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US 2013/0274263 A1Published application
Tubulin inhibitors
AssigneeYM Biosciences Australia Pty Ltd
InventorsChristopher John Burns, Andrew Frederick Wilks, Michael Francis Harte, Harrison Sikanyika, Emmanuelle Fantino
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Abstract
Compounds of general formula (I), (II), (III) and (V) are described for use in modulating microtubule polymerisation and in the treatment of associated disease states. Use of compounds (I), (III) and (V) in the treatment of kinase-associated disease states is also described. Further described are novel compounds of formula (II), (III) and (V).
Claims19
A method of modulating microtubule polymerisation in a subject, said method comprising administering a therapeutically effective amount of at least one compound of formula (I)
- or pharmaceutically acceptable salts, enantiomers, or diastereomers thereof, wherein:
- R1 is H or C1-4alkyl;
- Q is a bond or C1-4alkyl;
- A is aryl or hetaryl optionally substituted with 0-3 substituents independently selected from halogen, C1-4alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4alkylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5 and NR4SO2R5;
- R4 and R5 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR';
- R6 is selected from H and C1-4alkyl;
- R7 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
- R2 is 0-2 substituents independently selected from halogen, C1-4alkyl, OH, OC1-4alkyl, CH2F, CHF2, CF3, OCF3, CN, C1-4alkylNR8R9, OC1-4alkylNR8R9, CO2R8, CONR8R9, NR8R9, NR8COR9, NR10CONR8R9 and NR8SO2R9;
- R8 and R9 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR11;
- R10 is selected from H, C1-4alkyl, aryl and hetaryl;
- R11 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
- Y is halogen, OH, NR12R13, NR14COR12, NR14CONR12R13 or NR14SO2R13;
- R12 and R13 are each independently H, CH2F, CHF2, CF3, CN, C1-4alkyl optionally substituted with OH, OC1-4alkyl, NR15R16, cycloalkyl, cyclohetalkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-6 membered ring optionally containing an atom selected from O, S and NR14;
- R14, R15 and R16 are each independently selected from H and C1-4alkyl;
- n=0-4;
- W is selected from H, C1-4alkyl and C2-6alkenyl;
- where C1-3alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, and NR17;
- R17 is selected from H and C1-4alkyl.
16 more elements
A compound of formula (II)
- or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
- R1 is H or C1-4alkyl;
- Q is a bond, or C1-4alkyl;
- A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CH2F, CHF2, CF3, CN, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR4R5, Oaryl, Ohetaryl, CO2R4, CONR4R5, nitro, NR4R5, C1-4alkylNR4R5, NR6C1-4alkylNR4R5, NR4COR5, NR6CONR4R5 and NR4SO2R5;
- R4 and R5 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
- R6 is selected from H and C1-4alkyl;
- R7 is selected from H, C1-4alkyl, aryl, hetaryl, C1-4alkyl aryl and C1-4alkyl hetaryl;
- R2 is 0-2 substituents independently selected from C1-4alkyl and OC1-4alkyl;
- Y is CH2OH, OC1-4alkylOH, OC1-4alkylR12, OC1-4alkylNR12NR13, C(O)R12, CH2R12, COOR12, CONR12R13, OCONR12R13, CH2NR12R13, NHCOR12 or NHCONR12R13;
- R12 and R13 are each independently H, C1-2 alkyl, (CH2)3NEt2, (CH2)2NMe2 (CH2)5NH2, (CH2)2OH,
- W is selected from H, C1-4alkyl and C2-6alkenyl;
- where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
- R15, and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4 alkyl cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S, NR17;
- R17 is selected from H and C1-4alkyl;
- wherein when Y is CH2R12 then R12 is not H or C1-2alkyl.
12 more elements
A compound of formula (III)
- or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
- X1, X2, X3, X4 are selected from the following:
- (i) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (ii) X1 and X3 are N and X2 and X4 are C independently substituted with Y;
- (iii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (iv) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (v) X3 is N and X1, X2 and X4 are C independently substituted with Y;
- (vi) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (vii) X2 is N and X1, X3, and X4 are C independently substituted with Y;
- and
- (viii) X1, X2, and X3 are N and X4 is C substituted with Y;
- R1 is H, C1-6alkyl, C1-6alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5 or C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-2alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
- R7 is selected from H and C1-4alkyl;
- R2 is selected from C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9 and NR8COR12;
- R8 and R9 are each independently H, C1-4alkylNR11R13, hetaryl, cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
- R12 K is C2-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl;
- R11 and R13 are each independently H, C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
- R14 is selected from H and C1-4alkyl;
- R10 is H or C1-4alkyl;
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3 or OCF3;
- Q is a bond, or C1-4alkyl;
- W is selected from H, C1-4alkyl and C2-6alkenyl;
- where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR
- R15 and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR17;
- R17 is selected from H and C1-4alkyl;
- A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19,C1-4alkyl NR18R19, NR20C1-4l alkylNR18R19, NR18COR19, NR20CONR18R19 and NR18SO2R19;
- R18 and R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl, C1-4 alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR21;
- R21 is selected from H and C1-4alkyl;
- R20 is selected from H and C1-4alkyl;
- Y is selected from H, OH and NR22R23;
- R22, R23 are each independently H or C1-4alkyl.
28 more elements
A compound of formula (V)
- or pharmaceutically acceptable salts, enantiomers or diastereomers thereof, wherein:
- (i) X1 and X4 are N and X2 and X3 are C independently substituted with Y;
- (ii) X2 and X4 are N and X1 and X3 are C independently substituted with Y;
- (iii) X1 is N and X2, X3, and X4 are C independently substituted with Y;
- (iv) X3 is N and X1, X2, and X4 are C independently substituted with Y;
- (v) X4 is N and X1, X2, and X3 are C independently substituted with Y;
- (vi) X2 is N and X1, X3, and X4 are C independently substituted with Y;
- and
- (vii) X1, X2 and X3 are N and X4 is C substituted with Y;
- R1 is H, C1-6alkyl, C1-6alkylNR5R6, C1-6alkylNR5COR6, C1-6alkylNR5SO2R6, C1-6alkylCO2R5 or C1-6alkylCONR5R6, where R5 and R6 are each independently H, C1-4alkyl, aryl, hetaryl, C1-4alkylaryl, C1-4alkylhetaryl or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR7;
- R7 is selected from H and C1-4alkyl;
- R2 is selected from OH, OC1-6alkyl, C1-6alkylOH, OC2-6alkylOH, C1-6alkylNR8R9, OC2-6alkylNR8R9, C1-6alkylNR8COR9, OC2-6alkylNR8COR9, C1-6alkylhetaryl, OC2-6alkylhetaryl, OCONR8R9, NR8COOR9, NR10CONR8R9, CONR8R9 and NR8COR12;
- R8 and R9 are each independently H, C1-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
- R12 is C2-4alkyl, C1-4alkylNR11R13, hetaryl or cyclohetalkyl;
- R11 and R13 are each independently H or C1-4alkyl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR14;
- R14 is selected from H and C1-4alkyl;
- R10 is H or C1-4alkyl;
- R3 and R4 are each independently H, halogen, C1-4alkyl, OH, OC1-4alkyl, CF3 or OCF3;
- Q is a bond or C1-4alkyl;
- W is selected from H, C1-4alkyl and C2-6alkenyl;
- where C1-4alkyl or C2-6alkenyl may be optionally substituted with C1-4alkyl, OH, OC1-4alkyl or NR15R16;
- R15 and R16 are each independently H, C1-4alkyl, C1-4alkyl cycloalkyl, C1-4alkyl cyclohetalkyl, aryl or hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR17;
- R17 is selected from H and C1-4alkyl;
- A is aryl or hetaryl optionally substituted with 0-3 substituents independently chosen from halogen, C1-4alkyl, CF3, aryl, hetaryl, OCF3, OC1-4alkyl, OC2-5alkylNR18R19, Oaryl, Ohetaryl, CO2R18, CONR18R19, NR18R19, C1-4alkylNR18R19, NR20C1-4alkylNR18R19, NR18COR19, NR20CONR18R19 and NR18SO2R19;
- R18 and R19 are each independently H, C1-4alkyl, C1-4alkyl cyclohetalkyl, aryl, hetaryl, C1-4alkyl aryl or C1-4alkyl hetaryl, or may be joined to form an optionally substituted 3-8 membered ring optionally containing an atom selected from O, S and NR21;
- R21 is selected from H and C1-4alkyl;
- R2° is selected from H and C1-4alkyl;
- Y is selected from H, C1-4alkyl, OH and NR22R23;
- R22, R23 are each independently H or C1-4alkyl.
26 more elements
A compound of the formula:
- or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Dependencies are inferred from the claim text.