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US20070032487A1 - Inhibitors of phosphatidylinositol 3-kinase - Google Patents

Inhibitors of phosphatidylinositol 3-kinase Download PDF

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Publication number
US20070032487A1
US20070032487A1 US10/554,559 US55455906A US2007032487A1 US 20070032487 A1 US20070032487 A1 US 20070032487A1 US 55455906 A US55455906 A US 55455906A US 2007032487 A1 US2007032487 A1 US 2007032487A1
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alkyl
amino
nitrogen
group
sulphur
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Inventor
Ian Bruce
Bernard Cuenoud
Thomas Keller
Gaynor Pilgrim
Nicola Press
Darren Le Grand
Cathy Ritchie
Barbara Valade
Judy Hayler
Emma Budd
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Novartis AG
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Publication of US20070032487A1 publication Critical patent/US20070032487A1/en
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: RITCHIE, CATHY, PRESS, NICOLA, LE GRAND, DARREN MARK, BUDD, EMMA, HAYLER, JUDY, BRUCE, IAN, PILGRIM, GAYNOR ELIZABETH, KELLER, THOMAS HUGO, VALADE, BARBARA, CUENOUD, BERNARD
Priority to US13/005,132 priority Critical patent/US8404684B2/en
Priority to US13/774,305 priority patent/US20130172349A1/en
Abandoned legal-status Critical Current

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • A61K31/4965—Non-condensed pyrazines
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    • 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

Definitions

  • the present invention relates to organic compounds, their preparation and their use as pharmaceuticals.
  • the present invention provides compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 alkyl) aminocarbonyl, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is aminocarbonyl optionally substituted by a C 3 -C 15 -carbocycle or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is —CO—NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 12-membered N-heterocyclic ring optionally including one or more ring hetero, atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted in the alkyl group by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)amino-
  • R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is hydrogen
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 1 when R 1 is unsubstituted C 1 -C 8 -alkylcarbonyl and Y is carbon then R 3 is halo, hydrbxy, cyano, amino, carboxy, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl) amino, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl) amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -
  • R 3 and R 4 are each independently hydrogen, halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkylsulfanyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl) aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy, C 1 -C 8 -acylamino, aminocarbony
  • Optionally substituted as used herein means the group referred to can be substituted at one or more positions by any one or any combination of the radicals listed thereafter.
  • Aminocarbonyl as used herein denotes amino attached through the nitrogen atom to a carbonyl group.
  • Halogen or “halo” as used herein may be fluorine, chlorine, bromine or iodine; preferably it is fluorine or chlorine.
  • C 1 -C 8 -alkyl denotes straight chain or branched alkyl having 1 to 8 carbon atoms.
  • C 1 -C 8 -alkyl is C 1 -C 4 -alkyl.
  • C 3 -C 15 -carbocyclic group denotes a carbocyclic group having 3 to 15 ring carbon atoms, for example a monocyclic group, either cycloaliphatic, such as a C 3 -C 8 -cycloalkyl, for example cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or aromatic such as phenyl, or a bicyclic group such as bicyclooctyl, bicyclononyl including indanyl and indenyl, and bicyclodecyl including naphthyl.
  • cycloaliphatic such as a C 3 -C 8 -cycloalkyl
  • aromatic such as phenyl
  • bicyclic group such as bicyclooctyl, bicyclononyl including indanyl and indenyl, and bicyclodecyl including naphthyl.
  • the C 3 -C 15 -carbocyclic group is a C 3 -C 10 -carbocyclic group, for example cyclopropyl, phenyl, or naphthyl.
  • the C 3 -C 15 -carbocyclic group can be substituted or unsubstituted.
  • Preferred substituents include halo, cyano, amino, nitro, carboxy, C 1 -C 8 -alkyl, halo-C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkylsulfonyl, —SO 2 NH 2 , a C 3 -C 15 -carbocyclic group and a 5- to 12-membered heterocyclic group having at least one ring heteroatom selected from nitrogen, oxygen and sulphur.
  • C 3 -C 8 -cycloalkyl denotes cycloalkyl having 3 to 8 ring carbon atoms, for example a monocyclic group such as a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, any of which can be substituted by one or more, usually one or two, C 1 -C 4 -alkyl groups, or a bicyclic group such as bicycloheptyl or bicyclooctyl.
  • “C 3 -C 8 -cycloalkyl” is C 3 -C 5 -cycloalkyl i.e. cyclopropyl, cyclobutyl or cyclopentyl.
  • C 1 -C 8 -alkylsulfanyl (or “C 1 -C 8 -alkylthio”) as used herein denotes C 1 -C 8 -alkyl as hereinbefore defined linked to —S—.
  • C 1 -C 8 -alkylsulfanyl is C 1 -C 4 - alkylsulfanyl, especially methylsulfanyl.
  • C 1 -C 8 -alkylsulfinyl is C 1 -C 4 -alkylsulfinyl, especially methylsulfinyl.
  • C 1 -C 8 -alkylsulfonyl denotes C 1 -C 8 -alkyl as hereinbefore defined linked to —SO 2 —.
  • C 1 -C 8 -alkylsulfonyl is C 1 -C 4 -alkylsulfonyl, especially methylsulfonyl”.
  • C 1 -C 8 -alkoxy denotes straight chain or branched alkoxy having 1 to 8 carbon atoms.
  • C 1 -C 8 -alkoxy is C 1 -C 4 -alkoxy.
  • C 1 -C 8 -haloalkyl denotes C 1 -C 8 -alkyl as hereinbefore defined substituted by one or more halogen atoms, preferably one, two or three halogen atoms, preferably fluorine or chlorine atoms.
  • C 1 -C 8 -haloalkyl is C 1 -C 4 -alkyl substituted by one, two or three fluorine or chlorine atoms.
  • amino-C 1 -C 8 -alkyl and “amino-C 1 -C 8 -alkoxy” as used herein denote amino attached by a nitrogen atom to C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy respectively as hereinbefore defined.
  • amino-C 1 -C 8 -alkyl and amino-C 1 -C 8 -alkoxy are respectively amino-C 1 -C 4 -alkyl and amino-C 1 -C 4 -alkoxy.
  • Carboxy-C 1 -C 8 -alkyl and “carboxy-C 1 -C 8 -alkoxy” as used herein denote carboxy attached by a carbon atom to C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy respectively as hereinbefore defined.
  • carboxy-C 1 -C 8 -alkyl and carboxy-C 1 -C 8 -alkoxy are respectively carboxy-C 1 -C 4 -alkyl and carboxy-C 1 -C 4 -alkoxy.
  • C 1 -C 8 -alkylcarbonyl denotes C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy or C 1 -C 8 -haloalkyl respectively as hereinbefore defined attached by a carbon atom to a carbonyl group.
  • C 1 -C 8 -alkylcarbonyl, C 1 -C 8 -alkoxycarbonyl and C 1 -C 8 -haloalkylcarbonyl are respectively C 1 -C 4 -alkylcarbonyl, C 1 -C 4 -alkoxycarbonyl and C 1 -C 4 -haloalkyl-carbonyl.
  • C 1 -C 8 -alkylamino “di(C 1 -C 8 -alkyl)amino” and “C 3 -C 8 -cycloalkylamino” as used herein denote C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy and C 3 -C 8 -cycloalkyl respectively as hereinbefore defined attached by a carbon atom to an amino group.
  • the C 1 -C 8 -alkyl groups in di(C 1 -C 8 -alkyl)-amino may be the same or different.
  • C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino and C 3 -C 8 -cycloalkylamino are respectively C 1 -C 4 -alkylamino, di(C 1 -C 4 -alkyl)amino and C 3 -C 5 -cycloalkylamino.
  • C 1 -C 8 -alkylaminocarbonyl “di(C 1 -C 8 -alkyl)aminocarbonyl” and “C 3 -C 8 -cycloalkylamino-carbonyl” as used herein denote C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino and C 3 -C 8 cycloalkylamino respectively as hereinbefore defined attached by a nitrogen atom to the carbon atom of a carbonyl group.
  • C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)-aminocarbonyl and C 3 -C 8 -cycloalkylaminocarbonyl are respectively C 1 -C 4 -alkylaminocarbonyl, di(C 1 -C 4 -alkyl)-aminocarbonyl and C 3 -C 5 -cycloalkylaminocarbonyl.
  • di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl and “di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy” as used herein denote di(C 1 -C 8 -alkyl)amino as hereinbefore defined attached by a nitrogen atom to the carbon atom of a C 1 -C 8 -alkyl or a C 1 -C 8 -alkoxy group respectively.
  • di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl and di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkoxy are respectively di(C 1 -C 4 -alkyl)amino-C 1 -C 4 -alkyl and di(C 1 -C 4 -alkyl)amino-C 1 -C 4 -alkoxy.
  • C 1 -C 8 -acylamino denotes amino substituted by C 1 -C 8 -alkylcarbonyl as hereinbefore defined.
  • C 1 -C 8 -acylamino is C 1 -C 4 -acylamino, especially acetylamino.
  • “5- or 6-membered heterocyclic ring containing at least one ring heteroatom selected from the group consisting of nitrogen, oxygen and sulphur” as used herein may be, for example, furan, pyrrole, pyrrolidine, pyrazole, imidazole, triazole, isotriazole, tetrazole, thiadiazole, isothiazole, oxadiazole, pyridine, piperidine, pyrazine, oxazole, isoxazole, pyrazine, pyridazine, pyrimidine, piperazine, pyrrolidine, morpholino, triazine, oxazine or thiazole.
  • Preferred heterocyclic rings include piperazine, pyrrolidine, morpholino, imidazole, isotriazole, pyrazole, tetrazole, thiazole, thiadiazole, pyridine, piperidine, pyrazine, furan, oxazole, isoxazole, oxadiazole and azetidine.
  • the 5- or 6-membered heterocyclic ring can be unsubstituted or substituted.
  • Preferred substituents include halo, cyano, oxo, hydroxy, carboxy, nitro, C 1 -C 8 -alkyl, C 1 -C 8 -alkylsulfonyl, aminocarbonyl, C 1 -C 8 -alkylcarbonyl and C 1 -C 8 -alkoxy optionally substituted by aminocarbonyl.
  • Especially preferred substituents include halo, oxo, hydroxy, C 1 -C 4 -alkyl , C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkylcarbonyl and aminocarbonyl.
  • “5- to 12-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur” as used herein may be, for example, azetidine, pyrrolidine, imidazolidine, piperidine, piperazine, morpholino or tetrahydro-imidazo-pyridine.
  • the 5- to 12-membered N-heterocyclic ring is preferably a 5- to 9-membered N-heterocyclic ring.
  • Preferred 5- to 12-membered N-heterocyclic rings include pyrrolidine, morpholino and tetrahydro-imidazo-pyridine.
  • the 5- to 12-membered N-heterocyclic ring can be unsubstituted or substituted.
  • Preferred substituents include halo, cyano, oxo, hydroxy, carboxy, nitro, C 1 -C 8 -alkylcarbonyl, —SO 2 —CH 3 , and C 1 -C 8 -alkyl or C 1 -C 8 -alkoxy in each case optionally substituted by carboxy, aminocarbonyl, C 1 -C 8 -alkoxy-carbonyl, or C 1 -C 5 -alkylaminocarbonyl or di(C 1 -C 4 -alkyl)aminocarbonyl in each case being optionally substituted by hydroxy.
  • Especially preferred substituents include hydroxy, —SO 2 —CH 3 and aminocarbonyl.
  • the present invention provides compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl) aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is aminocarbonyl optionally substituted by a C 3 -C 15 -carbocycle or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is C 1 -C 8 -alkylaminocarbonyl or C 3 -C 8 -cycloalkylaminocarbonyl in either case optionally substituted in the alkyl group by halo, hydroxy, cyano, amino, carboxy, C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, C 1 -C 8 -alkylamino, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)amino-carbonyl, C 1 -C 8 -alkoxycarbonyl, a C 3 -C 15 -carbocycle, or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur;
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 3 is [not hydrogen] halo, hydroxy, cyano, amino, carboxy, —SO 2 NH 2 , C 1 -C 8 -alkyl, C 1 -C 8 -alkoxy, C 1 -C 8 -haloalkyl, amino-C 1 -C 8 -alkyl, amino-C 1 -C 8 -alkoxy, C 1 -C 8 -alkylaminocarbonyl, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)aminocarbonyl, di(C 1 -C 8 -alkyl)amino-C 1 -C 8 -alkyl, di(C 1 -C 8 -alkyl) amino-C 1 -C 8 -alkoxy, aminocarbonyl, C 1 -C 8 -alkoxycarbonyl, carboxy-C 1 -C 8 -alkyl, carboxy-C 1 -
  • Preferred compounds of the present invention include compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 8 -alkylcarbonyl optionally substituted by di(C 1 -C 8 -alkyl)amino, C 1 -C 8 -alkylcarbonyl or C 1 -C 8 -alkoxycarbonyl,
  • R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is —CO—NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 12-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted in the alkyl group by hydroxy, C 1 -C 8 -alkoxy, hydroxy-substituted C 1 -C 8 -alkoxy, di(C 1 -C 8 -alkyl)amino, di(C 1 -C 8 -alkyl)amino-carbonyl, C 1 -C 8 -alkoxycarbonyl, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylaminocarbonyl optionally substituted by hydroxy,
  • R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is hydrogen
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 3 is halo, C 1 -C 8 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, and R 4 is hydrogen or C 1 -C 8 -alkyl,
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1 -C 8 -alkylsulfanyl, C 1 -C 8 -alkylsulfinyl, C 1 -C 8 -alkylsulfonyl, C 1 -C 8 -alkyl, C 1 -C 8 -acylamino, a C 3 -C 15 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 8 -alkylamino or di(C 1 -C 8 -alkyl)amino each being optionally substituted by amino, hydroxy, di(C 1 -C 8 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1
  • Preferred compounds of the present invention also include compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 8 -alkylcarbonyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or R 1 is C 1 -C 8 -alkylaminocarbonyl optionally substituted in the alkyl group by C 1 -C 8 -alkoxycarbonyl, di(C 1 -C 8 -alkyl)aminocarbonyl or by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur;
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 3 is halo, C 1 -C 8 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur
  • R 4 is hydrogen or C 1 -C 8 -alkyl, otherwise R 3 and R 4 are each independently hydrogen, halo, C 1 -C 8 -alkyl, C 1 -C 8 -cycloalkyl, a 5-or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 8 -alkylamino optionally substituted by hydroxy or di(C 1 -C 8 -alkyl)amino.
  • Especially preferred compounds of the present invention include compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 4 -alkylcarbonyl optionally substituted by di(C 1 -C 4 -alkyl)amino, C 1 -C 4 -alkylcarbonyl or C 1 -C 4 -alkoxycarbonyl,
  • R 1 is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is —CO—NR x R y , where R x and R y together with the nitrogen to which they are attached form a 5- to 9-membered N-heterocyclic ring optionally including one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted in the alkyl group by hydroxy, C 1 -C 4 -alkoxy, hydroxy-substituted C 1 -C 4 -alkoxy, di(C 1 -C 4 -alkyl)amino, di(C 1 -C 4 -alkyl)amino-carbonyl, C 1 -C 4 -alkoxycarbonyl, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 4 -alkylaminocarbonyl optionally substituted by hydroxy, or by C 1 -C 4 -alkoxy,
  • R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted by aminocarbonyl optionally substituted by a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is hydrogen
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 3 is halo, C 1 -C 4 -alkyl or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 4 is hydrogen or C 1 -C 4 -alkyl
  • R 3 and R 4 are each independently hydrogen, halo, cyano, C 1 -C 4 -alkylsulfanyl, C 1 -C 4 -alkylsulfinyl, C 1 -C 4 -alkylsulfonyl, C 1 -C 4 -alkyl, C 1 -C 4 -acylamino, a C 3 -C 10 -carbocycle, a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, C 1 -C 4 -alkylamino or di(C 1 -C 4 -alkyl)amino each being optionally substituted by amino, hydroxy, di(C 1 -C 4 -alkyl)amino or a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1
  • Especially preferred compounds of the present invention also include compounds of formula I in free or salt form, wherein
  • R 1 is C 1 -C 4 -alkylcarbonyl or a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 1 is C 1 -C 4 -alkylaminocarbonyl optionally substituted in the alkyl group by C 1 -C 4 -alkoxycarbonyl, di(C 1 -C 4 -alkyl)aminocarbonyl or by a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur;
  • R 2 is C 1 -C 3 -alkyl
  • Y is carbon or nitrogen
  • R 3 is halo, C 1 -C 4 -alkyl or a 5- or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur,
  • R 4 is hydrogen or C 1 -C 4 -alkyl
  • R 3 and R 4 are each independently hydrogen, halo, C 1 -C 4 -alkyl, C 3 -C 5 -cycloalkyl, a 5-or 6-membered N-heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or C 1 -C 4 -alkylamino optionally substituted by hydroxy or di(C 1 -C 4 -alkyl)amino.
  • compositions represented by formula I are capable of forming acid addition salts, particularly pharmaceutically acceptable acid addition salts.
  • Pharmaceutically acceptable acid addition salts of the compound of formula I include those of inorganic acids, for example, hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid or hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid; and organic acids, for example aliphatic monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids such as maleic acid or succinic acid, aromatic carboxylic acids such as benzoic acid, p-chlorobenzoic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acids such as o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene-2-car
  • Compounds of formula I which contain acidic, e.g. carboxyl, groups, are also capable of forming salts with bases, in particular pharmaceutically acceptable bases such as those well known in the art; suitable such salts include metal salts, particularly alkali metal or alkaline earth metal salts such as sodium, potassium, magnesium or calcium salts, or salts with ammonia or pharmaceutically acceptable organic amines or heterocyclic bases such as ethanolamines, benzylamines or pyridine. These salts may be prepared from compounds of formula I by known salt-forming procedures.
  • the invention provides, in another aspect, a process for preparing a compound of formula I in free or salt form which comprises the steps of:
  • Process variant (A) may be carried out using known procedures for preparing aminothiazoles, or analogously, e.g. as hereinafter described in the Examples.
  • the halogen X is preferably bromine.
  • the reaction may be carried out in an organic solvent, e.g. an alcohol such as ethanol.
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 50° C. to about 70° C.
  • Process variant (B) may be carried out using known procedures for reacting halides with nucleophilic N-heterocyclic rings, or analogously, e.g. as hereinafter described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. dimethylsulphoxide (DMSO).
  • DMSO dimethylsulphoxide
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 80° C. to about 150° C.
  • the temperature may be achieved by conventional heating or by microwave irradiation.
  • Process variant (C) may be carried out using known procedures for reacting heterocyclic halides with amines, or analogously, e.g. as hereinafter described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. dimethylsulphoxide (DMSO).
  • DMSO dimethylsulphoxide
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 80° C. to about 150 ° C.
  • the temperature may be achieved by conventional heating or by microwave irradiation.
  • Process variant (D) may be carried out using known procedures for reacting amines with carboxylic acids or an amide-forming derivative thereof such as an acid halide or anhydride, or analogously, e.g. as hereinafter described in the Examples.
  • the reaction may be carried out in an organic solvent, for example dichloromethane (DCM). It is preferably carried out in the presence of a base, for example diisopropylethylamine (DIPEA).
  • DIPEA diisopropylethylamine
  • a peptide coupling agent for example 1-hydroxybenzotriazole (HOBT).
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 60° C. to about 80° C.
  • Process variant (E) may be carried out using known procedures for reacting amines with isocyanates, or analogously, e.g. as hereinafter described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. DCM or dimethylformamide (DMF), preferably in the presence of a base, for example diisopropylethylamine (DIPEA).
  • DIPEA diisopropylethylamine
  • the reaction temperature may be from room temperature to the reflux temperature of the solvent, but conveniently from about 50° C. to about 70° C.
  • Process variant (F) may be carried out using known procedures for reacting carbonyl diheterocyclic intermediates (e.g. acylimidazolides when T is imidazole) with amines to form ureas, or analogously, e.g. as hereinafter described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. dimethylformamide (DMF).
  • the reaction temperature may be from about 10° C. to about 50° C., but conveniently room temperature.
  • Process variant (H) may be carried out using known procedures for reacting sulfinyl groups or sulfonyl groups with secondary amines to form di(alkyl)amines or analogously e.g. as hereinafter described in the Examples.
  • the reaction is conveniently carried out in an organic solvent such as DMF.
  • the reaction temperature may be e.g. from 60 to 100° C., preferably from 70 to 90 ° C.
  • Process variant (I) may be carried out using known procedures for reacting alkylsulfinyl groups with alkali metal alkoxides to form alkoxy groups or analogously e.g. as hereinafter described in the Examples.
  • the alkali metal alkoxide is preferably a sodium alkoxide.
  • the reaction is conveniently carried out in an organic solvent such as methanol.
  • the reaction temperature may be e.g. from 0 to 40 ° C., preferably room temperature.
  • Process variant (K) may be carried out using known procedures for reducing alkylsulfonyl groups to a cyano group or analogously e.g. as hereinafter described in the Examples.
  • the alkali metal cyanide is preferably sodium cyanide.
  • the reaction is conveniently carried out in an organic solvent such as dimethylsulphoxide (DMSO).
  • DMSO dimethylsulphoxide
  • the reaction temperature may be e.g. from 40 to 60 ° C., but preferably about 50 ° C.
  • the compounds of formula I in free or salt form can be recovered from reaction mixtures and purified in a conventional manner.
  • Isomer mixtures can be separated into individual isomers, e.g. enantiomers, in a conventional manner, e.g. by fractional crystallisation.
  • Compounds of formula II may be prepared by reacting a compound of formula XI wherein R 2 , R 3 , R 4 and Y are as hereinbefore defined, with a halogenating agent, for example bromine, or analogously, for example as described in the Examples.
  • a halogenating agent for example bromine, or analogously, for example as described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. dioxane.
  • the reaction temperature may be from about 0° C. to about 30° C., but conveniently about 10° C.
  • Compounds of formula IX may be prepared by reacting a compound of formula VI wherein R 2 , R 3 , R 4 , and Y are as hereinbefore defined with a compound of formula XIII wherein each T 1 , which may be the same or different, is a 5- or 6-membered heterocyclic ring having one or more ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur, or analogously, for example as described in the Examples.
  • the compound of formula XIII is preferably carbonyl diimidazole (CDI).
  • the reaction may be carried out in an organic solvent, e.g. dichloromethane (DCM) .
  • the reaction temperature may be from 20° C. to about 60° C., but conveniently about 40° C.
  • Compounds of formula XI are commercially available or may be prepared by reacting a compound of formula XIV wherein R 3 , R 4 and Y are as hereinbefore defined with a base, such as butyllithium (n-BuLi) or lithium diisopropyl amide (LDA), then adding of a compound of formula XV (a Weinreb amide) wherein R 2 is as hereinbefore using known procedures for reacting alkyl-substituted aromatic compounds with Weinreb amides, or analogously, for example as described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the reaction temperature may be from ⁇ 20° C. to about 10° C., but conveniently about 0° C.
  • compounds of formula XI wherein R 3 , R 4 and Y are as hereinbefore defined and R 2 is methyl may be prepared by reacting a compound of formula XIII wherein R 3 , R 4 and Y are as hereinbefore defined with a base such as butyllithium (n-BuLi) or lithium diisopropyl amide (LDA), then adding ethyl acetate using known methods for reacting alkyl-substituted aromatic compounds with esters, or analogously, for example as described in the Examples.
  • the reaction may be carried out in an organic solvent, e.g. tetrahydrofuran (THF).
  • THF tetrahydrofuran
  • the reaction temperature may be from ⁇ 10° C. to about 10° C., but conveniently about 0° C.
  • Compounds of formula XII may be prepared by reacting a compound of formula XVI wherein R 2 and R 4 are as hereinbefore defined, with a compound of formula XVII wherein R 3 is as hereinbefore defined using the procedure described in international patent specification WO 01/72745, or analogously, for example as described in the Examples.
  • Compounds of formula XVI may be prepared by reacting a compound of formula XVIII wherein R 2 is as hereinbefore defined, with a compound of formula XIX wherein R 4 is as hereinbefore defined using the procedure described in international patent specification WO 01/72745, or analogously, for example as described in the Examples.
  • the protecting groups may be chosen in accordance with the nature of the functional group, for example as described in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, John Wiley & Sons Inc, Third Edition, 1999, which reference also describes procedures suitable for replacement of the protecting groups by hydrogen.
  • Compounds of formula I in free form may be converted into salt form, and vice versa, in a conventional manner.
  • the compounds in free or salt form can be obtained in the form of hydrates or solvates containing a solvent used for crystallization.
  • Compounds of formula I can be recovered from reaction mixtures and-purified in a conventional manner.
  • Isomers, such as enantiomers may be obtained in a conventional manner, e.g. by fractional crystallization or asymmetric synthesis from correspondingly asymmetrically substituted, e.g. optically active, starting materials.
  • Residues 38-1102 of human PI3K ⁇ are subcloned into the BamH1 and EcoR1 sites of the transfer vector pAcG2T (Pharmingen) to create a GST-P13K ⁇ lacking the first 37 residues of PI3K ⁇ .
  • Sf9 Spodoptera frugiperda 9
  • insect cells are routinely maintained at densities between 3 ⁇ 10 5 and 3 ⁇ 10 6 cells/ml in serum containing TNMFH medium (Sigma).
  • Sf9 cells, at a density of 2 ⁇ 10 6 are infected with human GST-PI3K ⁇ 34 baculovirus at a multiplicity of infection (m.o.i.) of 1 for 72 hours.
  • Sf9 cells (1 ⁇ 10 9 ) are resuspended in 100 ml cold (4° C.) lysis buffer (50 mM Tris-HCl pH 7.5, 1% Triton X-100, 150 mM NaCl, 1 mM NaF, 2 mM DTT and protease inhibitors. Cells are incubated on ice for 30 minutes then centrifuged at 15000 g for 20 minutes at 4° C. Purification of the supernatant sample is carried out at 4° C.
  • a cell lysate/GST resin ratio of 50:1 is used.
  • the GST resin is firstly pre-rinsed to remove ethanol preservative and then equilibrated with lysis buffer.
  • Cell lysate (supernatant) is added (usually as 50 ml lysate to 1 ml GST resin in 50 ml tubes) and gently rotated on a mixer at 4° C. for 2-3 hours.
  • the unbound flow through sample is collected by centrifugation at 1000 g for 5 minutes at 4° C. using a DENLEYTM centrifuge.
  • the washed GST resin is finally eluted with 4 cycles of 1 ml ice cold elution buffer (50 mM Tris-HCl pH 7.5, 10 mM reduced glutathione, 2 mM DTT, 150 mM NaCl, 1 mM NaF, 50% ethylene glycol and protease inhibitors) interspersed with centrifugation at 1000 g for 5 minutes at 4° C. Samples are aliquoted and stored at ⁇ 20° C.
  • 1 ml ice cold elution buffer 50 mM Tris-HCl pH 7.5, 10 mM reduced glutathione, 2 mM DTT, 150 mM NaCl, 1 mM NaF, 50% ethylene glycol and protease inhibitors
  • An in vitro kinase assay is established that measures the transfer of the terminal phosphate of adenosine triphosphate to phosphatidylinositol.
  • the kinase reaction is performed in a white 96 well microtitre plate as a Scintillation Proximity Assay.
  • Each well contains 10 ⁇ l test compound in 5% dimethylsulphoxide and 20 ⁇ l assay mix (40 mM Tris, 200 mM NaCl, 2 mM ethyleneglycol-aminoethyl-tetraacetic acid (EGTA), 15 ⁇ g/ml phosphatidylinositol, 12.5 ⁇ M adenosine triphosphate (ATP), 25 mM MgCl 2, 0.1 ⁇ Ci [ 33 P] ATP).
  • the reaction is started by the addition of 20 ⁇ l of enzyme mix (40 mM Tris, 200 mM NaCl, 2 mM EGTA containing recombinant GST-p110 ⁇ ).
  • the plate is incubated at room temperature for 60 minutes and the reaction terminated by the adding 150 ⁇ l of WGA-bead stop solution (40 mM Tris, 200 mM NaCl, 2 mM EGTA, 1.3 mM ethylene diamine tetraacetic acid (EDT A), 2.6 , ⁇ M ATP and 0.5 mg of Wheat Germ Agglutinin-SPA beads (Amersham Biosciences) to each well.
  • WGA-bead stop solution 40 mM Tris, 200 mM NaCl, 2 mM EGTA, 1.3 mM ethylene diamine tetraacetic acid (EDT A), 2.6 , ⁇ M ATP and 0.5 mg of Wheat Germ Agglutinin-SPA beads (Amersham Biosciences) to each well.
  • the plate is sealed, incubated at room temperature for 60 minutes, centrifuged at 1200 rpm and then counted for 1 minute using a scintillation counter. Total activity is determined by
  • IC 50 values below 0.5 ⁇ M in the aforementioned assay For example the compounds of Examples 1, 6, 11, 17, 22, 27, 33, 56, 67, 82, 91, 108, 120 and 133 have IC 50 values of 0.075, 0.165, 0.093, 0.106, 0.050, 0.017, 0.073, 0.127, 0.016, 0.164, 0.025, 0.005, 0.008 and 0.057 respectively.
  • agents of the invention are useful in the treatment of conditions which are mediated by the activation of the Pi3 kinase enzymes, particularly inflammatory or allergic conditions. Treatment in accordance with the invention may be symptomatic or prophylactic.
  • agents of the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodelling or disease progression.
  • Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection.
  • Treatment of asthma is also to be understood as embracing treatment of subjects, e.g.
  • Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended to restrict or abort symptomatic attack when it occurs, for example anti-inflammatory (e.g. corticosteroid) or bronchodilatory.
  • Prophylactic benefit in asthma may in particular be apparent in subjects prone to “morning dipping”. “Morning dipping” is a recognised asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.
  • inflammatory or obstructive airways diseases and conditions to which the present invention is applicable include acute lung injury (ALI), adultlacute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy.
  • the invention is also applicable to the treatment of bronchitis of whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis.
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • pneumoconiosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts
  • aluminosis anthracosis
  • asbestosis chalicosis
  • ptilosis ptilosis
  • siderosis silicosis
  • tabacosis tabacosis and byssinosis.
  • agents of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g.
  • eosinophilic infiltration of pulmonary tissues including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.
  • eosinophil-related disorders of the airways consequential or concomitant to Loffler's syndrome
  • eosinophilic pneumonia including parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg
  • Agents of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphisus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.
  • Treatment in accordance with the invention may be symptomatic or prophylactic.
  • Agents of the invention may also be used for the treatment of other diseases or conditions, in particular diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or aetiology, including autoimmune haematological disorders (e.g.
  • haemolytic anaemia haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia
  • systemic lupus erythematosus polychondritis, sclerodoma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g.
  • ulcerative colitis and Crohn's disease endocrine opthalmopathy
  • Grave's disease sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary billiary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy).
  • diseases or conditions which may be treated with agents of the invention include septic shock, rheumatoid arthritis, osteoarthritis, proliferative diseases such as cancer, athersclerosis, allograft rejection following transplantation, stroke, obesity, restenosis, diabetes, e.g. diabetes mellitus type I (juvenile diabetes) and diabetes mellitus type II, diarrheal diseases, ischemia/reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, and conditions characterised by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma.
  • an agent of the invention in inhibiting inflammatory conditions, for example in inflammatory airways diseases, may be demonstrated in an animal model, e.g. a mouse or rat model, of airways inflammation or other inflammatory conditions, for example as described by Szarka et al, J. Immunol. Methods (1997) 202:49-57; Renzi et al, Am. Rev. Respir. Dis. (1993) 148:932-939; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931; and Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.
  • the agents of the invention are useful in the manufacture of a medicament for treatment of a disease mediated by phosphatidylinositol 3-kinase. More specifically the agents of the invention are useful in the manufacture of a medicament for treatment of respiratory diseases, allergies, rheumatoid arthritis, osteoarthritis, rheumatic disorders, psoriasis, ulcerative colitis, Crohn's disease, septic shock, proliferative disorders such as cancer, atherosclerosis, allograft rejection following transplantation, diabetes, stroke, obesity or restenosis. Treatment in accordance with the invention may be symptomatic or prophylactic.
  • the agents of the invention are also useful as co-therapeutic agents for use in combination with other drug substances such as anti-inflammatory, bronchodilatory or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for example as potentiators of therapeutic activity of such drugs or as a means of reducing required dosaging or potential side effects of such drugs.
  • An agent of the invention may be mixed with the other drug substance in a fixed pharmaceutical composition or it may be administered separately, before, simultaneously with or after the other drug substance.
  • the invention includes a combination of an agent of the invention as hereinbefore described with an anti-inflammatory, bronchodilatory, antihistamine or anti-tussive drug substance, said agent of the invention and said drug substance being in the same or different pharmaceutical composition.
  • Such anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate, or steroids described in WO 02/88167, WO 02/12266, WO 02/1100879, WO 02/00679 (especially those of Examples 3, 11, 14, 17, 19, 26, 34, 37, 39, 51, 60, 67, 72, 73, 90, 99 and 101), WO 03/035668, WO 03/048181, WO 03/062259, WO 03/064445, WO 03/072592, non-steroidal glucocorticoid receptor agonists such as those described in WO 00/00531, WO 02/10143, WO 03/082280, WO 03/082787, WO 03/104195, WO 04/005229; LTB4 antagonists such as those described in U.S.
  • Such bronchodilatory drugs include anticholinergic or antimuscarinic agents, in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), but also those described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02/00652, WO 03/53966, EP 424021, U.S. Pat. No. 5,171,744, U.S. Pat. No. 3,714,357 and WO 03/33495.
  • anticholinergic or antimuscarinic agents in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), but also those described in WO 01/04118, WO 02/51841, WO 02/53564, WO 03/00840, WO 03/87094, WO 04/05285, WO 02
  • Such co-therapeutic antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride.
  • Combinations of agents of the invention and steroids, beta-2 agonists, PDE4 inhibitors or LTD4 antagonists may be used, for example, in the treatment of COPD or, particularly, asthma.
  • Combinations of agents of the invention and anticholinergic or antimuscarinic agents, PDE4 inhibitors, dopamine receptor agonists or LTB4 antagonists may be used, for example, in the treatment of asthma or, particularly, COPD.
  • chemokine receptors e.g. CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770), and CCR-5 antagonists described in U.S. Pat. No. 6,166,037 (particularly claims 18 and 19 ), WO 0066558 (TAK-770), and CCR-5 antagonists described in U.S. Pat
  • the agents of the invention may be administered by any appropriate route, e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • any appropriate route e.g. orally, for example in the form of a tablet or capsule; parenterally, for example intravenously; by inhalation, for example in the treatment of inflammatory or obstructive airways disease; intranasally, for example in the treatment of allergic rhinitis; topically to the skin, for example in the treatment of atopic dermatitis; or rectally, for example in the treatment of inflammatory bowel disease.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I in free form or in the form of a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable diluent or carrier therefor.
  • the composition may contain a co-therapeutic agent such as an anti-inflammatory, bronchodilatory or antihistamine drug as hereinbefore described.
  • Such compositions may be prepared using conventional diluents or excipients and techniques known in the galenic art.
  • oral dosage forms may include tablets and capsules.
  • Formulations for topical administration may take the form of creams, ointments, gels or transdermal delivery systems, e.g. patches.
  • Compositions for inhalation may comprise aerosol or other atomizable formulations or dry powder formulations.
  • the composition comprises an aerosol formulation
  • it preferably contains, for example, a hydro-fluoro-alkane (HFA) propellant such as HFA134a or HFA227 or a mixture of these, and may contain one or more co-solvents known in the art such as ethanol (up to 20% by weight), and/or one or more surfactants such as oleic acid or sorbitan trioleate, and/or one or more bulking agents such as lactose.
  • HFA hydro-fluoro-alkane
  • the composition comprises a dry powder formulation, it preferably contains, for example, the compound of formula I having a particle diameter up to 10 microns, optionally together with a diluent or carrier, such as lactose, of the desired particle size distribution and a compound that helps to protect against product performance deterioration due to moisture.
  • a diluent or carrier such as lactose
  • the composition comprises a nebulised formulation, it preferably contains, for example, the compound of formula I either dissolved, or suspended, in a vehicle containing water, a co-solvent such as ethanol or propylene glycol and a stabiliser, which may be a surfactant.
  • the invention includes (A) an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form, (B) an inhalable medicament comprising an agent of the invention in inhalable form; (C) a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device; and (D) an inhalation device containing an agent of the invention in inhalable form.
  • A an agent of the invention in inhalable form, e.g. in an aerosol or other atomisable composition or in inhalable particulate, e.g. micronised form
  • B an inhalable medicament comprising an agent of the invention in inhalable form
  • C a pharmaceutical product comprising such an agent of the invention in inhalable form in association with an inhalation device
  • an inhalation device containing an agent of the invention in inhalable form.
  • Dosages of agents of the invention employed in practising the present invention will of course vary depending, for example, on the particular condition to be treated, the effect desired and the mode of administration. In general, suitable daily dosages for oral administration are of the order of 0.1 to 10 mg/kg.
  • Especially preferred compounds of formula I include compounds formula XXI
  • the reaction is diluted with DCM (100 ml) and washed with HCI (1 M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as a white solid.
  • the titled compound is prepared by an analogous procedure to (4-Methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) in this procedure with 1-(2-chloro-pyridin4-yl)-propan-2-one.
  • the titled compound is prepared following the same route as Example 3 by replacing 3-amino-propanol with N,N-diethylpropylamine.
  • This compound is prepared following the same route as Example 3 by replacing 3-amino-propanol with morpholine.
  • This compound is prepared following the same route as Example 6 by replacing [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Example 2) with [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine (Example 8).
  • This compound is prepared following the same route as Example 5 by replacing [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Example 2) with [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-(1H-pyrazol-3-yl)-amine (Example 8).
  • This compound is prepared following the same route as Example 5 by replacing [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyrazin-2-yl-amine (Example 2) with [5-(2-Chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-pyridin-3-yl-amine (Example 7).
  • the titled compound is prepared by an analogous procedure to (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) with 1-(2-morpholin-4-yl-pyridin-4-yl)-propan-2-one (13a) and pyrazin-2-yl-thiourea (1a) with N-acetylthiourea.
  • aqueous is adjusted to pH 8/9 and extracted with ethyl acetate (3 ⁇ 25 ml).
  • the organics are combined and dried (MgSO 4 ), filtered and concentrated in vacuo to yield a clear oil. Trituration with ether yields the titled compound as a white solid.
  • the titled compound is prepared by an analogous procedure to 3- ⁇ 3-[4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-yl]-ureido ⁇ -propionic acid ethyl ester (Example 14) by replacing ethyl 3-isocyanatopropionate with 4-isocyanato-butyric acid ethyl ester.
  • This compound is prepared by an analogous procedure to 3- ⁇ 3-[4-Methyl-5-(2-morpholin-4-yl-pyridin-4yl)-thiazol-2-yl]-ureido ⁇ -propionic acid ethyl ester (Example 14) by replacing 4-Methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-ylamine hydrobromide (13b) with 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (see Example 16 for reference).
  • Methylamine (0.030 ml of a 40% w/w/solution in water, 0.351 mmol) is added to a stirred suspension of imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (18a) (0.1 g, 0.351 mmol) in DMF (3 ml).
  • the reaction mixture is stirred at room temperature for 1 hour and then the solvent is removed in vacuo.
  • the crude product is dissolved in THF/DMF (10:1, 3 ml) and passed through a polymer supported isocyanate resin (0.9 g, 1.1 mmol/g loading) and washed through with THF. The solution is concentrated in vacuo and the residue washed with ethyl acetate and methanol to afford the titled compound.
  • the titled compound is prepared by an analogous procedure to (4-Methyl-5-pyridin-4-yl-thiazol-2-yl)-pyrazin-2-yl-amine (Example 1) by replacing 1-pyridin-4-yl-propan-2-one (1b) in this procedure with 1-(2,6-dimethyl-pyridin-4-yl)-propan-2-one and by replacing and pyrazin-2-yl-thiourea (1a) with N-acetylthiourea.
  • 1-(2,6-dimethyl-pyridin-4-yl)-propan-2-one was prepared according to a method described in Tetrahedron Letters, Vol.25, No.5, pp 515-518, 1984. (Authors: Claude Erre et al.)
  • the titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine with 5-(2,6-Dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-ylamine.
  • the titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine.
  • the preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described previously.
  • Acetic anhydride (3 ml) is added to 4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-ylamine (25d)(0.045 g, 0.162 mmol) and the reaction mixture is heated to 60° C. for 1 hour.
  • the solvent is removed in vacuo and the crude residue is dissolved in ethyl acetate (50 ml) and water (50 ml)
  • the layers are separated and the organic layer is washed with sodium carbonate solution, brine, dried over MgSO 4 and concentrated in vacuo to yield a brown oil.
  • the crude residue is purified by chromatography on silica eluting with ethyl acetate-hexane (3:2) to afford the titled compound.
  • the titled compound is prepared by an analogous procedure to imidazole-1-carboxylic acid (4-methyl-5-pyridin-4-yl-thiazol-2-yl)-amide (example 18a) by replacing 4-methyl-5-pyridin-4-yl-thiazol-2-ylamine (see example 16 for reference) with 4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-ylamine (25d).
  • the titled compound is prepared by an analogous procedure to 1-methyl-3-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-urea (example 18b) by replacing imidazole-1-carboxylic acid (4-methyl-5-pyridin-4yl-thiazol-2-yl)-amide (example 18a) with imidazole-1-carboxylic acid [4-methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-amide (26a) and by replacing methylamine with 2-(5-ethyl-oxazol-2-yl)-ethylamine.
  • the preparation of 2-(5-ethyl-oxazol-2-yl)-ethylamine is described in example 20d steps 1-4.
  • the titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with cyclopropanecarboxamidine hydrochloride.
  • the titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with isobutyramidine hydrochloride.
  • the titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with acetamidine hydrochloride.
  • the title compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with nicotinamidine hydrochloride.
  • Especially preferred compounds of formula I also include compounds of formula XXI R 1 , Y, R a and R b are as shown in Table 2 below, the methods of preparation being described thereafter. The table also shows mass spectrometry data. The Examples are in free form. TABLE 2 Ex.
  • CDI 1,1′-carbonyldiimidazole
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • DMF Dimethylformamide
  • THF tetrahydrofuran
  • HPLC High Performance Liquid Chromatography
  • DMF-DMA N,N-Dimethylformamide dimethylacetal
  • DMSO dimethyl sulfoxide
  • NMP 1-Methyl-2-pyrrolidine
  • HCI Hydrochloric acid
  • TFA Trifluoroacetic acid
  • m-CPBA meta-chloroperbenzoic acid.
  • 4,6-Dimethyl-pyrimidine-2-thiol (20 g, 142 mmol) is added slowly to a solution of sodium hydroxide (6.3 g, 156 mmol) in ethanol (120 ml) and water (60 ml). Methyl iodide (9.8 ml, 156 mmol) is added dropwise and the mixture is stirred at room temperature for 1 hour. The solvents are removed in vacuo and the residue is partitioned between diethyl ether (200 ml) and water (200 ml). The organic extract is dried (MgSO 4 ) and the solvent is removed to give the titled compound.
  • n-Butyllithium (1.6 M in hexanes, 67 ml, 107 mmol) is added dropwise to a stirred solution of diisopropylamine (15 ml, 107 mmol) in dry THF (90 ml) under argon at ⁇ 78° C. After 15 minutes at ⁇ 78° C. to 50° C. the mixture is cooled to ⁇ 78° C. and a solution of 4,6-dimethyl-2-methylsulfanyl-pyrimidine (15 g, 97.4 mmol) in dry THF (45 ml) is added dropwise. The reaction is stirred for 2.5 hours at ⁇ 78° C.
  • N-methoxy-N-methylacetamide (10.4 ml, 97.4 mmol) is added dropwise.
  • the reaction is allowed to warm to room temperature over 1 hour followed by quenching with saturated aqueous ammonium chloride solution (10 ml).
  • the mixture is concentrated to remove most of the THF then partitioned between water (200 ml) and DCM (200 ml).
  • the organic extract is separated, dried (MgSO 4 ), and the solvent is removed to afford the titled compound.
  • the material is a mixture of keto and enol forms as observed by 1 H nmr (CDCl 3 )
  • m-CPBA (57-86% purity, 6.0 g, 20-30 mmol) is added in portions to a rapidly stirring solution/suspension of 4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-ylamine (6.0 g, 23.8 mmol) in dry dichloromethane (200 ml) at 0° C. After the addition (15 minutes) the reaction is allowed to warm slowly to room temperature. The mixture is cautiously added to saturated sodium bicarbonate solution (300 ml), shaken, and the organic extract is separated and dried (MgSO 4 ). This first extract contains a 1:1 mixture of sulfoxide and sulfone. The aqueous phase is then partitioned with chloroform to extract the titled compound as yellow solid.
  • This material is prepared by the procedure outlined for intermediate AC, replacing 4,6-dimethyl-pyrimidine-2-thiol in the first step (AC1) with 4-methyl-2-methylsulfanyl-pyrimidine.
  • This material is prepared from 2,4,6-trimethyl-pyrimidine following the 2-step protocol used to prepare 1-bromo-1-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-propan-2-one (AC3) from 4,6-dimethyl-2-methylsulfanyl-pyrimidine (AC1).
  • This material is prepared by reaction of 1-bromo-1-(2,6-dimethyl-pyrimidin-4-yl)-propan-2-one with thiourea following the procedure described for intermediate AC4.
  • This compound is prepared by two different methods:
  • the titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with tert-butylcarbamide hydrochloride.
  • This material is prepared from 2-tert-butyl-4-methyl-pyrimidine following the protocol outlined for intermediate AC2.
  • imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (BA)
  • Imidazole-1-carboxylic acid [5-(2-tert-butyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide
  • BG Imidazole-1-carboxylic acid [5-(2,6-dimethyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide
  • Triethylamine or sodium hydride (7.17 mmol, 1.1 equivalents) is added to a stirred suspension of the aminothiazole (free base or hydrobromide salt, 6.53 mmol) and carbonyldiimidazole (1-2 equivalents) in dry CH 2 Cl 2 (40 ml) containing a few drops of DMF to aid solubility if necessary.
  • the reaction is heated at reflux under argon until no starting material remains (18 hours) as determined by HPLC and NMR. When cool the solid precipitate is removed by filtration and washed with diethyl ether.
  • This solid consists of the imidazole-urea intermediate (B) together with variable amounts of the corresponding isocyanate and imidazole. This solid is used in the subsequent steps since the imidazole-urea intermediate and isocyanate intermediate are equally suitable as precursors to ureas.
  • imidazole-1-carboxylic acid [5-(2-chloro-pyridin-4-yl)-4-methyl-thiazol-2-yl]-amide (BB)
  • imidazole-1-carboxylic acid [4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-amide
  • BC imidazole-1-carboxylic acid [5-(2-methanesulfinyl-6-methyl-pyrimidin4-yl)-4-methyl-thiazol-2-yl]-amide
  • BD imidazole-1-carboxylic acid [5-(2-methanesulfinyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide
  • BE imidazole-1-carboxylic acid [5-(2-methanesulfinyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide
  • the reaction mixture is diluted with water (150 ml) and extracted with dichloromethane (2 ⁇ 150 ml) The organic layers are combined, dried over MgSO 4, filtered and concentrated in vacuo to yield a crude white solid.
  • the product is purified by chromatography on silica eluting with ethanol-ethyl acetate (1:10) to give the titled compound.
  • the reaction is diluted with DCM (100 ml) and washed with HCl (1 M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO 4, filtered and concentrated in vacuo to yield the titled compound as a white solid.
  • Step 2 [2-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamic acid tert-butyl ester:
  • N-Hydroxy-propionamidine (0.10 g, 1.15 mmol) in DMF (2 ml) is added to a stirred suspension of sodium hydride (0.05 g of a 60% dispersion in oil, 1.26 mmol) in DMF (20 ml) in the presence of molecular sieves (0.1 g).
  • the reaction flask is then immersed in a pre-heated oil bath at 50° C. and stirring continued for 5 min.
  • 3-tert-Butoxycarbonylamino-propionic acid ethyl ester (0.25 g, 1.15 mmol) in DMF (2 ml) is added over 5 minutes. After 3 hours at 50° C. the mixture is cooled to 0° C.
  • DB (6-Methyl-pyridin-3-yl)-thiourea
  • DC (5-Bromo-[1,3,4]thiadiazol-2-yl)-thiourea
  • Step 2 [3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-pyrazol-1-yl]-acetic acid tert-butyl ester:
  • This material is prepared by an analogous procedure to (3-thioureido-pyrazol-1-yl)-acetic acid (intermediate DD) by replacing tert-butyl bromoacetate in step 2 with 3-bromo-propionic acid tert-butyl ester.
  • Carbethoxyisocyanate (0.49 ml, 3.73 mmol) in dry dichloromethane (10 ml) is added dropwise at room temperature to a stirred suspension of 3-(5-amino-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester (0.666 g, 3.56 mmol) in DCM (20 ml). The reaction is stirred under argon at room temperature for 18 h then the solvent is removed to afford the titled compound.
  • Carbethoxy-3-(5-thioureido-[1,3,4]thiadiazol-2-yl)-propionic acid methyl ester (0.675 g, 2.91 mmol) is suspended in 2 M NaOH (8 ml) and the reaction is stirred at reflux for 3.5 hours. When cool, the solution is acidified to pH 3 with 6 M HCl and the titled compound is removed by filtration and dried.
  • the amine (0.12 mmol) is added to a solution/suspension of the imidazole urea intermediate (0.11 mmol) in DMF (1.0 ml). Triethylamine may be added to enhance reaction rate and especially if one or both of the starting materials is present as a salt (1.1 equivalents Et 3 N per equiv. salt).
  • the reaction mixture is sonicated if necessary until a clear solution is obtained.
  • the reaction is allowed to proceed at between room temperature and 70° C. until the starting material is consumed (30 min to 24 hours). When complete, the mixture is concentrated in vacuo to remove the solvent.
  • the product is conveniently purified by dissolving the crude residue in THF (2 ml) and adding this to polymer supported isocyanate (Argonaut Technologies, 0.5 g, 1.10 mmol) which has been pre-swollen with THF (2 ml). The reaction mixture is allowed to drip through the resin under gravity and the solvent is removed in vacuo to yield the titled compound.
  • the product is purified by a standard procedure e.g. crystallisation, chromatography or HPLC.
  • N,N,N′-Trimethyl-ethane-1,2-diamine (0.62 g, 6.16 mmol) is added to a stirred solution of 5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AD, 0.33 g, 1.23 mmol) in NMP (15 ml).
  • NMP 15 ml
  • the reaction is heated at 70° C. for 18 hours then the solvent is removed in vacuo.
  • the residue is purified by reverse phase chromatography (C18 Jones FlashmasterTM chromatographic system, gradient elution conditions MeCN/H 2 O) to give the titled product.
  • Step 2 N-(5- ⁇ 2-[(2-Dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4-yl ⁇ -4-methyl-thiazol-2-yl)-acetamide:
  • N-[4-(2-Amino-4-methyl-thiazol-5-yl)-6-methyl-pyrimidin-2-yl]-N,N′,N′-trimethyl-ethane-1,2-diamine (0.020 g, 0.065 mmol) in acetic anhydride (1 ml) is heated at 60° C. for 2 hours. When cool, the solvent is removed in vacuo and the residue is partitioned between ethyl acetate (30 ml) and water (30 ml). The organic extract is removed, dried (MgSO 4 ) and the solvent removed to give the titled compound.
  • This compound is prepared by oxidation of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea with m-CPBA (meta-chloroperoxy-benzoic acid) following the protocol used to prepare 5-(2-Methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (intermediate AD).
  • m-CPBA metal-chloroperoxy-benzoic acid
  • Meta-chloroperoxybenzoic acid or m-CPBA (57-86% purity, 0.438 g, 1.8 mmol) is added in portions to a rapidly stirring solution of 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methane-sulfinyl-6-methyl-pyrimidin-4yl)-4-methyl-thiazol-2-yl]-urea (0.31 g, 0.74 mmol) in dry dichloromethane (5 ml) at room temperature. After 2 hours the mixture is diluted with dichloromethane and washed with aqueous sodium thiosulfite and brine. The organic extract is separated, dried over MgSO 4 and the solvent is removed. Purification by chromatography on silica, eluting with EtOAc, MeOH (97:3) affords the titled compound.
  • This material is prepared from 1-[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 40) and 2-aminomethyl-pyrrolidine-1-carboxylic acid tert-butyl ester by an analogous procedure to Example 42 but replacing DMF by dioxane.
  • Step 2) 1-[2-(5-Ethyl-oxazol-2-yl)-ethyl]-3-(4-methyl-5- ⁇ 6-methyl-2-[(pyrrolidin-2-ylmethyl)-amino]-pyrimidin-4-yl ⁇ -thiazol-2-yl)-urea:
  • the product is extracted into 1 M HCl and the aqueous phase is washed with DCM.
  • the aqueous phase is then basified with aq. NaOH and the product is re-extracted into DCM. After drying (MgSO 4 ) the solvent is removed to give the titled compound.
  • This compound is prepared from imidazole-1-carboxylic acid [5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-amide (imidazole-urea intermediate BD) and 2-(1-ethyl-1H-imidazol-4-yl)-ethylamine (thiourea intermediate CC1) using general procedure A.
  • This material is prepared from 1-[2-(1-ethyl-1H-imidazol-4-yl)-ethyl]-3-[5-(2-methanesulfinyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea and N,N,N′-trimethyl-ethane-1,2-diamine using the protocol described for Example 42 but replacing DMF by dioxane.
  • Step 1) 1-[2-(1-Isopropyl-1H-imidazol-4-yl)-ethyl]-3-[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea:
  • This material is prepared from imidazole-1-carboxylic acid [4-methyl-5-(6-methyl-2-methyl-sulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-amide (imidazole-urea intermediate BC) and 2-(1-iso-propyl-1H-imidazol-4-yl)-ethylamine (thiourea intermediate CC3) using general procedure A.
  • Step 2) 1-[2-(1-Isopropyl-1H-imidazol-4-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea:
  • This material is prepared from 1-[2-(1-isopropyl-1H-imidazol-4-yl)-ethyl]-3-[4-methyl-5-(6-methyl-2-methylsulfanyl-pyrimidin-4-yl)-thiazol-2-yl]-urea by the same protocol described for 1 -[2-(5-ethyl-oxazol-2-yl)-ethyl]-3-[5-(2-methanesulfonyl-6-methyl-pyrimidin-4-yl)-4-methyl-thiazol-2-yl]-urea (Example 41).
  • This material is prepared by acylating 5-(2-tert-Butyl-pyrimidin-4-yl)-4-methyl-thiazol-2-ylamine (Intermediate AG) with acetic anhydride as described for N-(5- ⁇ 2-[(2-dimethylamino-ethyl)-methyl-amino]-6-methyl-pyrimidin-4yl ⁇ -4-methyl-thiazol-2-yl)-acetamide (Example 39, step 2).
  • reaction mixture is filtered under gravity through a cartridge containing polymer supported isocyanate resin (0.5 g, pre-washed with 4 ml THF). The solvents are removed to give the titled products which are purified by HPLC if required.

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070173506A1 (en) * 2006-01-18 2007-07-26 Amgen Inc. Thiazole compounds and methods of use
WO2008150446A1 (fr) * 2007-05-30 2008-12-11 Congxin Liang Inhibiteurs des protéines kinases
US20090298836A1 (en) * 2007-07-17 2009-12-03 Amgen Inc. Thiadiazole modulators of PKB
US20100105696A1 (en) * 2007-02-20 2010-04-29 Novartis Ag IMIDAZOQUINOLINES AS DUAL LIPID KINASE AND mTOR INHIBITORS
US20110003818A1 (en) * 2009-07-02 2011-01-06 Robin Alec Fairhurst Substituted 2-Carboxamide Cycloamino Ureas
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US20110105535A1 (en) * 2003-05-02 2011-05-05 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
WO2017147526A1 (fr) * 2016-02-26 2017-08-31 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de la pi-kinase à activité anti-infectieuse
US12415788B2 (en) 2019-03-21 2025-09-16 The Board Of Trustees Of The Leland Stanford Junior University PI4-kinase inhibitors and methods of using the same

Families Citing this family (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TW200533357A (en) 2004-01-08 2005-10-16 Millennium Pharm Inc 2-(amino-substituted)-4-aryl pyrimidines and related compounds useful for treating inflammatory diseases
SE0402735D0 (sv) 2004-11-09 2004-11-09 Astrazeneca Ab Novel compounds
JP4932735B2 (ja) * 2004-12-17 2012-05-16 アムジエン・インコーポレーテツド アミノピリミジン化合物および使用方法
US20060178388A1 (en) 2005-02-04 2006-08-10 Wrobleski Stephen T Phenyl-substituted pyrimidine compounds useful as kinase inhibitors
AU2006251159B2 (en) 2005-05-24 2011-09-22 Merck Serono Sa Thiazole derivatives and use thereof
EP1888573A1 (fr) * 2005-05-24 2008-02-20 Laboratoires Serono S.A. Derives de thiazole et leur utilisation
EP1893607A4 (fr) * 2005-06-09 2010-07-21 Merck Sharp & Dohme Inhibiteurs de kinases checkpoint
GB2431156A (en) * 2005-10-11 2007-04-18 Piramed Ltd 1-cyclyl-3-substituted- -benzenes and -azines as inhibitors of phosphatidylinositol 3-kinase
EP1991528A2 (fr) * 2006-01-18 2008-11-19 Siena Biotech S.p.A. Modulateurs de la sous-unité alpha 7 du récepteur nicotinique de l'acétylcholine et leurs applications thérapeutiques
WO2007082956A1 (fr) * 2006-01-23 2007-07-26 Laboratoires Serono S.A. Dérivés de thiazole et leur utilisation
EP2007393B1 (fr) * 2006-04-07 2013-08-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Thiazole et thiophene analogues et leur utilisation pour traiter des maladies auto-immunes et des cancers
EP2016075A1 (fr) * 2006-05-03 2009-01-21 AstraZeneca AB Dérivés de thiazole et leur utilisation comme agents anti-tumoraux
GB0612630D0 (en) * 2006-06-26 2006-08-02 Novartis Ag Organic compounds
WO2008027584A2 (fr) * 2006-09-01 2008-03-06 Vertex Pharmaceuticals Incorporated Inhibiteurs de la phosphatidylinositol 3-kinase
GB0620059D0 (en) 2006-10-10 2006-11-22 Ucb Sa Therapeutic agents
GB0620818D0 (en) * 2006-10-19 2006-11-29 Ucb Sa Therapeutic agents
EP2581081A3 (fr) 2007-06-01 2013-07-31 The Trustees Of Princeton University Traitement d'infections virales par modulation de voies métaboliques de cellules hôtes
WO2009080705A2 (fr) * 2007-12-20 2009-07-02 Novartis Ag Composés organiques
EP2240475B1 (fr) 2007-12-20 2013-09-25 Novartis AG Dérivés de thiazole utilisés comme inhibiteur de la pi 3 kinase
JP5581219B2 (ja) 2008-01-25 2014-08-27 ミレニアム ファーマシューティカルズ， インコーポレイテッド チオフェンおよびホスファチジルイノシトール３−キナーゼ（ｐｉ３ｋ）阻害薬としてのその使用
CA2716898A1 (fr) 2008-02-27 2009-09-03 Takeda Pharmaceutical Company Limited Compose contenant un cycle aromatique a 6 chainons
UA104147C2 (uk) * 2008-09-10 2014-01-10 Новартис Аг Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань
CN102395585A (zh) * 2009-01-30 2012-03-28 米伦纽姆医药公司 杂芳基化合物和其作为pi3k抑制剂的用途
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
JPWO2010125799A1 (ja) * 2009-04-27 2012-10-25 塩野義製薬株式会社 Ｐｉ３ｋ阻害活性を有するウレア誘導体
UA101098C2 (xx) * 2009-04-30 2013-02-25 Глаксо Груп Лимитед Заміщені оксазолом індазоли як інгібітори pi3-кінази$замещенные оксазолом индазолы как ингибиторы pi3-киназы
EP2440556A1 (fr) * 2009-06-10 2012-04-18 Vertex Pharmaceuticals Incorporated Inhibiteurs de la phosphatidylinositol 3-kinase
JP2012531454A (ja) 2009-07-02 2012-12-10 ノバルティス アーゲー Ｐｉ３ｋ阻害剤として有用な２−カルボキサミドシクロアミノウレア類
US8637557B2 (en) 2009-10-19 2014-01-28 Taisho Pharmaceutical Co., Ltd Aminothiazole derivative
SG183155A1 (en) 2010-02-03 2012-09-27 Signal Pharm Llc Identification of lkb1 mutation as a predictive biomarker for sensitivity to tor kinase inhibitors
SG187795A1 (en) 2010-08-11 2013-03-28 Millennium Pharm Inc Heteroaryls and uses thereof
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
JP2013533318A (ja) 2010-08-11 2013-08-22 ミレニアム ファーマシューティカルズ， インコーポレイテッド ヘテロアリールおよびその使用
SG189396A1 (en) 2010-10-13 2013-05-31 Millennium Pharm Inc Heteroaryls and uses thereof
AU2015203865B2 (en) * 2010-11-08 2016-11-03 Novartis Ag Use of 2-carboxamide cycloamino urea derivatives in the treatment of EGFR dependent diseases or diseases that have acquired resistance to agents that target EGFR family members
BR112013009624A2 (pt) * 2010-11-08 2016-07-12 Novartis Ag uso de derivados de 2-carboxamida cicloamino ureia no tratamento de doenças dependemtes de egfr pu doenças que tenham adquirido resistência a agentes que tenham como alvo membros da família egfr
UA112539C2 (uk) * 2011-03-03 2016-09-26 Новартіс Аг Спосіб одержання похідних 2-карбоксамідциклоаміносечовини
CA2833962A1 (fr) * 2011-04-25 2012-11-01 Novartis Ag Association d'un inhibiteur de phosphatidylinositol-3-kinase (pi3k) et d'un inhibiteur de mtor
PH12013502697A1 (en) 2011-07-01 2014-02-10 Novartis Ag Combination therapy comprising a cdk4/6 inhibitor and a pi3k inhibitor for use in the treatment of cancer
CA2843887A1 (fr) 2011-08-03 2013-02-07 Signal Pharmaceuticals, Llc Identification d'un profil d'expression genique a titre de biomarqueur predictif de l'etat lkb1
US9926309B2 (en) 2011-10-05 2018-03-27 The Board Of Trustees Of The Leland Stanford Junior University Pi-kinase inhibitors with anti-infective activity
CA2865993A1 (fr) * 2012-03-30 2013-10-03 Novartis Ag Composes pour utilisation dans le traitement de neuroblastome, sarcome d'ewing ou un rhabdomyosarcome
AU2013203714B2 (en) 2012-10-18 2015-12-03 Signal Pharmaceuticals, Llc Inhibition of phosphorylation of PRAS40, GSK3-beta or P70S6K1 as a marker for TOR kinase inhibitory activity
EP3251673A1 (fr) 2012-12-13 2017-12-06 IP Gesellschaft für Management mbH Polythérapie comportant un inhibiteur de cdk4/6 et un inhibiteur de pi3k à utiliser dans le traitement du cancer
TWI628170B (zh) 2013-02-05 2018-07-01 先正達合夥公司 植物生長調節化合物
BR112015026300A2 (pt) 2013-04-17 2017-07-25 Signal Pharm Llc formulações farmacêuticas, processos, formas sólidas e métodos de uso relativos a 1-etil-7-(2-metil-6-(1h-1,2,4-triazol-3-il)piridina-3-il)-3,4-dihidropirazina[2,3-b] pirazina-2(1h)-ona
CN105473142A (zh) 2013-04-17 2016-04-06 西格诺药品有限公司 用二氢吡嗪并-吡嗪治疗癌症
SG11201508302PA (en) 2013-04-17 2015-11-27 Signal Pharm Llc Combination therapy comprising a dihydropyrazino-pyrazine compound and an androgen receptor antagonist for treating prostate cancer
CN105392499B (zh) 2013-04-17 2018-07-24 西格诺药品有限公司 用于治疗癌症的包含tor激酶抑制剂和胞苷类似物的组合疗法
KR102221029B1 (ko) 2013-04-17 2021-02-26 시그날 파마소티칼 엘엘씨 디하이드로피라지노-피라진을 사용한 암의 치료
WO2014172436A1 (fr) 2013-04-17 2014-10-23 Signal Pharmaceuticals, Llc Polythérapie comprenant un inhibiteur de kinase tor et un composé de quinazolinone substitué en 5 pour le traitement du cancer
AU2014254057A1 (en) 2013-04-17 2015-11-05 Signal Pharmaceuticals, Llc Combination therapy comprising a TOR kinase inhibitor and N-(3-(5-fluoro-2-(4-(2-methoxyethoxy)phenylamino)pyrimidin-4-ylamino)phenyl)acrylamide for treating cancer
US9604939B2 (en) 2013-05-29 2017-03-28 Signal Pharmaceuticals, Llc Pharmaceutical compositions of 7-(6-(2-hydroxypropan-2-YL)pyridin-3-YL)-1-((trans)-4-methoxycyclohexyl)-3,4-dihydropyrazino [2,3-B]pyrazin-2(1H)-one, a solid form thereof and methods of their use
NZ714742A (en) 2014-04-16 2017-04-28 Signal Pharm Llc Solid forms of 1-ethyl-7-(2-methyl-6-(1h-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1h)-one, compositions thereof and methods of their use
US9512129B2 (en) 2014-04-16 2016-12-06 Signal Pharmaceuticals, Llc Solid forms comprising 1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one and a coformer
CN104744376A (zh) * 2015-03-14 2015-07-01 长沙深橙生物科技有限公司 一种2-异丙基嘧啶衍生物的制备方法
CN104803921A (zh) * 2015-03-14 2015-07-29 长沙深橙生物科技有限公司 一种苯取代嘧啶衍生物的制备方法
JP7282045B2 (ja) 2017-06-22 2023-05-26 セルジーン コーポレイション Ｂ型肝炎ウイルス感染を特徴とする肝細胞癌の治療
US11325900B2 (en) 2018-01-15 2022-05-10 Aucentra Holdings Pty Ltd 5-(pyrimidin-4-yl)thiazol-2-yl urea derivatives as therapeutic agents
CN112752761B (zh) 2018-08-21 2024-03-29 杏林制药株式会社 双环杂芳族环衍生物
IL294507A (en) 2020-01-07 2022-09-01 Disarm Therapeutics Inc Inhibitors of sarm1
TWI786777B (zh) 2020-08-24 2022-12-11 美商達薩瑪治療公司 Sarm1之抑制劑
PE20240213A1 (es) * 2020-09-14 2024-02-16 Genzyme Corp Compuestos como moduladores de bis-fosfoglicerato mutasa para el tratamiento de la anemia de celulas falciforme
CN116987072A (zh) * 2023-07-27 2023-11-03 武汉呈瑞生物医药科技有限公司 化合物及其应用
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649146A (en) * 1983-01-31 1987-03-10 Fujisawa Pharmaceutical Co., Ltd. Thiazole derivatives and pharmaceutical composition comprising the same

Family Cites Families (111)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1219606A (en) 1968-07-15 1971-01-20 Rech S Et D Applic Scient Soge Quinuclidinol derivatives and preparation thereof
GB8302591D0 (en) * 1983-01-31 1983-03-02 Fujisawa Pharmaceutical Co Thiazole derivatives
DE3703435A1 (de) * 1987-02-05 1988-08-18 Thomae Gmbh Dr K Neue thiazole, diese verbindungen enthaltende arzneimittel und verfahren zu ihrer herstellung
US5229402A (en) 1988-04-15 1993-07-20 Taiho Pharmaceutical Company, Ltd. Carbamoyl-2-pyrrolidinone compounds
GB8916480D0 (en) 1989-07-19 1989-09-06 Glaxo Group Ltd Chemical process
GB8923590D0 (en) 1989-10-19 1989-12-06 Pfizer Ltd Antimuscarinic bronchodilators
CA2038379C (fr) 1990-03-22 2002-11-05 Norma G. Delaney Derives trifluoromethyle mercaptan et mercaptoacyle; methode d'utilisation
US5451700A (en) 1991-06-11 1995-09-19 Ciba-Geigy Corporation Amidino compounds, their manufacture and methods of treatment
GB9301000D0 (en) 1993-01-20 1993-03-10 Glaxo Group Ltd Chemical compounds
GB9414193D0 (en) 1994-07-14 1994-08-31 Glaxo Group Ltd Compounds
GB9414208D0 (en) 1994-07-14 1994-08-31 Glaxo Group Ltd Compounds
GB9622386D0 (en) 1996-10-28 1997-01-08 Sandoz Ltd Organic compounds
WO1998027108A2 (fr) 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. Nouveaux composes amide
US6187797B1 (en) 1996-12-23 2001-02-13 Dupont Pharmaceuticals Company Phenyl-isoxazoles as factor XA Inhibitors
TW528755B (en) 1996-12-24 2003-04-21 Glaxo Group Ltd 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives
US6166037A (en) 1997-08-28 2000-12-26 Merck & Co., Inc. Pyrrolidine and piperidine modulators of chemokine receptor activity
JP3329337B2 (ja) * 1997-10-14 2002-09-30 三菱ウェルファーマ株式会社 ピペラジン化合物およびその医薬としての用途
ATE257703T1 (de) 1997-10-27 2004-01-15 Takeda Chemical Industries Ltd 1,3-thiazole als adenosine a3 rezeptor antagonisten zur behandlung von asthma, allergien und diabetes
GB9723566D0 (en) 1997-11-08 1998-01-07 Glaxo Group Ltd Chemical compounds
GB9723589D0 (en) 1997-11-08 1998-01-07 Glaxo Group Ltd Chemical compounds
GB9723590D0 (en) 1997-11-08 1998-01-07 Glaxo Group Ltd Chemical compounds
YU44900A (sh) 1998-01-31 2003-01-31 Glaxo Group Limited Derivati 2-(purin-9-il)tetrahidrofuran-3,4-diola
AR017457A1 (es) 1998-02-14 2001-09-05 Glaxo Group Ltd Compuestos derivados de 2-(purin-9-il)-tetrahidrofuran-3,4-diol, procesos para su preparacion, composiciones que los contienen y su uso en terapia para el tratamiento de enfermedades inflamatorias.
ATE288904T1 (de) 1998-06-18 2005-02-15 Bristol Myers Squibb Co Durch kohlenstoff substituierte aminothiazole als inhibitoren von zyclin-abhägigen kinasen
GB9813535D0 (en) 1998-06-23 1998-08-19 Glaxo Group Ltd Chemical compounds
GB9813540D0 (en) 1998-06-23 1998-08-19 Glaxo Group Ltd Chemical compounds
DE69910213T2 (de) 1998-06-23 2004-07-01 Glaxo Group Ltd., Greenford 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivate
GB9813565D0 (en) 1998-06-23 1998-08-19 Glaxo Group Ltd Chemical compounds
WO2000000531A1 (fr) 1998-06-30 2000-01-06 The Dow Chemical Company Polymeres et leur procede de production
AU5879299A (en) 1998-10-16 2000-05-08 Monaghan, Sandra Marina Adenine derivatives
GB9913083D0 (en) 1999-06-04 1999-08-04 Novartis Ag Organic compounds
DK1180518T3 (da) * 1999-04-23 2007-05-21 Takeda Pharmaceutical 5-pyridyl-1,3-azolforbindelser, fremgangsmåde til fremstilling deraf og anvendelse deraf
CZ20013940A3 (cs) 1999-05-04 2002-04-17 Schering Corporation Piperazinové deriváty uľitečné jako CCR5 antagonisté
TR200103213T2 (tr) 1999-05-04 2002-03-21 Schering Corporation CCR5 antagonistleri olarak yararlì piperidin trevleri.
YU25500A (sh) 1999-05-11 2003-08-29 Pfizer Products Inc. Postupak za sintezu analoga nukleozida
GB9913932D0 (en) 1999-06-15 1999-08-18 Pfizer Ltd Purine derivatives
US6322771B1 (en) 1999-06-18 2001-11-27 University Of Virginia Patent Foundation Induction of pharmacological stress with adenosine receptor agonists
ES2165768B1 (es) 1999-07-14 2003-04-01 Almirall Prodesfarma Sa Nuevos derivados de quinuclidina y composiciones farmaceuticas que los contienen.
WO2001017995A1 (fr) * 1999-09-10 2001-03-15 Merck & Co., Inc. Inhibiteurs de tyrosine kinase
CO5180581A1 (es) 1999-09-30 2002-07-30 Pfizer Prod Inc Compuestos para el tratamiento de la isquemia ciones farmaceuticas que los contienen para el tratamiento de la isquemia
GB9924363D0 (en) 1999-10-14 1999-12-15 Pfizer Central Res Purine derivatives
GB9924361D0 (en) 1999-10-14 1999-12-15 Pfizer Ltd Purine derivatives
GB0003960D0 (en) 2000-02-18 2000-04-12 Pfizer Ltd Purine derivatives
JP5074653B2 (ja) * 2000-03-29 2012-11-14 サイクラセル リミテッド ２−置換４−ヘテロアリール−ピリミジンおよび増殖性障害におけるその使用
TWI227240B (en) 2000-06-06 2005-02-01 Pfizer 2-aminocarbonyl-9H-purine derivatives
GB0015727D0 (en) 2000-06-27 2000-08-16 Pfizer Ltd Purine derivatives
UA72632C2 (uk) 2000-06-27 2005-03-15 Лабораторіос С.А.Л.В.А.Т., С.А. Карбамати, похідні від арилалкіламінів
GB0015876D0 (en) 2000-06-28 2000-08-23 Novartis Ag Organic compounds
DE10038639A1 (de) 2000-07-28 2002-02-21 Schering Ag Nichtsteroidale Entzündungshemmer
ES2523930T3 (es) 2000-08-05 2014-12-02 Glaxo Group Limited Éster s-fluorometílico del ácido 6-alfa,9-alfa-difluoro-17-alfa-[(2-furanilcarbonil)oxi]-11-beta-hidroxi-16-alfa-metil-3-oxo-androst-1,4-dien-17-carbotioico como agente antiinflamatorio
GB0022695D0 (en) 2000-09-15 2000-11-01 Pfizer Ltd Purine Derivatives
WO2002032872A1 (fr) 2000-10-20 2002-04-25 Eisai Co., Ltd. Composes a noyau aromatique azote
GB0028383D0 (en) 2000-11-21 2001-01-03 Novartis Ag Organic compounds
KR100869722B1 (ko) 2000-12-22 2008-11-21 알미랄 에이쥐 퀴누클리딘 카르바메이트 유도체 및 ｍ3 길항제로서 그의사용
DK1353919T3 (da) 2000-12-28 2006-11-20 Almirall Prodesfarma Ag Hidtil ukendte quinuclidinderivater og medicinale sammensætninger indeholdende samme
EP1241176A1 (fr) 2001-03-16 2002-09-18 Pfizer Products Inc. Dérivés de purine pour le traitement de l'ischémie
PT1383786E (pt) 2001-04-30 2008-12-30 Glaxo Group Ltd Derivados anti-inflamatórios de éster 17.beta-carbotioato de androstano com um grupo éster ciclíco na posição 17.alfa
EP1256578B1 (fr) 2001-05-11 2006-01-11 Pfizer Products Inc. Dérivés de thiazole et leur utilisation comme inhibiteurs de cdk
HUP0400029A2 (hu) 2001-05-25 2004-04-28 Pfizer Inc. Obstruktív légúti megbetegedések kezelésére szolgáló adenozin A2a receptor agonista és antikolinerg hatóanyag-kombináció és ezt tartalmazó gyógyszerkészítmény
US20040248867A1 (en) 2001-06-12 2004-12-09 Keith Biggadike Novel anti-inflammatory 17.alpha.-heterocyclic-esters of 17.beta.carbothioate androstane derivatives
JP4405258B2 (ja) 2001-06-21 2010-01-27 ヴェレニウム コーポレイション ニトリラーゼ
MXPA04001399A (es) * 2001-08-13 2004-05-27 Janssen Pharmaceutica Nv Derivados de tiazolilo 2-amino-4,5-trisustituidos.
US7265134B2 (en) 2001-08-17 2007-09-04 Merck & Co., Inc. Tyrosine kinase inhibitors
CN100500663C (zh) 2001-09-28 2009-06-17 西克拉塞尔有限公司 作为抗增殖化合物的n-(4-(4-甲基噻唑-5-基)嘧啶-2-基)-n-苯胺
RU2004110717A (ru) 2001-10-17 2005-10-20 Юсиби, С.А. (Be) Производные хинуклидина, способы их получения и их применение в качестве и нгибиторов м2- и/или м3- мускариновых рецепторов
GB0125259D0 (en) 2001-10-20 2001-12-12 Glaxo Group Ltd Novel compounds
MY130622A (en) 2001-11-05 2007-07-31 Novartis Ag Naphthyridine derivatives, their preparation and their use as phosphodiesterase isoenzyme 4 (pde4) inhibitors
WO2003048181A1 (fr) 2001-12-01 2003-06-12 Glaxo Group Limited 17.alpha.-esters cycliques de 16-methylpregnan-3,20-dione en tant qu'agents anti-inflammatoires
UA76571C2 (en) 2001-12-20 2006-08-15 Derivatives of 1-alkyl-1-azoniabicyclo [2.2.2.]octanecarbamate and use thereof as antagonists of muscarin receptor
WO2003072592A1 (fr) 2002-01-15 2003-09-04 Glaxo Group Limited 17 alpha esters cycloalkyle/cycloalcenyle d'alkyle ou haloalkyle-androst-4-en-3-on-11 beta, 17 alpha-diol 17 beta-carboxylates comme agents anti-inflammatoires
WO2003062259A2 (fr) 2002-01-21 2003-07-31 Glaxo Group Limited Nouveaux composes
GB0202216D0 (en) 2002-01-31 2002-03-20 Glaxo Group Ltd Novel compounds
PE20030968A1 (es) 2002-02-28 2004-01-12 Novartis Ag Derivados de 5-feniltiazol como inhibidores de cinasas
ES2298508T3 (es) 2002-03-26 2008-05-16 Boehringer Ingelheim Pharmaceuticals Inc. Mimeticos de glucocorticoides, metodos para prepararlos, composiciones farmaceuticas y sus usos.
WO2003082787A1 (fr) 2002-03-26 2003-10-09 Boehringer Ingelheim Pharmaceuticals, Inc. Mimetiques du glucocorticoide, procedes de fabrication de ces mimetiques, compositions pharmaceutiques et leurs utilisations
JP2006515829A (ja) 2002-04-10 2006-06-08 ユニバーシティ オブ バージニア パテント ファウンデーション 炎症性疾病の処置のための、ａ２ａアデノシン受容体アゴニストの使用
ES2206021B1 (es) 2002-04-16 2005-08-01 Almirall Prodesfarma, S.A. Nuevos derivados de pirrolidinio.
DE10224888A1 (de) 2002-06-05 2003-12-24 Merck Patent Gmbh Pyridazinderivate
US7074806B2 (en) 2002-06-06 2006-07-11 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
DE10225574A1 (de) 2002-06-10 2003-12-18 Merck Patent Gmbh Aryloxime
DE10227269A1 (de) 2002-06-19 2004-01-08 Merck Patent Gmbh Thiazolderivate
EP1517895B1 (fr) 2002-06-25 2007-03-14 Merck Frosst Canada Ltd. Inhibiteurs de pde4 8-(biaryle)quinolines
AU2003281219A1 (en) 2002-07-02 2004-01-23 Bernard Cote Di-aryl-substituted-ethane pyridone pde4 inhibitors
ES2204295B1 (es) 2002-07-02 2005-08-01 Almirall Prodesfarma, S.A. Nuevos derivados de quinuclidina-amida.
MXPA05000345A (es) 2002-07-08 2005-03-31 Pfizer Prod Inc Moduladores del receptor de glucocorticoides.
AR040962A1 (es) 2002-08-09 2005-04-27 Novartis Ag Compuestos derivados de tiazol 1,3-2-ona, composicion farmaceutica y proceso de preparacion del compuesto
AU2003288956A1 (en) 2002-10-30 2004-06-07 Vertex Pharmaceuticals Incorporated Compositions useful as inhibitors of rock and other protein kinases
US7632858B2 (en) 2002-11-15 2009-12-15 Bristol-Myers Squibb Company Open chain prolyl urea-related modulators of androgen receptor function
GB0305152D0 (en) 2003-03-06 2003-04-09 Novartis Ag Organic compounds
AR044519A1 (es) 2003-05-02 2005-09-14 Novartis Ag Derivados de piridin-tiazol amina y de pirimidin-tiazol amina
GB0320197D0 (en) 2003-08-28 2003-10-01 Novartis Ag Organic compounds
CA2537841A1 (fr) 2003-09-06 2005-03-24 Vertex Pharmaceuticals Incorporated Modulateurs de transporteurs a cassette de liaison a l'atp
ATE369349T1 (de) 2004-01-12 2007-08-15 Applied Research Systems Thiazolderivate und deren verwendung
SE0402735D0 (sv) 2004-11-09 2004-11-09 Astrazeneca Ab Novel compounds
EP1888573A1 (fr) 2005-05-24 2008-02-20 Laboratoires Serono S.A. Derives de thiazole et leur utilisation
AU2006251159B2 (en) 2005-05-24 2011-09-22 Merck Serono Sa Thiazole derivatives and use thereof
US7655446B2 (en) 2005-06-28 2010-02-02 Vertex Pharmaceuticals Incorporated Crystal structure of Rho-kinase I kinase domain complexes and binding pockets thereof
DE102005048072A1 (de) 2005-09-24 2007-04-05 Bayer Cropscience Ag Thiazole als Fungizide
US7595398B2 (en) 2005-12-12 2009-09-29 Smithkline Beecham Corporation N-(5-membered aromatic ring)-amido anti-viral compounds
GB0525671D0 (en) 2005-12-16 2006-01-25 Novartis Ag Organic compounds
WO2007082956A1 (fr) 2006-01-23 2007-07-26 Laboratoires Serono S.A. Dérivés de thiazole et leur utilisation
GB0610243D0 (en) 2006-05-23 2006-07-05 Novartis Ag Organic compounds
EP2099778A2 (fr) 2006-11-21 2009-09-16 Smithkline Beecham Corporation Composés amido antiviraux
WO2008124000A2 (fr) 2007-04-02 2008-10-16 Ligand Pharmaceuticals Incorporated Dérivés de thiazole utilisés comme composés modulateurs de récepteurs d'androgènes
NZ581127A (en) 2007-05-25 2012-06-29 Abbott Gmbh & Co Kg Heterocyclic compounds as positive modulators of metabotropic glutamate receptor 2 (mglu2 receptor)
US20090004140A1 (en) 2007-06-26 2009-01-01 Yao-Ling Qiu 4-substituted pyrrolidine as anti-infectives
CA2691507C (fr) 2007-07-19 2016-06-21 H. Lundbeck A/S Amides heterocycliques a 5 chainons et composes associes
WO2009080705A2 (fr) 2007-12-20 2009-07-02 Novartis Ag Composés organiques
EP2240475B1 (fr) 2007-12-20 2013-09-25 Novartis AG Dérivés de thiazole utilisés comme inhibiteur de la pi 3 kinase
UA104147C2 (uk) * 2008-09-10 2014-01-10 Новартис Аг Похідна піролідиндикарбонової кислоти та її застосування у лікуванні проліферативних захворювань
US8293753B2 (en) 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4649146A (en) * 1983-01-31 1987-03-10 Fujisawa Pharmaceutical Co., Ltd. Thiazole derivatives and pharmaceutical composition comprising the same

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110105535A1 (en) * 2003-05-02 2011-05-05 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
US8404684B2 (en) 2003-05-02 2013-03-26 Novartis Ag Inhibitors of phosphatidylinositol 3-kinase
US7514566B2 (en) 2006-01-18 2009-04-07 Amgen, Inc. Thiazole compounds and methods of use
US20090270445A1 (en) * 2006-01-18 2009-10-29 Amgen Inc. Thiazole compounds and methods of use
US20070173506A1 (en) * 2006-01-18 2007-07-26 Amgen Inc. Thiazole compounds and methods of use
US8084479B2 (en) 2006-01-18 2011-12-27 Amgen Inc. Thiazole compounds and methods of use
US20100105696A1 (en) * 2007-02-20 2010-04-29 Novartis Ag IMIDAZOQUINOLINES AS DUAL LIPID KINASE AND mTOR INHIBITORS
US9370508B2 (en) * 2007-02-20 2016-06-21 Novartis Ag Imidazoquinolines as dual lipid kinase and mTOR inhibitors
WO2008150446A1 (fr) * 2007-05-30 2008-12-11 Congxin Liang Inhibiteurs des protéines kinases
US20090298836A1 (en) * 2007-07-17 2009-12-03 Amgen Inc. Thiadiazole modulators of PKB
US7919504B2 (en) 2007-07-17 2011-04-05 Amgen Inc. Thiadiazole modulators of PKB
US7897619B2 (en) 2007-07-17 2011-03-01 Amgen Inc. Heterocyclic modulators of PKB
US8293753B2 (en) * 2009-07-02 2012-10-23 Novartis Ag Substituted 2-carboxamide cycloamino ureas
US20110003818A1 (en) * 2009-07-02 2011-01-06 Robin Alec Fairhurst Substituted 2-Carboxamide Cycloamino Ureas
WO2017147526A1 (fr) * 2016-02-26 2017-08-31 The Board Of Trustees Of The Leland Stanford Junior University Inhibiteurs de la pi-kinase à activité anti-infectieuse
US11091472B2 (en) 2016-02-26 2021-08-17 The Regents Of The University Of California PI-kinase inhibitors with anti-infective activity
US11884657B2 (en) 2016-02-26 2024-01-30 The Board Of Trustees Of The Leland Stanford Junior University PI-kinase inhibitors with anti-infective activity
US12415788B2 (en) 2019-03-21 2025-09-16 The Board Of Trustees Of The Leland Stanford Junior University PI4-kinase inhibitors and methods of using the same

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