JP5498703B2 - プロテインキナーゼのインヒビターとして有用なチオフェン−カルボキサミド - Google Patents
プロテインキナーゼのインヒビターとして有用なチオフェン−カルボキサミド Download PDFInfo
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- JP5498703B2 JP5498703B2 JP2008551474A JP2008551474A JP5498703B2 JP 5498703 B2 JP5498703 B2 JP 5498703B2 JP 2008551474 A JP2008551474 A JP 2008551474A JP 2008551474 A JP2008551474 A JP 2008551474A JP 5498703 B2 JP5498703 B2 JP 5498703B2
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- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical class CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229940066842 petrolatum Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- 229950010765 pivalate Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 230000006595 positive regulation of spindle checkpoint Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
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- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 230000035945 sensitivity Effects 0.000 description 1
- 208000015891 sexual disease Diseases 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
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- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 201000002314 small intestine cancer Diseases 0.000 description 1
- AWUCVROLDVIAJX-GSVOUGTGSA-N sn-glycerol 3-phosphate Chemical compound OC[C@@H](O)COP(O)(O)=O AWUCVROLDVIAJX-GSVOUGTGSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 230000020347 spindle assembly Effects 0.000 description 1
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
- 229910000080 stannane Inorganic materials 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
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- 238000007920 subcutaneous administration Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
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- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- 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
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、プロテインキナーゼのインヒビターとして有用な化合物に関する。本発明はまた、本発明の化合物を含む薬学的に受容可能な組成物、および様々な障害の処置に該組成物を使用する方法を提供する。本発明はまた、本発明の化合物を調製するための方法を提供する。
近年、酵素および疾患に関連する他の生体分子の構造の、より優れた理解によって、新規の治療剤の探索は大いに助けられている。集中的な研究の対象であった1つの重要なクラスの酵素は、プロテインキナーゼである。
Hardie,GおよびHanks,S.、The Protein Kinase Facts Book、I and II、Academic Press、San Diego、CA、1995年 Hanks,S.K.、Hunter,T.、FASEB J.、1995年、第9巻、p.576−596 Knightonら、Science、1991年、第253巻、p.407−414 Hilesら、Cell、1992年、第70巻、p.419−429 Kunzら、Cell、1993年、第73巻、p.585−596 Garcia−Bustosら、EMBO J、1994年、第13巻、p.2352−2361 Lowery DMら、Oncogene、2005年、第24巻、p.248−259 Hamanaka,Rら、J Biol Chem、1995年、第270巻、p.21086−21091 Macmillan,JCら、Ann Surg Oncol、2001年、第8巻、p.729−740 Smith,MRら、Biochem Blophys Res Commun、1997年、第234巻、p.397−405 Guan,Rら、Cancer Res、2005年、第65巻、p.2698−2704 Liu,Xら、Proc Natl Acad Sci U S A、2003年、第100巻、p.5789−5794 Fan,Yら、World J Gastroenterol、2005年、第11巻、p.4596−4599 Lane,HAら、J Cell Biol、1996年、第135巻、p.1701−1713 Ma,Sら、Mol Cell Biol、2003年、第23巻、p.6936−6943 Burns TFら、Mol Cell Biol、2003年、第23巻、p.5556−5571 Weichert,Wら、Br J Cancer、2004年、第90巻、p.815−821 Weichert,Wら、Virchows Arch、2005年、第446巻、p.442−450 Li,Zら、J Biol Chem、2005年、第280巻、p.16843−16850 Li,Jら、Neoplasia、2005年、第7巻、p.312−323 Hudson,JWら、Current Biology、2001年、第11巻、p.441−446
本発明の化合物およびその薬学的に受容可能な組成物は、プロテインキナーゼのインヒビターとして有効である。ある実施形態では、これらの化合物は、PLKプロテインキナーゼのインヒビターとして有効であり、ある実施形態では、PLK1プロテインキナーゼのインヒビターとして有効である。これらの化合物は、本明細書で定義する通りの式Iを有するか、またはその薬学的に受容可能な塩である。
本発明は、式I:
R1は、H、C1〜6脂肪族、またはC3〜6脂環式化合物であり;
Gは、−C(R)2−または−O−であり;
Lは、0個〜3個のJLで必要に応じて置換されたC0−3脂肪族であり;
環Aは、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜6員の芳香族単環式環であり;環Aは、0個〜3個のJAで必要に応じて置換されており;環Aは、環A’と縮合しており;
環A’は、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜8員の芳香族単環式環または非芳香族単環式環であり;環A’は、0個〜4個のJA’で必要に応じて置換されており;
環Bは、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜6員の芳香族単環式環であり;環Bは、0個〜5個のJBで必要に応じて置換されており、環B’と必要に応じて縮合されており;
環B’は、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜8員の芳香族単環式環または非芳香族単環式環であり;環B’は、0個〜4個のJB’で必要に応じて置換されており;
JA、JA’、JB、およびJB’はそれぞれ、独立して、C1〜6ハロアルキル、ハロ、NO2、CN、Q、または−Z−Qであり;
Zは、独立して、0個〜3個の−NR−、−O−、−S−、−C(O)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−の存在で必要に応じて割り込まれたC1〜6脂肪族であり;Zはそれぞれ、0個〜2個のJZで必要に応じて置換されており;
Qは、H;C1〜6脂肪族;O、N、およびSから独立して選択される0個〜3個のヘテロ原子を有する3員〜8員の芳香族単環式環または非芳香族単環式環;あるいはO、N、およびSから独立して選択される0個〜5個のヘテロ原子を有する8員〜12員の芳香族二環式環系または非芳香族二環式環系であり;Qはそれぞれ、0個〜5個のJQで必要に応じて置換されており;
JLおよびJZはそれぞれ、独立して、H、ハロ、C1〜6脂肪族、C3〜6脂環式化合物、NO2、CN、−NH2、−NH(C1〜4脂肪族)、−N(C1〜4脂肪族)2、−OH、−O(C1〜4脂肪族)、−CO2H、−CO2(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、またはハロ(C1〜4脂肪族)であり;
JQはそれぞれ、独立して、Mまたは−Y−Mであり;
Yはそれぞれ、独立して、0個〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−の存在で必要に応じて割り込まれた非置換のC1〜6脂肪族であり;
Mはそれぞれ、独立して、H、C1〜6脂肪族、C3〜6脂環式化合物、ハロ(C1〜4脂肪族)、−O(ハロC1〜4脂肪族)、C3〜6ヘテロシクリル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CONH2、CONHR’、C0NR’2、NHCOR’、NR’COR’、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、またはNR’SO2R’であり;
Rは、Hまたは非置換のC1〜6脂肪族であり;
R’は、非置換のC1〜6脂肪族であるか;または2個のR’基は、それらが結合されている原子と一緒になって、O、N、およびSから独立して選択される0個〜1個のヘテロ原子を有する非置換の3員〜8員の非芳香族単環式環を形成するが;
環A’と縮合される環Aが
の化合物を記載する。
PG 保護基
LG 脱離基
DCM ジクロロメタン
Ac アセチル
PdCl2(PPh3)2 ジクロロビス(トリフェニルホスフィン)パラジウム(II)
Pd(PPh3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
PdCl2(dppf) ジクロロ[1,1’−フェロセニルビス(ジフェニル―ホスフィン)]パラジウム(II)
TMS トリメチルシリル
TMSI トリメチルシリルヨージド
TMSCl トリメチルシリルクロリド
DMF ジメチルホルムアミド
EtOAc 酢酸エチル
DMSO ジメチルスルホキシド
MeCN アセトニトリル
TFA トリフルオロ酢酸
TCA トリクロロ酢酸
ATP アデノシン三リン酸
EtOH エタノール
Ph フェニル
Me メチル
Et エチル
Bu ブチル
DEAD ジエチルアゾジカルボキシレート
HEPES 4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸
BSA ウシ血清アルブミン
DTT ジチオスレイトール
MOPS 4−モルホリンプロパンスルホン酸
NMR 核磁気共鳴
HPLC 高速液体クロマトグラフィ
LCMS 液体クロマトグラフィ−質量分析
TLC 薄層クロマトグラフィ
Rt 保持時間
本発明のある実施形態では、Gは、−C(R)2−である。他の実施形態では、Gは、Oである。
本発明の化合物は、一般に、以下の一般的なスキーム、およびそれに続く調製のための実施例に記載したものなどの方法によって調製することができる。特に明記しない限り、以下のスキーム中のすべての変数は、本明細書で定義する通りである。
の化合物を調製するための方法であって、式Iの化合物を形成するために適切なアミド形成条件下で、式5:
の化合物を反応させることを含む方法を提供する。適切なアミド形成条件は、当業者に知られており、「March’s Advanced Organic Chemistry」に見出され得る。適切なアミド形成条件の例としては、それだけには限らないが、NH3/MeOHの存在下でカルボン酸メチルを加熱することが挙げられる。
の化合物を、式i:
の化合物と、適切なクロスカップリング条件下でカップリングさせて式5の化合物を形成する工程をさらに含む。
の化合物を、式5a:
の化合物を形成するために適したカップリング基形成条件下で、カップリング基前駆体とカップリングさせる工程をさらに含む。カップリング基前駆体は、クロスカップリング基を形成するために使用される試薬または試薬の基である。その例としては、それだけには限らないが、ボロン酸エステルの形成のためのビス(ピナコラート)ジボラン、ボロン酸の形成のためのホウ酸トリメチル、スタンナンの形成のためのBu3SnCl、および亜鉛酸塩の形成のためのZnCl2が挙げられる。Negishiカップリング反応における適切なカップリング基形成条件の例としては、それだけには限らないが、パラジウム媒介性触媒反応を介してボロン酸エステルを作製すること;ボロン酸エステルを加水分解することによってボロン酸を作製すること;2工程のプロセス:1)ハロゲン金属交換、それに続く2)Bu3SnClを用いる金属交換反応、を介してスタンナンを作製すること;および2工程のプロセス:1)ハロゲン金属交換、それに続く2)ZnCl2の付加、を介して亜鉛酸塩を作製することが挙げられる。
と、L、環A、環B、JA、およびJBが、本明細書で定義する通りである式5の化合物を形成するために適切なクロスカップリング条件下でカップリングさせる工程をさらに含む。
の化合物を、
と、式4の化合物を形成するために適切なO−C結合カップリング条件下でカップリングさせる工程をさらに含む。適切な脱離基としては、それだけには限らないが、ハロ、メシラート、およびトシラートが挙げられる。あるいは、LGは、Mitsunobu反応においてOHなどの基からインサイチュで産生することができる。適切なO−C結合カップリング反応としては、それだけには限らないが、Mitsunobu反応(DEAD/PPh3/THF)およびKOtBu、NaH、またはLiAlH4などの強塩基を用いる単純なアルキル化が挙げられる。
の化合物を調製するための方法であって、式:
と、式5の化合物を形成するために適切なO−C結合カップリング条件下で反応させることを含む方法を提供する。
a)式2:
の化合物と、適切なクロスカップリング条件下でカップリングさせて、式6:
b)式7の化合物を形成するために適切な脱保護条件下で、式6の化合物を脱保護する工程;と
をさらに含む。適切な脱保護条件の例としては、それだけには限らないが、BBr3、TMSI、TMSCl+NaI、および塩酸ピリジニウムが挙げられる。
a)式2:
の化合物を形成するために適切なカップリング基形成条件下で、カップリング基前駆体とカップリングさせる工程;と
b)式5bの化合物を、
とカップリングさせて、式6:
をさらに含む。
を、式8:
を調製するための方法を提供する。
カラム:ACE C8カラム、4.6×150mm
勾配:0〜100%アセトニトリル+メタノール60:40(20mM Trisリン酸)
流速:1.5mL/分
検出:225nm。
3−[1−(2−クロロ−フェニル)−エトキシ]−5−イミダゾ[1,2−a]ピリジン−3−イル−チオフェン−2−カルボキサミド(I−1)
方法B:5−ブロモ−3−ヒドロキシ−チオフェン−2−カルボン酸メチルエステル(中間体2)
方法C:5−ブロモ−3−[1−(2−クロロ−フェニル)−エトキシ]−チオフェン−2−カルボン酸メチルエステル(中間体3)
方法D:3−[1−(2−クロロ−フェニル)−エトキシ]−5−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−チオフェン−2−カルボン酸メチルエステル(中間体4)
3−[1−(2−クロロ−フェニル)−エトキシ]−5−(4,4,5,5−テトラメチル−[1,3,2]ジオキサボロラン−2−イル)−チオフェン−2−カルボン酸メチルエステル(中間体4)を調製する別の方法は、方法EおよびFを介する。
方法F:3−(1−(2−クロロフェニル)エトキシ)−5−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)チオフェン−2−カルボン酸メチル(中間体4)
方法G:3−[1−(2−クロロ−フェニル)−エトキシ]−5−イミダゾ[1,2−a]ピリジン−3−イル−チオフェン−2−カルボン酸メチルエステル(中間体6)
方法H:3−[1−(2−クロロ−フェニル)−エトキシ]−5−イミダゾ[1,2−a]ピリジン−3−イル−チオフェン−2−カルボキサミド(I−1)
実施例2
3−[1−(2−クロロ−フェニル)−エトキシ]−5−ピラゾロ[1,5−a]ピリジン−3−イル−チオフェン−2−カルボキサミド(I−2)
実施例3
3−(1−(2−クロロフェニル)エトキシ)−5−(6−アミノ−[1,2,4]トリアゾロ[4,3−b]ピリダジン−3−イル)チオフェン−2−カルボキサミド)(I−4)
実施例4
3−[1−(2−クロロ−フェニル)−エトキシ]−5−(1H−ピロロ[2,3−b]ピリジン−5−イル)−チオフェン−2−カルボキサミド(I−5)
3−[1−(2−クロロ−フェニル)−エトキシ]−5−(1H−ピロロ[2,3−b]ピリジン−5−イル)−チオフェン−2−カルボキサミド I−5
3−[1−(2−クロロ−フェニル)−エトキシ]−5−(5−メトキシ−1H−ピロロ[2,3−b]ピリジン−3−イル)−チオフェン−2−カルボキサミド(I−3)
実施例6
3−(1−(2−クロロフェニル)エトキシ)−5−(5−ビニル−1H−ピロロ[2,3−b]ピリジン−3−イル)チオフェン−2−カルボキサミド(I−6)
実施例7
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)−N−メチルイミダゾ[1,2−a]ピリジン−6−カルボキサミド(I−7)
3−(1−(2−クロロフェニル)エトキシ)−5−(6−フルオロイミダゾ[1,2−a]ピリジン−3−イル)チオフェン−2−カルボキサミド(I−8)
3−(1−(2−クロロフェニル)エトキシ)−5−(イミダゾ[1,2−a]ピラジン−3−イル)チオフェン−2−カルボキサミド(I−9)
3−(1−(2−クロロフェニル)エトキシ)−5−(6−(トリフルオロメチル)イミダゾ[1,2−a]ピリジン−3−イル)チオフェン−2−カルボキサミド(I−10)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)−N−メチルイミダゾ[1,2−a]ピリジン−7−カルボキサミド(I−11)
3−(1−(2−クロロフェニル)エトキシ)−5−(イミダゾ[1,2−b]ピリダジン−3−イル)チオフェン−2−カルボキサミド(I−12)
3−(1−(2−クロロフェニル)エトキシ)−5−(7−(トリフルオロメチル)イミダゾ[1,2−a]ピリジン−3−イル)チオフェン−2−カルボキサミド(I−13)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸エチル(I−14)
5−(7−アミノイミダゾ[1,2−a]ピリジン−3−イル)−3−(1−(2−クロロフェニル)エトキシ)チオフェン−2−カルボキサミド(I−15)
3−(1−(2−クロロフェニル)エトキシ)−5−(イミダゾ[1,2−a]ピリジン−3−イル)−N−メチルチオフェン−2−カルボキサミド(I−16)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イル(メチル)カルバミン酸エチル(I−17)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イル(メチル)カルバミン酸メチル(I−18)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(S)−メチル(I−19)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(S)−エチル(I−20)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)プロポキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(S)−メチル(I−21)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)プロポキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(S)−エチル(I−22)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(R)−メチル(I−23)
3−(5−カルバモイル−4−(1−(2−クロロフェニル)エトキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸(R)−エチル(I−24)
3−(5−カルバモイル−4−(2−(2−クロロフェニル)プロパン−2−イルオキシ)チオフェン−2−イル)イミダゾ[1,2−a]ピリジン−7−イルカルバミン酸エチル(I−25)
本発明の化合物を、以下のアッセイを使用して、ヒトPLKキナーゼのインヒビターとして評価する。
化合物を、放射性−リン酸取り込みアッセイを使用して、Plk1を阻害するその能力についてスクリーニングした。アッセイは、25mM HEPES(pH7.5)、10mM MgCl2、および1mM DTTの混合物中で実施した。最終の基質濃度は、50μM[γ−33P]ATP(136mCi 33P ATP/mmol ATP、Amersham Pharmacia Biotech/Sigma Chemicals)、および10μMペプチド(SAM68タンパク質Δ332−443)であった。アッセイは、15nM Plk1(A20−K338)の存在下で、25℃で実施した。ATPおよび目的の試験化合物を除く、上で列挙した試薬のすべてを含有するアッセイストック緩衝液を調製した。30μLのストック溶液を96ウェルプレートに入れ、次いで、試験化合物の連続希釈物(代表的に、10μMの最終濃度から開始する2倍連続希釈)を含有する2μLのDMSOストックを二連で添加した(最終のDMSO濃度5%)。プレートを、25℃で10分間にわたってプレインキュベートし、8μL[γ−33P]ATP(最終濃度50μM)を添加することによって、反応を開始した。
化合物を、放射性−リン酸取り込みアッセイを使用して、Plk1を阻害するその能力についてスクリーニングした。アッセイは、25mM HEPES(pH7.5)、10mM MgCl2、0.1% BSA、および2mM DTTの混合物中で実施した。最終の基質濃度は、100μM[γ−33P]ATP(115mCi 33P ATP/mmol ATP、Amersham Pharmacia Biotech/Sigma Chemicals)、および300μMペプチド(KKKISDELMDATFADQEAK)であった。アッセイは、25nM Plk1の存在下で25℃で実施した。ATPおよび目的の試験化合物を除く、上で列挙した試薬のすべてを含有するアッセイストック緩衝液を調製した。30μLのストック溶液を96ウェルプレートに入れ、次いで、試験化合物の連続希釈物(代表的に、10μMの最終濃度から開始する2倍連続希釈)を含有する2μLのDMSOストックを二連で添加した(最終のDMSO濃度5%)。プレートを、25℃で10分間にわたってプレインキュベートし、8μL[γ−33P]ATP(最終濃度100μM)を添加することによって、反応を開始した。
化合物を、放射性−リン酸取り込みアッセイを使用して、Plk2を阻害するその能力についてスクリーニングした。アッセイは、25mM HEPES(pH7.5)、10mM MgCl2、0.1% BSA、および2mM DTTの混合物中で実施した。最終の基質濃度は、200μM[γ−33P]ATP(57mCi 33P ATP/mmol ATP、Amersham Pharmacia Biotech/Sigma Chemicals)、および300μMペプチド(KKKISDELMDATFADQEAK)であった。アッセイは、25nM Plk2の存在下で25℃で実施した。ATPおよび目的の試験化合物を除く、上で列挙した試薬のすべてを含有するアッセイストック緩衝液を調製した。30μLのストック溶液を96ウェルプレートに入れ、次いで、試験化合物の連続希釈物(代表的に、10μMの最終濃度から開始する2倍連続希釈)を含有する2μLのDMSOストックを二連で添加した(最終のDMSO濃度5%)。プレートを、25℃で10分間にわたってプレインキュベートし、8μL[γ−33P]ATP(最終濃度200μM)を添加することによって、反応を開始した。
化合物を、放射性−リン酸取り込みアッセイを使用して、Plk3を阻害するその能力についてスクリーニングした。アッセイは、25mM HEPES(pH7.5)、10mM MgCl2、および1mM DTTの混合物中で実施した。最終の基質濃度は、75μM[γ−33P]ATP(60mCi 33P ATP/mmol ATP、Amersham Pharmacia Biotech/Sigma Chemicals)、および10μMペプチド(SAM68タンパク質Δ332−443)であった。アッセイは、5nM Plk3(S38−A340)の存在下で25℃で実施した。ATPおよび目的の試験化合物を除く、上で列挙した試薬のすべてを含有するアッセイストック緩衝液を調製した。30μLのストック溶液を96ウェルプレートに入れ、次いで、試験化合物の連続希釈物(代表的に、10μMの最終濃度から開始する2倍連続希釈)を含有する2μLのDMSOストックを二連で添加した(最終のDMSO濃度5%)。プレートを、25℃で10分間にわたってプレインキュベートし、8μL[γ−33P]ATP(最終濃度75μM)を添加することによって、反応を開始した。
化合物を、放射性−リン酸取り込みアッセイを使用して、Plk4を阻害するその能力についてスクリーニングする。アッセイは、8mM MOPS(pH7.5)、10mM MgCl2、0.1% BSA、および2mM DTTの混合物中で実施する。最終の基質濃度は、15μM[γ−33P]ATP(227mCi 33P ATP/mmol ATP、Amersham Pharmacia Biotech/Sigma Chemicals)および300μMペプチド(KKKMDATFADQ)である。アッセイは、25nM Plk4の存在下で25℃で実施する。ATPおよび目的の試験化合物を除く、上で列挙した試薬のすべてを含有するアッセイストック緩衝液を調製する。30μLのストック溶液を96ウェルプレートに入れ、次いで、試験化合物の連続希釈物(代表的に、10μMの最終濃度から開始する2倍連続希釈)を含有する2μLのDMSOストックを二連で添加する(最終のDMSO濃度5%)。プレートを、25℃で10分間にわたってプレインキュベートし、8μL[γ−33P]ATP(最終濃度15μM)を添加することによって、反応を開始する。
Claims (34)
- 式I:
R1は、H、C1〜6アルキル、アルケニルもしくはアルキニル、またはC3〜6シクロアルキル、シクロアルケニルもしくはシクロアルキニルであり;
Gは、−C(R)2−または−O−であり;
Lは、0個〜3個のJLで必要に応じて置換されたC0〜3アルキル、アルケニルもしくはアルキニルであり;
環Aは、環A’と縮合されており;環A−A’が、以下:
環Bは、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜6員の芳香族単環式環であり;環Bは、0個〜5個のJBで必要に応じて置換されており、環B’と必要に応じて縮合されており;
環B’は、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜8員の芳香族単環式環または非芳香族単環式環であり;環B’は、0個〜4個のJB’で必要に応じて置換されており;
JA、JB、およびJB’はそれぞれ、独立して、C1〜6ハロアルキル、ハロ、NO2、CN、Q、または−Z−Qであり;
JA’ はそれぞれ、独立して、−NHC(O)R、H,−CF2またはハロであり;
Zは、独立して、0個〜3個の−NR−、−O−、−S−、−C(O)−、−C(=NR)−、−C(=NOR)−、−SO−、または−SO2−の存在で必要に応じて割り込まれたC1〜6アルキル、アルケニルもしくはアルキニルであり、Zはそれぞれ、0個〜2個のJZで必要に応じて置換されており;
Qは、H;C1〜6アルキル、アルケニルもしくはアルキニル;O、N、およびSから独立して選択される0個〜3個のヘテロ原子を有する3員〜8員の芳香族単環式環または非芳香族単環式環;あるいはO、N、およびSから独立して選択される0個〜5個のヘテロ原子を有する8員〜12員の芳香族二環式環系または非芳香族二環式環系であり;Qはそれぞれ、0個〜5個のJQで必要に応じて置換されており;
JLおよびJZはそれぞれ、独立して、H、ハロ、C1〜6アルキル、アルケニルもしくはアルキニル、C3〜6シクロアルキル、シクロアルケニルもしくはシクロアルキニル、NO2、CN、−NH2、−NH(C1〜4アルキル、アルケニルもしくはアルキニル)、−N(C1〜4アルキル、アルケニルもしくはアルキニル)2、−OH、−O(C1〜4アルキル、アルケニルもしくはアルキニル)、−CO2H、−CO2(C1〜4アルキル、アルケニルもしくはアルキニル)、−O(ハロC1〜4アルキル、アルケニルもしくはアルキニル)、またはハロ(C1〜4アルキル、アルケニルもしくはアルキニル)であり;
JQはそれぞれ、独立して、Mまたは−Y−Mであり;
Yはそれぞれ、独立して、0個〜3個の−NR−、−O−、−S−、−C(O)−、−SO−、または−SO2−の存在で必要に応じて割り込まれた非置換のC1〜6アルキル、アルケニルもしくはアルキニルであり;
Mはそれぞれ、独立して、H、C1〜6アルキル、アルケニルもしくはアルキニル、C3〜6シクロアルキル、シクロアルケニルもしくはシクロアルキニル、ハロ(C1〜4アルキル、アルケニルもしくはアルキニル)、−O(ハロC1〜4アルキル、アルケニルもしくはアルキニル)、C3〜6ヘテロシクリル、ハロ、NO2、CN、OH、OR’、SH、SR’、NH2、NHR’、N(R’)2、COH、COR’、CONH2、CONHR’、CONR’2、NHCOR’、NR’COR’、NHCONH2、NHCONHR’、NHCON(R’)2、SO2NH2、SO2NHR’、SO2N(R’)2、NHSO2R’、またはNR’SO2R’であり;
Rは、Hまたは非置換のC1〜6アルキル、アルケニルもしくはアルキニルであり;
R’は、非置換のC1〜6アルキル、アルケニルもしくはアルキニルであるか;または2個のR’基は、それらが結合されている原子と一緒になって、O、N、およびSから独立して選択される0個〜1個のヘテロ原子を有する非置換の3員〜8員の非芳香族単環式環を形成し、ただし、環A−A’が
の化合物またはその薬学的に受容可能な塩。 - Gが、−C(R)2−である、請求項1に記載の化合物またはその薬学的に受容可能な塩。
- Gが、Oである、請求項1に記載の化合物またはその薬学的に受容可能な塩。
- R1が、Hである、請求項1から3のいずれか1項に記載の化合物またはその薬学的に受容可能な塩。
- 環A−A’が、
- 環Bが、0個〜2個の窒素原子を含有する6員の芳香環である、請求項1から5のいずれか1項に記載の化合物またはその薬学的に受容可能な塩。
- 環Bが、環B’と縮合されている、請求項1から5のいずれか1項に記載の化合物またはその薬学的に受容可能な塩。
- 環B’が、O、N、およびSから選択される0個〜3個のヘテロ原子を含有する5員〜6員の芳香環である、請求項7に記載の化合物またはその薬学的に受容可能な塩。
- JA’が、−NHCORであり、Rが、C1〜6アルキルである、請求項1に記載の化合物またはその薬学的に受容可能な塩。
- 前記アルキルが、メチルである、またはエチルである、請求項9に記載の化合物またはその薬学的に受容可能な塩。
- JBが、H、C1〜6アルキル、アルケニルもしくはアルキニル、C3〜6シクロアルキル、シクロアルケニルもしくはシクロアルキニル、ハロ(C1〜4アルキル、アルケニルもしくはアルキニル)、−O(ハロC1〜4アルキル、アルケニルもしくはアルキニル)、C3〜6ヘテロシクリル、ハロ、NO2、CN、OH、OR、SH、SR、NH2、NHR、N(R)2、COH、COR、CONH2、CONHR、CONR2、NHCOR、NRCOR、NHCONH2、NHCONHR、NHCON(R)2、SO2NH2、SO2NHR、SO2N(R)2、NHSO2R、またはNRSO2Rであり、そしてJB’が、H、C1〜6アルキル、アルケニルもしくはアルキニル、C3〜6シクロアルキル、シクロアルケニルもしくはシクロアルキニル、ハロ(C1〜4アルキル、アルケニルもしくはアルキニル)、−O(ハロC1〜4アルキル、アルケニルもしくはアルキニル)、C3〜6ヘテロシクリル、ハロ、NO2、CN、OH、OR、SH、SR、NH2、NHR、N(R)2、COH、COR、CONH2、CONHR、CONR2、NHCOR、NRCOR、NHCONH2、NHCONHR、NHCON(R)2、SO2NH2、SO2NHR、SO2N(R)2、NHSO2R、またはNRSO2Rである、請求項1から10のいずれか1項に記載の化合物またはその薬学的に受容可能な塩。
- 以下の化合物:
- 請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩と、薬学的に受容可能なキャリア、佐剤、またはビヒクルとからなる、組成物。
- 患者におけるプロテインキナーゼ活性を阻害するための組成物であって、
a)請求項13に記載の組成物;または
b)請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩;
を含む、組成物。 - 生物学的サンプルにおけるプロテインキナーゼ活性を阻害するエキソビボの方法であって、
a)請求項13に記載の組成物;または
b)請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩;
と該生物学的サンプルとを接触させる工程を含む、エキソビボの方法。 - 前記プロテインキナーゼが、PLKである、請求項15に記載の方法。
- 前記プロテインキナーゼが、PLK1である、請求項16に記載の方法。
- 患者における増殖性障害、神経変性障害、自己免疫障害、炎症性障害または免疫媒介性障害を処置するための組成物であって、
a)請求項13に記載の組成物;または
b)請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩;
を含む、組成物。 - 前記組成物が、化学療法剤または抗増殖性薬剤、抗炎症剤、免疫調節剤または免疫抑制剤、神経栄養因子、心臓血管疾患を処置するための薬剤、破壊性骨障害を処置するための薬剤、肝疾患を処置するための薬剤、抗ウイルス剤、血液障害を処置するための薬剤、糖尿病を処置するための薬剤、あるいは免疫欠損障害を処置するための薬剤から選択されるさらなる治療剤と組み合わせて投与されることを特徴する、請求項14または請求項18に記載の組成物であって、
該さらなる治療剤は、処置される疾患に適切であり;そして
該さらなる治療剤が、複数回用投薬形態の一部として該組成物とは別個に投与されることを特徴とする、組成物。 - 患者における黒色腫、骨髄腫、白血病、リンパ腫、神経芽細胞腫、あるいは大腸、乳房、胃、卵巣、子宮頸部、肺、中枢神経系(CNS)、腎臓、前立腺、膀胱、または膵臓から選択される癌を処置するための組成物であって、
a)請求項13に記載の組成物;または
b)請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩;
を含む、組成物。 - 患者における癌を処置するための組成物であって、
a)請求項13に記載の組成物;または
b)請求項1から12のいずれか1項に記載の化合物またはその薬学的に受容可能な塩;
を含む、組成物。 - 前記組成物は、PLKを阻害することによって癌細胞の有糸分裂を途絶させる、請求項21に記載の組成物。
- 式I:
の化合物を調製するための方法であって、式5:
の化合物を、式Iの化合物を形成するために適切なアミド形成条件下で反応させる工程を含む、方法。 - 式4;
の化合物と、式i;
の化合物とを、式5の化合物を形成するために適切なクロスカップリング条件下でカップリングさせる工程をさらに含む、請求項23に記載の方法。 - 式4;
の化合物を、カップリング基前駆体と、適切なカップリング基形成条件下でカップリングさせて、式5a:
の化合物を形成する工程をさらに含む、請求項23に記載の方法。 - 式5aの化合物を、式ii;
の化合物と、適切なクロスカップリング条件下でカップリングさせて、式5(式中、L、環A、環B、JA、およびJBは、請求項1から12のいずれか1項によって定義した通りである)の化合物を形成する工程をさらに含む、請求項25に記載の方法。 - 式3:
の化合物を、
と、適切なO−C結合カップリング条件下でカップリングさせて、式4の化合物を形成する工程をさらに含む、請求項24または請求項25に記載の方法。 - 式5:
Gは、Oであり、R1は、Hであり、環A、環B、JA、JB、およびLは、請求項1から12のいずれか1項によって定義した通りである)
の化合物を調製するための方法であって、式7:
と、適切なO−C結合カップリング条件下で反応させて、式5の化合物を形成する工程を含む、方法。 - a)式2:
の化合物と、適切なクロスカップリング条件下でカップリングさせて、式6:
b)式6の化合物を適切な脱保護条件下で脱保護して、式7の化合物を形成する工程;をさらに含む、請求項28に記載の方法。 - a)式2:
の化合物を形成する工程;
b)式5bの化合物を、
とカップリングさせて、式6:
c)式6の化合物を適切な脱保護条件下で脱保護して、式7の化合物を形成する工程;をさらに含む、請求項28に記載の方法。 - 式I:
の化合物を調製するための方法であって、式12a/b:
の化合物を、適切なボロナート化条件下で反応させて、式5aの化合物または式5a/b:
の化合物を形成する工程を含む、方法。 - 前記プロテインキナーゼが、PLKである、請求項14に記載の組成物。
- 前記プロテインキナーゼが、PLK1である、請求項32に記載の組成物。
- 前記組成物は、さらに、化学療法剤または抗増殖性薬剤、抗炎症剤、免疫調節剤または免疫抑制剤、神経栄養因子、心臓血管疾患を処置するための薬剤、破壊性骨障害を処置するための薬剤、肝疾患を処置するための薬剤、抗ウイルス剤、血液障害を処置するための薬剤、糖尿病を処置するための薬剤、あるいは免疫欠損障害を処置するための薬剤から選択されるさらなる治療剤を含む、請求項14または請求項18に記載の組成物であって、
該さらなる治療剤は、処置される疾患に適切であり;そして
該さらなる治療剤が、単一投薬形態として該組成物と一緒に投与されることを特徴とする、組成物。
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PE20070518A1 (es) | 2005-09-06 | 2007-06-12 | Smithkline Beecham Corp | Compuestos de tiofeno bencimidazol como agentes inhibidores de plk |
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US20070219205A1 (en) | 2007-09-20 |
AU2007208358A1 (en) | 2007-08-02 |
JP2013056942A (ja) | 2013-03-28 |
US7915305B2 (en) | 2011-03-29 |
EP1989205B1 (en) | 2012-06-13 |
EP2474546A1 (en) | 2012-07-11 |
EP1989205A2 (en) | 2008-11-12 |
CA2637335A1 (en) | 2007-08-02 |
WO2007087283A3 (en) | 2007-09-13 |
CN101400678A (zh) | 2009-04-01 |
US8759389B1 (en) | 2014-06-24 |
US8399478B2 (en) | 2013-03-19 |
JP2009523822A (ja) | 2009-06-25 |
WO2007087283A2 (en) | 2007-08-02 |
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