Enantiomers of Selected Fused Pyrimidones and Uses in the Treatment and Prevention of Cancer

Abstract

This invention relates to novel compounds having the structural formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds provide a treatment or prophylaxis of cancer.

1 . An enantiomer of a compound of formula (I): 
     
       
         
         
             
             
         
       
     
     including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, 
     wherein:
 X is selected from —C(CH 3 )— or —S— provided that when X is —S— then Y is —C(CH 3 )—; 
 Y is selected from —C(CH 3 )— or —O— or —S— provided that when Y is —C(CH 3 )— then X is not —C(CH 3 )—; 
 m is 0 or 1; 
 R 1  is F when m is 1; 
 R 2  and R 3  are independently selected from H or C 1-3 alkyl; wherein if both R 2  and R 3  are selected from C 1-3 alkyl they are identical; 
 n is 2 or 3; 
 R 4  and R 5  are independently selected from H or C 1-3 alkyl; 
 Z is optionally substituted phenyl, or optionally substituted benzothiophene wherein the number of optional substituents is 1 or 2 and each is independently selected from F, Cl, Br, CH 3  or CH 2 CH 3 ; and 
 “*” represents a chiral center; 
 
     wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of 1 mg/ml in methanol, at 20.0° C. measured at 589 nM is (+). 
   
   
       2 . An enantiomer of a compound of formula (I) according to  claim 1  wherein X is —C(CH 3 )— or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       3 . An enantiomer of a compound of formula (I) according to  claim 1  wherein X is —S— or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       4 . An enantiomer of a compound of formula (I) according to  claim 1  wherein Y is —C(CH 3 )— or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       5 . An enantiomer of a compound of formula (I) according to  claim 1  wherein Y is —S— or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       6 . An enantiomer of a compound of formula (I) according to  claim 1  wherein Y is —O— or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       7 . An enantiomer of a compound of formula (I) according to  claim 1  wherein m is 0 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       8 . An enantiomer of a compound of formula (I) according to  claim 1  wherein m is 1 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       9 . An enantiomer of a compound of formula (I) according to  claim 1  wherein R 2  and R 3  are both methyl or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       10 . An enantiomer of a compound of formula (I) according to  claim 1  wherein R 2  is methyl and R 3  is H or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       11 . An enantiomer of a compound of formula (I) according to  claim 1  wherein n is 2 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       12 . An enantiomer of a compound of formula (I) according to  claim 1  wherein n is 3 or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       13 . An enantiomer of a compound of formula (I) according to  claim 1  wherein R 4  and R 5  are both H or both methyl, or R 4  is H and R 5  is isopropyl or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       14 . An enantiomer of a compound of formula (I) according to  claim 1  wherein Z is 4-methylphenyl, benzothiophen-2-yl, 4-chlorophenyl, 4-bromophenyl, 4-methyl-3-fluorophenyl or 2,3-dichlorophenyl or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof. 
   
   
       15 . An enantiomer of a compound of formula (I), as recited in  claim 1 , including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, 
     wherein:
 X is selected from —C(CH 3 )— or —S— provided that when X is —S— then Y is —C(CH 3 )—; 
 Y is selected from —C(CH 3 )— or —O— or —S— provided that when Y is —C(CH 3 )— then X is not —C(CH 3 )—; 
 m is 0 or 1; 
 R 1  is F when m is 1; 
 one of R 2  and R 3  is H and the other is methyl or both R 2  and R 3  are methyl; 
 n is 2 or 3; 
 R 4  and R 5  are independently selected from H or C 1-3 alkyl; 
 Z is 4-methylphenyl, benzothiophen-2-yl, 4-chlorophenyl, 4-bromophenyl, 4-methyl-3-fluorophenyl or 2,3-dichlorophenyl; and 
 “*” represents a chiral center; 
 
     wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of 1 mg/ml in methanol, at 20.0° C. measured at 589 nM is (+). 
   
   
       16 . An enantiomer of a compound of formula (I), as recited in  claim 1 , including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, 
     wherein:
 Y is —S— and X is —C(CH 3 )—; 
 m is 0 or 1; 
 R 1  is F when m is 1; 
 one of R 2  and R 3  is H and the other is methyl or both R 2  and R 3  are methyl; 
 n is 2 or 3; 
 R 4  and R 5  are independently selected from H or C 1-3 alkyl; 
 Z is 4-methylphenyl, benzothiophen-2-yl, 4-chlorophenyl, 4-bromophenyl, 4-methyl-3-fluorophenyl or 2,3-dichlorophenyl; and 
 “*” represents a chiral center; 
 
     wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of 1 mg/ml in methanol, at 20.0° C. measured at 589 nM is (+). 
   
   
       17 . An enantiomer of a compound of formula (I), as recited in  claim 1 , including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, 
     wherein:
 Y is —O— and X is —C(CH 3 )—; 
 m is 0 or 1; 
 R 1  is F when m is 1; 
 one of R 2  and R 3  is H and the other is methyl or both R 2  and R 3  are methyl; 
 n is 2 or 3; 
 R 4  and R 5  are independently selected from H or C 1-3 alkyl; 
 Z is 4-methylphenyl, benzothiophen-2-yl, 4-chlorophenyl, 4-bromophenyl, 4-methyl-3-fluorophenyl or 2,3-dichlorophenyl; and 
 “*” represents a chiral center; 
 
     wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of 1 mg/ml in methanol, at 20.0° C. measured at 589 nM is (+). 
   
   
       18 . An enantiomer of a compound of formula (I), as recited in  claim 1 , including a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof, 
     wherein:
 Y is —C(CH 3 )— and X is —S—; 
 m is 0 or 1; 
 R 1  is F when m is 1; 
 one of R 2  and R 3  is H and the other is methyl or both R 2  and R 3  are methyl; 
 n is 2 or 3; 
 R 4  and R 5  are independently selected from H or C 1-3 alkyl; 
 Z is 4-methylphenyl, benzothiophen-2-yl, 4-chlorophenyl, 4-bromophenyl, 4-methyl-3-fluorophenyl or 2,3-dichlorophenyl; and 
 “*” represents a chiral center; 
 
     wherein said enantiomer is substantially free of the other enantiomer; and wherein the optical rotation of the enantiomer, when said enantiomer is dissolved at a concentration of 1 mg/ml in methanol, at 20.0° C. measured at 589 nM is (+). 
   
   
       19 . An enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof selected from: 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl]-propyl}-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-bromo-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-chloro-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-3-fluoro-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-2,3-dichloro-benzamide; 
     (+) Benzo[b]thiophene-2-carboxylic acid (3-amino-propyl)-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]amide; 
     (+) N-(2-Amino-ethyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide; 
     (+) N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide; 
     (+) N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-propyl]-N-(3-isopropylamino-propyl)-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-propyl]-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide; 
     (+) N-(2-Amino-ethyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide; 
     (+) N-(2-Amino-ethyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide; 
     (+) N-(2-Amino-ethyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-3-fluoro-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-bromo-benzamide; 
     (+) N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-N-(3-dimethylamino-propyl)-4-methyl-benzamide; 
     (+) N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-N-(3-dimethylamino-propyl)-4-bromo-benzamide; 
     (+) N-[1-(5-Benzyl-3-methyl-4-oxo-4,5-dihydro-isothiazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-N-(3-dimethylamino-propyl)-3-fluoro-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-[1-(5-benzyl-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl)-2-methyl-propyl]-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(4-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide; 
     (+) N-(3-Amino-propyl)-N-{1-[5-(3-fluoro-benzyl)-3-methyl-4-oxo-4,5-dihydro-isoxazolo[5,4-d]pyrimidin-6-yl]-2-methyl-propyl}-4-methyl-benzamide; or 
     (+) N-(3-Amino-propyl)-N-[1-(6-benzyl-3-methyl-7-oxo-6,7-dihydro-isothiazolo[4,5-d]pyrimidin-5-yl)-propyl]-4-methyl-benzamide. 
   
   
       20 . An enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as recited in  claim 1  which is substantially free of its corresponding (−) enantiomer. 
   
   
       21 . An enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as recited in  claim 1 , having no more than 1% w/w of the corresponding (−) enantiomer. 
   
   
       22 . An enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as recited in  claim 1 , having no more than 2% w/w of the corresponding (−) enantiomer. 
   
   
       23 - 26 . (canceled) 
   
   
       27 . A method for the prophylaxis treatment of cancers associated with comprising administering to a human in need of such treatment a therapeutically effective amount of an enantiomer of a compound of formula (I) as defined in  claim 1 . 
   
   
       28 . A method for the treatment of cancer comprising administering to a human a therapeutically effective amount of an enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined in  claim 1 . 
   
   
       29 . A method for producing an Eg5 inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of an enantiomer of a compound of formula (I), or a pharmaceutically acceptable salt or an in vivo hydrolysable thereof, as defined in  claim 1 . 
   
   
       30 . A method of treating carcinomas of the brain, breast, ovary, lung, colon and prostate, multiple myeloma leukemias, lymphomas, tumors of the central and peripheral nervous system, melanoma, fibrosarcoma, Ewing's sarcoma and osteosarcoma, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of an enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable thereof, as defined in  claim 1 . 
   
   
       31 . A pharmaceutical composition comprising an enantiomer of a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof as defined in  claim 1  together with at least one pharmaceutically acceptable carrier, diluent or excipient. 
   
   
       32 - 34 . (canceled)