PRMT5 inhibitors

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein

X is O or CH 2 ;

Y is O or CH 2 ;

R 1 is H or —NHR 3 ;

R 2 is

R 3 is H, CH 3 , C 2 H 5 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CHF 2 , CH 2 CF 3 , or CH 2 —C 3-8 cycloalkyl;

R 4 is H, C 1-6 alkyl, CF 3 or CHF 2 ;

R 5 is H, halogen, CH 3 , CF 3 , or CHF 2 ;

R 6 is NH 2 or C 1-6 alkyl;

Z 1 is CH or N;

Z 2 is CH or N;

Z 3 is CH or N;

Z 4 is CR 5 or N;

Z is CH or N; and

A is CH, N or C—NH 2 .

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is Br or H, R 1 is NH 2 or NHCH 2 CHF 2 , R 4 is H or CH 3 , and R 6 is NH 2 or CH 3 .

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is

4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is

3-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-3H-purin-6-amine,

4-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-4H-imidazo[4,5-b]pyridin-7-amine,

2-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-2H-imidazo[4,5-d][1,2,3]triazin-4-amine,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(7-amino-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(6-amino-3H-purin-3-yl)-1,2-cyclopentanediol,

(1R,2S,3R,5S)-3-(7-amino-4H-imidazo[4,5-b]pyridin-4-yl)-5-(2-{2-[(2,2-difluoroethyl)amino]-7-quinolinyl}ethyl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-(2-{2-[(2,2-difluoroethyl)amino]-7-quinolinyl}ethyl)-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol, or

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(6-methyl-3H-purin-3-yl)-1,2-cyclopentanediol,

(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(7-methyl-4H-imidazo [4,5-b]pyridin-4-yl)tetrahydrofuran-3,4-diol, or

(1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)cyclopentane-1,2-diol.

5. A compound of claim 4 , which is

3-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-3H-purin-6-amine,

4-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-4H-imidazo[4,5-b]pyridin-7-amine,

2-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-2H-imidazo[4,5-d][1,2,3]triazin-4-amine

2-[5-O-(2-amino-3-bromo-7-quinolinyl)-b-D-ribofuranosyl]-2H-imidazo[4,5-d][1,2,3]triazin-4-amine trifluoroacetate,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(7-amino-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(6-amino-3H-purin-3-yl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(6-amino-3H-purin-3-yl)-1,2-cyclopentanediol hydrochloride,

(1R,2S,3R,5S)-3-(7-amino-4H-imidazo[4,5-b]pyridin-4-yl)-5-(2-{2-[(2,2-difluoroethyl)amino]-7-quinolinyl}ethyl)-1,2-cyclopentanediol,

(1S,2R,3S,5R)-3-(2-{2-[(2,2-difluoroethyl)amino]-7-quinolinyl}ethyl)-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)-1,2-cyclopentanediol, or

(1S,2R,3S,5R)-3-[2-(2-amino-3-bromo-7-quinolinyl)ethyl]-5-(6-methyl-3H-purin-3-yl)-1,2-cyclopentanediol,

(2R,3S,4R,5R)-2-(2-(2-amino-3-bromoquinolin-7-yl)ethyl)-5-(7-methyl-4H-imidazo [4,5-b]pyridin-4-yl)tetrahydrofuran-3,4-diol, or

(1S,2R,3R,5R)-3-(((2-amino-3-bromoquinolin-7-yl)oxy)methyl)-5-(7-methyl-4H-imidazo[4,5-b]pyridin-4-yl)cyclopentane-1,2-diol.

6. A composition for treating cancer comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for treating cancer comprising administering to a patient in need thereof a composition of claim 6 .

8. A method for treating cancer comprising administering to a patient in need thereof a compound of claim 1 .

9. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein formula I is formula Ia

10. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 5 is Br or H, R 1 is NH 2 or NHCH 2 CHF 2 , R 4 is H or CH 3 , and R 6 is NH 2 or CH 3 .

11. A compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is

12. A composition for treating cancer comprising a compound of claim 9 , a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

13. A method for treating cancer comprising administering to a patient in need thereof a composition of claim 12 .

14. A method for treating cancer comprising administering to a patient in need thereof a compound of claim 9 .