WO2008141140A1 - Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de protéines kinases - Google Patents

Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de protéines kinases Download PDF

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WO2008141140A1
WO2008141140A1 PCT/US2008/063189 US2008063189W WO2008141140A1 WO 2008141140 A1 WO2008141140 A1 WO 2008141140A1 US 2008063189 W US2008063189 W US 2008063189W WO 2008141140 A1 WO2008141140 A1 WO 2008141140A1
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amino
nhc
phenyl
nhr
carboxamide
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PCT/US2008/063189
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English (en)
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Michael R. Michaelides
Ji Zhiqin
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Abbott Laboratories
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention pertains to compounds that inhibit protein kinases such as Aurora-kinases, compositions containing the compounds and methods of treating diseases using the compounds.
  • Mitosis is a process by which a complete copy of a duplicated genome is segregated by the microtuble spindle apparatus into two daughter cells.
  • Aurora- kinases key mitotic regulators required for genome stability, have been found to be overexpressed in human tumors. There is therefore an existing need in the therapeutic arts for compounds which inhibit Aurora-kinases, compositions comprising the inhibitors and methods of treating diseases during which Aurora-kinases are unregulated or overexpressed.
  • One embodiment of this invention pertains to compounds that inhibit Aurora-kinases, the compounds having Formula I
  • a 1 is C(O)NHR 1 , C(O)N(R ⁇ 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R ⁇ 2 , SO 2 NHR 1 , SO 2 N(R ⁇ 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , OC(O)OR 1 , NHC(O)OR 1 , NR 1 C(O)OR 1 or R 5 ;
  • B 1 and C 1 are independently H, C(O)NHR 1 , C(O)N(R ⁇ 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R ⁇ 2 , SO 2 NHR 1 , SO 2 N(R 1 H NHSO 2 R 1 , NR 1 SO 2 R 1 , OC(O)OR 1 , NHC(O)OR 1 , NR 1 C(O)OR 1 or R 5 ; wherein
  • R 1 is R 2 , R 3 or R 4 ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R , OR , SR , S(O)R , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 ,
  • R 6 is R 7 , R 8 , R 9 , or R 9A ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of
  • 9A 9A which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected NH 2 , C(O)NH 2 , SO 2 NH 2 , NHC(O)NH 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
  • each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three or four or five of independently selected R , OR 30 , OCH 2 R 30 , SR 30 , S(O)R 30 , SO 2 R 30 , C(O)R 30 , CO(O)R 30 , OC(O)R 30 , OC(O)OR 30 , NO 2 , NH 2 , NHR 30 , N(R 3 °) 2 , C(O)NH 2 , C(O)NHR 30 , C(O)N(R 3 °) 2 , NHC(O)R 30 , NHC(O)NHR 30 , NHC(O)N(R 3 °) 2 , NR 30 C(O)NHR 30 , NR 3 °C(O)N(R 3 °) 2 , C(O)NHOH, C(O)NHOR 30 , C(O)NHSO 2 R 30 , C(O)NR 30
  • R is R , R , R or R ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R , OR , SR , S(O)R , SO 2 R 35 , NH 2 , NHR 35 , N(R 35 ) 2 , C(O)R 35 , C(O)NH 2 , C(O)NHR 35 , C(O)N(R 35 ) 2 , NHC(O)R 35 , NR 35 C(O)R 35 , NHSO 2 R 35 , NR 35 SO 2 R 35 , NHC(O)OR 35 , NR 35 C(O)OR 35 , SO 2 NH 2 , SO 2 NHR 35 , SO 2 N(R 35 ) 2 , NHC(O)NH 2 , NHC(O)NHR 35 , NHC(O)R 35 , NHC(O)N(R 35 ) 2 , NR 35 C(O)N
  • R is R , R , R or R ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with R 40 ;
  • R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;
  • R , R , R R , R and R are independently unsubstituted or substituted with one or two or three of independently selected F, Cl, Br, I, OH, (O)OH, NO 2, NH 2, CF 3 , OH, R 45 , OR 45 , SR 45 , S(O)R 45 , SO 2 R 45 , C(O)NHR 45 , C(O)N(R 45 ) 2 , NHC(O)R 45 , NR 45 C(O)R 45 , NHC(O)NHR 45 , NHC(O)N(R 45 ) 2 , NR 45 C(O)NHR 45 , NR 45 C(O)N(R 45 ) 2 , SO 2 NHR 45 , SO 2 N(R 45 ) 2 , NHSO 2 R 45 , NR 1 SO 2 R 45 , OC(O)OR 45 , NHC(O)OR 45 Or NR 45 C(O)OR 45 ; R is
  • R is is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl.
  • compositions comprising an excipient and a therapeutically effective amount of a compound having Formula I.
  • Still another embodiment pertains to methods of treating diseases involving overexpression or unregulation of Aurora-kinases in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having Formula I,
  • a 1 is C(O)NHR 1 , C(O)N(R ⁇ 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R 1 ) 2 , SO 2 NHR 1 , SO 2 N(R ⁇ 2 , NHSO 2 R 1 , NR 1 SO 2 R 1 , OC(O)OR 1 , NHC(O)OR 1 , NR 1 C(O)OR 1 or R 5 ;
  • B 1 and C 1 are independently H, C(O)NHR 1 , C(O)N(R ⁇ 2 , NHC(O)R 1 , NR 1 C(O)R 1 , NHC(O)NHR 1 , NHC(O)N(R 1 ) 2 , NR 1 C(O)NHR 1 , NR 1 C(O)N(R ⁇ 2 , SO 2 NHR 1 , SO 2 N(R 1 H NHSO 2 R 1 , NR 1 SO 2 R 1 , OC(O)OR 1 , NHC(O)OR 1 , NR 1 C(O)OR 1 or R 5 ; wherein
  • R 1 is R 2 , R 3 or R 4 ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R , OR , SR , S(O)R , SO 2 R 6 , NH 2 , NHR 6 , N(R 6 ) 2 , C(O)R 6 , C(O)NH 2 , C(O)NHR 6 , C(O)N(R 6 ) 2 , NHC(O)R 6 , NR 6 C(O)R 6 , NHSO 2 R 6 , NR 6 SO 2 R 6 , NHC(O)OR 6 , NR 6 C(O)OR 6 , SO 2 NH 2 , SO 2 NHR 6 , SO 2 N(R 6 ) 2 , NHC(O)NH 2 , NHC(O)R 6 , NHC(O)N(R 6 ) 2 , NR 6 C(O)N(R 6 )
  • R 6 is R 7 , R 8 , R 9 , or R 9A ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl, or alkynyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected NH 2 , C(O)NH 2 , SO 2 NH 2 , NHC(O)NH 2 , OH, (O), C(O)OH, CN, CF 3 , OCF 3 , CF 2 CF 3 , F, Cl, Br or I;
  • each foregoing cyclic moiety is independently unsubstituted or substituted with one or two or three or four or five of independently selected R , OR 30 , OCH 2 R 30 , SR 30 , S(O)R 30 , SO 2 R 30 , C(O)R 30 , CO(O)R 30 , OC(O)R 30 , OC(O)OR 30 , NO 2 , NH 2 , NHR 30 , N(R 3 °) 2 , C(O)NH 2 , C(O)NHR 30 , C(O)N(R 3 °) 2 , NHC(O)R 30 , NHC(O)NHR 30 , NHC(O)N(R 3 °) 2 , NR 30 C(O)NHR 30 , NR 3 °C(O)N(R 3 °) 2 , C(O)NHOH, C(O)NHOR 30 , C(O)NHSO 2 R 30 , C(O)NR 30
  • R is R , R , R or R ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl, or alkenyl, each of which is unsubstituted or substituted with one, two, three, four or five of independently selected R , OR , SR , S(O)R , SO 2 R 35 , NH 2 , NHR 35 , N(R 35 ) 2 , C(O)R 35 , C(O)NH 2 , C(O)NHR 35 , C(O)N(R 35 ) 2 , NHC(O)R 35 , NR 35 C(O)R 35 , NHSO 2 R 35 , NR 35 SO 2 R 35 , NHC(O)OR 35 , NR 35 C(O)OR 35 , SO 2 NH 2 , SO 2 NHR 35 , SO 2 N(R 35 ) 2 , NHC(O)NH 2 , NHC(O)NHR 35 , NHC(O)R 35 , NHC(O)N(R 35 ) 2 , NR 35 C(O)N
  • R is R , R , R or R ;
  • R is phenyl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is heteroaryl which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene
  • R is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unfused or fused with benzene, heteroarene or R ;
  • R is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;
  • R is alkyl, alkenyl or alkenyl, each of which is unsubstituted or substituted with
  • R is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl;
  • R , R , R R , R and R are independently unsubstituted or substituted with one or two or three of independently selected F, Cl, Br, I, OH, (O)OH, NO 2 , NH 2, CF 3 , OH, R 45 , OR 45 , SR 45 , S(O)R 45 , SO 2 R 45 , C(O)NHR 45 , C(O)N(R 45 ) 2 , NHC(O)R 45 , NR 45 C(O)R 45 , NHC(O)NHR 45 , NHC(O)N(R 45 ) 2 , NR 45 C(O)NHR 45 , NR 45 C(O)N(R 45 ) 2 , SO 2 NHR 45 , SO 2 N(R 45 ) 2 , NHSO 2 R 45 , NR 1 SO 2 R 45 , OC(O)OR 45 , NHC(O)OR 45 Or NR 45 C(O)OR 45 ;
  • R is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two or three of independently selected R , F, Cl, Br, I, OH, C(O)OH, NO 2 or NH 2 ; and
  • R is is phenyl, heteroaryl, cycloalkyl, cycloalkenyl or heterocycloalkyl. with or without also administering radiotherapy thereto.
  • Still another embodiment pertains to methods of treating bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer and thyroid cancer in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having Formula I, with or without also administering radiotherapy thereto.
  • compositions comprising an excipient and a therapeutically effective amount of a compound having Formula I and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent.
  • Still another embodiment pertains to methods of treating diseases involving overexpression or unregulation of Aurora-kinases in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having Formula I and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent with or without also administering radiotherapy thereto .
  • Still another embodiment pertains to methods of treating bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer and thyroid cancer in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having Formula I and a therapeutically effective amount of one additional therapeutic agent or more than one additional therapeutic agent, with or without also administering radiotherapy thereto.
  • Variable moieties of compounds herein are represented by identifiers (capital letters with numerical and/or alphabetical superscripts) and may be specifically embodied.
  • variable moiety means benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and phenyl.
  • cycloalkane means C 3 -cycloalkane, C 4 - cycloalkane, Cs-cycloalkane and C 6 -cycloalkane.
  • cycloalkyl means C 3 -cycloalkyl, C 4 -cycloalkyl, C 5 -cycloalkyl and Cg-cycloalkyl.
  • cycloalkene means C 4 -cycloalkene, C 5 - cycloalkene and C 6 -cycloalkene.
  • cycloalkenyl means C 4 -cycloalkenyl, C 5 - cycloalkenyl and C 6 -cycloalkenyl.
  • heteroene means furan, imidazole, isothiazole, isoxazole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine and 1,2,3- triazole.
  • heteroaryl means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl.
  • heterocycloalkane means cycloalkane having one or two or three CH 2 moieties replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkane having one or two or three CH 2 moieties unreplaced or replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties replaced with N.
  • heterocycloalkyl means cycloalkyl having one or two or three CH 2 moieties replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkyl having one or two or three CH 2 moieties unreplaced or replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties replaced with N.
  • heterocycloalkene means cycloalkene having one or two or three CH 2 moieties replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkene having one or two or three CH 2 moieties unreplaced or replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties replaced with N.
  • heterocycloalkenyl means cycloalkenyl having one or two or three CH 2 moieties replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties unreplaced or replaced with N and also means cycloalkenyl having one or two or three CH 2 moieties unreplaced or replaced with independently selected O, S, S(O), SO 2 or NH and one or two CH moieties replaced with N.
  • alkenyl means C 2 -alkenyl, C 3 -alkenyl, C 4 -alkenyl, Cs-alkenyl and Cg-alkenyl.
  • alkyl as used herein, means Ci-alkyl, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 -alkyl and C 6 -alkyl.
  • alkynyl means C 2 -alkynyl, C 3 -alkynyl, C 4 - alkynyl, Cs-alkynyl and C 6 -alkynyl.
  • Compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R” and “S” are as defined in Pure Appl. Chem. (1976) 45, 13-10.
  • Compounds having asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic at those atoms. Atoms having excess of one configuration over the other are assigned the configuration in excess, preferably an excess of about 85%-90%, more preferably an excess of about 95%-99%, and still more preferably an excess greater than about 99%. Accordingly, this invention is meant to embrace racemic mixtures and relative and absolute diastereoisomers of the compounds thereof.
  • Compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z or E configuration, in which the term “Z” represents the larger two substituents on the same side of a carbon-carbon or carbon-nitrogen double bond and the term “E” represents the larger two substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond.
  • the compounds of this invention may also exist as a mixture of "Z” and "E” isomers.
  • Compounds of this invention may also exist as tautomers or equilibrium mixtures thereof wherein a proton of a compound shifts from one atom to another.
  • tautomers include, but are not limited to, keto-enol, phenol-keto, oxime- nitroso, nitro-aci, imine-enamine and the like.
  • Compounds of this invention containing NH, C(O)OH, OH or SH moieties may have attached thereto prodrug-forming moieties.
  • the prodrug-forming moieties are removed by metabolic processes and release the compounds having the freed NH, C(O)OH, OH or SH in vivo.
  • Prodrugs are useful for adjusting such pharmacokinetic properties of the compounds as solubility and/or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of clearance.
  • Metabolites of compounds having Formula I produced by in vitro or in vivo metabolic processes may also have utility for treating diseases associated with overexpression or unregulation of protein kinases.
  • Certain precursor compounds which may be metabolized in vitro or in vivo to form compounds having Formula I may also have utility for treating diseases associated with overexpression or unregulation of protein kinases.
  • Compounds having Formula I may exist as acid addition salts, basic addition salts or zwitterions. Salts of compounds having Formula I are prepared during their isolation or following their purification. Acid addition salts are those derived from the reaction of a compound having Formula I with acid.
  • salts including the acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsufonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, para-toluenesulfonate and undecan
  • Compounds having Formula I may be administered, for example, bucally, ophthalmically, orally, osmotically, parenterally (intramuscularly, intraperintoneally intrasternally, intravenously, subcutaneously), rectally, topically, transdermally, vaginally and intraarterially as well as by intraarticular injection, infusion, and placement in the body, such as, for example, the vasculature.
  • Therapeutically effective amounts of a compound having Formula I depend on recipient of treatment, disease treated and severity thereof, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of clearance and whether or not another drug is co-administered.
  • the amount of a compound having Formula I used to make a composition to be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg/kg body weight.
  • Single dose compositions contain these amounts or a combination of submultiples thereof.
  • Excipients include, but are not limited to, encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • encapsulators and additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having Formula I to be administered orally include, but are not limited to, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, groundnut oil, hydroxypropylmethyl celluose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ring
  • Excipients for preparation of compositions comprising a compound having Formula I to be administered ophthalmically or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having Formula I to be administered osmotically include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having Formula I to be administered parenterally include, but are not limited to, 1,3- butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. or isotonic sodium chloride solution, water, mixtures thereof and the like.
  • Excipients for preparation of compositions comprising a compound having Formula I to be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like.
  • Compounds having Formula I are also expected to be useful as chemotherapeutic agents in combination with actinomycins, alkylating agents, anthracyclines, antifolates, antiestrogen agents, anti-metabolites, anti-androgens, 2+ antimicrotubule agents, aromatase inhibitors, bleomycins, Ca adenosine triphosphate (ATP)ase inhibitors, cytosine analogs, deltoids/retinoids, dihydrofolate reductase inhibitors, deoxyribonucleic acid (DNA) topoisomerase inhibitors, dopaminergic neurotoxins, glucocorticoids, histone deacetylase inhibitors, hormonal therapies, immunotherapeutic agents, inosine monophosphate (IMP) dehydrogenase inhibitors, isoprenylation inhibitors, luteinizing hormone-releasing hormone agonists, mammalian target of rapamycin (mtor) inhibitors, multi-drug resistance (MDR) inhibitor
  • Active Aurora B enzyme (recombinant residues 1-344) and INCENP (recombinant GST fusion protein from Upstate) were incubated in wells of a 384 well plate with biotinylted histone H3 peptide residues 1-21 (Upstate), 1 mM ATP, and various concentrations of inhibitors in a Hepes buffer, pH 7.4 containing MgCl 2 , sodium othro vanadate, and Triton X-IOO. After 1 hour, the reaction was stopped with EDTA and anti-phospho-histone H3 Europium Cryptate (Cis-Bio) and SA-APC (Phycolink, Prozyme) were added to detect the phosphopeptide.
  • the amount of phosphorylation was determined by the time-resolved fluorescence ratio of signals at 665 nm and 615 nm.
  • the ICso's were calculated by an exponential fit of the inhibition values with the inhibitor concentrations using Assay Explorer software and are shown in TABLE 1.
  • compounds having Formula I are expected to have utility in treatment of diseases during which protein kinases such as any or all Aurora-kinase family members are expressed.
  • Aurora-kinase family members include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocyte), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myleogeneous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative
  • compounds having Formula I would inhibit the growth of cells derived from a cancer or neoplasm such as breast cancer (including estrogen- receptor positive breast cancer), colorectal cancer, endometrial cancer, lung cancer (including small cell lung cancer), lymphoma (including follicular or Diffuse Large B-cell), lymphoma (including non-Hodgkin's lymphoma), neuroblastoma, ovarian cancer, prostate cancer (including hormone-insensitive prostate cancer) and testicular cancer (including germ cell testicular cancer).
  • a cancer or neoplasm such as breast cancer (including estrogen- receptor positive breast cancer), colorectal cancer, endometrial cancer, lung cancer (including small cell lung cancer), lymphoma (including follicular or Diffuse Large B-cell), lymphoma (including non-Hodgkin's lymphoma), neuroblastoma, ovarian cancer, prostate cancer (including hormone-insensitive prostate cancer) and testicular cancer (including germ cell testicular cancer).
  • compounds having Formula I would inhibit the growth of cells derived from a pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous syatem, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric
  • Compounds having Formula I are expected to be useful when used with alkylating agents, angiogenesis inhibitors, antibodies, antimetabolites, antimitotics, antiproliferatives, aurora kinase inhibitors, Bcl-2 family protein (for example, Bcl-xL, Bcl-2, Bcl-w, BfI-I) inhibitors, Bcr-Abl kinase inhibitors, biologic response modifiers, cyclin-dependent kinase inhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growth factor inhibitors, heat shock protein HSP-90 inhibitors, histone deacetylase (HDAC) inhibitors inhibitors, hormonal therapies, immunologicals, intercalating antibiotics, kinase inhibitors, mammalian target of rapomycin inhibitors, mitogen-activated extracellular signal-regulated kinase inhibitors, non-steroidal anti-inflammatory drugs (NSAID
  • Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, CloretazineTM (VNP 4010 IM), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide and the like.
  • Angiogenesis inhibitors include endothelial- specific receptor tyrosine kinase
  • Tie-2 inhibitors epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrix metalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9 (MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospondin analogs vascular endothelial growth factor receptor tyrosine kinase (VEGFR) inhibitors and the like.
  • EGFR epidermal growth factor receptor
  • IGFR-2 insulin growth factor-2 receptor
  • MMP-2 matrix metalloproteinase-2
  • MMP-9 matrix metalloproteinase-9
  • PDGFR platelet-derived growth factor receptor
  • VEGFR thrombospondin analogs vascular endothelial growth factor receptor tyrosine kinase
  • Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like.
  • BcI protein family member inhibitors include AT-101 ((-)gossypol), GENASENSE (G3139 or oblimersen (Bcl-2 -targeting antisense oglionucleotide)), IPI-194, IPI-565, N-(4-(4-((4'-chloro(l ,l'-biphenyl)-2-yl)methyl)piperazin-l- yl)benzoyl)-4-((( 1 R)-3 -(dimethylamino)- 1 -((phenylsulfanyl)methyl)propyl)amino)-3 - nitrobenzenesulfonamide) (ABT-737), N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-l- cyclohex- 1 -en- 1 -yl)methyl)piperazin- 1 -yl)benzoyl)-4-(((
  • Bcr-Abl kinase inhibitors include DASATINIB ® (BMS-354825), GLEEVEC ® (imatinib) and the like.
  • CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC- 202, R-roscovitine), ZK-304709 and the like.
  • COX-2 inhibitors include ABT-963, ARCOXIA ® (etoricoxib), BEXTRA ® (valdecoxib), BMS347070, CELEBREXTM (celecoxib), COX- 189 (lumiracoxib), CT- 3, DERAMAXX ® (deracoxib), JTE-522, 4-methyl-2-(3,4-dimethylphenyl)-l-(4- sulfamoylphenyl-lH-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX ® (rofecoxib) and the like.
  • EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF- vaccine, EMD-7200, ERBITUX ® (cetuximab), HR3, IgA antibodies, IRESSA ® (gefitinib), TARCEVA ® (erlotinib or OSI-774), TP-38, EGFR fusion protein, TYKERB ® (lapatinib) and the like.
  • ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),
  • Herceptin ® (trastuzumab), TYKERB ® (lapatinib), OMNITARG ® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209, mAB 2B-1 and the like.
  • Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid and the like.
  • HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,
  • MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-
  • mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-OOl, rapamycin, temsirolimus and the like.
  • Non-steroidal anti-inflammatory drugs include AMIGESIC (salsalate), DOLOBID ® (diflunisal), MOTRIN ® (ibuprofen), ORUDIS ® (ketoprofen),
  • RELAFEN nabumetone
  • FELDENE piroxicam
  • ibuprofm cream ALEVE and NAPROSYN ® (naproxen)
  • VOLTAREN ® diclofenac
  • INDOCIN ® indomethacin
  • CLINORIL ® sulindac
  • TOLECTIN ® tolmetin
  • LODINE ® etodolac
  • TORADOL ® ketorolac
  • DAYPRO ® oxaprozin
  • PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.
  • Platinum chemotherapeutics include cisplatin, ELOXATIN (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN (carboplatin), satraplatin and the like.
  • Polo-like kinase inhibitors include BI-2536 and the like.
  • Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-I and the like.
  • VEGFR inhibitors include AVASTIN ® (bevacizumab), ABT-869, AEE-788, ANGIOZYMETM, axitinib (AG- 13736), AZD-2171, CP-547,632, IM-862, Macugen (pegaptamib), NEXAVAR ® (sorafenib, BAY43-9006), pazopanib (GW-786034), (PTK-787, ZK-222584), SUTENT ® (sunitinib, SU-11248), VEGF trap, vatalanib, ZACTIMATM (vandetanib, ZD-6474) and the like.
  • Antimetabolites include ALIMTA (premetrexed disodium, LY231514,
  • MTA 5-azacitidine
  • XELODA capecitabine
  • LEUSTAT cladribine
  • clofarabine cytarabine, cytarabine ocfosfate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine, ethnylcytidine, fludarabine, hydroxyurea, 5-fluorouracil (5-FU) alone or in combination with leucovorin, GEMZAR (gemcitabine), hydroxyurea, ALKERAN (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosate, pelitrexol, pentostatin, raltitrexed, Ribavirin, triapine, tri
  • Antibiotics include intercalating antibiotics aclarubicin, actinomycin D, amrubicin, annamycin, adriamycin, BLENOXANE (bleomycin), daunorubicin, CAELYX or MYOCET (doxorubicin), elsamitrucin, epirbucin, glarbuicin,
  • Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR
  • Antibodies include AVASTIN (bevacizumab), CD40-specific antibodies, chTNT-1/B, denosumab, ERBITUX ® (cetuximab), HUMAX-CD4 ® (zanolimumab), IGFlR-specif ⁇ c antibodies, lintuzumab, PANOREX ® (edrecolomab), RENC AREX ® (WX G250), RITUXAN ® (rituximab), ticilimumab, trastuzimab and and the like.
  • Hormonal therapies include ARIMIDEX ® (anastrozole), AROMASIN ®
  • FASLODEX full vestrant
  • FEM ARA full vestrant
  • FEM ARA fuller
  • formestane glucocorticoids
  • HECTOROL or RENAGEL
  • doxercalciferol lasofoxifene
  • leuprolide acetate MEGACE ® (megesterol), MIFEPREX ® (mifepristone), NILANDRONTM (nilutamide), NOLVADEX ® (tamoxifen citrate), PLENAXISTM (abarelix), predisone
  • PROPECIA ® farinasteride
  • rilostane SUPREF ACT ® (buserelin)
  • LHRH luteinizing hormone releasing hormone
  • vantas VETORYL
  • Deltoids and retinoids include seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, PANRETIN ® (aliretinoin), ATRAGEN ® (liposomal tretinoin), TARGRETIN ® (bexarotene), LGD-1550 and the like.
  • Plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like.
  • Proteasome inhibitors include VELCADE ® (bortezomib), MG 132, NPI-0052, PR-171 and the like.
  • immunologicals examples include interferons and other immune-enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-la, ACTIMMUNE (interferon gamma-lb), or interferon gamma-nl, combinations thereof and the like.
  • Other agents include
  • CamPath (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileukin, epratuzumab, GRANOCYTE (lenograstim), lentinan, leukocyte alpha interferon, imiquimod, MDX-OlO, melanoma vaccine, mitumomab, molgramostim, MYLOTARGTM (gemtuzumab ozogamicin), NEUPOGEN ® (filgrastim), OncoVAC- CL, OvaRex ® (oregovomab), pemtumomab (Y-muHMFGl), PROVENGE ® ,
  • ZEVALIN 90Y-Ibritumomab tiuxetan
  • Biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity and include include krestin, lentinan, sizofiran, picibanil PF-3512676 (CpG-8954), ubenimex and the like.
  • Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosine arabinoside, doxifluridine, FLUDARA (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR ® (gemcitabine), TOMUDEX ® (ratitrexed), TROXATYLTM (triacetyluridine troxacitabine) and the like.
  • Purine analogs include LANVIS ® (thioguanine) and PURI-NETHOL ® (mercaptopurine) .
  • Antimitotic agents include batabulin, epothilone D (KOS-862), N-(2-((4- hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE ® (docetaxel), PNU100940 (109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like.
  • Radiotherapy examples include, but are not limited to, external beam radiotherapy, teletherapy, brachtherapy and sealed and unsealed source radiotherapy.
  • compounds having Formula I may be combined with other chemptherapeutic agents such as ABRAXANETM (ABI-007), ABT- 100 (farnesyl transferase inhibitor), ADVEXIN ® , ALTOCOR ® or MEVACOR ® (lovastatin), AMPLIGEN ® (poly Lpoly C 12U, a synthetic RNA), APTOSYNTM (exisulind),
  • ABRAXANETM ABSI-007
  • ABT- 100 farnesyl transferase inhibitor
  • ADVEXIN ® ALTOCOR ® or MEVACOR ®
  • AMPLIGEN ® poly Lpoly C 12U, a synthetic RNA
  • APTOSYNTM exisulind
  • AREDIA pamidronic acid
  • arglabin arglabin
  • L-asparaginase atamestane (l-methyl-3,17- dione-androsta-l,4-diene)
  • AV AGE ® tazarotne
  • AVE-8062 BEC2 (mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CeaVacTM (cancer vaccine), CELEUK (celmoleukin), CEPLENE (histamine dihydrochloride), CERVARIXTM (human papillomavirus vaccine), CHOP ® (C: CYTOXAN ®
  • GMK ganglioside conjugate vaccine
  • GVAX prostate cancer vaccine
  • halofuginone histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonas exotoxin, interferon- ⁇ , interferon- ⁇ , JUNO V ANTM or MEP ACTTM (mifamurtide), lonafarnib, 5,10- methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT ® (AE-941), NEUTREXIN ® (trimetrexate glucuronate), NIPENT ® (pentostatin), ONCONASE ® (a ribonuclease enzyme), ONCOPHAGE ® (melanoma vaccine treatment), OncoVAX (IL-2
  • OSIDEM antibody-based cell drug
  • OvaRex MAb murine monoclonal antibody
  • paditaxel PANDIMEXTM (aglycone saponins from ginseng comprising 20(S)protopanaxadiol (aPPD) and 20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC -VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB (catumaxomab), REVLIMID (lenalidomide), RSRl 3 (efaproxiral), SOMATULINE ® LA (lanreotide),
  • SORIATANE acitretin
  • staurosporine Streptomyces staurospores
  • talabostat PTlOO
  • TARGRETIN ® bexarotene
  • Taxoprexin ® DHA-paclitaxel
  • TELCYT ATM TELCYT ATM (TLK286)
  • temilifene TEMOD AR ® (temozolomide)
  • tesmilifene thalidomide
  • THERATOPE ® STn-KLH
  • thymitaq (2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4- pyridylthio)quinazoline dihydrochloride
  • TNFeradeTM (adenovector: DNA carrier containing the gene for tumor necrosis factor- ⁇ ), TRACLEER or ZAVESCA (bosentan), tretinoin (Retin-A), tetrandrine, TRISENOX (arsenic trioxide), VIRULIZIN , ukrain (derivative of alkaloids from the greater celandine plant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN (motexafm gadolinium), XINLAYTM (atrasentan), XYOTAXTM (paclitaxel poliglumex), YONDELISTM
  • compounds having Formula I would inhibit growth of cells derived from a pediatric cancer or neoplasm including embryonal rhabdomyosarcoma, pediatric acute lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric atypical teratoid/rhabdoid tumor of the central nervous syatem, pediatric biphenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of Ewing's family of tumors such as primitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm's tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-
  • autoimmune disorders include, acquired immunodeficiency disease syndrome, autoimmune lymphoproliferative syndrome, hemolytic anemia, inflammatory diseases, thrombocytopenia and the like (Current Allergy and Asthma Reports 2003, 3:378-384; Br. J. Haematol. 2000 Sep; 110(3): 584-90; Blood 2000 Feb 15;95(4):1283-92; and New England Journal of Medicine 2004 Sep; 351(14): 1409-1418).
  • Compounds having Formula I may be made by synthetic chemical processes, examples of which are shown hereinbelow. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
  • Protecting groups for C(O)OH moieties include, but are not limited to, acetoxymethyl, allyl, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl, diphenylmethyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2-(trimethylsilyl)ethyl, 2- (trimethylsilyl)ethoxymethyl, triphenylmethyl and the like.
  • Protecting groups for C(O) and C(O)H moieties include, but are not limited to, 1,3-dioxylketal, diethylketal, dimethylketal, 1,3-dithianylketal, O-methyloxime, O-phenyloxime and the like.
  • Protecting groups for NH moieties include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl, methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl, triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl and the like.
  • Protecting groups for OH and SH moieties include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethy lsilyl, tert-butyldiphenylsilyl, 3 ,4-dimethoxybenzyl, 3,4-dimethoxybenzyloxycarbonyl, l,l-dimethyl-2-propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloroethyl, triethylsilyl, trifluor
  • ADDP means l,l'-(azodicarbonyl)dipiperidine
  • AD-mix- ⁇ means a mixture of (DHQD) 2 PHAL, K 3 Fe(CN) 6 , K 2 CO 3 and K 2 SO 4 );
  • AIBN means 2,2'-azobis(2- methylpropionitrile);
  • 9-BBN means 9-borabicyclo(3.3.1)nonane;
  • Cp means cyclopentadiene;
  • DHQD) 2 PHAL means hydroquinidine 1 ,4-phthalazinediyl diethyl ether;
  • DBU means l,8-diazabicyclo(5.4.0)undec-7-ene;
  • DCC means 1,3- dicyclohexylcarbodiimide, DIBAL means diisobutylaluminum hydride;
  • DIEA means diisopropylethylamine;
  • DMAP means N,N-dimethylaminopyridine;
  • compounds having Formula (1) can be converted to compounds having Formula (3) by reacting the former, compounds having Formula (2), a coupling agent, and a first base, with or without a coupling auxiliary.
  • coupling agents include DCC, EDCI, HATU, TBTU and the like.
  • bases include DIEA, TEA, NMM and the like.
  • coupling auxiliaries include DMAP, HOAT, HOBT and the like.
  • the reaction is typically conducted between about 25 0 C to 45 0 C, over about 1 to about 24 hours, in solvents such as THF, DMF, dichloromethane, ethyl acetate, mixtures thereof and the like.
  • Formula (4) by reacting the former, POCI 3 and DMF.
  • the reaction is typically conducted, over about 0.5 to about two hours, in refluxing acetonitrile.
  • Compounds having Formula (4) can be converted to compounds having Formula (5) by reacting the former and NIS.
  • the reaction is typically conducted, over about one to about five hours, between about 4O 0 C and 8O 0 C in solvents such as DMF and the like.
  • Compounds having Formula (5) can be converted to compounds having Formula (6) by reacting the former and ammonia.
  • the reaction is typically conducted in a sealed container between about 4O 0 C and 15O 0 C in the ammonia or in solvents such as methanol, ethanol, isopropanol, mixtures thereof and the like.
  • Compounds having Formula (6) can be converted to compounds having Formula (7) by reacting the former, carbon monoxide, methanol, a palladium catalyst, and a second base.
  • palladium catalysts include palladium acetate, (1,1'- bis(diphenylphosphino)ferrocene)dichloropalladium(II), and the like.
  • second bases include TEA, pyridine and the like. The reaction is typically conducted (in a sealed container), over about one to about three hours, between about 8O 0 C and 12O 0 C, in methanol.
  • Compounds having Formula (7) can be converted to compounds having Formula (8) by reacting the former and a third base.
  • third bases include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.
  • the reaction is typically conducted over about 1 hour to about 48 hours, between about O 0 C and 35 0 C, in solvents such as water, methanol, ethanol, isopropanol, mixtures thereof and the like.
  • moieties represented by A can be accomplished by reacting compounds having formula (8), a primary or a secondary amine, a coupling agent, a first base, with or without a coupling auxiliary, using the reaction conditions described hereinabove for conversion of compounds having Formula (1) to compounds having Formula (3).
  • Formula (9) by reacting the former and DPPA followed by hydrolysis of the isocyanate intermediate with water.
  • the reactions are typically conducted over about 1 hour to about 24 hours, between about 5O 0 C and HO 0 C, in solvents such as benzene, toluene, THF, water, mixtures thereof and the like.
  • moieties represented by A can be accomplished by reacting the compounds having formula (9) and the appropriate isocyanate, carbonyl chloride, sulfonyl chloride, carbamoyl chloride. The reactions are typically conducted over about 1 hour to about 48 hours, between about O 0 C and HO 0 C, in solvents such as THF, ethyl acetate, dichloromethane, DMF, DMSO, chloroform, mixtures thereof and the like.
  • solvents such as THF, ethyl acetate, dichloromethane, DMF, DMSO, chloroform, mixtures thereof and the like.
  • EXAMPLE ID In a stainless steel reactor, EXAMPLE 1C (3.3 g) in 2M NH 3 in isopropanol
  • EXAMPLE IE A mixture of EXAMPLE ID (1.3 g), PdCl 2 (dppf) (150 mg) and triethylamine
  • EXAMPLE IE (0.87 g) and 2N LiOH (10 mL) in methanol (10 mL) was stirred at room temperature for 3 hours, neutralized with 2N HCl to pH 6-7, and filtered.
  • EXAMPLE IG l-fluoro-3-isocyanatobenzene (0.56 mL) was added to a solution of (4- aminophenyl)carbamic acid tert-butyl ester (1.04 g) in dichloromethane (20 mL) at O 0 C. The mixture was stirred at ambient temperature for 4 hours and filtered.
  • the f ⁇ ltrant was collected was suspended in dichloromethane (20 mL), cooled in an ice bath, treated with TFA (5 mL), stirred for 15 minutes at ambient temperature for 3 hours and concentrated. The concentrate was concentrated twice from methanol and toluene and dried to provide the title compound as the trifluoroacetate salt.
  • EXAMPLE 5 This example was prepared as described in EXAMPLE IG-H by substituting tert-butyl 3-(aminomethyl)phenylcarbamate for (4-aminophenyl)carbamic acid tert- butyl ester in EXAMPLE IG.
  • EXAMPLE 6 This example was prepared as described in EXAMPLE IG-H by substituting tert-butyl 3-(aminomethyl)phenylcarbamate and isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3 -isocyanatobenzene, respectively in EXAMPLE IG.
  • EXAMPLE 12E This example was prepared by substituting EXAMPLE 12D for EXAMPLE
  • EXAMPLE IG and EXAMPLE 12D for IF in EXAMPLE IH.
  • EXAMPLE 17 This example was prepared as described in EXAMPLES IG- IH by substituting l-isocyanato-3-methylbenzene for l-fluoro-3-isocyanatobenzene in EXAMPLE IG and EXAMPLE 12D for IF in EXAMPLE IH.
  • EXAMPLE 23 This example was prepared as described in EXAMPLES IG- IH by substituting isocyanatocyclopropane for l-fluoro-3-isocyanatobenzene in EXAMPLE IG and EXAMPLE 12D for IF in EXAMPLE IH.
  • EXAMPLE 28 This example was prepared as described in EXAMPLES IG- IH by substituting l-fluoro-2-isocyanato-4-methylbenzene for l-fluoro-3-isocyanatobenzene in EXAMPLE IG and EXAMPLE 12D for IF in EXAMPLE IH.
  • EXAMPLE 36A A solution of 3-(morpholinomethyl)aniline (0.46 g), TEA (0.37 mL) and A- nitrophenyl carbonochloridate (530 mg) in THF (18 mL) was stirred at ambient temperature for 2 hours, treated with tert-butyl 4-aminophenylcarbamate (500mg) and an additional 0.37mL of TEA. the resulting mixture was stirred at ambient temperature for 48 hours, poured into water and exatrcted 3x with ethyl acetate. The extract was washed with brine, dried (MgSO 4 ), filtered and concentrated.
  • the concentrate was purified by flash chromatography on silica gel with 2% methanol/dichloromethane to provide l-(3-(morpholinomethyl)phenyl)-3-(4- nitrophenyl)urea which was dissolved in dichloromethane (30 mL), cooled in an ice bath, and treated with TFA (1.8 rnL). The reaction mixture was stirred for 30 minutes at O 0 C and for 12 hours at ambient temperature, and concentrated three times from methanol/toluene.
  • This example was prepared as described in EXAMPLE 37 by substituting tert- butyl 3-aminobenzylcarbamate for tert-butyl 4-aminobenzylcarbamate in 37A and l-fluoro-3-isocyanatobenzene for l-isocyanato-3-methylbenzene in EXAMPLE 37B.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 4-trifluoromethyl-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3 -isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 1, 2-difluoromethyl-4-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3 -isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 4-chloro-2-fluoro-l -isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3 -isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 3-chloro-l-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3-isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 4-chloro-l-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3-isocyanatobenzene, respectively in EXAMPLE 1 G, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 4-difluoromethoxy-l-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3-isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 2,4-difluoro-l-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3-isocyanatobenzene, respectively in EXAMPLE IG, then reacting the product with EXAMPLE 12D as described in EXAMPLE IH.
  • EXAMPLE 61 8-amino-3-cyclopropyl-N-(4-((((2-fluorophenyl)amino)carbonyl)amino)-3- methylphenyl)imidazo[ 1 ,5-a]pyrazine- 1 -carboxamide
  • the title compound was prepared as described in EXAMPLES IG- IH by substituting l-fluoro-2-isocyanatobenzene and tert-butyl 4-amino-3- methylphenylcarbamate for l-fluoro-3 -isocyanatobenzene and (4- aminophenyl)carbamic acid tert-butyl ester, respectively in EXAMPLE 1 G and EXAMPLE 54A for EXAMPLE IF in EXAMPLE IH.
  • EXAMPLE 70 8-amino-N-(3-(((((3-chlorophenyl)amino)carbonyl)amino)methyl)phenyl)-3- cy clopropy limidazo [ 1 , 5 -ajpyrazine- 1 -carboxamide
  • the title compound was prepared as described in EXAMPLE 37B by substituting l-chloro-3-isocyanatobenzene and EXAMPLE 68A for l-isocyanato-3- methylbenzene and EXAMPLE 37A, respectively.
  • EXAMPLE 71 8-amino-N-(3-(((((4-chlorophenyl)amino)carbonyl)amino)methyl)phenyl)-3- cy clopropy limidazo [ 1 , 5 -ajpyrazine- 1 -carboxamide
  • the title compound was prepared as described in EXAMPLE 37B by substituting l-chloro-4-isocyanatobenzene and EXAMPLE 68A for l-isocyanato-3- methylbenzene and EXAMPLE 37A, respectively.
  • the title compound was prepared by substituting tert-butyl 3- (aminomethyl)phenylcarbamate and 4-trifluoromethyl-isocyanatobenzene for (4- aminophenyl)carbamic acid tert-butyl ester and l-fluoro-3-isocyanatobenzene, respectively in EXAMPLE 1 G, then reacting the product with EXAMPLE 74D as described in EXAMPLE IH.
  • EXAMPLE 75 8-amino-N-(3-(((((4-chloro-2-fluorophenyl)amino)carbonyl)amino)methyl)phenyl)-3- (3-(ethyl(2-hydroxyethyl)amino)-3-oxopropyl)imidazo[ 1 ,5-a]pyrazine- 1 -carboxamide

Abstract

L'invention concerne des composés de formule (I) qui inhibent des kinases Aurora, des compositions contenant ces composés et des procédés de traitement de maladies au moyen de ces composés.
PCT/US2008/063189 2007-05-09 2008-05-09 Composés hétérocycliques condensés utilisés en tant qu'inhibiteurs de protéines kinases WO2008141140A1 (fr)

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WO2009136966A1 (fr) * 2008-05-09 2009-11-12 Abbott Laboratories Inhibiteurs de protéine kinases
WO2014052669A1 (fr) * 2012-09-26 2014-04-03 The Regents Of The University Of California Modulation de ire1

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WO2005097800A1 (fr) * 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
WO2007041712A1 (fr) * 2005-10-06 2007-04-12 Schering Corporation Pyrazolopyrimidines en tant qu’inhibiteurs de protéines kinases
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WO2007064993A2 (fr) * 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
WO2007087395A2 (fr) * 2006-01-25 2007-08-02 Osi Pharmaceuticals, Inc. INHIBITEURS DE mTOR INSATURES
WO2007106503A2 (fr) * 2006-03-13 2007-09-20 Osi Pharmaceuticals, Inc. Traitement combiné avec un inhibiteur de kinase egfr et un agent sensibilisant les cellules tumorales aux effets des inhibiteurs de kinase egfr

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WO2005037836A2 (fr) * 2003-10-15 2005-04-28 Osi Pharmaceuticals, Inc. Imidazopyrazines utilisees comme inhibiteurs de la tyrosine kinase
WO2005097800A1 (fr) * 2004-04-02 2005-10-20 Osi Pharmaceuticals, Inc. Inhibiteurs de la proteine kinase heterobicycliques a substitution de noyau bicyclique 6,6
WO2007041712A1 (fr) * 2005-10-06 2007-04-12 Schering Corporation Pyrazolopyrimidines en tant qu’inhibiteurs de protéines kinases
WO2007061737A2 (fr) * 2005-11-17 2007-05-31 Osi Pharmaceuticals, Inc. INHIBITEURS mTOR BICYCLIQUES CONDENSES
WO2007064993A2 (fr) * 2005-12-02 2007-06-07 Osi Pharmaceuticals, Inc. Inhibiteurs bicycliques de la proteine kinase
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WO2007106503A2 (fr) * 2006-03-13 2007-09-20 Osi Pharmaceuticals, Inc. Traitement combiné avec un inhibiteur de kinase egfr et un agent sensibilisant les cellules tumorales aux effets des inhibiteurs de kinase egfr

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009136966A1 (fr) * 2008-05-09 2009-11-12 Abbott Laboratories Inhibiteurs de protéine kinases
WO2014052669A1 (fr) * 2012-09-26 2014-04-03 The Regents Of The University Of California Modulation de ire1
CN104995192A (zh) * 2012-09-26 2015-10-21 加利福尼亚大学董事会 Ire1的调节
US10131668B2 (en) 2012-09-26 2018-11-20 The Regents Of The University Of California Substituted imidazo[1,5-a]pYRAZINES for modulation of IRE1
US10822340B2 (en) 2012-09-26 2020-11-03 The Regents Of The University Of California Substituted imidazolopyrazine compounds and methods of using same
US11613544B2 (en) 2012-09-26 2023-03-28 The Regents Of The University Of California Substituted imidazo[1,5-a]pyrazines for modulation of IRE1

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