1H-pyrrolo [2,3-D] pyrimidine derivatives and methods of use thereof

1. A compound of Formula I:

or a pharmaceutically-acceptable salt thereof;

wherein:

Y is CR 5 ;

Z is NR 3 R 4 , halo, H, OH, alkyl, alkyloxy, or haloalkyl;

R 1a is phenyl substituted with —OH, wherein said phenyl is additionally substituted with at least one of —OH, —CN, NO 2 , C(═O)OH, —C(═O)O-alkyl, (C 1 -C 4 )alkyl, halo, haloalkyl or haloaryl;

R 2 is C 1 -C 6 alkyl or C 4 -C 7 cycloalkyl, wherein said alkyl or said cycloalkyl is optionally substituted with mono- or di-alkoxy, mono- or di-halophenyl, mono- or di-(C 1-4 )alkoxy phenyl, mono- or di-(C 1-4 )alkyl phenyl, perhalo(C 1-4 )alkyl phenyl, carboxyl, tert-butyl carboxyl, phosphoryl, (C 1-6 )alkyl, (C 4-7 )cycloalkyl, indolyl, isoindolyl, pyridyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, or alkylmorpholino;

R 3 and R 4 are independently H, C 1 -C 6 alkyl, tert-butyloxycarbonyl (t-Boc), morpholino(C 1 -C 4 )alkyl, carboxy(C 1 -C 3 )alkyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 3 )alkyl, aryl, heteroaryl, aryloxy, heterocyclyl, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, —S(O) 2 alkyl, —S(O) 2 aryl, —(C═O)heteroaryl, —(C═O)aryl, —(C═O)(C 1 -C 6 )alkyl, —(C═O)cycloalkyl, —(C═O)heterocyclyl, alkyl-heterocyclyl, aralkyl, arylalkenyl, —CON R 6 R 7, —SO 2 R 6 R 7 , arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkylamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;

R 5 is H, —OH, halo, optionally monosubstituted (C 1 -C 6 )alkyl, optionally monosubstituted (C 1 -C 4 )alkoxycarbonyl, optionally monosubstituted (C 1 -C 4 )alkanoyl, carbamoyl, optionally monosubstituted (C 1 -C 4 )alkyl carbamoyl, phenyl, halophenyl, optionally monosubstituted (C 1 -C 4 )alkylphenyl, optionally monosubstituted (C 1 -C 4 )alkoxyphenyl, or optionally monosubstituted perhalo(C 1 -C 4 )alkylphenyl, wherein said optional substitution is (C 1 -C 4 )alkyl, OH, or halogen;

R 6 and R 7 are independently H, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl.

2. A compound according to claim 1 , wherein R 1a is phenyl substituted with mono, di, or tri-OH and further substituted with a halo.

3. A compound according to claim 2 , wherein said halo is F.

4. A compound according to claim 1 , wherein R 3 and R 4 are H.

5. A compound according to claim 1 , wherein R 5 is H.

6. A compound according to claim 1 , wherein R 6 is H and R 7 is methyl.

7. A compound according to claim 1 , wherein, independently, R 1a is phenyl substituted at a meta position with —OH, —CH 3 , tert-butyl, —CF 3 or halo.

8. A compound according to claim 1 , wherein, independently, R 1a is phenyl substituted at a meta position with halo, (C 1 -C 4 )alkyl, haloalkyl, haloaryl, CN, NO 2 , —C(═O)OH, or —C(═O)O-alkyl.

9. A compound according to claim 1 , wherein Z is F, Br, Cl, or I.

10. A compound selected from the group consisting of:

3-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

[5-(3-amino-phenyl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-methyl-amine;

3-(4-benzylamino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-(4-dibenzylamino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-[5-(3-hydroxy-phenyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid tert-butyl ester;

3-[5-(3-hydroxy-phenyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid;

3-bromo-5-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-methyl-phenol;

3-tert-butyl-5-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-(7-Isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-trifluoromethyl-phenol;

3-bromo-5-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol;

3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-methyl-phenol;

3-tert-butyl-5-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; and

3-(4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-trifluoromethyl-phenol or a pharmaceutically-acceptable salt thereof.

11. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier, and a compound according to claim 1 .

12. A pharmaceutical composition according to claim 11 , further comprising at least one anthracycline.

13. A pharmaceutical composition according to claim 12 , wherein said anthracycline is daunorubicin, doxorubicin, epirubicin, idarubicin, or a mixture thereof.

14. A compound according to claim 1 , wherein R 1a is meta-hydroxyphenyl, wherein said phenyl is additionally substituted with at least one of OH, —CN, NO 2 , —C(═O)OH, —C(═O)O-alkyl, (C 1 -C 4 )alkyl, halo, haloalkyl or haloaryl.