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US 2008/0176830 A1Published application
Compounds, Compositions, and Methods
OwnerNicholas D. Adams, Michael Gerard Darcy +6inventors
InventorsNicholas D. Adams, Michael Gerard Darcy, Dashyant Dhanak, Kevin J. Duffy, Duke M. Fitch, Steven David Knight, Kenneth Allen Newlander, Antony N. Shaw
Life of this patent
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Abstract
Compounds useful for treating cellular proliferative diseases and disorders by modulating the activity of KSP are disclosed.
Claims20
A compound of Formula (I):
- where
- W is NR1, O, CH2, or CH(OH);
- R1 is H, C1-4alkyl, C1-4alkylaryl, CO2But, CO1-4alkyl, CH2CONMe2, or CO2CH2Ph;
- X is C═O, C═S, C═NOH, SO2, CH2, or CH(OH), provided that, when W is CH(OH), X is not SO2;
- Y-Z is V—CHR2;
- where
- V is O, NR3, or CHR4;
- R2 is H or C1-4alkyl;
- R3 is H, C1-2alkylOH, or C1-2alkyl;
- and
- R4 is H, C1-4alkyl, COSEt, NH2, OH, NHCHO, NHCOC1-4alkyl, NHSO2C1-4alkyl, CO2H, CH2OH, or CONH2;
- or Y-Z is V2═CR5, where
- V2 is N or CH;
- and
- R5 is H, Me or NH2;
- or Y-Z is V3—U, where
- V3 is CMe2, CO or CHR4;
- U is NR7, O, S, or SO2;
- R7 is H, CHO, or CH2R8, and
- R8 is H, CN, CO2Me, CONH2, CO2H, or CH2OH;
- or Y-Z is CH═N;
- A is N or CR10;
- R10 is H, F, CO2H, NH2, or NO2;
- D is selected from:
- B is N or CR11;
- R11 is H or F;
- R12 is H, halogen, Me, NH2, NHAc, NO2, CF3, 1-pyrryl, or CH2CN;
- R13 is H, CF3, CN, SO2CF3, SO2NMe2, SO2C1-3alkyl, SC1-3alkyl, halogen, 1-indolyl, Pri, But, NMe2, or NO2;
- or R12 and R13 taken together are OCF2O;
- provided that, when R13 is H, B and R12 are CH and CF3 respectively or CF and F respectively;
- and
- R14 is CF3 or C2-5alkyl;
- or a pharmaceutically acceptable derivative or solvate thereof.
30 more elements
A compound of Formula (II):
- where
- W is NR1, O, CH2, or CH(OH);
- R1 is H, C1-4alkyl, C1-4alkylaryl, CO2But, CO1-4alkyl, CH2CONMe2, or CO2CH2Ph;
- X is C═O, C═S, C═NOH, SO2, CH2, or CH(OH), provided that, when W is CH(OH), X is not SO2;
- Y2 is O, NR3, CHR4, or CMe2;
- Y3 is CH2, O, S, or NH;
- Z2 is CHR2, NR7, O, S, or SO2;
- or Y3-Z2 taken together is N═CH when Y2 is CHR4;
- provided that, when Y2 is O or NR3, Y3 is CH2 and Z2 is CHR2;
- and
- provided that, when Y3 is O, S, or NH, Z2 is CHR2 and Y2 is CHR4;
- and
- provided that, when Z2 is NR7, O, S, or SO2, Y2 is CHR4, or CMe2 and Y3 is CH2;
- R2 is H or C1-4alkyl;
- R3 is H, C1-2alkylOH, or C1-2alkyl;
- R4 is H, C1-4alkyl, COSEt, NH2, OH, NHCHO, NHCOC1-4alkyl, NHSO2C1-4alkyl, CO2H, CH2OH, or CONH2;
- R7 is H, CHO, or CH2R8;
- R8 is H, CN, CO2Me, CONH2, CO2H, or CH2OH;
- A is N or CR10;
- R10 is H, F, CO2H, NH2, or NO2;
- D is selected from:
- B is N or CR11;
- R11 is H or F;
- R12 is H, halogen, Me, NH2, NHAc, NO2, CF3, 1-pyrryl, or CH2CN;
- R13 is H, CF3, CN, SO2CF3, SO2NMe2, SO2C1-3alkyl, SC1-3alkyl, halogen, 1-indolyl, Pri, But, NMe2, or NO2;
- or R12 and R13 taken together are OCF2O;
- provided that, when R13 is H, B and R12 are CH and CF3 respectively or CF and F respectively;
- and
- R14 is CF3 or C2-5alkyl;
- or a pharmaceutically acceptable derivative or solvate thereof.
27 more elements
A compound of Formula (III):
- where
- A is N or CR10;
- R10 is H, F, CO2H, NH2, or NO2;
- D is selected from:
- B is N or CR11;
- R11 is H or F;
- R12 is H, halogen, Me, NH2, NHAc, NO2, CF3, 1-pyrryl, or CH2CN;
- R13 is H, CF3, CN, SO2CF3, SO2NMe2, SO2C1-3alkyl, SC1-3alkyl, halogen, 1-indolyl, Pri, But, NMe2, or NO2;
- or R12 and R13 taken together are OCF2O;
- provided that, when R13 is H, B and R12 are CH and CF3 respectively or CF and F respectively;
- and
- R14 is CF3 or C2-5alkyl;
- or a pharmaceutically acceptable derivative or solvate thereof.
10 more elements
A compound selected from:
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide
- 6-[4-(trifluoromethyl)phenyl]-1H-2,1,3-benzothiadiazine 2,2-dioxide
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 1-(phenylmethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinethione
- 6-[4-(trifluoromethyl)phenyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one
- 4-methyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 7-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinoxalinone
- 4-methyl-6-[4-(trifluoromethyl)phenyl]-2(1H)-quinazolinone
- 4-ethyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 8-fluoro-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinethione
- 6-(4-Trifluoromethyl-phenyl)-3,4-dihydro-1H-quinolin-2-one
- 6-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinoxalinone
- 6-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinethione
- 7-[4-(trifluoromethyl)phenyl]-2H-1,4-benzothiazin-3(4H)-one
- 7-[4-(trifluoromethyl)phenyl]-2H-1,4-benzoxazin-3(4H)-one
- 6-[4-(Trifluoromethyl)phenyl]-2(1H)-quinolinone
- 6-[4-(Trifluoromethyl)phenyl]-2(1H)-quinoxalinone
- 7-[4-(trifluoromethyl)phenyl]-2H-1,4-benzothiazin-3(4H)-one 1,1-dioxide
- 3-Oxo-7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinoxalinecarbaldehyde
- [3-Oxo-7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinoxalinyl]acetonitrile
- Methyl [3-oxo-7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinoxalinyl]acetate
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,8-naphthyridin-2(1H)-one
- [3-Oxo-7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinoxalinyl]acetic acid
- 1-methyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one
- 3-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 6-[4-(Trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline
- 1,1-dimethylethyl 2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinolinecarboxylate
- S-ethyl 2-oxo-6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-3-quinolinecarbothioate
- 6-[4-(trifluoromethyl)phenyl]-1H-4,2,1-benzoxathiazine 2,2-dioxide
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-naphthalenone
- 6-[4-(Trifluoromethyl)phenyl]-3,4-dihydro-1H-2,1-benzothiazine 2,2-dioxide
- 7-[4-(trifluoromethyl)phenyl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one
- 2-[3-oxo-7-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinoxalinyl]acetamide
- 7-[3-(trifluoromethyl)phenyl]-2H-1,4-benzothiazin-3(4H)-one
- 3,3-Dimethyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinoxalinone
- 1,1-dimethylethyl 3-oxo-7-[4-(trifluoromethyl)phenyl]-2,3-dihydro-4H-1,4-benzothiazine-4-carboxylate
- 6-(4-Fluoro-3-methyl-phenyl)-3,4-dihydro-1H-quinolin-2-one
- 4-(2-hydroxyethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinoxalinone
- 4-methyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinoxalinone
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-naphthalenone oxime
- 8-fluoro-6-[4-(trifluoromethyl)phenyl]-2(1H)-quinolinone
- 8-fluoro-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-(3,5-Difluoro-phenyl)-3,4-dihydro-1H-quinolin-2-one
- 6-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-3,4-dihydro-1H-quinolin-2-one
- 7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one
- 6-(3-Fluoro-4-(trifluoromethyl)phenyl)-3,4-dihydro-1H-quinolin-2-one
- 7-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one
- 6-(4-Isopropyl-phenyl)-3,4-dihydro-1H-quinolin-2-one
- 6-(4-Trifluoromethanesulfonyl-phenyl)-3,4-dihydro-1H-quinolin-2-one
- ±6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-2-naphthalenol
- 7-(2,2-Difluorobenzo[1,3]dioxol-5-yl)-4H-benzo[1,4]thiazin-3-one
- 3-methyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinazolinone
- 8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
- 7-(4-Trifluoromethanesulfonyl-phenyl)-4H-benzo[1,4]thiazin-3-one
- 7-(3-Fluoro-4(trifluoromethyl)phenyl)-4H-benzo[1,4]thiazin-3-one
- 8-fluoro-6-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[3-nitro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[3-chloro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[6-(trifluoromethyl)-3-pyridinyl]-3,4-dihydro-2(1H)-quinolinone
- N,N-dimethyl-4-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)benzenesulfonamide
- 6-[4-(dimethylamino)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-(4-tert-Butyl-phenyl)-3,4-dihydro-1H-quinolin-2-one
- 6-{4-[(1-methylethyl)thio]phenyl}-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2H-chromen-2-one
- 7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one
- 6-[3-amino-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 8-amino-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-(4-Trifluoromethanesulfonyl-phenyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one
- 6-[4-(methylsulfonyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-(4-nitrophenyl)-3,4-dihydro-2(1H)-quinolinone
- 4-Amino-6-[4-(trifluoromethyl)phenyl]-2(1H)-quinolinone
- 6-{4-[(1-methylethyl)sulfonyl]phenyl}-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-1-naphthalenol
- 7-(3-Fluoro-4(trifluoromethyl)phenyl)-1,3,4,5-tetrahydro-benzo[b]azepin-2-one
- 8-nitro-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one
- 3-amino-8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one trifluoroacetate
- 6-(4-bromophenyl)-3,4-dihydro-2(1H)-quinolinone
- 1-(3-methylbutanoyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- N,N-dimethyl-2-[2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinolinyl]acetamide
- (3S)-3-amino-8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate
- 8-[4-(trifluoromethyl)phenyl]-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one
- ±3-Hydroxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
- 1,1-dimethylethyl 4-oxo-8-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1,5-benzothiazepine-5(2H)-carboxylate
- N-[5-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-(trifluoromethyl)phenyl]acetamide
- N-{(3S)-4-oxo-8-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl}acetamide
- N-{(3S)-4-oxo-8-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl}methanesulfonamide
- 1-acetyl-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-[4-(trifluoromethyl)phenyl]-1,5-dihydro-4,1-benzoxazepin-2(3H)-one
- phenylmethyl 2-oxo-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1(2H)-quinolinecarboxylate
- 5-(3-methylbutanoyl)-8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one
- 6-[3,5-difluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 3-methyl-7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-2-one
- (3R)-3-amino-8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one trifluoroacetate
- 7-[4-(Trifluoromethyl)phenyl]-1,3-dihydro-2H-1,4-benzodiazepin-2-one
- 8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one
- 8-[4-(trifluoromethyl)phenyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one 1,1-dioxide
- 8-amino-6-[3-fluoro-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(1,1-dimethylpropyl)-1-cyclohexen-1-yl]-3,4-dihydro-2(1H)-quinolinone
- [5-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)-2-(trifluoromethyl)phenyl]acetonitrile
- 2-Oxo-6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-3-quinolinecarboxylic acid
- (3S)-3-methyl-7-[4-(trifluoromethyl)phenyl]-1,3,4,5-tetrahydro-2H-1,4-benzodiazepin-2-one
- 2-Oxo-6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-8-quinolinecarboxylic acid
- 2-{4-oxo-8-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-1-yl}acetamide
- (+)-3-Hydroxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 3-Hydroxy-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(1,1-dimethylethyl)-1-cyclohexen-1-yl]-3,4-dihydro-2(1H)-quinolinone
- 6-(4-ethyl-1-cyclohexen-1-yl)-3,4-dihydro-2(1H)-quinolinone
- 6-(4-bromo-3-nitrophenyl)-3,4-dihydro-2(1H)-quinolinone
- 6-(4-bromo-3-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone
- 6-[4-bromo-3-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(1H-indol-1-yl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-(4-bromo-3-methylphenyl)-3,4-dihydro-2(1H)-quinolinone
- 6-(3-amino-4-bromophenyl)-3,4-dihydro-2(1H)-quinolinone
- 8-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-2,3-dihydro-5H-benzo[b][1,4]thiazepin-4-one
- 2-Oxo-6-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-3-quinolinecarboxamide
- 6-[3-(1H-pyrrol-1-yl)-4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(trifluoromethyl)-1-cyclohexen-1-yl]-3,4-dihydro-2(1H)-quinolinone
- 6-[4-(1-methylethyl)-1-cyclohexen-1-yl]-3,4-dihydro-2(1H)-quinolinone
- ±6-[3,5-difluoro-4-(trifluoromethyl)phenyl]-3-hydroxy-3,4-dihydro-2(1H)-quinolinone
- ±3-(Hydroxymethyl)-6-[4-(trifluoromethyl)phenyl]-3,4-dihydro-2(1H)-quinolinone
- 7-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-4H-benzo[1,4]oxazin-3-one
- 4-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)benzonitrile
- 2-fluoro-4-(2-oxo-1,2,3,4-tetrahydro-6-quinolinyl)benzonitrile
- ±3-hydroxy-6-{4-[(trifluoromethyl)sulfonyl]phenyl}-3,4-dihydro-2(1H)-quinolinone
- ±6-[3-fluoro-4-(trifluoromethyl)phenyl]-3-hydroxy-3,4-dihydro-2(1H)-quinolinone;
- and pharmaceutically acceptable derivatives and solvates thereof.
128 more elements
Dependencies are inferred from the claim text.