US20130324532A1 - Fak inhibitors - Google Patents
Fak inhibitors Download PDFInfo
- Publication number
- US20130324532A1 US20130324532A1 US13/985,812 US201213985812A US2013324532A1 US 20130324532 A1 US20130324532 A1 US 20130324532A1 US 201213985812 A US201213985812 A US 201213985812A US 2013324532 A1 US2013324532 A1 US 2013324532A1
- Authority
- US
- United States
- Prior art keywords
- mmol
- phenyl
- trifluoromethyl
- amino
- pyrimidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- OSRYXPPMXLKGKY-UHFFFAOYSA-N C#CC1=C(CC(=O)OC)C=CC=C1.CB(O)CC1CCNCC1.COC(=O)CC1=C(C#CC2=NC(CC3=CC=C(N4CCC(NBC=O)CC4)C=C3)=NC=C2C(F)(F)F)C=CC=C1.COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCC(NBC=O)CC3)C=C2)=NC=C1C(F)(F)F.FC(F)(F)C1=CN=C(Cl)N=C1Cl.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCC(NBC=O)CC3)C=C2)=NC=C1C(F)(F)F.NC1=CC=C(N2CCC(NBC=O)CC2)C=C1.O=CBNC1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1.O=CBNC1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.O=[N+]([O-])C1=CC=C(F)C=C1 Chemical compound C#CC1=C(CC(=O)OC)C=CC=C1.CB(O)CC1CCNCC1.COC(=O)CC1=C(C#CC2=NC(CC3=CC=C(N4CCC(NBC=O)CC4)C=C3)=NC=C2C(F)(F)F)C=CC=C1.COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCC(NBC=O)CC3)C=C2)=NC=C1C(F)(F)F.FC(F)(F)C1=CN=C(Cl)N=C1Cl.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCC(NBC=O)CC3)C=C2)=NC=C1C(F)(F)F.NC1=CC=C(N2CCC(NBC=O)CC2)C=C1.O=CBNC1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1.O=CBNC1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.O=[N+]([O-])C1=CC=C(F)C=C1 OSRYXPPMXLKGKY-UHFFFAOYSA-N 0.000 description 1
- YTVRNWBLHHASON-UHFFFAOYSA-N C#CC1=C(CC(=O)OC)C=CC=N1.COC(=O)CC1=C(C#CC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.COC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=C(CC(=O)O)C=CC=N4)=N3)C=C2)C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)C1 Chemical compound C#CC1=C(CC(=O)OC)C=CC=N1.COC(=O)CC1=C(C#CC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.COC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CCCN(BC=O)C4)C=C3)=NC=C2C(F)(F)F)N=CC=C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=C(CC(=O)O)C=CC=N4)=N3)C=C2)C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)C1 YTVRNWBLHHASON-UHFFFAOYSA-N 0.000 description 1
- ZRAGUXOJJZTNGA-UHFFFAOYSA-N C#CC1=C2C(=O)CCC2=CC=C1.CC1=C(C(=O)O)C(I)=CC=C1.CC1=C(C(=O)O)C=CC=C1.COC(=O)C1=C(C)C=CC=C1I.C[Si](C)(C)C#CC1=C2C(=O)CCC2=CC=C1.FC(F)(F)C1=CN=C(CC2=CC=C(N3CCCCC3)C=C2)N=C1Cl.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=C1CCC2=C1C(C#CC1=NC(CC3=CC=C(N4CCCCC4)C=C3)=NC=C1C(F)(F)F)=CC=C2.O=C1CCC2=C1C(CCC1=NC(CC3=CC=C(N4CCCCC4)C=C3)=NC=C1C(F)(F)F)=CC=C2.O=C1CCC2=CC=CC(I)=C12 Chemical compound C#CC1=C2C(=O)CCC2=CC=C1.CC1=C(C(=O)O)C(I)=CC=C1.CC1=C(C(=O)O)C=CC=C1.COC(=O)C1=C(C)C=CC=C1I.C[Si](C)(C)C#CC1=C2C(=O)CCC2=CC=C1.FC(F)(F)C1=CN=C(CC2=CC=C(N3CCCCC3)C=C2)N=C1Cl.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=C1CCC2=C1C(C#CC1=NC(CC3=CC=C(N4CCCCC4)C=C3)=NC=C1C(F)(F)F)=CC=C2.O=C1CCC2=C1C(CCC1=NC(CC3=CC=C(N4CCCCC4)C=C3)=NC=C1C(F)(F)F)=CC=C2.O=C1CCC2=CC=CC(I)=C12 ZRAGUXOJJZTNGA-UHFFFAOYSA-N 0.000 description 1
- MINXLUXQBHRBLW-UHFFFAOYSA-N C#CC1=CC(C(N)=O)=CC=C1.C[Si](C)(C)C#CC1=CC(C(N)=O)=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)C1=CC=CC(C#CC2=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=C1.NC(=O)C1=CC=CC(CCC2=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=C1.NC(=O)C1=CC=CC(I)=C1.O=C(O)C1=CC=CC(I)=C1.O=CBN1CCN(CC2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 Chemical compound C#CC1=CC(C(N)=O)=CC=C1.C[Si](C)(C)C#CC1=CC(C(N)=O)=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)C1=CC=CC(C#CC2=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=C1.NC(=O)C1=CC=CC(CCC2=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=C1.NC(=O)C1=CC=CC(I)=C1.O=C(O)C1=CC=CC(I)=C1.O=CBN1CCN(CC2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 MINXLUXQBHRBLW-UHFFFAOYSA-N 0.000 description 1
- VOJJXWVNELNFSK-UHFFFAOYSA-N C#CC1=CC=CC(C(=O)OC(C)(C)C)=C1.C#CC1=CC=CC(C(=O)OC)=C1.COC(=O)C1=CC(C#CC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.COC(=O)C1=CC(CCC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.COC(=O)C1=CC(CCC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 Chemical compound C#CC1=CC=CC(C(=O)OC(C)(C)C)=C1.C#CC1=CC=CC(C(=O)OC)=C1.COC(=O)C1=CC(C#CC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.COC(=O)C1=CC(CCC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.COC(=O)C1=CC(CCC2=NC(CC3=CC=C(N4CCN(BC=O)CC4)C=C3)=NC=C2C(F)(F)F)=CC=C1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 VOJJXWVNELNFSK-UHFFFAOYSA-N 0.000 description 1
- DVPRFLQBDAQADO-UHFFFAOYSA-M C#CC1=CC=CC=C1C(C)C(=O)OC.C#CC1=CC=CC=C1C(C)C(=O)OC.CC(C)(C)OC(=O)N1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.COC(=O)C(C)C1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)C(C)C1=CC=CC=C1C#C[Si](C)(C)C.COC(=O)C(C)C1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)CC1=CC=CC=C1C#C[Si](C)(C)C.II(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.[Li]OC(=O)C(C)C1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1 Chemical compound C#CC1=CC=CC=C1C(C)C(=O)OC.C#CC1=CC=CC=C1C(C)C(=O)OC.CC(C)(C)OC(=O)N1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.COC(=O)C(C)C1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)C(C)C1=CC=CC=C1C#C[Si](C)(C)C.COC(=O)C(C)C1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)CC1=CC=CC=C1C#C[Si](C)(C)C.II(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.[Li]OC(=O)C(C)C1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1 DVPRFLQBDAQADO-UHFFFAOYSA-M 0.000 description 1
- MTWIBPBUXCAKAM-UHFFFAOYSA-N C#CC1=CC=CC=C1CC(=O)OC.CC(C)(C)OC(=O)N1CC=C(C2=CC=C([N+](=O)[O-])C=C2)CC1.CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1.CC(C)(C)OC(=O)N1CCC(=O)CC1.CC(C)(C)OC(=O)N1CCC(C2=CC=C(N)C=C2)CC1.CC(C)(C)OC(=O)N1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)CC1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I Chemical compound C#CC1=CC=CC=C1CC(=O)OC.CC(C)(C)OC(=O)N1CC=C(C2=CC=C([N+](=O)[O-])C=C2)CC1.CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1.CC(C)(C)OC(=O)N1CCC(=O)CC1.CC(C)(C)OC(=O)N1CCC(C2=CC=C(N)C=C2)CC1.CC(C)(C)OC(=O)N1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.COC(=O)CC1=CC=CC=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(C(=O)OC(C)(C)C)CC3)C=C2)=N1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I MTWIBPBUXCAKAM-UHFFFAOYSA-N 0.000 description 1
- UOGNWWREQXVFTF-UHFFFAOYSA-N C#CC1=CC=CC=C1CC(=O)OC.CN1CCN(C2=CC(NC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(=O)O)=N3)=CC=C2)CC1.CN1CCN(C2=CC=CC(N)=C2)CC1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(S(C)(=O)=O)=N1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(SC)=N1.COC(=O)CC1=CC=CC=C1CCC1=NC(NC2=CC=CC(N3CCN(C)CC3)=C2)=NC=C1C(F)(F)F.COC(=O)CC1=CC=CC=C1CCC1=NC(S(C)(=O)=O)=NC=C1C(F)(F)F.CSC1=NC(I)=C(C(F)(F)F)C=N1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I Chemical compound C#CC1=CC=CC=C1CC(=O)OC.CN1CCN(C2=CC(NC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(=O)O)=N3)=CC=C2)CC1.CN1CCN(C2=CC=CC(N)=C2)CC1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(S(C)(=O)=O)=N1.COC(=O)CC1=CC=CC=C1C#CC1=C(C(F)(F)F)C=NC(SC)=N1.COC(=O)CC1=CC=CC=C1CCC1=NC(NC2=CC=CC(N3CCN(C)CC3)=C2)=NC=C1C(F)(F)F.COC(=O)CC1=CC=CC=C1CCC1=NC(S(C)(=O)=O)=NC=C1C(F)(F)F.CSC1=NC(I)=C(C(F)(F)F)C=N1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I UOGNWWREQXVFTF-UHFFFAOYSA-N 0.000 description 1
- CWCPHNXSQOWTGE-UHFFFAOYSA-N C#CC1=CC=CC=C1CC(=O)OC.COC(=O)CC1=CC=CC=C1C#CC1=NC(CC2=CC=C(C3CCCN(BC=O)C3)C=C2)=NC=C1C(F)(F)F.COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(C3CCCN(BC=O)C3)C=C2)=NC=C1C(F)(F)F.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC1=CC=C(C2CCCN(BC=O)C2)C=C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)C1.O=[N+]([O-])C1=CC=C(C2=CC=CN=C2)C=C1.O=[N+]([O-])C1=CC=C(I)C=C1.OB(O)C1=CC=CN=C1 Chemical compound C#CC1=CC=CC=C1CC(=O)OC.COC(=O)CC1=CC=CC=C1C#CC1=NC(CC2=CC=C(C3CCCN(BC=O)C3)C=C2)=NC=C1C(F)(F)F.COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(C3CCCN(BC=O)C3)C=C2)=NC=C1C(F)(F)F.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC1=CC=C(C2CCCN(BC=O)C2)C=C1.O=CBN1CCCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)C1.O=[N+]([O-])C1=CC=C(C2=CC=CN=C2)C=C1.O=[N+]([O-])C1=CC=C(I)C=C1.OB(O)C1=CC=CN=C1 CWCPHNXSQOWTGE-UHFFFAOYSA-N 0.000 description 1
- KCQBUUMESUVHIJ-UHFFFAOYSA-N C#CC1=CC=CC=C1CC(=O)OC.COC(=O)CC1=CC=CC=C1C#CC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.Cl.I.II.II(I)I.I[IH]I.I[IH]I(I)I.NC1=CC=C(N2CCN(BC=O)CC2)C=C1.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1.O=CBN1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.O=[N+]([O-])C1=CC=C(N2CCNCC2)C=C1 Chemical compound C#CC1=CC=CC=C1CC(=O)OC.COC(=O)CC1=CC=CC=C1C#CC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.Cl.I.II.II(I)I.I[IH]I.I[IH]I(I)I.NC1=CC=C(N2CCN(BC=O)CC2)C=C1.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1.O=CBN1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.O=[N+]([O-])C1=CC=C(N2CCNCC2)C=C1 KCQBUUMESUVHIJ-UHFFFAOYSA-N 0.000 description 1
- BLYWZMATYVINBU-UHFFFAOYSA-N C#CC1=CC=CC=C1CC(N)=O.C#CC1=CC=CC=C1CC(N)=O.CB(O)N1CCCCC1C1=CC=C(CC2=NC=C(C(F)(F)F)C(Cl)=N2)C=C1.CB(O)N1CCCCC1C1=CC=C(CC2=NC=C(C(F)(F)F)C(Cl)=N2)C=C1.CB(O)N1CCCCC1C1=CC=C(N)C=C1.ClC1=CC=CC=N1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=CC=CC=C1I.O=C(O)CC1=CC=CC=C1I.O=[N+]([O-])C1=CC=C(B(O)O)C=C1 Chemical compound C#CC1=CC=CC=C1CC(N)=O.C#CC1=CC=CC=C1CC(N)=O.CB(O)N1CCCCC1C1=CC=C(CC2=NC=C(C(F)(F)F)C(Cl)=N2)C=C1.CB(O)N1CCCCC1C1=CC=C(CC2=NC=C(C(F)(F)F)C(Cl)=N2)C=C1.CB(O)N1CCCCC1C1=CC=C(N)C=C1.ClC1=CC=CC=N1.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=CC=CC=C1I.O=C(O)CC1=CC=CC=C1I.O=[N+]([O-])C1=CC=C(B(O)O)C=C1 BLYWZMATYVINBU-UHFFFAOYSA-N 0.000 description 1
- RKZHYQGXDIJBCR-UHFFFAOYSA-M C#CC1=NC=CC=C1CC(=O)OC.CC[Si](C#CC1=NC=CC=C1CC(=O)OC)(CC)CC.COC(=O)CC1=CC=CN=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1.COC(=O)CC1=CC=CN=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1.COC(=O)CC1=CC=CN=C1Cl.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.N#CCC1=CC=CN=C1.N#CCC1=CC=CN=C1Cl.N#CCC1=CC=C[N+]([O-])=C1.O=C(O)CC1=CC=CN=C1Cl.O=CBN1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.[Li]OC(=O)CC1=CC=CN=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1 Chemical compound C#CC1=NC=CC=C1CC(=O)OC.CC[Si](C#CC1=NC=CC=C1CC(=O)OC)(CC)CC.COC(=O)CC1=CC=CN=C1C#CC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1.COC(=O)CC1=CC=CN=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1.COC(=O)CC1=CC=CN=C1Cl.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.N#CCC1=CC=CN=C1.N#CCC1=CC=CN=C1Cl.N#CCC1=CC=C[N+]([O-])=C1.O=C(O)CC1=CC=CN=C1Cl.O=CBN1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.[Li]OC(=O)CC1=CC=CN=C1CCC1=C(C(F)(F)F)C=NC(NC2=CC=C(C3CCN(BC=O)CC3)C=C2)=N1 RKZHYQGXDIJBCR-UHFFFAOYSA-M 0.000 description 1
- UAESEQFMDHWMPP-UHFFFAOYSA-N C#CC1=NC=NC=C1CC(=O)OCC.CCOC(=O)CC(C=O)C(=O)OCC.CCOC(=O)CC1=CN=CN=C1C#CC1=NC(CC2=CC=C(C3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.CCOC(=O)CC1=CN=CN=C1C#C[Si](CC)(CC)CC.CCOC(=O)CC1=CN=CN=C1Cl.CCOC(=O)CC1=CN=CNC1=O.CCOC(=O)CC1=CNC(=S)NC1=O.CCOC(=O)CCC(=O)OCC.CCOC=O.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=CBN1CCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 Chemical compound C#CC1=NC=NC=C1CC(=O)OCC.CCOC(=O)CC(C=O)C(=O)OCC.CCOC(=O)CC1=CN=CN=C1C#CC1=NC(CC2=CC=C(C3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.CCOC(=O)CC1=CN=CN=C1C#C[Si](CC)(CC)CC.CCOC(=O)CC1=CN=CN=C1Cl.CCOC(=O)CC1=CN=CNC1=O.CCOC(=O)CC1=CNC(=S)NC1=O.CCOC(=O)CCC(=O)OCC.CCOC=O.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=CBN1CCC(C2=CC=C(CC3=NC=C(C(F)(F)F)C(Cl)=N3)C=C2)CC1 UAESEQFMDHWMPP-UHFFFAOYSA-N 0.000 description 1
- WEVJAVOPCZKYMB-UHFFFAOYSA-M C.C#CC1=C(CC(=O)OC)C=CC=C1.COC(=O)CC1=C(C#CC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.COC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.NC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCNCC4)C=C3)=N2)C=CC=C1.NC1=CC=C(CN2CCN(BC=O)CC2)C=C1.O=CBN1CCN(CC2=CC=C(CC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.O=CBN1CCN(CC2=CC=C([N+](=O)[O-])C=C2)CC1.O=CBN1CCNCC1.O=[N+]([O-])C1=CC=C(CBr)C=C1.[Li]OC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1 Chemical compound C.C#CC1=C(CC(=O)OC)C=CC=C1.COC(=O)CC1=C(C#CC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.COC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.II(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.NC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1.NC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCNCC4)C=C3)=N2)C=CC=C1.NC1=CC=C(CN2CCN(BC=O)CC2)C=C1.O=CBN1CCN(CC2=CC=C(CC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.O=CBN1CCN(CC2=CC=C([N+](=O)[O-])C=C2)CC1.O=CBN1CCNCC1.O=[N+]([O-])C1=CC=C(CBr)C=C1.[Li]OC(=O)CC1=C(CCC2=C(C(F)(F)F)C=NC(CC3=CC=C(CN4CCN(BC=O)CC4)C=C3)=N2)C=CC=C1 WEVJAVOPCZKYMB-UHFFFAOYSA-M 0.000 description 1
- MAZJMIPRTUJPKQ-UHFFFAOYSA-N C.C#CC1=CC(C(=O)OC(C)(C)C)=CC=C1.CC(C)(C)OC(=O)C1=CC(C#C[Si](C)(C)C)=CC=C1.CC(C)(C)OC(=O)C1=CC(I)=CC=C1.CN1CCN(C2=CC=C(N)C=C2)CC1.CN1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.CSC1=NC=C(C(F)(F)F)C(C#CC2=CC(C(=O)OC(C)(C)C)=CC=C2)=N1.CSC1=NC=C(C(F)(F)F)C(CCC2=CC(C(=O)OC(C)(C)C)=CC=C2)=N1.CSC1=NC=C(C(F)(F)F)C(Cl)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.FC(F)(F)C1=CN=C(Cl)N=C1Cl.II(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=C(O)C1=CC(I)=CC=C1.O=[N+]([O-])C1=CC=C(N2CCNCC2)C=C1 Chemical compound C.C#CC1=CC(C(=O)OC(C)(C)C)=CC=C1.CC(C)(C)OC(=O)C1=CC(C#C[Si](C)(C)C)=CC=C1.CC(C)(C)OC(=O)C1=CC(I)=CC=C1.CN1CCN(C2=CC=C(N)C=C2)CC1.CN1CCN(C2=CC=C([N+](=O)[O-])C=C2)CC1.CSC1=NC=C(C(F)(F)F)C(C#CC2=CC(C(=O)OC(C)(C)C)=CC=C2)=N1.CSC1=NC=C(C(F)(F)F)C(CCC2=CC(C(=O)OC(C)(C)C)=CC=C2)=N1.CSC1=NC=C(C(F)(F)F)C(Cl)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.FC(F)(F)C1=CN=C(Cl)N=C1Cl.II(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I.II(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.I[IH]I(I)I(I)I(I)I(I)I(I)I(I)I(I)I(I)I.O=C(O)C1=CC(I)=CC=C1.O=[N+]([O-])C1=CC=C(N2CCNCC2)C=C1 MAZJMIPRTUJPKQ-UHFFFAOYSA-N 0.000 description 1
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- MPZDMUNLMNPAAO-UHFFFAOYSA-N CN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(N)=O)=N3)C=C2)CC1.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCNCC3)C=C2)=NC=C1C(F)(F)F Chemical compound CN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(N)=O)=N3)C=C2)CC1.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCNCC3)C=C2)=NC=C1C(F)(F)F MPZDMUNLMNPAAO-UHFFFAOYSA-N 0.000 description 1
- NAVXYOUJJMFEHG-UHFFFAOYSA-N CN1CCN(CC2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=C(CC(N)=O)C=CC=C4)=N3)C=C2)CC1.NC(=O)CC1=C(CCC2=NC(CC3=CC=C(CN4CCNCC4)C=C3)=NC=C2C(F)(F)F)C=CC=C1 Chemical compound CN1CCN(CC2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=C(CC(N)=O)C=CC=C4)=N3)C=C2)CC1.NC(=O)CC1=C(CCC2=NC(CC3=CC=C(CN4CCNCC4)C=C3)=NC=C2C(F)(F)F)C=CC=C1 NAVXYOUJJMFEHG-UHFFFAOYSA-N 0.000 description 1
- WBPQQFJEVNMELX-UHFFFAOYSA-N CN1CCN(CC2=CC=C(N)C=C2)CC1.CN1CCN(CC2=CC=C([N+](=O)[O-])C=C2)CC1.CN1CCNCC1.O=[N+]([O-])C1=CC=C(CBr)C=C1 Chemical compound CN1CCN(CC2=CC=C(N)C=C2)CC1.CN1CCN(CC2=CC=C([N+](=O)[O-])C=C2)CC1.CN1CCNCC1.O=[N+]([O-])C1=CC=C(CBr)C=C1 WBPQQFJEVNMELX-UHFFFAOYSA-N 0.000 description 1
- ACIBTFUWZHGTPF-UHFFFAOYSA-N CN1CCN(Cc(cc2)ccc2Nc2nc(CCc3c(CC(N)=O)cccc3)c(C(F)(F)F)cn2)CC1 Chemical compound CN1CCN(Cc(cc2)ccc2Nc2nc(CCc3c(CC(N)=O)cccc3)c(C(F)(F)F)cn2)CC1 ACIBTFUWZHGTPF-UHFFFAOYSA-N 0.000 description 1
- UYJNQQDJUOUFQJ-UHFFFAOYSA-N CNC(=O)C1=C(NC2=NC(NC3=CC=C(N4CCOCC4)C=C3OC)=NC=C2Cl)C=CC=C1 Chemical compound CNC(=O)C1=C(NC2=NC(NC3=CC=C(N4CCOCC4)C=C3OC)=NC=C2Cl)C=CC=C1 UYJNQQDJUOUFQJ-UHFFFAOYSA-N 0.000 description 1
- AURKVKJFXLEWPJ-ZFUDADJSSA-N COC(=O)C1=CC(/C=C/B2OC(C)(C)C(C)(C)O2)=NC=C1.COC(=O)C1=CC(/C=C/C2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.COC(=O)C1=CC(Br)=NC=C1.COC(=O)C1=CC(C#C[Si](C)(C)C)=NC=C1.COC(=O)C1=CC(CCC2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.NC(=O)C1=CC(CCC2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.O=CBN1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.[H]C#CC1=NC=CC(C(=O)OC)=C1 Chemical compound COC(=O)C1=CC(/C=C/B2OC(C)(C)C(C)(C)O2)=NC=C1.COC(=O)C1=CC(/C=C/C2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.COC(=O)C1=CC(Br)=NC=C1.COC(=O)C1=CC(C#C[Si](C)(C)C)=NC=C1.COC(=O)C1=CC(CCC2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.NC(=O)C1=CC(CCC2=C(C(F)(F)F)C=NC(NC3=CC=C(C4CCN(BC=O)CC4)C=C3)=N2)=NC=C1.O=CBN1CCC(C2=CC=C(NC3=NC(Cl)=C(C(F)(F)F)C=N3)C=C2)CC1.[H]C#CC1=NC=CC(C(=O)OC)=C1 AURKVKJFXLEWPJ-ZFUDADJSSA-N 0.000 description 1
- OSCITMQHLYMVLH-UHFFFAOYSA-M COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.II(I)I(I)I.II(I)I(I)I(I)I.I[IH]I(I)I(I)I.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCNCC3)C=C2)=NC=C1C(F)(F)F.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(=O)[Li]O)=N3)C=C2)CC1 Chemical compound COC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.II(I)I(I)I.II(I)I(I)I(I)I.I[IH]I(I)I(I)I.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCN(BC=O)CC3)C=C2)=NC=C1C(F)(F)F.NC(=O)CC1=CC=CC=C1CCC1=NC(CC2=CC=C(N3CCNCC3)C=C2)=NC=C1C(F)(F)F.O=CBN1CCN(C2=CC=C(CC3=NC=C(C(F)(F)F)C(CCC4=CC=CC=C4CC(=O)[Li]O)=N3)C=C2)CC1 OSCITMQHLYMVLH-UHFFFAOYSA-M 0.000 description 1
- WIPOJTKIDYJFPY-UHFFFAOYSA-L CSC1=NC=C(C(F)(F)F)C(Cl)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.CS[Na].FC(F)(F)C1=CN=C(Cl)N=C1Cl.I.[K]I Chemical compound CSC1=NC=C(C(F)(F)F)C(Cl)=N1.CSC1=NC=C(C(F)(F)F)C(I)=N1.CS[Na].FC(F)(F)C1=CN=C(Cl)N=C1Cl.I.[K]I WIPOJTKIDYJFPY-UHFFFAOYSA-L 0.000 description 1
- NGMLUEPMHOLOEJ-UHFFFAOYSA-N NC(=O)C1=CC=CC(CCC2=NC(CC3=CC=C(CN4CCNCC4)C=C3)=NC=C2C(F)(F)F)=C1 Chemical compound NC(=O)C1=CC=CC(CCC2=NC(CC3=CC=C(CN4CCNCC4)C=C3)=NC=C2C(F)(F)F)=C1 NGMLUEPMHOLOEJ-UHFFFAOYSA-N 0.000 description 1
- YMOMVMRSCMUYPM-UHFFFAOYSA-N NC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CNCCO4)C=C3)=NC=C2C(F)(F)F)C=CC=C1 Chemical compound NC(=O)CC1=C(CCC2=NC(CC3=CC=C(C4CNCCO4)C=C3)=NC=C2C(F)(F)F)C=CC=C1 YMOMVMRSCMUYPM-UHFFFAOYSA-N 0.000 description 1
- GBCXYOCSGZXBNP-UHFFFAOYSA-N NC(Cc1c(CCc2c(C(F)(F)F)cnc(Nc3ccc(C4CCNCC4)cc3)n2)cccc1)=O Chemical compound NC(Cc1c(CCc2c(C(F)(F)F)cnc(Nc3ccc(C4CCNCC4)cc3)n2)cccc1)=O GBCXYOCSGZXBNP-UHFFFAOYSA-N 0.000 description 1
- JMPGEXWVQNGSIV-UHFFFAOYSA-N NC(Cc1c(CCc2c(C(F)(F)F)cnc(Nc3ccc(CN4CCNCC4)cc3)n2)cccc1)=O Chemical compound NC(Cc1c(CCc2c(C(F)(F)F)cnc(Nc3ccc(CN4CCNCC4)cc3)n2)cccc1)=O JMPGEXWVQNGSIV-UHFFFAOYSA-N 0.000 description 1
- GVJPWZNVTKRZBM-UHFFFAOYSA-N NC(c1cccc(CCc2c(C(F)(F)F)cnc(Nc(cc3)ccc3N3CCNCC3)n2)c1)=O Chemical compound NC(c1cccc(CCc2c(C(F)(F)F)cnc(Nc(cc3)ccc3N3CCNCC3)n2)c1)=O GVJPWZNVTKRZBM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
Definitions
- This invention relates to 2,4,5-substituted pyrimidines that inhibit Focal Adhesion Kinase (FAK), also known as protein tyrosine kinase 2 (PTK2), and VEGFR3, and to pharmaceutical compositions containing such compounds.
- FAK Focal Adhesion Kinase
- PTK2 protein tyrosine kinase 2
- VEGFR3 VEGFR3
- FAK Focal Adhesion Kinase
- PTK2 protein tyrosine kinase 2
- VEGFR3 protein tyrosine kinase 2
- This invention also relates to a method of using such compounds for the prevention and/or treatment of proliferative diseases, such as cancer.
- Directional cell migration is important in many physiological and pathological processes including embryonic development, wound healing, angiogenesis, tumour invasion and metastasis.
- Transduction of extracellular signals, that stimulate cells to move directionally may be induced by a number of processes including trans-membrane integrins binding to extra cellular matrix proteins and the action of growth factors (for example EGF, IGF and VEGF) on the extracellular domains of their cognate receptors.
- FAK is a non receptor tyrosine kinase that mediates signals from both trans-membrane integrins and growth factor receptors. FAK has been reported to play a central role in coordinating these diverse extra cellular signals, integrating them in a fashion that results in directional movement of cells through their external environment (Tomar and Schlaepfer. Current Opinion in Cell Biology: 2009, 21, 676-683).
- Integrin clustering or the activation of a growth factor receptor promotes FAK autophosphorylation at Y397.
- Phosphorylated Y397 FAK then binds to c-Src (referred to as Src herein) and Src mediated phosphorylation of FAK at Y576 and Y577 occurs to give rise to an active FAK-Src complex.
- Active FAK-Src then facilitates signaling via a number of biochemical pathways which influence processes such as cell adhesion, migration, invasion, cell survival, proliferation, acquisition of chemotherapy resistance and metastasis (Brunton and Frame. Current Opinion in Pharmacology: 2008, 8, 437-432 and Chatzizacharias et al. Expert Opinion in Therapeutic Targets: 2007, 11(10), 1315-1328).
- FAK is a key regulator of cell migration (Angelucci and Bologna. Current Pharmaceutical Design: 2007, 13, 2129-2145 and Mitra et al. Nature Reviews Molecular Cell Biology: 2005, 6, 56-68).
- Cells derived from FAK ⁇ / ⁇ mouse embryos exhibit reduced migration as a result of impaired adhesion turnover (Ili ⁇ et al. Nature: 1995, 377, 539-544).
- displacement of FAK from focal adhesions reduces cell migration (Gilmore and Romer. Molecular Biology of the Cell: 1996, 7(8), 1209-1224), whilst over-expression in CHO cells stimulates migration (Cary et al. Journal of Cell Science: 1996, 7, 1787-1794).
- FAK activation has been shown to enhance matrix degrading invasive behaviour.
- FAK-Src signaling through cellular apoptosis susceptibility protein (CAS) leads to the expression of matrix metalloproteases (MMPs) including MMP2 and MMP9.
- MMPs matrix metalloproteases
- MMP14 then activates MMP2 by cleavage of pro-MMP2 to its active form (Siesser and Hanks. Clinical Cancer Research: 2006, 12(11), 3233-3237).
- invadopodia Highly invasive cancer cells form specialized actin-rich extra cellular matrix degrading membrane protrusions known as invadopodia which are rich in matrix-degrading proteases such as MMPs. Both FAK and Src have been shown to be instrumental in the formation of invadopodia (Chan et al. Journal of Chemical Biology: 2009, 185(2), 357-370).
- FAK has been shown to play an important role in cell survival. Activation of FAK has been shown to result in suppression of anoikis (apopotosis in response to an inappropriate extra cellular matrix environment) (Frisch et al Journal of Cell Biology. 1996, 134(3), 793-799 and Xu et al Cell Growth and Differentiation. 1996, 7(4), 413-418). Studies have demonstrated that FAK activates multiple downstream pathways to suppress anoikis in both fibroblasts and epithelial cells (Zouq et al. Journal of Cell Science: 2008, 122, 357-367).
- PI3-K/Akt-1 signalling Activation of PI3-K/Akt-1 signalling, a process associated with FAK activation in a number of studies, was identified as a probable cause of the cyclin expression/activation (Yamamoto et al. Cellular Signaling: 2003, 15. 575-583).
- TAE226 has the structure:
- TAE226 inhibited the phosphorylation of FAK at both Y397 and Y861 sites, inhibited cell growth in a time- and dose-dependent manner, and enhanced docetaxel-mediated growth inhibition by 10- and 20-fold in the taxane-sensitive and taxane-resistant cell lines, respectively.
- FAK inhibition by TAE226 significantly reduced tumour burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models (46-64%) compared with vehicle-treated controls.
- the greatest efficacy was observed with concomitant administration of TAE226 and docetaxel in all three models (85-97% reduction).
- TAE226 in combination with docetaxel significantly prolonged survival in tumour-bearing mice (Halder et al. Cancer Res: 2007, 67(22), 10976-10983).
- FAK mRNA and/or protein has been reported in numerous human cancers including colorectal cancer (de Heer. European Journal of Surgical Oncology: 2008, 34(11), 1253-1261), prostate cancer (Tremblay, L., W. Hauck, et al. International Journal of Cancer: 1996, 68(2), 164-171), breast cancer (Watermann et al. British Journal of Cancer 2005, 93(6), 694-698) and melanomas (Hess et al. Cancer Research: 2005, 65(21), 9851-60). Furthermore FAK over expression is frequently correlated with more aggressive phenotypes of these cancers.
- a FAK inhibitor would have application for the reduction of cell adhesion, cell migration, cell invasion, cell proliferation and chemo-resistance. Furthermore, a FAK inhibitor would have applicability to induce apoptosis for cells in inappropriate extra cellular matrix environments and reduce angiogenesis.
- VEGFR3 vascular endothelial growth factor receptor VEGFR3
- VEGF-C and VEGF-D vascular endothelial growth factors C and D
- ligands of VEGFR3 are significantly correlated with lymphatic metastasis and lymphatic vessel invasion in early-stage invasive cervical carcinoma (Journal of Experimental & Clinical Cancer Research 2009, 28).
- PF-562,271 is described in WO2004/056786, WO2004/056807, WO2005/023780, WO2007/063384 and Roberts et al. Cancer Res 2008, 68(6), 1935-1944.
- PF-573,228 is described in Slack-Davis et al. J. Biol. Chem. 2007, 282(20), 14845-14852.
- the present inventors have discovered a particular class of compounds which are effective as FAK inhibitors, and also inhibit VEGFR3. These compounds may exhibit selectivity for FAK over kinases such as VEGFR1, IGF-1R (Insulin-like growth factor 1 receptor). IR (insulin receptor) and CDKs (cyclin-dependent kinases). Additionally, the compounds of the invention may have enhanced selectivity for the inhibition of cytochrome p450 enzymes, specifically the 2C9 and 3A4 isoforms. Furthermore, the compounds of the invention may be less prone to the formation of adducts with glutathione.
- the present invention provides compounds of the following formula (I):
- R 1 is selected from: H and
- R 6 is selected from H, (CHR C1 ) n1 C(O)N(R N13 )Z 1 and (CH 2 ) n2 C(O)OZ 2 ; wherein:
- R N13 is H or CH 3 ;
- a second aspect of the present invention provides a composition comprising a compound of the first aspect and a pharmaceutically acceptable carrier or diluent.
- a third aspect of the invention provides a compound of the first aspect for use in a method of therapy.
- a fourth aspect of the invention provides for the use of a compound of the first aspect in the preparation of a medicament for treating a disease ameliorated by the inhibition of FAK and VEGFR 3 .
- the fourth aspect of the invention also provides a compound of the first aspect for use in the method of treatment of a disease ameliorated by the inhibition of FAK VEGFR 3 .
- a further aspect of the invention provides an active compound as described herein for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical composition.
- Another aspect of the invention provides a method of inhibiting FAK and VEGFR 3 in vitro or in vivo, comprising contacting a cell with an effective amount of an active compound as described herein.
- R 1 may have one of the following structures:
- R 1 is H
- R 2 (discussed below) is not H.
- R N1 , R N2 and R N3 is independently selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) and C( ⁇ O)Me and R N4 is selected from either H or methyl.
- R N7 is either H or methyl.
- R N7 and R N8 are independently selected from H and CH 3 .
- Each of R N9 , R N10 and R N11 are also independently selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) and C( ⁇ O)Me.
- R 2 may have one of the following structures:
- R 1 (discussed above) is not H.
- R N5 and R N6 are independently selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) and C( ⁇ O)Me.
- R N12 is selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) and C( ⁇ O)Me.
- R 4 is selected from CF 3 , halo (i.e. F, Cl, Br, I), CF 2 H and CN.
- the halo group is either Cl or Br.
- R 5 is selected from groups of the following formulae:
- R 6 is selected from H, (CHR C1 ) n1 C(O)N(R N13 )Z 1 and (CH 2 ) n2 C(O)OZ 2 ; wherein:
- R 7 (discussed below) is not H.
- R 6 is (CHR C1 ) n1 C(O)N(R N6 )Z 1 , it may be selected from: CH 2 C(O)NH 2 , CH 2 C(O)NHCH 3 , CH 2 C(O)NHOCH 3 , CH 2 C(O)NCH 3 OCH 3 , CHCH 3 C(O)NH 2 , CHCH 3 C(O)NHCH 3 , CHCH 3 C(O)NHOCH 3 , and CHCH 3 C(O)NCH 3 OCH 3 .
- R 6 is (CH 2 ) n2 C(O)OZ 2 , it is CH 2 C(O)OCH 3 .
- R 7 is selected from H, and (CH 2 ) m1 C(O)N(R M1 )Y 1 , wherein:
- R 7 is H
- R 6 discussed above
- R 6 is not H.
- R 7 is (CH 2 ) m1 C(O)N(R M1 )Y 1 , it may be selected from C(O)NH 2 , C(O)NHCH 3 , C(O)NHOCH 3 , CH 2 C(O)NH 2 , CH 2 C(O)NHCH 3 and CH 2 C(O)NHOCH 3 .
- R 8 is H, except for when R 7 is C( ⁇ O)NH 2 , it may alternatively be C 1-2 alkyl, i.e. methyl or ethyl.
- a reference to carboxylic acid also includes the anionic (carboxylate) form (—COO ⁇ ), a salt or solvate thereof, as well as conventional protected forms.
- a reference to an amino group includes the protonated form (—N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
- a reference to a hydroxyl group also includes the anionic form (—O ⁇ ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
- Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and I-forms: (+) and ( ⁇ ) forms: keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as “isomers” (or “isomeric forms”).
- isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
- a reference to a methoxy group, —OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, —CH 2 OH.
- a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl.
- a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
- C 1-7 alkyl includes n-propyl and iso-propyl
- butyl includes n-, iso-, sec-, and tert-butyl
- methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
- keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
- H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.
- a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
- Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
- a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below.
- a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
- a salt may be formed with a suitable cation.
- suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca2 + and Mg 2+ , and other cations such as Al 3+ .
- Suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4+ ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2+ , NHR 3+ , NR 4+ ).
- suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
- An example of a common quaternary ammonium ion is N(CH 3 ) 4+ .
- a salt may be formed with a suitable anion.
- suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulphuric, sulphurous, nitric, nitrous, phosphoric, and phosphorous.
- Suitable organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2-acetyoxybenzoic, fumaric, phenylsulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, pantothenic, isethionic, valeric, lactobionic, and gluconic.
- suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
- solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.
- chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
- a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
- a hydroxy group may be protected as an ether (—OR) or an ester (—OC( ⁇ O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl)ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (—OC( ⁇ O)CH 3 , —OAc).
- ether —OR
- an ester —OC( ⁇ O)R
- an aldehyde or ketone group may be protected as an acetal or ketal, respectively, in which the carbonyl group (>C ⁇ O) is converted to a diether (>C(OR) 2 ), by reaction with, for example, a primary alcohol.
- the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
- an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (—NHCO—CH 3 ); a benzyloxy amide (—NHCO—OCH 2 C6H 5 , —NH-Cbz); as a t-butoxy amide (—NHCO—OC(CH 3 ) 3 , —NH-Boc); a 2-biphenyl-2-propoxy amide (—NHCO—OC(CH 3 ) 2 C 6 H 4 C 6 H 5 , —NH-Bpoc), as a 9-fluorenylmethoxy amide (—NH-Fmoc), as a 6-nitroveratryloxy amide (—NH-Nvoc), as a 2-trimethylsilylethyloxy amide (—NH-Teoc), as a 2,2,2-trichloroethyloxy amide (—NH-Troc), as an allyloxy amide (—NH-All
- a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g. a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a C 1-7 trihaloalkyl ester); a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
- an C 1-7 alkyl ester e.g. a methyl ester; a t-butyl ester
- a C 1-7 haloalkyl ester e.g., a C 1-7 trihaloalkyl ester
- a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
- SR thioether
- benzyl thioether an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
- prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
- the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
- some prodrugs are esters of the active compound (e.g. a physiologically acceptable metabolically labile ester). During metabolism, the ester group (—C( ⁇ O)OR) is cleaved to yield the active drug.
- esters may be formed by esterification, for example, of any of the carboxylic acid groups (—C( ⁇ O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
- metabolically labile esters include those wherein R is C 1-7 alkyl (e.g. -Me, -Et); C 1-7 aminoalkyl (e.g. aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C 1-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g.
- pivaloyloxymethyl acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).
- prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
- the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
- the selectivity of the compounds for inhibiting FAK and VEGFR3 over other kinases, such as IGF-1R, IR and CDKs can be demonstrated by biochemical assay results (see, for example, the FAK kinase assay and VEGFR 3 assays described below).
- the compounds of the invention may also be selective over VEGFR1 and/or VEGFR 2 .
- the selectivity of the compounds for FAK over the inhibition of cytochrome p450 enzymes, specifically the 2C9 and 3A4 isoforms may be determined using standard inhibition assays.
- R 2 is H and R 1 is:
- R N1 is selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) and C( ⁇ O)Me. In some of these embodiments, it may be preferred that R N1 is C( ⁇ O)Me. In others of these embodiments, it may be preferred that R N1 is H, methyl or ethyl.
- R 2 is H and R 1 is:
- R N2 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N2 is selected from H and methyl. In other of these embodiments, it may be preferred that R N2 is ethyl.
- R 2 is H and R 1 is:
- R N3 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N3 is selected from H and methyl. In other of these embodiments, it may be preferred that R N3 is ethyl.
- R 2 is H and R 1 is:
- R N4 is selected from H and methyl. In these embodiments, it may be preferred that R N4 is H.
- R 2 is H and R 1 is:
- R N7 and R N8 are both H or both methyl. In some of these embodiments, it may be preferred that R N7 and R N8 are both H.
- R 2 is H and R 1 is:
- R N9 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N9 is H.
- R 2 is H and R 1 is:
- R N10 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N10 is selected from H and methyl.
- R 2 is H and R 1 is:
- R N11 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N11 is H.
- R 1 is H and R 2 is:
- R N5 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N5 is selected from H and methyl.
- R 1 is H and R 2 is:
- R N6 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N6 is selected from H and methyl.
- R 1 is H and R 2 is:
- R N12 is selected from H and C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl). In these embodiments, it may be preferred that R N12 is selected from H and methyl, and it may be more preferred that R N12 is methyl.
- R 4 is selected from CF 3 , Cl, Br, CF 2 H, and CN.
- R 4 is selected from CF 3 , Cl and CF 2 H. In further embodiments, R 4 is selected from CF 3 and Cl. It may be preferred that R 4 is CF 3 .
- R 5 is a group of the following formulae:
- R 5 is a group selected from:
- R 5 may be preferably selected from R 5e and R 5c , and may more preferably be R 5e .
- R 7 is H and R 6 is (CHR C1 ) n1 C(O)N(R N6 )Z 1 .
- R 7 is H and R 6 is selected from CH 2 C(O)NH 2 , CH 2 C(O)NHCH 3 , CHCH 3 C(O)NH 2 and CHCH 3 C(O)NHCH 3 .
- R 7 is H and R 6 is selected from CH 2 C(O)NH 2 , CHCH 2 C(O)NH 2 and CH 2 C(O)NHCH 3 , and more preferably from CH 2 C(O)NH 2 , and CHCH 3 C(O)NH 2 .
- R 6 is H and R 7 is (CH 2 ) m1 C(O)N(R M1 )Y 1 .
- R 6 is H and R 7 is selected from C(O)NH 2 , C(O)NHCH 3 , CH 2 C(O)NH 2 and CH 2 C(O)NHCH 3 .
- R 6 is H and R 7 is C(O)NH 2 .
- R 8 is methyl
- R 5 is a group of the following formula:
- the compounds may of formula Ia:
- R 1a is selected from:
- R N2 , R N3 and R N4 apply here as well.
- the compounds may of formula Ib:
- R 1b is selected from:
- R N1 , R N2 , R N3 , R N4 , R N7 , R N8 , R N9 , R N10 and R N11 apply here as well.
- Embodiments of the inventions are compounds of the examples, including compounds 1 to 40.
- Embodiments of particular interest include compounds 4, 5, 8, 11 and 16.
- Further embodiments of particular interest include compounds 21, 22, 25, 31 and 36.
- the compounds of the invention can be prepared employing the following general methods and using procedures described in detail in the experimental section.
- the reaction conditions referred to are illustrative and non-limiting.
- 2,4-dichloro-5-(trifluoromethyl)pyrimidine (G1) can be selectively reacted with sodium thiomethoxide in the presence of zinc(II) chloride to give 2-thiomethyl-4-chloro-5-(trifluoromethyl)pyrimidine (G2).
- 2-Thiomethyl-4-chloro-5-(trifluoromethyl)pyrimidine (G2) can be further reacted, for example by conversion to 2-thiomethyl-4-iodo-5-(trifluoromethyl)pyrimidine (G3) under Finkelstein conditions and/or by oxidation with mCPBA to give the corresponding sulfone if further differentiation of the 2 and 4-position is required or if additional activation is desirable.
- a catalyst for example palladium on charcoal
- the corresponding 4-piperidine analogues of G6 can be prepared by a sequence of reactions starting with the conversion of commercially available tert-butyl 4-oxopiperidine-1-carboxylate (G10) to vinyl triflate G1. Coupling of G1 in a Suzuki type reaction with (4-nitrophenyl)boronic acid (G12) gives tetrahydropyridine (G13). Subsequent reduction via hydrogenation in the presence of a catalyst, for example palladium on charcoal, gives gives tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (G14).
- a catalyst for example palladium on charcoal
- the corresponding 4-(3-aminophenyl)piperidine analogue of G9 can be prepared by a sequence of reactions starting with the conversion of commercially available tert-butyl 4-oxopiperidine-1-carboxylate (G10) to vinyl triflate G11. Coupling of G11 in a Suzuki type reaction with (3-nitrophenyl)boronic acid (G15) gives tetrahydropyridine (G16). Subsequent reduction via hydrogenation in the presence of a catalyst, for example palladium on charcoal, gives tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (G17).
- a catalyst for example palladium on charcoal
- G23 pyridin-2-ylboronic acid
- G23 Reduction of G23 with hydrogen in the presence of a catalyst, for example platinum oxide, gives 4-(piperidin-2-yl)aniline (G24) which may be protected using Boc anhydride to give tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (G25).
- tert-Butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate can be prepared by nucleophilic aromatic substitution of commercially available tert-butyl piperidin-4-ylcarbamate (G26) and 1-fluoro-4-nitrobenzene (G27) under thermal conditions to give tert-butyl (1-(4-nitrophenyl)piperidin-4-yl)carbamate (G28). Reduction of G28 with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal gives tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G29).
- tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G32) can be prepared by the nucleophilic displacement of commercially available 1-(bromomethyl)-4-nitrobenzene (G30) with tert-butyl piperazine-1-carboxylate (G7) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (G31). Subsequent reduction with hydrogen in the presence of a catalyst, for example 10% % palladium on charcoal, gives tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G32).
- a catalyst for example 10% % palladium on charcoal
- tert-butyl 3-oxopyrrolidine-1-carboxylate (G33) can be converted to a mixture of vinyl triflates (G34) and (G35) in the presence of a triflamide and a suitable base, for example NaHMDS.
- a triflamide and a suitable base for example NaHMDS.
- Coupling of the mixture with (4-nitrophenyl)boronic acid (G12) under Suzuki conditions gives dihydropyrroles (G36) and (G37).
- Reduction of this mixture using hydrogen in the presence of a catalyst, for example 10% palladium on charcoal gives tert-butyl 3-(4-aminophenyl)pyrrolidine-1-carboxylate (G38).
- R O1 t-Bu
- R 9 may then be removed to generate compounds of the formula F10.
- R 9 TMS or TES potassium carbonate or tetra-n-butyl ammonium fluoride may be employed to induce this transformation.
- Carboxylic acids of the formula F13 can be converted to amides of the formula F14 using a suitable amine or ammonia salt in the presence of a peptide coupling agent, for example HATU.
- a suitable amine or ammonia salt in the presence of a peptide coupling agent, for example HATU.
- esters of the formula F12 may be directly converted to amides of the formula F14 by reaction with an amine at elevated temperatures.
- compounds of the formula F18 may then be further modified by derivitisation of the amine functionality.
- heteroaryl analogues of F10 may be prepared as outlined in Schemes T, U and V. These heteroaryl acetylenes can be coupled to compounds of the formula F3, and then further elaborated in an analogous manner to that described above in schemes N, O, P, R and S.
- 2,3-di-chloropyrazine (G46) can be reacted with ethyl acetate in the presence of LiHMDS to give ester G47.
- Coupling of G47 with TMS acetylene under Sonagashira conditions gives acetylene G48.
- Removal of the trimethylsilyl group using TBAF gives ethyl 2-(3-ethynylpyrazin-2-yl)acetate (G49).
- diethyl succinate (G50) and ethyl formate (G51) can be condensed to give aldehyde G52 in the presence of sodium metal.
- Cyclisation using thiourea gives 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine (G53).
- Desulfurisation using Raney-nickel gives pyrimidone G54, which can be converted to 4-chloro pyrimidine G55 using phosphorous oxychloride.
- 2-(pyridin-3-yl)acetonitrile (G58) can be oxidised to N-oxide G59.
- Chlorination with phosphorous oxychloride gives 2-chloropyridine G60 which can be hydrolysed with sodium hydroxide to acetic acid G61.
- Ester formation using methanol gives 2-chloropyridine ester G62.
- Coupling of TES-acetylene under Sonagashira conditions, followed by removal of the triethylsilyl group using TBAF gives methyl 2-(2-ethynylpyridin-3-yl)acetate (G64).
- heteroaryl acetylenes analagous to F10 can be hydroborylated to give vinyl boranes as in scheme W.
- These can be coupled using Suzuki chemistry to compounds of the formula F3, then further elaborated in an analogous manner to that described above in schemes N, O, P, R and S.
- Methyl 2-bromoisonicotinate (G65) can be coupled using Sonagashira conditions to give acetylene G66. Removal of the trimethylsilyl group with TBAF gives terminal acetylene G67 which can be hydroborylated to give (E)-methyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)vinyl)isonicotinate (G68).
- the present invention provides active compounds, specifically, active 2,4,5-substituted pyrimidines.
- active pertains to compounds which are capable of inhibiting FAK activity as well as the activity of VEGFR3, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
- the present invention further provides a method of inhibiting FAK inhibition, as well as the activity of VEGFR3, in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition.
- a method of inhibiting FAK inhibition, as well as the activity of VEGFR3, in a cell comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition.
- Such a method may be practised in vitro or in vivo.
- the present invention further provides active compounds which inhibit FAK activity, as well as the activity of VEGFR3, as well as methods of methods of inhibiting FAK activity, as well as the activity of VEGFR3, comprising contacting a cell with an effective amount of an active compound, whether in vitro or in vivo.
- Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
- the invention further provides active compounds for use in a method of treatment of the human or animal body.
- a method may comprise administering to such a subject a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
- treatment pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
- Treatment as a prophylactic measure i.e. prophylaxis is also included.
- terapéuticaally-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
- the present invention provides active compounds which are anticancer agents.
- One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.
- cancers include, but are not limited to, bone cancer, brain stem glioma, breast Cancer, cancer of the adrenal gland, cancer of the anal region, cancer of the bladder, cancer of the endocrine system, cancer of the oesophagus, cancer of the head or neck, cancer of the kidney or ureter, cancer of the liver, cancer of the parathyroid gland, cancer of the penis, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina, carcinoma of the vulva, chronic or acute leukemia, colon cancer, cutaneous or intraocular melanoma, haemetological malignancies, Hodgkin's disease, lung cancer, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), ovarian cancer, pancreatic cancer, pituitary adenoma, primary CNS lymph
- Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.
- gastrointestinal including, e.g., bowel, colon
- breast mammary
- ovarian prostate
- liver hepatic
- kidney renal
- bladder pancreas
- brain and skin.
- anti-tumour agents may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
- Such chemotherapy may include one or more of the following categories of anti-tumour agents:—
- antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine
- inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinT], the anti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stem et al.
- inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the epidermal growth factor family
- EGFR family tyrosine kinase inhibitors
- antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
- gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene directed enzyme pro drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi drug resistance gene therapy
- immunotherapy approaches including for example ex vivo and in vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected immune cells such as cytokine transfected den
- a combination of particular interest is with docetaxel.
- Other possible combinations of interest include with gemcitabine, cisplatin and the camptothecin prodrug irinotecan.
- the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, oral (e.g. by ingestion); topical (including e.g. transdermal, intranasal, ocular, buccal, and sublingual); pulmonary (e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g.
- vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot, for example, subcutaneously or intramuscularly.
- the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g.
- a mouse canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
- canine e.g. a dog
- feline e.g. a cat
- equine e.g. a horse
- a primate e.g. a monkey or ape
- a monkey e.g. marmoset, baboon
- an ape e.g. gorilla, chimpanzee, orang-utan, gibbon
- a human e.g. gorilla, chimpanzee, orang-utan, gibbon
- the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
- a pharmaceutical composition e.g. formulation
- the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
- pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
- a subject e.g. human
- Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
- Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
- Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
- Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
- a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
- Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
- a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
- Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
- Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
- Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
- Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
- Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
- a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
- Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
- the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base.
- the active compounds may be formulated in a cream with an oil-in-water cream base.
- the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
- the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
- an emulsifier otherwise known as an emulgent
- a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
- the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
- the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
- Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
- the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
- the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
- Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
- mono-isoadipate such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the
- high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
- Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
- Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
- Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
- concentration of the active compound in the solution is from about 1 ng/ml to about 10 ⁇ g/ml, for example from about 10 ng/ml to about 1 ⁇ g/ml.
- the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
- Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
- appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
- the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
- the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
- Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
- a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
- the active compound is a salt, an ester, prodrug, or the like
- the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
- LC/MS data was generated using either a Finnigan LCQ Advantage Max (LCMS-A), a Waters ZQ 3100 system (LCMS-B) or an Agilent 6100 Series Single Quad LC/MS (LCMS-C).
- LCMS-A Finnigan LCQ Advantage Max
- LCMS-B Waters ZQ 3100 system
- LCMS-C Agilent 6100 Series Single Quad LC/MS
- Ion Source Ion trap Ion Mode: ES positive
- Ion Source Single-quadrupole
- Drying gas temp 300° C.
- Vaporizer temperature 200° C.
- Step size 0.1 sec Acquisition time: 10 min
- Analytical thin-layer chromatography was performed on Merck silica gel 60F254 aluminium-backed plates which were visualised using fluorescence quenching under UV light or acidic anisaldehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purifi-cation system using standard RediSep® cartridges or a Biotage Isolera purification system using either Grace or Biotage silica cartridges.
- anhydrous solvents were prepared using a Braun purification system or purchased from Sigma-Aldrich.
- tert-Butyl 4-(4-nitrophenyl)piperazine-1-carboxylate (I1) (3.24 g, 10.5 mmol) was dissolved in EtOAc (90 mL) under an atmosphere of nitrogen and a slurry of 10% Pd/C (0.500 g) in EtOAc (10 mL) was added. The resulting suspension was then stirred vigorously under an atmosphere of hydrogen at room temperature for 42 hours.
- 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (2.39 g, 11.0 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (80 mL) at 0° C. and a 1.0 M ZnCl 2 solution in diethyl ether (12.6 mL, 12.6 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes.
- Methyl 2-(2-iodophenyl)acetate (I9) (4.65 g, 16.8 mmol), PdCl 2 (PPh 3 ) 2 (295 mg, 421 ⁇ mol) and Cu(I)I (80.0 mg, 421 ⁇ mol) were placed into an oven dried reaction flask under nitrogen.
- dry degassed THF (20 mL) and triethylamine (20 mL) were added and the reaction mixture was stirred at room temperature for 16 hours.
- This material was dissolved in dry THF (3 mL) and dry DMF (0.2 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (0.009 g, 0.064 mmol) and EDCI (0.012 g, 0.064 mmol) and N,N-diisopropylethylamine (0.048 mL, 0.276 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (0.018 g, 0.18 mmol) was added in one portion, and the reaction was stirred room temperature for 20 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (20 mL) and saturated aq. NaHCO 3 (10 mL).
- 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.355 g, 1.64 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C. and a 1.0 M ZnCl 2 solution in diethyl ether (1.87 mL, 1.87 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes.
- the reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the catalyst was removed by filtration through Celite and the solvent was removed in vacuo.
- the resulting solid was again dissolved in EtOAc (12 mL) and absolute ethanol (8 mL) under an atmosphere of nitrogen and 10% Pd/C (0.250 g) in EtOAc (4 mL) was added to the solution and the atmosphere was changed to hydrogen gas (balloon).
- the reaction was sealed with a balloon and stirred at room temperature for 24 hours.
- the catalyst was removed by filtration through Celite, which was washed with EtOAc (7 ⁇ 10 mL) and the solvent was removed in vacuo to give a pale yellow viscous oil.
- tert-Butyl 3-ethynylbenzoate (I17) (1.50 g, 9.37 mmol) was dissolved in dry DCM (70 mL) and TFA (35.9 mL, 468 mmol) was added carefully. The reaction was stirred at room temperature for 3 hours, concentrated in vacuo and toluene was added and then removed in vacuo to give a pale yellow solid. This material was dissolved in methanol (50 mL) and conc. H 2 SO 4 ( ⁇ 1 mL) was added and the resulting solution was stirred at 65° C. for 20 hours.
- the reaction was sealed with a balloon and stirred at room temperature for 18 hours after which the reaction was flushed with nitrogen gas and Pearlman's catalyst (0.150 g) in EtOAc (5 mL) was added. The atmosphere was again changed to hydrogen gas (balloon) and the reaction was sealed with balloon and stirred for 20 hours at room temperature. The catalyst was removed by filtration through Celite, which was washed with EtOAc (5 ⁇ 10 mL).
- 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.101 g, 0.464 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (10 mL) at 0° C. and a 1.0 M ZnCl 2 solution in diethyl ether (0.530 mL, 0.530 mmol) was added cautiously over 20 minutes. After addition, the reaction was left stirring at 0° C.
- 2-Iodophenylacetic acid (2.00 g, 7.63 mmol) was dissolved in dry THF (70 mL) and dry DMF (10 mL) under an atmosphere of nitrogen. To the solution were added 1-hydroxybenzotriazole (1.134 g, 8.396 mmol) and EDCI (1.609 g, 8.396 mmol) and N,N-diisopropylethylamine (5.318 mL, 30.53 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Ammonium carbonate (2.933 g, 30.53 mmol) was added in one portion, and the reaction was stirred room temperature for 17 hours.
- reaction mixture was then stirred at room temperature for 18 hours, concentrated in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a beige solid.
- This material was dissolved in dry THF (25 mL) under an atmosphere of nitrogen and TBAF (1.0 M in THF, 2.805 mL. 2.805 mmol) was added dropwise at 0° C. The solution was stirred at this temperature for 1 hour and 15 minutes after which water (5 mL) was added.
- the reaction mixture was concentrated in vacuo and diluted with EtOAc (100 mL) and sat. aq. NaHCO 3 (100 mL).
- reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes.
- the reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g.
- Lithium diisopropylamide (2 M in heptane/THF/ethylbenzene; 15.1 mL, 30.1 mmol) was added dropwise to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (3.00 g. 15.1 mmol) in THF (50 mL) at ⁇ 78° C. and the mixture left to stir for 30 minutes.
- a solution of N-phenyl-bis(trifluoromethanesulfonimide) (6.46 g, 18.1 mmol) in THF (60 mL) was then added dropwise over 30 minutes to the reaction and mixture left to stir for 30 minutes-78° C. The resulting mixture was then allowed to warm to room temperature and was stirred for 24 hours.
- the solvent was partially removed (ca 80 mL) and the reaction mixture quenched with saturated NaHCO 3 solution (50 mL).
- Zinc chloride (1.0 M in Et 2 O) (1.97 mL, 1.97 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.384 g, 1.77 mmol) in 1:1 DCE/t-BuOH (10 mL) at 0° C. under a stream of N 2 gas. The mixture was stirred for 1 hour at 0° C. and then tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (I44) (0.453 g, 1.64 mmol) in 1:1 DCE/tBuOH (7 mL) was added.
- the reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes.
- the reaction was cooled and the mixture diluted with EtOAc and passed through a plug of celite and washed through with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2 ⁇ 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na 2 SO 4 . After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I46) (0.157 g, 80%) as a brown viscous oil.
- Ammonium carbonate (84.8 mg, 0.883 mmol) was added in one portion to the stirred reaction mixture after 10 minutes. The reaction was left stirred at room temperature for 18 hours. The volatiles were removed in vacuo and the residual solution was diluted with EtOAc (50 mL), transferred to a separating funnel and washed with saturated NaHCO 3 (50 mL). The aqueous layer was extracted with EtOAc (2 ⁇ 50 mL). The combined organic layers were washed with water (50 mL) and brine (2 ⁇ 50 mL) and dried over Na 2 SO 4 . After filtration the solvent was removed in vacuo to afford a pale yellow solid.
- Trifluoroacetic acid (0.595 mL, 7.78 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I49) (90.8 mg, 0.156 mmol) in dry DCM (5 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (30 mL) and 2M NaOH (30 mL).
- the reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes.
- the reaction was cooled and the mixture diluted with EtOAc and passed through a plug of Celite washing with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2 ⁇ 50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na 2 SO 4 . After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I52) (0.108 g, 54%) as a brown viscous oil.
- Trifluoroacetic acid (0.417 mL, 5.46 mmol) was added to a solution of tert-butyl 4-(4-((4-(2-(1-amino-1-oxopropan-2-yl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I55) (65.2 mg, 0.109 mmol) in dry DCM (8 mL) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 23 hours. The volatiles were removed in vacuo and the residue partitioned between EtOAc (20 mL) and 2 M NaOH (20 mL).
- Formaldehyde (37% in H 2 O; 15.6 ⁇ L, 0.210 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (25 mg, 0.053 mmol) in anhydrous methanol (5 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.111 g, 0.525 mmol) was then added in one portion to the reaction mixture. The reaction was stirred at room temperature for 1.5 hours.
- 3-(4-Methylpiperizin-1-nyl)aniline (36.0 mg, 186 ⁇ mol) was dissolved in trifluoroethanol (1 mL), then methyl 2-(2-(2-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I66) (50 mg, 124 ⁇ mol) was added followed by trifluoroacetic acid (48 ⁇ L). The resulting mixture was stirred at 100° C. under microwave irradiation for 10 minutes.
- tert-Butyl piperidin-4-ylcarbamate (1.200 g, 5.992 mmol) and 4-fluoronitrobenzene (0.705 g, 4.99 mmol) were placed in a 30 mL microwave vial then acetonitrile (20 mL) followed by diisopropylethylamine (1.778 mL, 9.986 mmol) were added. The reaction was heated under microwave irradiation at 150° C. for 15 minutes. The reaction mixture was diluted with EtOAc (200 mL) and 2 M aq.
- 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.551 g, 2.54 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C.
- a 1.0 M ZnCl 2 solution in diethyl ether (2.903 mL, 2.903 mmol) was added cautiously over 10 minutes, after addition the reaction was left stirring at 0° C. for 30 minutes.
- the organic solvents were evaporated in vacuo and the crude oily solid was suspended in water (200 mL), the suspension was sonicated for 30 minutes and the product was separated by filtration, the solid was washed with water (10 ⁇ 20 mL) and dried under a high vacuum.
- the material was further purified by silica gel chromatography using a gradient of 0-50% ethyl acetate in petroleum benzine 40-60° C.
- Lithium hydroxide mono hydrate (43.0 mg, 1.03 mmol) was added to a suspension of methyl 2-(2-(2-((4-(4-((tert-butoxycarbonyl)amino)piperidin-1-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I78) (211 mg, 0.344 mmol) in THF (10 mL), MeOH (1.0 mL) and water (1.5 mL) and the resulting mixture was stirred at room temperature for 16 hours. The organics were removed in vacuo then 2 M aqueous NaOH solution (100 mL) was added.
- the cooled mixture was concentrated, co-evaporated with toluene (3 ⁇ 20 mL) and loaded onto a 10 g SCX cartridge in methanol.
- the cartridge was eluted with methanol (200 mL), then with 1% methanolic methylamine (200 mL).
- the methanolic methylamine eluent was concentrated to give a brown oil (0.850 g).
- the oil was dissolved in DCM (5 mL), and Boc anhydride (549 mg, 2.52 mmol) was added. The resulting mixture was stirred under an oil bubbler for 18 hours, then diluted with DCM (50 mL) and washed with water (50 mL).
- Lithium 2-(2-(2-(2-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetate (I81) (205 mg, 0.37 mmol) was dissolved in DMF (3 mL) and HATU (154 mg. 0.41 mmol) was added. After stirring for 3 minutes, ammonium carbonate (212 mg, 2.20 mmol) and DIPEA (0.26 mL, 1.5 mmol) were added and the mixture was stirred at room temperature for 18 hours.
- N-(2-Hydroxy-2-(4-nitrophenyl)ethyl)-4-methylbenzenesulfonamide (I84) (0.610 g, 1.34 mmol) was sonicated in DCM (20 mL) for five minutes and cooled to 0° C. under nitrogen. A 60% dispersion of NaH (0.220 g, 5.44 mmol) was added and the mixture stirred for five minutes before (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate (1.21 g, 2.72 mmol) was added. The mixture was stirred for 17 hours, allowing the cooling bath to come to room temperature over this time.
- the cartridge was washed with methanol (50 mL), and then eluted with 1% methylamine/methanol (50 mL). The basic eluent was concentrated, and taken up in dichloromethane (5 mL). Boc anhydride (0.062 mL, 0.27 mmol) was added, and the mixture stirred at room temperature for 18 hours.
- Triethylamine (34.6 ⁇ L, 0.248 mmol) and acetic anhydride (23.4 ⁇ L, 0.248 mmol) were added to a solution of the 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (30 mg, 0.062 mmol) in DMF (10 mL).
- the reaction mixture was stirred at room temperature for 20 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (20 mL) and sat. aq. NaHCO 3 (20 mL).
- aqueous phase was washed with ethyl acetate (3 ⁇ 20 mL) then the combined ethyl acetate phases were washed with brine (50 mL), dried (sodium sulfate) and evaporated.
- the residue was chromatographed (12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C.
- a mixture of diethyl succinate (26.1 g, 25.0 mL, 0.150 mol) and ethyl formate (11.1 g, 12.1 mL, 0.150 mol) was added drop wise over 1.5 hours to a stirred suspension of sodium (3.40 g, 0.150 mol) in diethyl ether (120 mL) at 0° C. under nitrogen. On completion of addition, stirring was continued at room temperature for 17 hours. Water (120 mL) was cautiously added to the resulting suspension and stirring continued until all the solids were dissolved. The layers were separated and the aqueous layer was washed with diethyl ether (100 mL).
- the aqueous layer was then acidified to pH 5 using 11 N HCl and extracted with diethyl ether (3 ⁇ 100 mL), the ethereal extracts of the acidified layer were combined, dried (Na 2 SO 4 ) then evaporated to dryness under reduced pressure to give the title compound (I105) (16.5 g) as a yellow mobile liquid.
- the crude product was not purified further and was used directly in the following step.
- Lithium 2-(4-(2-(2-((4-(1-(tert-butoxycarbonyl)piperidin-4-yl)phenyl)amino)-5-(trifluoro-methyl)pyrimidin-4-yl)ethyl)pyrimidin-5-yl)acetate (I113) (0.092 g, 0.16 mmol) was dissolved in dry THF (7 mL) and dry DMF (1 mL) under an atmosphere of nitrogen.
- Acetaldehyde (84.5 ⁇ L, 1.51 mmol) was added to a suspension of 2-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide (11) (91.0 mg, 0.188 mmol) in anhydrous methanol (10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (0.638 g, 3.01 mmol) was then added in one portion and the reaction was stirred at room temperature for 24 hours. The volatiles were removed in vacuo and the residue was diluted with EtOAc (35 mL) and sat. aq.
- Acetyl chloride (0.651 mL, 9.16 mmol) was added to a suspension of (2-chloropyridin-3-yl)acetic acid (I117) (1.048 g, 6.108 mmol) in MeOH (30 mL). The mixture was heated at reflux for 20 hours. The volatiles were removed in vacuo and the residue partitioned between DCM (100 mL) and sat. NaHCO 3 (100 mL). The layers were separated and the aqueous layer extracted with DCM (2 ⁇ 100 mL).
- the cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL). Water (75 mL) was added to the filtrate and the layers separated. The aqueous layer was extracted with EtOAc (2 ⁇ 75 mL). The combined organic extracts were washed with brine (100 mL) and dried over Na 2 SO 4 . After filtration the solvent was removed under reduced pressure to give a dark brown residue.
- the reaction mixture was heated under microwave irradiation at 120° C. for 10 minutes.
- the cooled mixture was diluted with EtOAc and passed through a plug of celite, washing with ethyl acetate (100 mL).
- the solvent was removed under reduced pressure and the residue partitioned between EtOAc (70 mL) and water (50 mL).
- the layers separated and the aqueous layer extracted with EtOAc (2 ⁇ 50 mL).
- the combined organic extracts were washed with brine (70 mL) and dried over Na 2 SO 4 .
- After filtration the solvent was removed under reduced pressure to give a dark brown residue.
- the residue was purified by column chromatography on silica gel (0-40% EtOAc in petroleum benzine 40-60° C.) to yield the title compound (I121) (81.5 mg, 72%) as a brown viscous oil which was used without further purification.
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US13/985,812 US20130324532A1 (en) | 2011-02-17 | 2012-02-17 | Fak inhibitors |
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US201161443773P | 2011-02-17 | 2011-02-17 | |
US201161523503P | 2011-08-15 | 2011-08-15 | |
US201161579719P | 2011-12-23 | 2011-12-23 | |
US13/985,812 US20130324532A1 (en) | 2011-02-17 | 2012-02-17 | Fak inhibitors |
PCT/GB2012/000175 WO2012110773A1 (fr) | 2011-02-17 | 2012-02-17 | Inhibiteurs de fak |
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US13/985,812 Abandoned US20130324532A1 (en) | 2011-02-17 | 2012-02-17 | Fak inhibitors |
US13/543,276 Active 2032-08-06 US9012461B2 (en) | 2011-02-17 | 2012-07-06 | FAK inhibitors |
US14/619,674 Active US9421205B2 (en) | 2011-02-17 | 2015-02-11 | FAK inhibitors |
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US13/543,276 Active 2032-08-06 US9012461B2 (en) | 2011-02-17 | 2012-07-06 | FAK inhibitors |
US14/619,674 Active US9421205B2 (en) | 2011-02-17 | 2015-02-11 | FAK inhibitors |
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US (3) | US20130324532A1 (fr) |
EP (1) | EP2675793B1 (fr) |
JP (1) | JP5937111B2 (fr) |
CN (1) | CN103534241B (fr) |
AU (1) | AU2012216893B2 (fr) |
CA (1) | CA2827171C (fr) |
DK (1) | DK2675793T3 (fr) |
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Cited By (2)
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US20130158005A1 (en) * | 2010-08-18 | 2013-06-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Pyrimidine derivatives as fak inhibitors |
US10106834B2 (en) | 2013-10-09 | 2018-10-23 | The General Hospital Corporation | Methods of diagnosing and treating B cell acute lymphoblastic leukemia |
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-
2012
- 2012-02-17 US US13/985,812 patent/US20130324532A1/en not_active Abandoned
- 2012-02-17 CA CA2827171A patent/CA2827171C/fr active Active
- 2012-02-17 JP JP2013553995A patent/JP5937111B2/ja active Active
- 2012-02-17 WO PCT/GB2012/000175 patent/WO2012110773A1/fr active Application Filing
- 2012-02-17 DK DK12705383.3T patent/DK2675793T3/en active
- 2012-02-17 CN CN201280018969.0A patent/CN103534241B/zh active Active
- 2012-02-17 AU AU2012216893A patent/AU2012216893B2/en active Active
- 2012-02-17 ES ES12705383.3T patent/ES2691673T3/es active Active
- 2012-02-17 EP EP12705383.3A patent/EP2675793B1/fr active Active
- 2012-07-06 US US13/543,276 patent/US9012461B2/en active Active
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2015
- 2015-02-11 US US14/619,674 patent/US9421205B2/en active Active
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130158005A1 (en) * | 2010-08-18 | 2013-06-20 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Pyrimidine derivatives as fak inhibitors |
US8906916B2 (en) * | 2010-08-18 | 2014-12-09 | Merck Patent Gmbh | Pyrimidine derivatives as FAK inhibitors |
US10106834B2 (en) | 2013-10-09 | 2018-10-23 | The General Hospital Corporation | Methods of diagnosing and treating B cell acute lymphoblastic leukemia |
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Publication number | Publication date |
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CA2827171C (fr) | 2019-04-09 |
WO2012110773A1 (fr) | 2012-08-23 |
EP2675793B1 (fr) | 2018-08-08 |
ES2691673T3 (es) | 2018-11-28 |
US9421205B2 (en) | 2016-08-23 |
AU2012216893A1 (en) | 2013-09-05 |
JP2014505718A (ja) | 2014-03-06 |
CN103534241A (zh) | 2014-01-22 |
EP2675793A1 (fr) | 2013-12-25 |
US9012461B2 (en) | 2015-04-21 |
CN103534241B (zh) | 2015-11-25 |
US20130017194A1 (en) | 2013-01-17 |
AU2012216893B2 (en) | 2016-08-11 |
JP5937111B2 (ja) | 2016-06-22 |
US20150231135A1 (en) | 2015-08-20 |
CA2827171A1 (fr) | 2012-08-23 |
DK2675793T3 (en) | 2018-11-12 |
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