Stereoisomerically enriched 3-aminocarbonyl bicycloheptene pyrimidinediamine compounds and their uses
View Patent ↗The present invention provides stereoisomers and stereoisomeric mixtures of 3-amino carbonyl-bicycloheptene-2,4-pyrimidinediamine compounds having antiproliferative activity, compositions comprising the compounds and methods of using the compounds to inhibit cellular proliferation and to treat proliferate diseases such as tumorigenic cancers.
1. A method for preparing a compound of formula (I),
or a salt or N-oxide thereof, comprising
contacting a compound of the formula,
with a compound of the formula,
under suitable reaction conditions to provide the compound of formula (I), wherein
each R 1 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —C(O)OR a , halo, —CF 3 and —OCF 3 ;
each R 2 is independently selected from the group consisting of hydrogen, lower alkyl, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , —NHC(O)R a , halo, —CF 3 , —OCF 3 ,
each R 3 is independently selected from the group consisting of hydrogen, lower alkyl, —(CH 2 ) n —OH, —OR a , —O(CH 2 ) n —R a , —O(CH 2 ) n —R b , halo, —CF 3 , —OCF 3 ,
each R 4 is independently selected from the group consisting of hydrogen, lower alkyl, arylalkyl, —OR a , —NR c R c , —C(O)R a , —C(O)OR a and —C(O)NR c R c ;
R 5 is hydrogen, halo, fluoro, —CN, —NO 2 , CO 2 R a or —CF 3 ;
each n is independently an integer from 1 to 3;
each R a is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl;
each R b is independently selected from the group consisting of —OR a , —CF 3 , —OCF 3 , —NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c and —C(O)NR a R d ;
each R c is independently selected from the group consisting of hydrogen and lower alkyl, or, alternatively, two R c substituents may be taken together with the nitrogen atom to which they are bonded to form a 5-7 membered saturated ring which optionally includes 1-2 additional heteroatomic groups selected from O, NR a , NR a —C(O)R a , NR a —C(O)OR a and NR a —C(O)NR a ;
each R d is independently lower mono-hydroxyalkyl or lower di-hydroxyalkyl; and X is a halogen.
2. The method of claim 1 , wherein the compound of formula (I) is enriched in the corresponding diastereomer of structural formula (Ia), designated the (1R,2R,3S,4S) diastereomer:
3. The method of claim 2 , wherein
R 1 is hydrogen;
R 2 is
and
R 3 is other than
4. The method of claim 3 , wherein R 3 is hydrogen, methyl, methoxy, trifluoromethyl or chloro.
5. The method of claim 2 , wherein
R 1 is hydrogen,
R 2 is other than
and
R 3 is
6. The method of claim 5 , wherein R 2 is hydrogen, methyl, methoxy, trifluoromethyl or chloro.
7. The method of claim 2 , wherein
R 2 is other than
and
R 3 is other than
8. The method of claim 2 , wherein R 1 and R 2 are each hydrogen and R 3 is —OCH 2 NHR a .
9. The method of claim 2 , wherein R 1 , R 2 and R 3 are each, independently of one another selected from the group consisting of hydrogen, methyl, methoxy, trifluoromethyl and chloro, with the proviso that at least two of R 1 , R 2 and R 3 are other than hydrogen.
10. The method of claim 2 , wherein
R 1 is hydrogen,
R 2 is selected from the group consisting of hydrogen,
and
R 3 is selected from the group consisting of hydrogen, lower alkyl, halo, —CF 3 ,
11. The method of claim 10 , wherein
R 3 is selected from the group consisting of hydrogen, methyl, chloro, —CF 3 ,
and
R 4 is methyl, —COR a or —CO(O)R a where R a is methyl or ethyl.
12. The method of claim 2 , wherein
R 2 is selected from the group consisting of hydrogen,
and
R 3 is selected from the group consisting of hydrogen, lower alkyl, halo, —CF 3 ,
13. The method of claim 12 , wherein
R 3 is selected from the group consisting of hydrogen, methyl, chloro, —CF 3 ,
and R 4 is methyl, —COR a or —CO(O)R a wherein R a is methyl or ethyl.
14. The method of claim 2 , wherein R 2 is
R 4 is —COR a wherein R a is methyl; and R 3 is hydrogen.
15. The method of claim 2 , wherein R 2 is
R 4 is —CO(O)R a wherein R a is ethyl, and R 3 is hydrogen.
16. The method of claim 2 , wherein R 2 is
and R 3 is hydrogen.
17. The method of claim 2 , wherein
R 2 is hydrogen;
R 3 is
and
R 4 is methyl, —COR a or —CO(O)R a where R a is methyl or ethyl.
18. The method of claim 2 , wherein R 2 is
R 4 is methyl and R 3 is selected from the group consisting of hydrogen, methyl, chloro and —CF 3 .
19. The method of claim 18 , wherein R 3 is methyl.
20. The method of claim 2 , wherein R 5 is fluoro.
21. The method of claim 2 , wherein the compound of formula (I) is substantially stereoisomerically pure or stereoisomerically pure (1R,2R,3S,4S)-N4-(3-aminocarbonylbicyclo[2.2.1]hept-5-ene-2-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine.
22. The method of claim 2 , wherein the compound of formula (I) comprises at least about 90% of the diastereomer of structural formula (Ia).
23. The method of claim 2 , wherein the compound of formula (I) comprises the substantially pure diastereomer of structural formula (Ia).
24. The method of claim 1 , wherein the compounds are contacted in the presence of trifluoroacetic acid.