Cycloalkyl substituted pyrimidinediamine compounds and their uses

1. A compound according to structural formula (I):

or a salt or N-oxide thereof, wherein:

R 2 is a substituted phenyl of the formula

 where one of R 11 , R 12 and R 13 is a water-solubilizing group and the other two of R 11 , R 12 and R 13 are, independently of one another, selected from hydrogen, (C 1 -C 8 ) alkyl, halo, hydroxy, (C 1 -C 3 ) hydroxyalkyl, —O(CH 2 ) x —R b , —NR c R c , —C(O)NR c R c , —C(O)NHR a and —C(O)NHCH 3 ,

R 4 is a saturated or unsaturated, bridged or unbridged (C 3 -C 16 )cycloalkyl ring substituted with an R 7 group;

R 5 is selected from hydrogen, (C 1 -C 8 )alkyl optionally substituted with one or more of the same or different R 8 groups provided the (C 1 -C 8 )alkyl optionally substituted with one or more of the same or different R 8 groups is not —CF 3 , and an electronegative group; and

R 7 is —C(O)OR d or —C(O)NR d R d ,

wherein

the electronegative group is selected from the group consisting of —CN, —NC, halo, (C 1 -C 3 ) haloalkoxy, (C 1 -C 3 ) perhaloalkoxy, —C(O)R a , —C(O)OR a , —C(O)CF 3 , and —C(O)OCF 3 ;

each R 8 group is, independently of the others, selected from a water-solubilizing group, R a , R b , (C 3 -C 8 )cycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, lower heterocycloalkyl optionally substituted with one or more of the same or different R a and/or R b groups, (C 1 -C 8 )alkoxy optionally substituted with one or more of the same or different R b groups and —O—(CH 2 ) x —R b , where x is an integer ranging from 1 to 6;

each R a is, independently of the others, selected from hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 6 -C 14 ) aryl, naphthyl, (C 7 -C 20 ) arylalkyl and benzyl;

each R b is, independently of the others, selected from ═O, —OR a , (C 1 -C 3 ) haloalkyloxy, —OCF 3 , ═S, —SR a , ═NR a —NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ═N 2 —N 3 , —S(O)R a , —S(O) 2 R a , —S(O) 2 OR a , —S(O)NR c R c , —S(O) 2 NR c R c , —OS(O)R a , —OS(O) 2 R a , —OS(O) 2 OR a , —OS(O) 2 NR c R c , —C(O)R a , —C(O)OR a , —C(O)NR c R c , —C(NH)NR c R c , —C(NR a )NR c R c , —C(NOH)R a , —C(NOH)NR c R c , —OC(O)R a , —OC(O)OR a , —OC(O)NR c R c , —OC(NH)NR c R c and OC(NR a )NR c R c ;

each R c is, independently of the others, selected from R a or, alternatively, two R c that are bonded to the same nitrogen atom may be taken together with this nitrogen atom to form a 5-8 membered heterocycloalkyl group which may optionally include from 1 to 3 additional heteroatomic groups selected from O, S, N—(CH 2 ) y —R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR a R a , where y is an integer ranging from 0 to 6, and which may optionally include one or more of the same or different R 8 and/or (C 1 -C 8 )alkyl substituents; and

each R d is, independently of the others, selected from R a , R c and a chiral auxiliary group;

the water-solubilizing groups are independently:

 morpholino, piperidinyl, (C 1 -C 6 ) N-alkyl piperidinyl, N-methyl piperidinyl, piperazinyl, (C 1 -C 6 ) N-alkylpiperazinyl, N-methylpiperazinyl, N-ethyl piperidinyl, N-ethyl piperazinyl, pyrrolidinyl, N-alkyl pyrrolidinyl, N-methyl pyrrolidinyl, diazepinyl, N-ethyl pyrrolidinyl, N-alkyl azepinyl, N-methyl azepinyl, N-ethyl azepinyl, homopiperazinyl, N-methyl homopiperazinyl, N-ethyl homopiperazinyl, or imidazoyl, where Y is selected from CH and N, Z is selected from CH 2 , O, S, N, NH, N—(CH 2 ) y -R a , N—(CH 2 ) y —C(O)R a , N—(CH 2 ) y —C(O)OR a , N—(CH 2 ) y —S(O) 2 R a , N—(CH 2 ) y —S(O) 2 OR a and N—(CH 2 ) y —C(O)NR c R c , with the proviso that Y and Z are not both simultaneously CH and CH 2 , respectively; and

the chiral auxiliary group is

wherein R 9 is hydrogen or (C 1 -C 8 ) alkyl.

2. The compound of claim 1 in which R 5 is an electronegative group.

3. The compound of claim 2 in which R 5 selected from cyano, halo, and trifluoromethoxy.

4. The compound of claim 1 in which R 11 is hydrogen and one of R 12 and R 13 is the water-solubilizing group.

5. The compound of claim 1 in which R 11 is hydrogen, R 12 is the water-solubilizing group and R 13 is selected from hydrogen, (C 1 -C 3 ) alkyl, and an electronegative group.

6. The compound of claim 5 in which the electronegative group is selected from (C 1 -C 3 ) alkoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyano, —(CH 2 ) x , —OR f and —(CH 2 ) x —C(O)NRHR f , where x is as previously defined and R f is selected from hydrogen lower alkyl and (C 1 -C 3 ) alkanyl.

7. The compound of claim 1 in which R 2 is 3-methyl -4-(1-methyl-piperazin-4-yl)phenyl.

8. The compound of claim 1 in which R 4 is a substituted unbridged saturated lower cycloalkyl of the formula

where x is an integer ranging from 1 to 6 or a substituted unsaturated unbridged lower cycloalkyl selected from

9. The compound of claim 8 which is enriched in one or more of the (1S, 2R), (1R, 2S)and (1R, 2R)diastereomer.

10. The compound of claim 8 which is enriched in the (1R, 2S)diastereomer.

11. The compound of claim 8 which is substantially free of the (1S, 2S) diastereomer.

12. The compound of claim 8 which is substantially pure in the (1R, 2S)diastereomer.

13. The compound of claim 1 in which R 4 is an unsaturated unbridged lower cycloalkyl selected from

14. The compound of claim 13 which is enriched in one or more respective diastereomers selected from (1S, 3S or 4S), (1S, 3R or 4R), (1R, 3S or 4S) and (1R, 3R or 4R).

15. The compound of claim 13 which is enriched in the (1R, 3S or 4S) diastereomer.

16. The compound of claim 13 which is substantially free of the (1S, 3S or 4S) diastereomer.

17. The compound of claim 13 which is substantially pure in the (1R, 3S or 4S) diastereomer.

18. A compound according to claim 1 , which is:

(1S, 2R)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1R, 2S)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1S, 2S)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1R, 2R)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1S, 2R)-N4-(2-Aminocarbonylcyclopent-1yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-methyl-3-(4-methylpiperazin-1-yl)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;

cis N4-(2-amino-carbonylcyclopent-1yl)-5- fluoro N2[3- methyl-4-(piperazin-1-yl) phenyl]-2,4- pyrimidinediamine;

cis-N4-[2-(N-cyclopropylmethyl)aminocarbonylcyclopent-1-yl]-5-fluoro-N2[4-4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

cis-N4-[2-(N-cyclopropyl)aminocarbonylcyclopent-1-yl]-5-fluoro-N2[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-5-fluoro-N2-[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl))-5-fluoro-N2[3-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

N2[4-(4-Acetylpiperazino)phenyn-N4-(2-carboxamidocyclopentyl)-5-fluoro -2,4-pyrimidinediamine;

N2-[3-(4-Acetylpiperazino)phenyl]-N4-(2-carboxamidocyclopentyl)-5-fluoro -2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-5-fluoro-N2-(4-morpholinophenyl)-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-N2-[4-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-5-fluoro-N2-(3-morpholinophenyl)-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-N2-[3-(4-ethoxycarbonylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-N2-[3-chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine;

N4-(2-Carboxamidocyclopentyl)-5-fluoro-N2[4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine Monohydrochloride Salt;

cis-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(cis)-N4-(2-Carboxamidocyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazino)-3-trifluoromethylphenyl]-2,4-pyrimidinediamine;

(cis)-N4-(2-Carboxamidocyclopent-1-yl)-N2-[3-chloro-4-(4-methylpiperazino)phenyl]-5-fluoro-2,4-pyrimidinediamine;

(cis)-N4-(2-Carboxamidocyclopent-1-yl)-5-fluoro-N2[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

(cis)-N4-(2-Carboxamidocyclopent-1-yl)]-5-fluoro-N2[4-(4-methylpiperazino)-3-trifluoromethylphenyl]-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt;

(1S 2R)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1S,2S)-5-fluoro-N4-(2-methoxycarbonylcyclopent-1-yl)-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

(1S,2S)-5-fluoro-N4-(2-hydroxycarbonylcyclopent-1-yl)-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

(1S,2S)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1R,2S)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1R,2R)-N4-(2-Ethoxycarbonylcyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

(1R,2R)- 5-fluoro-N4-(2-hydroxycarbonylcyclopent-1-yl)-N2-[3-methyl-4-(4-methylpiperazino)phenyl]-2,4-pyrimidinediamine;

(1R,2R)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazin-1-yl)-3-methylphenyl]-2,4-pyrimidinediamine;

(1S,3R)-N4-(3-Methoxycarbonylcyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[4-(4-methylpiperazin-1-yl)-3-methoxymethylenephenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2[3-hydroxymethylene-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

cis-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-N4-(2-methoxycarbonylcyclopent-1-yl)-2,4-pyrimidinediamine (1S,3R)-N4-(3-Carboxycyclopent-1-yl)-5-fluoro-N2[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

(1S,3S)-N4-(3-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

(1R,2S)-N4-(2-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine Bis Hydrogen Chloride Salt;

cis-N4-(2-aminocarbonylcyclohex-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

(cis)-N4-(2-aminocarbonylcyclohex-4-en-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl) phenyl]-2,4-pyrimidinediamine;

(1S,4R)-cis-N4-(4-Aminocarbonylcyclopent-2-ene-1-yl)-5-fluoro-N2[3-methyl -4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

(1R,4S)-cis-N4-(4-Aminocarbonylcyclopent-2-ene-1-yl)-5-fluoro-N2[3-methyl -4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclohex-5-ene-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(2-am inocarbonylcyclohex-4-ene-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(1-Aminocarbonylcyclopent-3-ene-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

5-Fluoro-N4-(1-methoxycarbonylcyclopent-1-yl)-N2-[3- methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(1-Cyclopropylaminocarbonylcyclopent-3-en-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(1-Carboxycyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(1-Cyclopropylaminocarbonylcyclopent-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

N4-(1-Aminocarbonylcyclopent-1-yl)-5-fluoro-N2[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2-{4[-(4-methylpiperazin-1-yl)-butan-1-one-4-yl]phenyl}-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2-{4-[(4-methylpiperazin-1-yl)-ethan-1-one-2-yl]phenyl}-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2-{4[-(4-methylpiperazin-1-yl)-propan-1-one-3-yl] } phenyl-2,4-pyrimidinediamine;

c is-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2[4-(4-methylpiperazin-1-yl-carbonyl)phenyl]-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-1-yl)-N24-(2,6-dimethylmorpholino)-3-methyl]phenyl-5-fluoro-2,4-pyrimidinediamine;

cis-N4-(2-aminocarbonylcyclopent-4-en-1-yl)-5-fluoro-N2-[3-methyl-4-(4-methylpiperazin-1-yl)phenyl]-2,4-pyrimidinediamine; or cis-N4-(2-aminocarbonylcyclopent-1-yl)-5-fluoro-N2[3-methyl-4-(pyrrolidino)phenyl]-2,4-pyrimidinediamine.

19. A method of treating cancer, the method comprising administering to a subject in need thereof an amount of a compound according to claim 1 effective to treat the cancer, wherein the cancer is selected from colon, lung, and pancreatic cancer.

20. The method of claim 19 in which the compound is administered in the form of a pharmaceutical composition.

21. The method of claim 19 in which the compound is administered orally.

22. The method of claim 19 in which the compound is administered intravenously.

23. The method of claim 19 in which the subject is a human.

24. The method of claim 19 in which the compound is administered in an amount effective to achieve a serum concentration that is at or above the IC 50 of the compound, as measured in an in vitro assay.