man Co Ltd AROMATIC HETEROCYCLES CONTAINING NITROGEN
US7776315B2 (en) 2000-10-31 2010-08-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and additional active ingredients
US7067532B2 (en) 2000-11-02 2006-06-27 Astrazeneca Substituted quinolines as antitumor agents
US7253184B2 (en) 2000-11-02 2007-08-07 Astrazeneca Ab 4-Substituted quinolines as antitumor agents
US7019012B2 (en) 2000-12-20 2006-03-28 Boehringer Ingelheim International Pharma Gmbh & Co. Kg Quinazoline derivatives and pharmaceutical compositions containing them
HRP20030627A2 (en) 2001-01-05 2005-06-30 Abgenix Pfizer Inc. Antibodies to insulin-like growth factor i receptor
WO2002056912A2 (en) * 2001-01-16 2002-07-25 Glaxo Group Limited Pharmaceutical combination for the treatment of cancer containing a 4-quinazolineamine and another anti-neoplastic agent
EP1488809A1 (en) 2001-01-16 2004-12-22 Glaxo Group Limited Pharmaceutical combination containing a 4-quinazolineamine and another anti-neoplastic agent for the treatment of cancer
WO2002074294A1 (en) * 2001-03-15 2002-09-26 Rhode Island Hospital, A Lifespan Partner Taurine compounds
MY142915A (en) * 2001-03-23 2011-01-31 Bayer Healthcare Llc Rho-kinase inhibitors
MXPA03008658A (en) * 2001-03-23 2005-04-11 Bayer Ag Rho-kinase inhibitors.
ES2263743T3 (en) 2001-04-13 2006-12-16 Pfizer Products Inc. DERIVATIVES OF 4-AMINOPIRIDOPIRIMIDINE REPLACED WITH A BICYCLE GROUP.
WO2002092578A1 (en) * 2001-05-14 2002-11-21 Astrazeneca Ab Quinazoline derivatives
WO2003000194A2 (en) 2001-06-21 2003-01-03 Pfizer Inc. Thienopyridine and thienopyrimidine anticancer agents
US20090197852A9 (en) * 2001-08-06 2009-08-06 Johnson Robert G Jr Method of treating breast cancer using 17-AAG or 17-AG or a prodrug of either in combination with a HER2 inhibitor
US7829566B2 (en) 2001-09-17 2010-11-09 Werner Mederski 4-amino-quinazolines
AR039067A1 (en) 2001-11-09 2005-02-09 Pfizer Prod Inc ANTIBODIES FOR CD40
WO2003059913A1 (en) 2002-01-10 2003-07-24 Bayer Healthcare Ag Roh-kinase inhibitors
BR0306982A (en) 2002-01-17 2004-10-26 Neurogen Corp Compound or a pharmaceutically acceptable salt thereof, pharmaceutical composition, methods to reduce the calcium conductance of a cell capsaicin receptor, to inhibit the binding of vanilloid ligand to a capsaicin receptor in vitro and in a patient, to treat a condition responsive to modulation of the capsaicin receptor in a patient, to treat pain in a patient, to treat itching in a patient, to treat coughing or hiccups in a patient, to promote weight loss in an obese patient, and to determine the presence or absence capsaicin receptor in a sample, packaged pharmaceutical preparation, and use of a compound
US6924290B2 (en) 2002-01-23 2005-08-02 Bayer Pharmaceuticals Corporation Rho-kinase inhibitors
ES2298497T3 (en) 2002-01-23 2008-05-16 Bayer Pharmaceuticals Corporation QUINASA RHO INHIBITORS.
WO2003064413A1 (en) 2002-02-01 2003-08-07 Astrazeneca Ab Quinazoline compounds
AU2003207291A1 (en) * 2002-02-06 2003-09-02 Ube Industries, Ltd. Process for producing 4-aminoquinazoline compound
EP1492568A1 (en) * 2002-04-08 2005-01-05 SmithKline Beecham Corporation Cancer treatment method comprising administration of an erb-family inhibitor and a raf and/or ras inhibitor
DE10221018A1 (en) 2002-05-11 2003-11-27 Boehringer Ingelheim Pharma Use of inhibitors of EGFR-mediated signal transduction for the treatment of benign prostatic hyperplasia (BPH) / prostatic hypertrophy
WO2003101491A1 (en) * 2002-06-03 2003-12-11 Mitsubishi Pharma Corporation PREVENTIVES AND/OR REMEDIES FOR SUBJECTS WITH THE EXPRESSION OR ACTIVATION OF Her2 AND/OR EGFR
UA77303C2 (en) 2002-06-14 2006-11-15 Pfizer Derivatives of thienopyridines substituted by benzocondensed heteroarylamide useful as therapeutic agents, pharmaceutical compositions and methods for their use
US20040048887A1 (en) * 2002-07-09 2004-03-11 Boehringer Ingelheim Pharma Gmbh & Co. Kg Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
GB0215823D0 (en) 2002-07-09 2002-08-14 Astrazeneca Ab Quinazoline derivatives
WO2004004732A1 (en) 2002-07-09 2004-01-15 Astrazeneca Ab Quinazoline derivatives for use in the treatment of cancer
GB0304367D0 (en) * 2003-02-26 2003-04-02 Pharma Mar Sau Methods for treating psoriasis
US8505468B2 (en) * 2002-11-19 2013-08-13 Sharp Kabushiki Kaisha Substrate accommodating tray
US7432275B2 (en) * 2002-12-13 2008-10-07 Neurogen Corporation Carboxylic acid, phosphate or phosphonate substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators
PL377713A1 (en) 2002-12-19 2006-02-06 Pfizer Inc. 2-(1h-indazol-6-ylamino)-benzamide compounds as protein kinases inhibitors useful for the treatment of ophtalmic diseases
AU2003292435A1 (en) * 2002-12-23 2004-07-14 Astrazeneca Ab 4- (pyridin-4-ylamino) -quinazoline derivatives as anti-tumor agents
WO2004060400A1 (en) * 2003-01-06 2004-07-22 Mitsubishi Pharma Corp Antipsychotic molecular-targeting epithelial growth factor receptor
US7223749B2 (en) 2003-02-20 2007-05-29 Boehringer Ingelheim International Gmbh Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them
MEP52808A (en) 2003-02-26 2011-05-10 Sugen Inc Aminoheteroaryl compounds as protein kinase inhibitors
EP1633870B1 (en) 2003-05-30 2013-03-27 OncoTherapy Science, Inc. Process for screening a drug response in cancer patients
TW200510373A (en) 2003-07-14 2005-03-16 Neurogen Corp Substituted quinolin-4-ylamine analogues
US7329664B2 (en) 2003-07-16 2008-02-12 Neurogen Corporation Substituted (7-pyridyl-4-phenylamino-quinazolin-2-yl)-methanol analogues
AR042955A1 (en) 2003-07-18 2005-07-13 Amgen Inc UNION AGENTS SPECIFIC TO THE GROWTH FACTOR OF HEPATOCITS
US20060204966A1 (en) 2003-08-01 2006-09-14 Spector Neil L Treatment of cancers expressing p95 erbb2
HN2004000285A (en) 2003-08-04 2006-04-27 Pfizer Prod Inc ANTIBODIES DIRECTED TO c-MET
CA2536321A1 (en) 2003-08-29 2005-03-10 Pfizer Inc. Thienopyridine-phenylacet amides and their derivatives useful as new anti-angiogenic agents
GB0321066D0 (en) * 2003-09-09 2003-10-08 Pharma Mar Sau New antitumoral compounds
AR045563A1 (en) 2003-09-10 2005-11-02 Warner Lambert Co ANTIBODIES DIRECTED TO M-CSF
DE10349113A1 (en) 2003-10-17 2005-05-12 Boehringer Ingelheim Pharma Process for the preparation of aminocrotonyl compounds
EP1682123A1 (en) * 2003-11-07 2006-07-26 SmithKline Beecham (Cork) Limited Cancer treatment method
WO2005044788A1 (en) 2003-11-11 2005-05-19 Eisai Co., Ltd. Urea derivative and process for producing the same
GB0326459D0 (en) 2003-11-13 2003-12-17 Astrazeneca Ab Quinazoline derivatives
MXPA06007017A (en) * 2003-12-18 2006-08-31 Janssen Pharmaceutica Nv Pyrido- and pyrimidopyrimidine derivatives as anti- proliferative agents.
GB0330002D0 (en) 2003-12-24 2004-01-28 Astrazeneca Ab Quinazoline derivatives
EP1755394A4 (en) * 2004-04-16 2009-08-05 Smithkline Beecham Corp Cancer treatment method
MXPA06012756A (en) 2004-05-06 2007-01-16 Warner Lambert Co 4-phenylamino-quinazolin-6-yl-amides.
BRPI0511754A (en) * 2004-06-03 2008-01-02 Smithkline Beechman Cork Ltd use of a compound or salts or solvates thereof
MXPA06013952A (en) * 2004-06-04 2007-02-08 Smithkline Beecham Cork Ltd Cancer treatment method.
US20100226931A1 (en) * 2004-06-24 2010-09-09 Nicholas Valiante Compounds for immunopotentiation
CA2571421A1 (en) * 2004-06-24 2006-01-05 Nicholas Valiante Compounds for immunopotentiation
AU2005264063B2 (en) 2004-07-16 2009-09-10 Pfizer Products Inc. Combination treatment for non-hematologic malignancies using an anti-igf-1r antibody
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
WO2006021884A2 (en) 2004-08-26 2006-03-02 Pfizer Inc. Enantiomerically pure aminoheteroaryl compounds as protein kinase inhibitors
ES2322175T3 (en) 2004-09-17 2009-06-17 EISAI R&amp;D MANAGEMENT CO., LTD. MEDICINAL COMPOSITION WITH IMPROVED STABILITY AND REDUCED GELIFICATION.
TW200621251A (en) 2004-10-12 2006-07-01 Neurogen Corp Substituted biaryl quinolin-4-ylamine analogues
US7652009B2 (en) 2004-11-30 2010-01-26 Amgem Inc. Substituted heterocycles and methods of use
GB0427131D0 (en) * 2004-12-10 2005-01-12 Glaxosmithkline Biolog Sa Novel combination
CN101124228B (en) 2004-12-14 2011-06-15 阿斯利康(瑞典)有限公司 Pyrazolopyrimidine compounds as antitumor agents
NZ555462A (en) * 2004-12-17 2009-03-31 Smithkline Beecham Cork Ltd Cancer treatment method
ATE430747T1 (en) * 2004-12-21 2009-05-15 Smithkline Beecham Corp 2-PYRIMIDINYL-PYRAZOLOPYRIDINE ERBB KINASE INHIBITORS
US7812022B2 (en) * 2004-12-21 2010-10-12 Glaxosmithkline Llc 2-pyrimidinyl pyrazolopyridine ErbB kinase inhibitors
PE20060777A1 (en) 2004-12-24 2006-10-06 Boehringer Ingelheim Int INDOLINONE DERIVATIVES FOR THE TREATMENT OR PREVENTION OF FIBROTIC DISEASES
CA2593482A1 (en) * 2005-01-14 2006-07-20 Neurogen Corporation Heteroaryl substituted quinolin-4-ylamine analogues
US8735394B2 (en) * 2005-02-18 2014-05-27 Abraxis Bioscience, Llc Combinations and modes of administration of therapeutic agents and combination therapy
WO2006089290A1 (en) * 2005-02-18 2006-08-24 Abraxis Bioscience Inc.. Combinations and modes of administration of therapeutic agents and combination therapy
US20060216288A1 (en) * 2005-03-22 2006-09-28 Amgen Inc Combinations for the treatment of cancer
NZ562453A (en) 2005-03-31 2010-04-30 Agensys Inc Antibodies and related molecules that bind to 161P2F10B proteins
PL1871347T3 (en) * 2005-04-19 2017-04-28 Novartis Ag Pharmaceutical composition
EP2444419A1 (en) 2005-04-26 2012-04-25 Pfizer Inc. P-Cadherin antibodies
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
CN107056943B (en) 2005-09-07 2021-06-08 安进弗里蒙特公司 Human monoclonal antibody to activin receptor-like kinase-1
DE602006018331D1 (en) 2005-09-20 2010-12-30 Astrazeneca Ab 4- (1H-INDAZOL-5-YLAMINO) CHINAZOLINE COMPOUNDS AS INHIBITORS OF ERBB RECEPTORT ROSINKINASE FOR THE TREATMENT OF CANCER
EP1926996B1 (en) 2005-09-20 2011-11-09 OSI Pharmaceuticals, Inc. Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
UA96139C2 (en) 2005-11-08 2011-10-10 Дженентек, Інк. Anti-neuropilin-1 (nrp1) antibody
JP5688877B2 (en) 2005-11-11 2015-03-25 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Quinazoline derivatives for the treatment of cancer diseases
ES2421450T3 (en) * 2005-12-05 2013-09-02 Glaxosmithkline Llc ErbB kinase inhibitor pyrimidinyl-pyrazolopyridines
JO2660B1 (en) 2006-01-20 2012-06-17 نوفارتيس ايه جي PI-3 Kinase inhibitors and methods of their use
CN101003514A (en) 2006-01-20 2007-07-25 上海艾力斯医药科技有限公司 Derivative of quinazoline, preparation method and usage
AR059066A1 (en) 2006-01-27 2008-03-12 Amgen Inc COMBINATIONS OF THE ANGIOPOYETINE INHIBITOR -2 (ANG2) AND THE VASCULAR ENDOTELIAL GROWTH FACTOR INHIBITOR (VEGF)
CN101374840B (en) * 2006-01-31 2011-09-28 霍夫曼-拉罗奇有限公司 7h-pyrido[3,4-d]pyrimidin-8-ones, their manufacture and use as protein kinase inhibitors
PE20070978A1 (en) * 2006-02-14 2007-11-15 Novartis Ag HETEROCICLIC COMPOUNDS AS INHIBITORS OF PHOSPHATIDYLINOSITOL 3-KINASES (PI3Ks)
TW200808739A (en) * 2006-04-06 2008-02-16 Novartis Vaccines & Diagnostic Quinazolines for PDK1 inhibition
US20090203718A1 (en) * 2006-04-13 2009-08-13 Smithkline Beecham (Cork) Ltd. Cancer treatment method
CN101472915A (en) 2006-04-19 2009-07-01 诺瓦提斯公司 Indazole compounds and methods for inhibition of CDC7
RS20080525A (en) 2006-05-09 2009-09-08 Pfizer Products Inc., Cycloalkylamino acid derivatives and pharmaceutical compositions thereof
NL2000613C2 (en) 2006-05-11 2007-11-20 Pfizer Prod Inc Triazole pyrazine derivatives.
US20090209580A1 (en) 2006-05-18 2009-08-20 Eisai R & D Management Co., Ltd. Antitumor agent for thyroid cancer
ATE417274T1 (en) * 2006-06-01 2008-12-15 Cellzome Ag METHOD FOR IDENTIFYING MOLECULES INTERACTING WITH ZAP-70 AND FOR ZAP-70 PURIFICATION
ES2427924T3 (en) 2006-06-30 2013-11-04 Merck Sharp & Dohme Corp. IGFBP2 biomarker
PE20080403A1 (en) 2006-07-14 2008-04-25 Amgen Inc FUSED HETEROCYCLIC DERIVATIVES AND METHODS OF USE
US8217177B2 (en) 2006-07-14 2012-07-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
US20110053964A1 (en) * 2006-08-22 2011-03-03 Roger Tung 4-aminoquinazoline derivatives and methods of use thereof
KR20090042994A (en) * 2006-08-22 2009-05-04 콘서트 파마슈티컬즈, 인크. 4-aminoquinazoline derivatives and methods of use thereof
EP2065372B1 (en) 2006-08-28 2012-11-28 Eisai R&D Management Co., Ltd. Antitumor agent for undifferentiated gastric cancer
AU2007299080B2 (en) 2006-09-18 2013-04-18 Boehringer Ingelheim International Gmbh Method for treating cancer harboring EGFR mutations
EP2079739A2 (en) * 2006-10-04 2009-07-22 Pfizer Products Inc. Pyrido[4,3-d]pyrimidin-4(3h)-one derivatives as calcium receptor antagonists
WO2008044045A1 (en) 2006-10-12 2008-04-17 Astex Therapeutics Limited Pharmaceutical combinations
JP5528806B2 (en) 2006-10-12 2014-06-25 アステックス、セラピューティックス、リミテッド Compound drug
WO2008054633A1 (en) * 2006-10-31 2008-05-08 Janssen Pharmaceutica N.V. Hydrazone derivatives as kinase inhibitors
WO2008063888A2 (en) 2006-11-22 2008-05-29 Plexxikon, Inc. Compounds modulating c-fms and/or c-kit activity and uses therefor
MX2009006466A (en) 2006-12-13 2009-06-26 Schering Corp Methods of treatment.
CA2672438A1 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
ES2449482T3 (en) 2007-01-09 2014-03-19 Amgen Inc. Bis-aryl-amide derivatives useful for cancer treatment
JP5319306B2 (en) 2007-01-29 2013-10-16 エーザイ・アール・アンド・ディー・マネジメント株式会社 Composition for treatment of undifferentiated gastric cancer
CN101245050A (en) 2007-02-14 2008-08-20 上海艾力斯医药科技有限公司 4-aniline quinazoline derivative salt
JP2010519204A (en) 2007-02-16 2010-06-03 アムジエン・インコーポレーテツド Nitrogen-containing heterocyclic ketones and their use as c-Met inhibitors
AU2008239594B2 (en) 2007-04-13 2013-10-24 Beth Israel Deaconess Medical Center Methods for treating cancer resistant to ErbB therapeutics
KR20090130347A (en) * 2007-05-09 2009-12-22 화이자 인코포레이티드 Substituted heterocyclic derivatives and compositions and their pharmaceutical use as antibacterial agents
US20110245496A1 (en) * 2007-06-11 2011-10-06 Andrew Simon Craig Quinazoline Salt Compounds
UY31137A1 (en) * 2007-06-14 2009-01-05 Smithkline Beecham Corp DERIVATIVES OF QUINAZOLINE AS INHIBITORS OF THE PI3 QUINASA
CA2696761C (en) 2007-08-21 2017-02-14 Amgen Inc. Human c-fms antigen binding proteins
HRP20130649T1 (en) 2007-09-07 2013-08-31 Agensys, Inc. Antibodies and related molecules that bind to 24p4c12 proteins
US20090215802A1 (en) * 2007-09-13 2009-08-27 Protia, Llc Deuterium-enriched lapatinib
RU2010119922A (en) * 2007-10-19 2011-11-27 Фарма Мар, С.А. (Es) ADVANCED ANTITUMOR TREATMENT
RU2010120674A (en) 2007-10-22 2011-11-27 Шеринг Корпорейшн (US) TOTALLY HUMAN ANTI-VEGF ANTIBODIES AND METHODS OF APPLICATION
EA018716B1 (en) 2007-10-29 2013-10-30 Натко Фарма Лимитед Novel 4-(tetrazol-5-yl)quinazoline derivatives as anti cancer agents
WO2009060945A1 (en) 2007-11-09 2009-05-14 Eisai R & D Management Co., Ltd. Combination of anti-angiogenic substance and anti-tumor platinum complex
CA2710122A1 (en) 2007-12-20 2009-07-02 Novartis Ag Thiazole derivatives used as pi 3 kinase inhibitors
CN101492445A (en) * 2008-01-22 2009-07-29 孙飘扬 Heteroaromatic compound, preparation method and uses thereof
WO2009095480A1 (en) * 2008-01-30 2009-08-06 Pharma Mar, S.A. Improved antitumoral treatments
AU2009221120A1 (en) * 2008-03-07 2009-09-11 Pharma Mar, S.A. Improved antitumoral treatments
KR102784999B1 (en) 2008-03-18 2025-03-21 제넨테크, 인크. Combinations of an anti-HER2 antibody-drug conjugate and chemotherapeutic agents, and methods of use
US8252805B2 (en) * 2008-05-07 2012-08-28 Teva Pharmaceutical Industries Ltd. Forms of lapatinib ditosylate and processes for preparation thereof
US20090306106A1 (en) * 2008-05-15 2009-12-10 Leonid Metsger Forms of crystalline lapatinib and processes for preparation thereof
CN101584696A (en) 2008-05-21 2009-11-25 上海艾力斯医药科技有限公司 Composition containing quinazoline derivatives, preparation method and use
WO2010017387A2 (en) * 2008-08-06 2010-02-11 Teva Pharmaceutical Industries Ltd. Lapatinib intermediates
EP2158913A1 (en) 2008-08-25 2010-03-03 Ratiopharm GmbH Pharmaceutical composition comprising N-[3-chhloro-4-[(3-fluorophenyl)methoxy]phenyl]6-(5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine
EP2158912A1 (en) 2008-08-25 2010-03-03 Ratiopharm GmbH Pharmaceutical composition comprising N-[3-chhloro-4-[3-fluorophenyl)methoxy)phenyl]6-[5[[[2-(methylsulfonyl)ethyl]amino]methyl]-2-furyl]-4-quinazolinamine
WO2010027848A2 (en) * 2008-08-26 2010-03-11 Teva Pharmaceutical Industries Ltd. Forms of lapatinib compounds and processes for the preparation thereof
JP5836125B2 (en) 2008-10-16 2015-12-24 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション Fully human antibodies against high molecular weight melanoma-related antigens and uses thereof
CA2740977A1 (en) 2008-11-03 2010-06-03 Natco Pharma Limited A novel process for the preparation of lapatinib and its pharmaceutically acceptable salts
CA2742986C (en) 2008-11-07 2015-03-31 Triact Therapeutics, Inc. Use of catecholic butane derivatives in cancer therapy
CN101787017A (en) * 2009-01-23 2010-07-28 岑均达 Optical pure quinazoline compound
CA2748943A1 (en) 2009-02-09 2010-08-12 Supergen, Inc. Pyrrolopyrimidinyl axl kinase inhibitors
WO2010099139A2 (en) 2009-02-25 2010-09-02 Osi Pharmaceuticals, Inc. Combination anti-cancer therapy
EP2400990A2 (en) 2009-02-26 2012-01-04 OSI Pharmaceuticals, LLC In situ methods for monitoring the emt status of tumor cells in vivo
JP2012519282A (en) 2009-02-27 2012-08-23 オーエスアイ・ファーマシューティカルズ，エルエルシー Methods for identifying mesenchymal tumor cells or agents that inhibit their production
WO2010099138A2 (en) 2009-02-27 2010-09-02 Osi Pharmaceuticals, Inc. Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
US8642834B2 (en) 2009-02-27 2014-02-04 OSI Pharmaceuticals, LLC Methods for the identification of agents that inhibit mesenchymal-like tumor cells or their formation
TW201035088A (en) 2009-02-27 2010-10-01 Supergen Inc Cyclopentathiophene/cyclohexathiophene DNA methyltransferase inhibitors
WO2010101734A1 (en) 2009-03-06 2010-09-10 Merck Sharp & Dohme Corp. Combination cancer therapy with an akt inhibitor and other anticancer agents
US20120064072A1 (en) 2009-03-18 2012-03-15 Maryland Franklin Combination Cancer Therapy Comprising Administration of an EGFR Inhibitor and an IGF-1R Inhibitor
US20120121596A1 (en) 2009-03-20 2012-05-17 Germaine Fuh Bispecific anti-her antibodies
US8530492B2 (en) 2009-04-17 2013-09-10 Nektar Therapeutics Oligomer-protein tyrosine kinase inhibitor conjugates
US8816077B2 (en) 2009-04-17 2014-08-26 Nektar Therapeutics Oligomer-protein tyrosine kinase inhibitor conjugates
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
HUE044629T2 (en) 2009-07-06 2019-11-28 Boehringer Ingelheim Int Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
JP5876827B2 (en) 2009-08-21 2016-03-02 ノバルティス アーゲー How to treat cancer
EP2473500A2 (en) 2009-09-01 2012-07-11 Pfizer Inc. Benzimidazole derivatives
JP2013505899A (en) 2009-09-28 2013-02-21 チールー ファーマシューティカル カンパニー、リミテッド 4- (Substituted anilino) quinazoline derivatives useful as tyrosine kinase inhibitors
WO2011039759A1 (en) * 2009-09-29 2011-04-07 Natco Pharma Limited A new process for the preparation of lapatinib and its pharmaceutically acceptable salts
CA2780875A1 (en) 2009-11-13 2011-05-19 Pangaea Biotech, S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
CN102079759B (en) * 2009-12-01 2014-09-17 天津药物研究院 6-substituted quinazoline derivative, preparation method and application thereof
AR079256A1 (en) 2009-12-04 2012-01-04 Genentech Inc METHOD FOR THE TREATMENT OF METASTASIC BREAST CANCER WITH TRASTUZUMAB-MCC-DM1
PH12012501361A1 (en) 2009-12-31 2012-10-22 Centro Nac De Investigaciones Oncologicas Cnio Tricyclic compounds for use as kinase inhibitors
WO2011089400A1 (en) 2010-01-22 2011-07-28 Centro Nacional De Investigaciones Oncológicas (Cnio) Inhibitors of pi3 kinase
LT3150610T (en) 2010-02-12 2019-11-11 Pfizer 8-FLUOR-2- {4 - [(METHYL-AMINO] -methyl] -phenyl} -1,3,4,5-TETRAHYDRO-6H-AZEPINO [5,4,3-CD] INDOL-6-ONO SALTS AND POLYMORPHES
US20130065883A1 (en) 2010-02-18 2013-03-14 Centro Nacional de Investigaceiones Oncologicas (CNIO) Triazolo [4, 5- B] Pyridin Derivatives
JP2013527748A (en) 2010-03-03 2013-07-04 オーエスアイ・ファーマシューティカルズ，エルエルシー Biological markers useful for predicting anticancer responses to insulin-like growth factor 1 receptor kinase inhibitors
WO2011109584A2 (en) 2010-03-03 2011-09-09 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors
US8710221B2 (en) 2010-03-23 2014-04-29 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
US8563719B2 (en) 2010-03-23 2013-10-22 Scinopharm Taiwan, Ltd. Process and intermediates for preparing lapatinib
CN102985086A (en) 2010-03-29 2013-03-20 阿布拉科斯生物科学有限公司 Methods of enhancing drug delivery and effectiveness of therapeutic agents
LT2552415T (en) 2010-03-29 2016-12-27 Abraxis Bioscience, Llc Methods of treating cancer
WO2011121317A1 (en) 2010-04-01 2011-10-06 Centro Nacional De Investigaciones Oncologicas (Cnio) Imidazo [2,1-b] [1,3,4] thiadiazoles as protein or lipid kinase inhibitors
JP2013526578A (en) 2010-05-21 2013-06-24 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー combination
US9180129B2 (en) 2010-05-21 2015-11-10 Novartis Ag Combination of lapatinib and trametinib
KR20180049180A (en) 2010-06-04 2018-05-10 아브락시스 바이오사이언스, 엘엘씨 Methods of treatment of pancreatic cancer
CA2802857C (en) 2010-06-16 2018-09-11 University Of Pittsburgh-Of The Commonwealth System Of Higher Education Antibodies to endoplasmin and their use
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
US9012458B2 (en) 2010-06-25 2015-04-21 Eisai R&D Management Co., Ltd. Antitumor agent using compounds having kinase inhibitory effect in combination
AU2011274528B2 (en) 2010-07-09 2015-04-23 Genentech, Inc. Anti-neuropilin antibodies and methods of use
CN102344445B (en) * 2010-07-23 2015-11-25 岑均达 Optical pure quinazoline compound
CN102344444B (en) * 2010-07-23 2015-07-01 岑均达 Optically pure quinazoline compounds
AR082418A1 (en) 2010-08-02 2012-12-05 Novartis Ag CRYSTAL FORMS OF 1- (4-METHYL-5- [2- (2,2,2-TRIFLUORO-1,1-DIMETHYL-Ethyl) -PIRIDIN-4-IL] -TIAZOL-2-IL) -AMIDE OF 2 -AMIDA OF THE ACID (S) -PIRROLIDIN-1,2-DICARBOXILICO
SG10201408229WA (en) 2010-08-31 2015-02-27 Genentech Inc Biomarkers and methods of treatment
EP2630134B9 (en) 2010-10-20 2018-04-18 Pfizer Inc Pyridine-2- derivatives as smoothened receptor modulators
WO2012052745A1 (en) 2010-10-21 2012-04-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Combinations of pi3k inhibitors with a second anti -tumor agent
WO2012069557A1 (en) 2010-11-24 2012-05-31 Glaxo Group Limited Multispecific antigen binding proteins targeting hgf
CN102558159A (en) * 2010-12-20 2012-07-11 天津药物研究院 4-subsittution m sulfonylurea amide aniline-quinazoline derivate and preparation method and application thereof
CN102558160B (en) * 2010-12-20 2015-09-23 天津药物研究院 4-replaces Toluidrin anilino-quinazoline derivatives and its production and use
EP2468883A1 (en) 2010-12-22 2012-06-27 Pangaea Biotech S.L. Molecular biomarkers for predicting response to tyrosine kinase inhibitors in lung cancer
EP2655364A4 (en) 2010-12-23 2014-06-11 Apotex Pharmachem Inc A process for the preparation of lapatinib and its ditosylate salt
US9134297B2 (en) 2011-01-11 2015-09-15 Icahn School Of Medicine At Mount Sinai Method and compositions for treating cancer and related methods
WO2012098387A1 (en) 2011-01-18 2012-07-26 Centro Nacional De Investigaciones Oncológicas (Cnio) 6, 7-ring-fused triazolo [4, 3 - b] pyridazine derivatives as pim inhibitors
CA2825605C (en) 2011-01-31 2019-05-07 Novartis Ag Heterocyclic derivatives
US20120214830A1 (en) 2011-02-22 2012-08-23 OSI Pharmaceuticals, LLC Biological markers predictive of anti-cancer response to insulin-like growth factor-1 receptor kinase inhibitors in hepatocellular carcinoma
EP2492688A1 (en) 2011-02-23 2012-08-29 Pangaea Biotech, S.A. Molecular biomarkers for predicting response to antitumor treatment in lung cancer
CN103857288B (en) 2011-03-04 2016-09-21 葛兰素史密斯克莱知识产权发展有限公司 Amino-quinolin as inhibitors of kinases
WO2012122058A2 (en) 2011-03-04 2012-09-13 Newgen Therapeutics, Inc. Alkyne substituted quinazoline compound and methods of use
CA2829219C (en) 2011-03-09 2021-03-16 Richard G. Pestell Prostate cancer cell lines, gene signatures and uses thereof
US9295676B2 (en) 2011-03-17 2016-03-29 The Trustees Of The University Of Pennsylvania Mutation mimicking compounds that bind to the kinase domain of EGFR
CN103648500B (en) 2011-03-17 2016-05-04 宾夕法尼亚大学理事会 Method and the purposes of bifunctional enzyme pincers type processed molecule
WO2012129145A1 (en) 2011-03-18 2012-09-27 OSI Pharmaceuticals, LLC Nscle combination therapy
MY161199A (en) 2011-03-23 2017-04-14 Amgen Inc Fused tricyclic dual inhibitors of cdk 4/6 and flt3
CN103857395A (en) 2011-04-01 2014-06-11 基因泰克公司 Combinations of AKT inhibitor compounds and abiraterone, and methods of use
US9150644B2 (en) 2011-04-12 2015-10-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Human monoclonal antibodies that bind insulin-like growth factor (IGF) I and II
JP6021805B2 (en) 2011-04-18 2016-11-09 エーザイ・アール・アンド・ディー・マネジメント株式会社 Tumor treatment
ES2724801T3 (en) 2011-04-19 2019-09-16 Pfizer Combinations of anti-4-1BB antibodies and ADCC inducing antibodies for cancer treatment
JP2014519813A (en) 2011-04-25 2014-08-21 オーエスアイ・ファーマシューティカルズ，エルエルシー Use of EMT gene signatures in cancer drug discovery, diagnosis, and treatment
CN102918029B (en) 2011-05-17 2015-06-17 江苏康缘药业股份有限公司 4-phenylamino-6-butenamide-7-alkyloxy quinazoline derivatives, preparative method and use thereof
AU2012257513B2 (en) 2011-05-19 2017-05-11 Fundación Del Sector Público Estatal Centro Nacional De Investigaciones Oncológicas Carlos III (F.S.P. CNIO) Macrocyclic compounds as protein kinase inhibitors
EP2524918A1 (en) 2011-05-19 2012-11-21 Centro Nacional de Investigaciones Oncológicas (CNIO) Imidazopyrazines derivates as kinase inhibitors
JP5414739B2 (en) 2011-05-25 2014-02-12 三菱電機株式会社 Semiconductor test jig
EP3444363B1 (en) 2011-06-03 2020-11-25 Eisai R&D Management Co., Ltd. Biomarkers for prediciting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
WO2013005057A1 (en) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) New compounds
WO2013005041A1 (en) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncológicas (Cnio) Tricyclic heterocyclic compounds as kinase inhibitors
WO2013004984A1 (en) 2011-07-07 2013-01-10 Centro Nacional De Investigaciones Oncologicas (Cnio) Tricyclic compounds for use as kinase inhibitors
US9416132B2 (en) 2011-07-21 2016-08-16 Tolero Pharmaceuticals, Inc. Substituted imidazo[1,2-b]pyridazines as protein kinase inhibitors
US9499530B2 (en) * 2011-08-01 2016-11-22 Hangzhou Minsheng Institutes For Pharma Research Quinazoline derivative, composition having the derivative, and use of the derivative in preparing medicament
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
TWI547494B (en) 2011-08-18 2016-09-01 葛蘭素史克智慧財產發展有限公司 Aminoquinazolines as kinase inhibitors
RU2614254C2 (en) 2011-08-31 2017-03-24 Дженентек, Инк. Diagnostic markers
WO2013042006A1 (en) 2011-09-22 2013-03-28 Pfizer Inc. Pyrrolopyrimidine and purine derivatives
RU2014110228A (en) 2011-09-30 2015-11-10 Дженентек, Инк. DIAGNOSTIC MARKERS
ES2654160T3 (en) 2011-10-04 2018-02-12 Igem Therapeutics Limited Anti-HMW-MAA IgE antibodies
EP2771342B1 (en) 2011-10-28 2016-05-18 Novartis AG Purine derivatives and their use in the treatment of disease
KR20140076602A (en) 2011-11-08 2014-06-20 화이자 인코포레이티드 Methods of treating inflammatory disorders using anti-m-csf antibodies
WO2013080218A1 (en) 2011-11-28 2013-06-06 Fresenius Kabi Oncology Ltd. Novel intermediates and process for the preparation of lapatinib and its pharmaceutically acceptable salts
WO2013113796A1 (en) 2012-01-31 2013-08-08 Smithkline Beecham (Cork) Limited Method of treating cancer
AR090263A1 (en) 2012-03-08 2014-10-29 Hoffmann La Roche COMBINED ANTIBODY THERAPY AGAINST HUMAN CSF-1R AND USES OF THE SAME
WO2013149581A1 (en) 2012-04-03 2013-10-10 Novartis Ag Combination products with tyrosine kinase inhibitors and their use
WO2013152252A1 (en) 2012-04-06 2013-10-10 OSI Pharmaceuticals, LLC Combination anti-cancer therapy
AU2013262977A1 (en) 2012-05-14 2015-01-22 Prostagene, Llc Using modulators of CCR5 for treating cancer
NZ700924A (en) 2012-05-16 2016-02-26 Novartis Ag Dosage regimen for a pi-3 kinase inhibitor
WO2013190089A1 (en) 2012-06-21 2013-12-27 Pangaea Biotech, S.L. Molecular biomarkers for predicting outcome in lung cancer
US9505749B2 (en) 2012-08-29 2016-11-29 Amgen Inc. Quinazolinone compounds and derivatives thereof
TWI592417B (en) 2012-09-13 2017-07-21 葛蘭素史克智慧財產發展有限公司 Aminoquinazoline kinase inhibitor prodrug
US9394257B2 (en) 2012-10-16 2016-07-19 Tolero Pharmaceuticals, Inc. PKM2 modulators and methods for their use
CZ2012712A3 (en) 2012-10-17 2014-04-30 Zentiva, K.S. Novel process for preparing key intermediate for the preparation of lapatinib o
CN102942561A (en) * 2012-11-06 2013-02-27 深圳海王药业有限公司 4-amino quinazoline heterocyclic compound and purpose of 4-amino quinazoline heterocyclic compound
US9260426B2 (en) 2012-12-14 2016-02-16 Arrien Pharmaceuticals Llc Substituted 1H-pyrrolo [2, 3-b] pyridine and 1H-pyrazolo [3, 4-b] pyridine derivatives as salt inducible kinase 2 (SIK2) inhibitors
CN104755463A (en) 2012-12-21 2015-07-01 卫材R&D管理有限公司 Quinoline derivatives in amorphous form and methods for their production
CN103896889B (en) * 2012-12-27 2016-05-25 上海创诺制药有限公司 Lapatinib intermediate and its preparation method and application
JP6669499B2 (en) 2013-02-15 2020-03-18 カラ ファーマシューティカルズ インコーポレイテッド Therapeutic compounds
ES2635620T3 (en) 2013-02-19 2017-10-04 Hexal Ag Pharmaceutical composition comprising n- [3-chloro-4- (3-fluorobenzyloxy) phenyl] -6- [5 ({[2- (methylsulfonyl) ethyl] amino} methyl) -2-furyl] quinazolin-4-amine or a pharmaceutically acceptable salt, solvate or solvated salt thereof
US9688688B2 (en) 2013-02-20 2017-06-27 Kala Pharmaceuticals, Inc. Crystalline forms of 4-((4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolin-7-yl)oxy)-1-(2-oxa-7-azaspiro[3.5]nonan-7-yl)butan-1-one and uses thereof
CA2900680C (en) 2013-02-20 2021-08-10 Kala Pharmaceuticals, Inc. Quinoline and quinazoline compounds and uses thereof for treating and/or preventing diseases
BR112015019624A2 (en) 2013-02-21 2017-07-18 Glaxosmithkline Ip Dev Ltd quinazolines as kinase inhibitors
BR112015018418A2 (en) 2013-02-22 2017-07-18 Hoffmann La Roche methods for treating cancer, for increasing the effectiveness of a treatment, for postponing and / or preventing cancer development, for increasing sensitivity to a targeted therapy, to extending the sensitivity period, to extending the response duration to a targeted therapy. and pharmaceutical
WO2014134202A1 (en) 2013-02-26 2014-09-04 Triact Therapeutics, Inc. Cancer therapy
CN103159747A (en) * 2013-02-26 2013-06-19 常州鸿创高分子科技有限公司 Synthetic method of lapatinib
US9468681B2 (en) 2013-03-01 2016-10-18 California Institute Of Technology Targeted nanoparticles
WO2014138364A2 (en) 2013-03-06 2014-09-12 Genentech, Inc. Methods of treating and preventing cancer drug resistance
EP2968565A2 (en) 2013-03-14 2016-01-20 Genentech, Inc. Methods of treating cancer and preventing cancer drug resistance
EP3590932B1 (en) 2013-03-14 2023-05-03 Sumitomo Pharma Oncology, Inc. Jak2 and alk2 inhibitors and methods for their use
MX2015011899A (en) 2013-03-15 2016-05-05 Genentech Inc Methods of treating cancer and preventing cancer drug resistance.
EP2976085A1 (en) 2013-03-21 2016-01-27 INSERM - Institut National de la Santé et de la Recherche Médicale Method and pharmaceutical composition for use in the treatment of chronic liver diseases associated with a low hepcidin expression
WO2014170910A1 (en) 2013-04-04 2014-10-23 Natco Pharma Limited Process for the preparation of lapatinib
US9206188B2 (en) 2013-04-18 2015-12-08 Arrien Pharmaceuticals Llc Substituted pyrrolo[2,3-b]pyridines as ITK and JAK inhibitors
CN105264380B (en) 2013-05-14 2017-09-05 卫材R&D管理有限公司 Biomarkers for predicting and evaluating responsiveness of endometrial cancer subjects to lenvatinib compounds
HU231012B1 (en) 2013-05-24 2019-11-28 Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság Lapatinib salts
US9714235B2 (en) * 2013-07-18 2017-07-25 Shanghai Fochon Pharmaceutical Co., Ltd. Quinazoline derivatives, compositions thereof, and use as pharmaceuticals
EP3044593A4 (en) 2013-09-09 2017-05-17 Triact Therapeutics, Inc. Cancer therapy
JP6946000B2 (en) 2013-10-04 2021-10-06 アプトース バイオサイエンシーズ， インコーポレイテッド Compositions and Methods for the Treatment of Cancer
US9890173B2 (en) 2013-11-01 2018-02-13 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
CN106061261B (en) 2013-11-01 2018-04-24 卡拉制药公司 Crystal form of therapeutic compounds and application thereof
CN103554091B (en) * 2013-11-05 2016-05-18 沈阳工业大学 Quinazoline derivant and its production and use
UA115388C2 (en) 2013-11-21 2017-10-25 Пфайзер Інк. 2,6-substituted purine derivatives and their use in the treatment of proliferative disorders
BR112016011811A2 (en) 2013-12-06 2017-08-08 Novartis Ag USE OF AN ALPHA-ISOFORM SELECTIVE PHOSPHATIDYLINOSITOL 3-KINASE INHIBITOR, THERAPEUTIC REGIME AND PACKAGE
US9242965B2 (en) 2013-12-31 2016-01-26 Boehringer Ingelheim International Gmbh Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
HRP20191283T1 (en) 2014-01-24 2019-10-18 Turning Point Therapeutics, Inc. DIARYL MACROCYCLES AS PROTEIN KINAZE MODULATORS
US20160361309A1 (en) 2014-02-26 2016-12-15 Glaxosmithkline Intellectual Property (No.2) Limited Methods of treating cancer patients responding to ezh2 inhibitor gsk126
WO2015148531A1 (en) 2014-03-24 2015-10-01 Genentech, Inc. Cancer treatment with c-met antagonists and correlation of the latter with hgf expression
WO2015155624A1 (en) 2014-04-10 2015-10-15 Pfizer Inc. Dihydropyrrolopyrimidine derivatives
WO2015156674A2 (en) 2014-04-10 2015-10-15 Stichting Het Nederlands Kanker Instituut Method for treating cancer
EP2937346A1 (en) 2014-04-24 2015-10-28 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Co-crystals of lapatinib
EP3556757A1 (en) 2014-04-30 2019-10-23 Pfizer Inc Cycloalkyl-linked diheterocycle derivatives
US9388239B2 (en) 2014-05-01 2016-07-12 Consejo Nacional De Investigation Cientifica Anti-human VEGF antibodies with unusually strong binding affinity to human VEGF-A and cross reactivity to human VEGF-B
WO2016001789A1 (en) 2014-06-30 2016-01-07 Pfizer Inc. Pyrimidine derivatives as pi3k inhibitors for use in the treatment of cancer
JP6811706B2 (en) 2014-07-31 2021-01-13 ザ ホンコン ユニヴァーシティ オブ サイエンス アンド テクノロジー Human monoclonal antibodies against EPHA4 and their use
SG10202100272RA (en) 2014-08-28 2021-02-25 Eisai R&D Man Co Ltd High-purity quinoline derivative and method for manufacturing same
EP3206717B1 (en) 2014-10-17 2020-11-25 Novartis AG Combination of ceritinib with an egfr inhibitor
CA2969974C (en) * 2014-12-15 2020-08-04 The Regents Of The University Of Michigan Small molecule inhibitors of egfr and pi3k
ES2746839T3 (en) 2014-12-18 2020-03-09 Pfizer Pyrimidine and triazine derivatives and their use as AXL inhibitors
WO2016105503A1 (en) 2014-12-24 2016-06-30 Genentech, Inc. Therapeutic, diagnostic and prognostic methods for cancer of the bladder
CN105801565B (en) * 2014-12-30 2020-04-03 天津法莫西医药科技有限公司 Preparation method of N- [ 3-chloro-4- [ (3-fluorophenyl) methoxy ] phenyl ] -6- [ (5-formyl) furan-2-yl ] -4-quinazolinamine
US11083755B2 (en) 2015-01-08 2021-08-10 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
MA41414A (en) 2015-01-28 2017-12-05 Centre Nat Rech Scient ICOS AGONIST BINDING PROTEINS
WO2016123706A1 (en) * 2015-02-03 2016-08-11 Trillium Therapeutics Inc. Novel fluorinated derivatives as egfr inhibitors useful for treating cancers
RS65049B1 (en) 2015-02-25 2024-02-29 Eisai R&D Man Co Ltd METHOD FOR SUPPRESSING THE BITTERNESS OF QUINOLINE DERIVATIVES
KR102662228B1 (en) 2015-03-04 2024-05-02 머크 샤프 앤드 돔 코포레이션 Combination of PD-1 antagonists and VEGFR/FGFR/RET tyrosine kinase inhibitors to treat cancer
AU2016252609B2 (en) 2015-04-20 2022-06-30 Sumitomo Pharma Oncology, Inc. Predicting response to alvocidib by mitochondrial profiling
EP3288957A4 (en) 2015-05-01 2019-01-23 Cocrystal Pharma, Inc. NUCLEOSIDE ANALOGUES FOR USE IN THE TREATMENT OF FLAVIVIRIDAE AND CANCER FAMILY VIRUS INFECTIONS
PL3298021T3 (en) 2015-05-18 2019-11-29 Tolero Pharmaceuticals Inc Alvocidib prodrugs having increased bioavailability
CN106279307B (en) * 2015-05-19 2019-07-26 正大天晴药业集团股份有限公司 Aromatic glucosamine derivative, its preparation method and antitumor use
CA2988707C (en) 2015-06-16 2023-10-10 Eisai R&D Management Co., Ltd. Combination of cbp/catenin inhibitor and immune checkpoint inhibitor for treating cancer
EP3795609B1 (en) 2015-07-01 2024-04-03 California Institute of Technology Cationic mucic acid polymer-based delivery systems
WO2017004342A1 (en) 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
KR102623734B1 (en) 2015-07-06 2024-01-10 터닝 포인트 테라퓨틱스, 인크. Diaryl macrocycle polymorph
WO2017009751A1 (en) 2015-07-15 2017-01-19 Pfizer Inc. Pyrimidine derivatives
SMT202400496T1 (en) 2015-07-21 2025-01-14 Turning Point Therapeutics Inc Chiral diaryl macrocycle and use thereof in the treatment of cancer
AU2016301315C1 (en) 2015-08-03 2022-07-07 Sumitomo Pharma Oncology, Inc. Combination therapies for treatment of cancer
EP3331919A1 (en) 2015-08-07 2018-06-13 GlaxoSmithKline Intellectual Property Development Limited Combination therapy comprising anti ctla-4 antibodies
JP6553726B2 (en) 2015-08-20 2019-07-31 エーザイ・アール・アンド・ディー・マネジメント株式会社 Tumor therapeutic agent
EP3350181B1 (en) * 2015-09-02 2023-11-01 The Regents of The University of California Her3 ligands and uses thereof
CN106632276B (en) * 2015-10-28 2021-06-15 上海天慈生物谷生物工程有限公司 Preparation method of medicine for treating breast cancer
CA3002954A1 (en) 2015-11-02 2017-05-11 Novartis Ag Dosage regimen for a phosphatidylinositol 3-kinase inhibitor
EP4015537A1 (en) 2015-12-01 2022-06-22 GlaxoSmithKline Intellectual Property Development Limited Combination treatments and uses and methods thereof
EP3383375A1 (en) 2015-12-03 2018-10-10 Agios Pharmaceuticals, Inc. Mat2a inhibitors for treating mtap null cancer
KR102511024B1 (en) 2016-03-15 2023-03-16 오리존 지노믹스 에스.에이. Combinations of LSD1 inhibitors for use in the treatment of solid tumors
RU2019105587A (en) 2016-07-28 2020-08-28 Тёрнинг Поинт Терапьютикс, Инк. MACROCYCLIC KINASE INHIBITORS
EP3494140A1 (en) 2016-08-04 2019-06-12 GlaxoSmithKline Intellectual Property Development Ltd Anti-icos and anti-pd-1 antibody combination therapy
EP3509422A4 (en) 2016-09-08 2020-05-20 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
AU2017324716B2 (en) 2016-09-08 2020-08-13 KALA BIO, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2018048746A1 (en) 2016-09-08 2018-03-15 Kala Pharmaceuticals, Inc. Crystalline forms of therapeutic compounds and uses thereof
WO2018060833A1 (en) 2016-09-27 2018-04-05 Novartis Ag Dosage regimen for alpha-isoform selective phosphatidylinositol 3-kinase inhibitor alpelisib
US11279694B2 (en) 2016-11-18 2022-03-22 Sumitomo Dainippon Pharma Oncology, Inc. Alvocidib prodrugs and their use as protein kinase inhibitors
KR20190099260A (en) 2016-12-19 2019-08-26 톨레로 파마수티컬스, 인크. Profiling Peptides and Methods for Sensitivity Profiling
UA124474C2 (en) 2016-12-22 2021-09-22 Емджен Інк. BENZIZOTIAZOLNI, IZOTIAZOLO [3,4-b] pyridine, quinazoline, FTALAZYNOVI, pyrido [2,3-d] pyridazin AND pyrido [2,3-d] pyrimidine derivatives as INHIBITORS KRAS G12C to treat lung cancer, pancreatic cancer or colorectal CANCER
TWI808958B (en) 2017-01-25 2023-07-21 美商特普醫葯公司 Combination therapy involving diaryl macrocyclic compounds
RU2750539C2 (en) 2017-02-08 2021-06-29 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Pharmaceutical composition for treating a tumour
KR20200013644A (en) 2017-05-16 2020-02-07 에자이 알앤드디 매니지먼트 가부시키가이샤 Treatment of Hepatocellular Carcinoma
JOP20190272A1 (en) 2017-05-22 2019-11-21 Amgen Inc Kras g12c inhibitors and methods of using the same
AU2018306328B2 (en) 2017-07-28 2023-03-09 Turning Point Therapeutics, Inc. Macrocyclic compounds and uses thereof
IL272512B (en) 2017-09-08 2022-07-01 Amgen Inc kras g12c inhibitors and methods of using them
WO2019055579A1 (en) 2017-09-12 2019-03-21 Tolero Pharmaceuticals, Inc. Treatment regimen for cancers that are insensitive to bcl-2 inhibitors using the mcl-1 inhibitor alvocidib
US20200237766A1 (en) 2017-10-13 2020-07-30 Tolero Pharmaceuticals, Inc. Pkm2 activators in combination with reactive oxygen species for treatment of cancer
EP3727387A4 (en) 2017-12-18 2021-12-15 Sterngreene, Inc. Pyrimidine compounds useful as tyrosine kinase inhibitors
EP3728271B1 (en) 2017-12-19 2022-09-28 Turning Point Therapeutics, Inc. Macrocyclic compounds for treating diseases
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019213516A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
ES2986917T3 (en) 2018-05-10 2024-11-13 Amgen Inc KRAS G12C inhibitors for cancer treatment
EP3802535B1 (en) 2018-06-01 2022-12-14 Amgen, Inc Kras g12c inhibitors and methods of using the same
US20190375749A1 (en) 2018-06-11 2019-12-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
MA51848A (en) 2018-06-12 2021-04-21 Amgen Inc KRAS G12C INHIBITORS AND THEIR PROCEDURES FOR USE
CA3099440A1 (en) 2018-06-13 2019-12-19 California Institute Of Technology Nanoparticles for crossing the blood brain barrier and methods of treatment using the same
MY204443A (en) 2018-06-27 2024-08-28 Oscotec Inc Pyridopyrimidinone derivatives for use as axl inhibitors
CA3103995A1 (en) 2018-07-26 2020-01-30 Sumitomo Dainippon Pharma Oncology, Inc. Methods for treating diseases associated with abnormal acvr1 expression and acvr1 inhibitors for use in the same
CN113194954A (en) 2018-10-04 2021-07-30 国家医疗保健研究所 EGFR inhibitors for the treatment of keratoderma
JP7516029B2 (en) 2018-11-16 2024-07-16 アムジエン・インコーポレーテツド Improved synthesis of key intermediates for KRAS G12C inhibitor compounds
JP7377679B2 (en) 2018-11-19 2023-11-10 アムジエン・インコーポレーテツド Combination therapy comprising a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancer
CA3117222A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
CA3119807A1 (en) 2018-12-04 2020-06-11 Sumitomo Dainippon Pharma Oncology, Inc. Cdk9 inhibitors and polymorphs thereof for use as agents for treatment of cancer
EP3898626A1 (en) 2018-12-19 2021-10-27 Array Biopharma, Inc. Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases
CN113474337A (en) 2018-12-19 2021-10-01 奥瑞生物药品公司 7- ((3, 5-dimethoxyphenyl) amino) quinoxaline derivatives as FGFR inhibitors for the treatment of cancer
WO2020132649A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
PE20211475A1 (en) 2018-12-20 2021-08-05 Amgen Inc KIF18A INHIBITORS
AU2019403488B2 (en) 2018-12-20 2025-07-24 Amgen Inc. KIF18A inhibitors
EP3898592B1 (en) 2018-12-20 2024-10-09 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020128981A1 (en) * 2018-12-21 2020-06-25 University Of Notre Dame Du Lac Discovery of bd oxidase inhibitors for the treatment of mycobacterial diseases
WO2020160375A1 (en) 2019-02-01 2020-08-06 Glaxosmithkline Intellectual Property Development Limited Combination treatments for cancer comprising belantamab mafodotin and an anti ox40 antibody and uses and methods thereof
US11471456B2 (en) 2019-02-12 2022-10-18 Sumitomo Pharma Oncology, Inc. Formulations comprising heterocyclic protein kinase inhibitors
JP2022522777A (en) 2019-03-01 2022-04-20 レボリューション メディシンズ インコーポレイテッド Bicyclic heteroaryl compounds and their use
JP2022522778A (en) 2019-03-01 2022-04-20 レボリューション メディシンズ インコーポレイテッド Bicyclic heterocyclyl compounds and their use
WO2020191326A1 (en) 2019-03-20 2020-09-24 Sumitomo Dainippon Pharma Oncology, Inc. Treatment of acute myeloid leukemia (aml) with venetoclax failure
MX2021011289A (en) 2019-03-22 2021-11-03 Sumitomo Pharma Oncology Inc Compositions comprising pkm2 modulators and methods of treatment using the same.
EP3738593A1 (en) 2019-05-14 2020-11-18 Amgen, Inc Dosing of kras inhibitor for treatment of cancers
JOP20210310A1 (en) 2019-05-21 2023-01-30 Amgen Inc Solid state forms
BR112021025476A2 (en) 2019-06-26 2022-10-11 Glaxosmithkline Ip Dev Ltd IL1RAP-BINDING PROTEINS
US20220281843A1 (en) 2019-08-02 2022-09-08 Amgen Inc. Kif18a inhibitors
CN114391012A (en) 2019-08-02 2022-04-22 美国安进公司 Pyridine derivatives as KIF18A inhibitors
CA3146693A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
AU2020324406A1 (en) 2019-08-02 2022-03-17 Amgen Inc. KIF18A inhibitors
WO2021046293A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and tremelimumab
WO2021043961A1 (en) 2019-09-06 2021-03-11 Glaxosmithkline Intellectual Property Development Limited Dosing regimen for the treatment of cancer with an anti icos agonistic antibody and chemotherapy
CA3155857A1 (en) 2019-10-24 2021-04-29 Amgen Inc. PYRIDOPYRIMIDINE DERIVATIVES USEFUL AS KRAS G12C AND KRAS G12D INHIBITORS IN THE TREATMENT OF CANCER
TW202132316A (en) 2019-11-04 2021-09-01 美商銳新醫藥公司 Ras inhibitors
CR20220243A (en) 2019-11-04 2022-08-04 Revolution Medicines Inc Ras inhibitors
KR20220109406A (en) 2019-11-04 2022-08-04 레볼루션 메디슨즈, 인크. RAS inhibitors
CA3156359A1 (en) 2019-11-08 2021-05-14 Adrian Liam Gill Bicyclic heteroaryl compounds and uses thereof
US20230192681A1 (en) 2019-11-14 2023-06-22 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
AR120456A1 (en) 2019-11-14 2022-02-16 Amgen Inc ENHANCED SYNTHESIS OF KRAS G12C INHIBITOR COMPOUND
CN114980976A (en) 2019-11-27 2022-08-30 锐新医药公司 Covalent RAS inhibitors and uses thereof
CA3163703A1 (en) 2020-01-07 2021-07-15 Steve Kelsey Shp2 inhibitor dosing and methods of treating cancer
BR112022014562A2 (en) 2020-01-28 2022-09-13 Glaxosmithkline Ip Dev Ltd COMBINATION TREATMENTS, USES AND METHODS THEREOF
WO2021155006A1 (en) 2020-01-31 2021-08-05 Les Laboratoires Servier Sas Inhibitors of cyclin-dependent kinases and uses thereof
EP4114530A4 (en) * 2020-03-02 2024-04-17 Turning Point Therapeutics, Inc. Therapeutic uses of macrocyclic compounds
CN115916194A (en) 2020-06-18 2023-04-04 锐新医药公司 Methods for delaying, preventing and treating acquired resistance to RAS inhibitors
JP2023541236A (en) 2020-09-03 2023-09-29 レボリューション メディシンズ インコーポレイテッド Use of SOS1 inhibitors to treat malignant tumors with SHP2 mutations
KR20230067635A (en) 2020-09-15 2023-05-16 레볼루션 메디슨즈, 인크. Indole derivatives as RAS inhibitors in the treatment of cancer
CN117396472A (en) 2020-12-22 2024-01-12 上海齐鲁锐格医药研发有限公司 SOS1 inhibitors and uses thereof
MX2023007550A (en) 2020-12-22 2023-11-14 Mekanistic Therapeutics Llc Substituted aminobenzyl heteroaryl compounds as egfr and/or pi3k inhibitors.
BR112023021111A2 (en) 2021-04-13 2023-12-19 Nuvalent Inc COMPOUND, PHARMACEUTICAL COMPOSITION, METHOD OF TREATMENT OF CANCER, METHOD OF SELECTIVELY INHIBITING HER2, METHOD OF REGULATING A LEVEL OF HER2, METHOD OF INCREASING A LEVEL OF HER2, METHOD OF DECREASING THE PHOSPHORYLATION OF HER2
AR125787A1 (en) 2021-05-05 2023-08-16 Revolution Medicines Inc RAS INHIBITORS
MX2023013085A (en) 2021-05-05 2023-11-16 Revolution Medicines Inc Ras inhibitors.
JP2024516450A (en) 2021-05-05 2024-04-15 レボリューション メディシンズ インコーポレイテッド Covalent RAS inhibitors and uses thereof
AR127308A1 (en) 2021-10-08 2024-01-10 Revolution Medicines Inc RAS INHIBITORS
TW202340214A (en) 2021-12-17 2023-10-16 美商健臻公司 Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
CN119136806A (en) 2022-03-08 2024-12-13 锐新医药公司 Methods for treating immune-refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
CR20250141A (en) 2022-10-14 2025-05-26 Black Diamond Therapeutics Inc Cancer treatment methods using isoquinoline or 6-azaquinoline derivatives
WO2024206858A1 (en) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions for inducing ras gtp hydrolysis and uses thereof
WO2024211663A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024211712A1 (en) 2023-04-07 2024-10-10 Revolution Medicines, Inc. Condensed macrocyclic compounds as ras inhibitors
WO2024216048A1 (en) 2023-04-14 2024-10-17 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
US20240352036A1 (en) 2023-04-14 2024-10-24 Revolution Medicines, Inc. Crystalline forms of ras inhibitors, compositions containing the same, and methods of use thereof
WO2024229406A1 (en) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Combination therapy for a ras related disease or disorder
US20250049810A1 (en) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Methods of treating a ras protein-related disease or disorder
US20250154171A1 (en) 2023-10-12 2025-05-15 Revolution Medicines, Inc. Ras inhibitors
WO2025137507A1 (en) 2023-12-22 2025-06-26 Regor Pharmaceuticals, Inc. Sos1 inhibitors and uses thereof

Citations (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4074057A (en) * 1973-12-12 1978-02-14 Takeda Chemical Co., Ltd. 2-Halopropionic acid and its derivatives
US4166735A (en) * 1977-01-21 1979-09-04 Shell Oil Company Cycloalkanecarboxanilide derivative herbicides
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5654307A (en) * 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5710158A (en) * 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5773476A (en) * 1994-03-07 1998-06-30 Sugen, Inc. Methods and compositions for inhibiting cell proliferative disorders
US5866572A (en) * 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US5955464A (en) * 1994-11-30 1999-09-21 Zeneca Limited 4-anilinoquinazoline derivatives bearing a heteroaryl substituted at the 6-position and possessing anti-cell-proliferation properties
US20020169165A1 (en) * 2000-06-22 2002-11-14 Kath John Charles Substituted bicyclic derivatives for the treatment of abnormal cell growth
US6828320B2 (en) * 1996-07-13 2004-12-07 Smithkline Beecham Corporation Heterocyclic compounds
US20050085465A1 (en) * 2002-02-01 2005-04-21 Hennequin Laurent F.A. Quinazoline compounds
US20050101617A1 (en) * 2003-11-10 2005-05-12 Eli Wallace Cyanoguanidines and cyanoamidines as ErbB2 and EGFR inhibitors
US20050130996A1 (en) * 1998-01-12 2005-06-16 Carter Malcolm C. Heterocyclic compounds

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986006718A1 (en) 1985-05-17 1986-11-20 The Australian National University Antimalarial compounds
US5141941A (en) 1988-11-21 1992-08-25 Ube Industries, Ltd. Aralkylamine derivatives, and fungicides containing the same
US5034393A (en) 1989-07-27 1991-07-23 Dowelanco Fungicidal use of pyridopyrimidine, pteridine, pyrimidopyrimidine, pyrimidopyridazine, and pyrimido-1,2,4-triazine derivatives
EP0452002A3 (en) 1990-03-30 1992-02-26 Dowelanco Thienopyrimidine derivatives
DE4131924A1 (en) 1991-09-25 1993-07-08 Hoechst Ag SUBSTITUTED 4-ALKOXYPYRIMIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A PEST CONTROL
GB9127252D0 (en) 1991-12-23 1992-02-19 Boots Co Plc Therapeutic agents
WO1993017682A1 (en) 1992-03-04 1993-09-16 Abbott Laboratories Angiotensin ii receptor antagonists
WO1993018035A1 (en) 1992-03-04 1993-09-16 Abbott Laboratories Angiotensin ii receptor antagonists
US5326766A (en) 1992-08-19 1994-07-05 Dreikorn Barry A 4-(2-(4-(2-pyridinyloxy)phenyl)ethoxy)quinazoline and analogues thereof
DE4308014A1 (en) 1993-03-13 1994-09-15 Hoechst Schering Agrevo Gmbh Condensed nitrogen heterocycles, processes for their preparation and their use as pesticides and fungicides
GB9312891D0 (en) 1993-06-22 1993-08-04 Boots Co Plc Therapeutic agents
IL112249A (en) * 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
GB9510757D0 (en) * 1994-09-19 1995-07-19 Wellcome Found Therapeuticaly active compounds
TW321649B (en) * 1994-11-12 1997-12-01 Zeneca Ltd
MX9709867A (en) 1995-06-07 1998-03-31 Pfizer Heterocyclic ring-fused pyrimidine derivatives.
GB9514265D0 (en) 1995-07-13 1995-09-13 Wellcome Found Hetrocyclic compounds
AR004010A1 (en) 1995-10-11 1998-09-30 Glaxo Group Ltd HETERO CYCLIC COMPOUNDS
JPH10512896A (en) 1995-11-14 1998-12-08 フアルマシア・エ・アツプジヨン・エツセ・ピー・アー Aryl and heteroaryl purine compounds
HRP970371A2 (en) * 1996-07-13 1998-08-31 Kathryn Jane Smith Heterocyclic compounds
WO1998002437A1 (en) * 1996-07-13 1998-01-22 Glaxo Group Limited Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors
ID18494A (en) 1996-10-02 1998-04-16 Novartis Ag PIRAZOLA DISTRIBUTION IN THE SEQUENCE AND THE PROCESS OF MAKING IT
EP1294715B1 (en) * 2000-06-30 2007-02-14 Glaxo Group Limited Quinazoline ditosylate salt compounds
WO2002056912A2 (en) * 2001-01-16 2002-07-25 Glaxo Group Limited Pharmaceutical combination for the treatment of cancer containing a 4-quinazolineamine and another anti-neoplastic agent

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4074057A (en) * 1973-12-12 1978-02-14 Takeda Chemical Co., Ltd. 2-Halopropionic acid and its derivatives
US4166735A (en) * 1977-01-21 1979-09-04 Shell Oil Company Cycloalkanecarboxanilide derivative herbicides
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5646153A (en) * 1991-05-10 1997-07-08 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5710158A (en) * 1991-05-10 1998-01-20 Rhone-Poulenc Rorer Pharmaceuticals Inc. Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
US5457105A (en) * 1992-01-20 1995-10-10 Zeneca Limited Quinazoline derivatives useful for treatment of neoplastic disease
US5616582A (en) * 1992-01-20 1997-04-01 Zeneca Limited Quinazoline derivatives as anti-proliferative agents
US5654307A (en) * 1994-01-25 1997-08-05 Warner-Lambert Company Bicyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family
US5773476A (en) * 1994-03-07 1998-06-30 Sugen, Inc. Methods and compositions for inhibiting cell proliferative disorders
US5789427A (en) * 1994-03-07 1998-08-04 Sugen, Inc. Methods and compositions for inhibiting cell proliferative disorders
US5955464A (en) * 1994-11-30 1999-09-21 Zeneca Limited 4-anilinoquinazoline derivatives bearing a heteroaryl substituted at the 6-position and possessing anti-cell-proliferation properties
US5866572A (en) * 1996-02-14 1999-02-02 Zeneca Limited Quinazoline derivatives
US6828320B2 (en) * 1996-07-13 2004-12-07 Smithkline Beecham Corporation Heterocyclic compounds
US20050130996A1 (en) * 1998-01-12 2005-06-16 Carter Malcolm C. Heterocyclic compounds
US20020169165A1 (en) * 2000-06-22 2002-11-14 Kath John Charles Substituted bicyclic derivatives for the treatment of abnormal cell growth
US20050085465A1 (en) * 2002-02-01 2005-04-21 Hennequin Laurent F.A. Quinazoline compounds
US20050101617A1 (en) * 2003-11-10 2005-05-12 Eli Wallace Cyanoguanidines and cyanoamidines as ErbB2 and EGFR inhibitors

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8658654B2 (en) 2002-07-15 2014-02-25 Symphony Evolution, Inc. Receptor-type kinase modulators and methods of use
US10266518B2 (en) 2002-07-15 2019-04-23 Symphony Evolution, Inc. Solid dosage formulations of substituted quinazoline receptor-type kinase modulators and methods of use thereof
US9359332B2 (en) 2002-07-15 2016-06-07 Symphony Evolution, Inc. Processes for the preparation of substituted quinazolines
US9796704B2 (en) 2002-07-15 2017-10-24 Symphony Evolution, Inc. Substituted quinazolines as receptor-type kinase inhibitors
US20090318373A1 (en) * 2002-07-15 2009-12-24 Rice Kenneth D Receptor-type kinase modulators and methods of use
US7173136B2 (en) 2002-11-02 2007-02-06 Astrazeneca Ab 3-Cyano-quinoline derivatives
US20110077233A1 (en) * 2003-09-26 2011-03-31 Exelixis, Inc. C-Met Modulators and Method of Use
US8067436B2 (en) 2003-09-26 2011-11-29 Exelixis, Inc. c-Met modulators and methods of use
US8178532B2 (en) 2003-09-26 2012-05-15 Exelixis, Inc. c-Met modulators and method of use
US8476298B2 (en) 2003-09-26 2013-07-02 Exelixis, Inc. c-Met modulators and method of use
US8497284B2 (en) 2003-09-26 2013-07-30 Exelixis, Inc. C-met modulators and method of use
US9174947B2 (en) 2003-09-26 2015-11-03 Exelixus, Inc. c-Met modulators and methods of use
US20070225307A1 (en) * 2003-09-26 2007-09-27 Exelixis, Inc. C-met modulators and method of use
US20070054928A1 (en) * 2003-09-26 2007-03-08 Exelixis, Inc. c-Met modulators and methods of use
US7452887B2 (en) 2004-06-04 2008-11-18 Amphora Discovery Corporation Quinoline- and isoquinoline-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
US20060009460A1 (en) * 2004-06-04 2006-01-12 Dickson John K Jr Quinoline- and isoquinoline-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions, and uses thereof
US8877776B2 (en) 2009-01-16 2014-11-04 Exelixis, Inc. (L)-malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
US9809549B2 (en) 2009-01-16 2017-11-07 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11091440B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)- N′-(4-fluorophenyl)cyclopropane-1,1 -dicarboxamide, and crystalline forms thereof for the treatment of cancer
US11091439B2 (en) 2009-01-16 2021-08-17 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms therof for the treatment of cancer
US11098015B2 (en) 2009-01-16 2021-08-24 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US12275706B2 (en) 2009-01-16 2025-04-15 Exelixis, Inc. Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer
US10736886B2 (en) 2009-08-07 2020-08-11 Exelixis, Inc. Methods of using c-Met modulators
US11433064B2 (en) 2009-08-07 2022-09-06 Exelixis, Inc. Methods of using c-Met modulators
US9606089B2 (en) 2011-05-20 2017-03-28 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Methods for detecting and reducing impurities of Lapatinib and salts thereof
US8927558B2 (en) 2011-05-20 2015-01-06 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Methods for detecting and reducing impurities of Lapatinib and salts thereof

Also Published As

Publication number Publication date
PE20000230A1 (en) 2000-04-03
EA200000637A1 (en) 2001-02-26
CY2008015I2 (en) 2009-11-04
TW477788B (en) 2002-03-01
HK1031883A1 (en) 2001-06-29
US20070015775A1 (en) 2007-01-18
PT1460072E (en) 2006-07-31
AU2278399A (en) 1999-07-26
DK1454907T3 (en) 2009-03-09
MY124055A (en) 2006-06-30
HRP20000469B1 (en) 2007-05-31
NO20003561L (en) 2000-09-11
CN1292788A (en) 2001-04-25
EP1047694A1 (en) 2000-11-02
US8513262B2 (en) 2013-08-20
RS49779B (en) 2008-06-05
SI1047694T1 (en) 2005-02-28
EE04616B1 (en) 2006-04-17
EP1047694B1 (en) 2004-07-07
IS2276B (en) 2007-09-15
US20160339027A1 (en) 2016-11-24
LU91475I9 (en) 2019-01-02
PT1047694E (en) 2004-11-30
EE200000411A (en) 2001-12-17
NO2008017I1 (en) 2008-12-01
OA11444A (en) 2004-04-29
CY2008015I1 (en) 2009-11-04
GB9800569D0 (en) 1998-03-11
IL137041A (en) 2006-10-05
US20050130996A1 (en) 2005-06-16
IS5549A (en) 2000-06-27
EP1454907A1 (en) 2004-09-08
BG104668A (en) 2001-04-30
ATE417847T1 (en) 2009-01-15
CZ20002587A3 (en) 2001-05-16
CN1134438C (en) 2004-01-14
EP1460072A1 (en) 2004-09-22
ES2319119T3 (en) 2009-05-04
KR20010015902A (en) 2001-02-26
AU2010276460A1 (en) 2011-02-17
US20150065527A1 (en) 2015-03-05
HUP0100941A3 (en) 2002-09-30
CY1108859T1 (en) 2014-07-02
US20130310562A1 (en) 2013-11-21
AP1446A (en) 2005-07-19
CO4820390A1 (en) 1999-07-28
CZ298047B6 (en) 2007-06-06
NZ505456A (en) 2003-06-30
CA2317589A1 (en) 1999-07-15
BR9906904B1 (en) 2011-05-03
HRP20060387A2 (en) 2008-02-29
DE69930773D1 (en) 2006-05-18
DE69930773T2 (en) 2006-09-28
TR200002015T2 (en) 2001-01-22
NO2008017I2 (en) 2011-10-17
CY1105618T1 (en) 2010-12-22
US9199973B2 (en) 2015-12-01
JP2002500225A (en) 2002-01-08
NL300360I2 (en) 2009-02-02
DE69918528D1 (en) 2004-08-12
DE69940128D1 (en) 2009-01-29
BG64825B1 (en) 2006-05-31
LU91475I2 (en) 2008-11-10
PT1454907E (en) 2009-02-18
CA2317589C (en) 2007-08-07
FR08C0038I1 (en) 2008-11-14
US20020147205A1 (en) 2002-10-10
SI1454907T1 (en) 2009-04-30
PL341595A1 (en) 2001-04-23
HRP20000469A2 (en) 2001-06-30
BR9906904A (en) 2000-10-17
US7109333B2 (en) 2006-09-19
DK1460072T3 (en) 2006-07-31
NO20003561D0 (en) 2000-07-11
EG24743A (en) 2010-07-14
US6713485B2 (en) 2004-03-30
ATE270670T1 (en) 2004-07-15
SI1460072T1 (en) 2006-08-31
AR066982A2 (en) 2009-09-23
ME00757B (en) 2008-06-05
UA66827C2 (en) 2004-06-15
US6727256B1 (en) 2004-04-27
NO316176B1 (en) 2003-12-22
HU227593B1 (en) 2011-09-28
EP1454907B1 (en) 2008-12-17
ES2262087T3 (en) 2006-11-16
ES2221354T3 (en) 2004-12-16
GEP20022678B (en) 2002-04-25
NL300360I1 (en) 2008-11-03
SK10502000A3 (en) 2001-08-06
ATE322491T1 (en) 2006-04-15
MA26596A1 (en) 2004-12-20
DE69918528T2 (en) 2005-07-28
AR015507A1 (en) 2001-05-02
FR08C0038I2 (en) 2012-02-22
US20070238875A1 (en) 2007-10-11
HUP0100941A2 (en) 2001-09-28
AU749549C (en) 2003-03-20
PL192746B1 (en) 2006-12-29
US20160051551A1 (en) 2016-02-25
SK285405B6 (en) 2007-01-04
IL137041A0 (en) 2001-06-14
EA002455B1 (en) 2002-04-25
KR100569776B1 (en) 2006-04-11
DK1047694T3 (en) 2004-11-08
EP1460072B1 (en) 2006-04-05
WO1999035146A1 (en) 1999-07-15
JP3390741B2 (en) 2003-03-31
YU44800A (en) 2002-11-15
US20100120804A1 (en) 2010-05-13
ZA99172B (en) 2000-07-11
AU749549B2 (en) 2002-06-27
DE122008000048I1 (en) 2009-01-02
JP2002326990A (en) 2002-11-15
US8912205B2 (en) 2014-12-16
AP2000001861A0 (en) 2000-09-30

Similar Documents

Publication Publication Date Title
US6713485B2 (en) Heterocyclic compounds
GB2345486A (en) Heteroaromatic protein tyrosine kinase inhibitors
US6828320B2 (en) Heterocyclic compounds
EP1192151B1 (en) Anilinoquinazolines as protein tyrosine kinase inhibitors
US6933299B1 (en) Anilinoquinazolines as protein tyrosine kinase inhibitors
MXPA00006824A (en) Bicyclic heteroaromatic compounds as protein tyrosine kinase inhibitors

Legal Events

Date Code Title Description
AS Assignment

Owner name: SMITHKLINE BEECHAM (CORK) LIMITED, IRELAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SMITHKLINE BEECHAM CORPORATION;REEL/FRAME:018184/0080

Effective date: 20060622

AS Assignment

Owner name: SMITHKLINE BEECHAM CORPORATION, PENNSYLVANIA

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SMITHKLINE BEECHAM (CORK) LIMITED;REEL/FRAME:018654/0335

Effective date: 20061219

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION

AS Assignment

Owner name: NOVARTIS AG, SWITZERLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:LEO OSPREY LIMITED;REEL/FRAME:036776/0261

Effective date: 20150302

Owner name: LEO OSPREY LIMITED, ENGLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:GLAXOSMITHKLINE LLC;REEL/FRAME:036776/0254

Effective date: 20150301

Owner name: GLAXOSMITHKLINE LLC, DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:SMITHKLINE BEECHAM CORPORATION;REEL/FRAME:036908/0903

Effective date: 20091027