GlyT1 inhibitors for use in the treatment of hematological disorders

1. A method of treating a hematological disorder characterized by elevated cellular hemoglobulin (Hb) levels comprising administering to a patient in need thereof a therapeutically effective amount of a GlyT1 inhibitor of formula I:

wherein

R 1 is independently in each occurrence halogen, lower haloalkyl, cyano or S(O) 2 -lower alkyl;

R 2 is lower alkyl, lower alkyl substituted by halogen or is (CH 2 ) 0 -cycloalkyl;

R 3 is lower alkyl, NH 2 or amino-substituted by one or two lower alkyl;

X C or N;

n is 1 or 2;

o is 0, 1 or 2; or

an enantiomer thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. The method of claim 1 wherein the disorder is sickle cell disease.

3. The method of claim 1 wherein the disorder is thalassemia.

4. The method of claim 1 wherein the disorder is iron overload syndrome.

5. The method of claim 4 wherein the iron overload syndrome is hereditary hemochromatosis.

6. The method of claim 1 wherein the GlyT1 inhibitor is selected from the group consisting of:

[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone;

[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl] -methanone;

4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide; and,

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

7. The method of claim 6 wherein the GlyT1 inhibitor is a compound of formula Ia

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

8. A method of treating a hematological disorder characterized by elevated cellular hemoglobulin (Hb) levels comprising administering to a patient in need thereof a therapeutically effective amount of a GlyT1 inhibitor of formula II:

wherein

R 1 is independently in each occurrence halogen, lower alkly, lower haloalkly, alkoxy, cyano or S(O) 2 -lower alkyl;

R 2 is lower alkyl, lower alkyl substituted by halogen or is (CH 2 ) o -cycloalkyl;

R 3 is lower alkyl, NH 2 or amino-substituted by one or two lower alkyl;

X and X 1 are N or C, provided both X and X 1 are not N;

n is 1 or 2;

o is 0, 1 or 2;

or an enantiomer thereof, or a pharmaceutically acceptable acid addition salt thereof.

9. The method of claim 8 wherein the GlyT1 inhibitor is selected from the group consisting of:

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone;

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone; and,

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(5-methoxy-6-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-methanone.

10. The method of claim 9 wherein the GlyT1 inhibitor is a compound of formula IIa

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone.

11. The method of claim 8 wherein the disorder is sickle cell disease.

12. The method of claim 8 wherein the disorder is thalassemia.

13. The method of claim 8 wherein the disorder is iron overload syndrome.

14. The method of claim 13 wherein the iron overload syndrome is hereditary hemochromatosis.