Substituted imidazo[1,2-c]pyrimidines as PRC2 inhibitors

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

is a single bond or a double bond;

Z is —O— or —S—;

X is CR 5 , C(R 5 ) 2 , CR 5 OH, or O;

R 1 is C 1-4 alkylene-cycloalkyl, C 1-4 alkylene-heterocyclyl, —NR 5 -heterocyclyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein any cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more independently selected R 4 substituents;

R 2 is CN, C(O)N(R 5 ) 2 , C(O)N(R 5a ) 2 , or C(O)OR 5 ;

each R 3 is independently H, halogen, or C 1-3 alkyl;

each R 4 is independently halogen, CN, C 1-6 alkyl, haloalkyl, C 1-4 alkylene-N(R 5 ) 2 , CH(CF 3 )N(R 5 ) 2 , hydroxyalkyl, heteroalkyl, C 1-4 alkylene-cycloalkyl, C 1-4 alkylene-heterocyclyl, aralkyl, C 1-4 alkylene-heteroaryl, C(O)C 1-6 alkyl, C(O)N(R 5 ) 2 , C(O)OR 5 , C(O)heterocyclyl, N(R 5 ) 2 , NHC(O)C 1-6 alkyl, NHC(O)N(R 5 ) 2 , NHC(O)heterocyclyl, NR 5 S(O) 2 C 1-6 alkyl, NR 5 S(O) 2 haloalkyl, NR 5 S(O) 2 N(R 5 ) 2 , NR 5 S(O) 2 heterocyclyl, O(alkyl), OC 1-4 alkylene-N(R 5 ) 2 , ON(R 5 ) 2 , ═O, P(O)(OC 1-3 alkyl) 2 , SC 1-6 alkyl, S(haloalkyl), SN(R 5 ) 2 , S(heterocyclyl), S(O)C 1-6 alkyl, S(O)haloalkyl, S(O)N(R 5 ) 2 , S(O)heterocyclyl, S(O) 2 C 1-6 alkyl, S(O) 2 haloalkyl, S(O) 2 N(R 5 ) 2 , S(O) 2 heterocyclyl, cycloalkyl, heterocyclyl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl of aralkyl, and heteroaryl is optionally and independently substituted with one or more independently selected R 7 substituents;

each R 5 is independently H or C 1-3 alkyl;

both R 5a , taken together with the nitrogen atom to which they are attached, form a 5- to 8-membered heterocyclyl, wherein the 5- to 8-membered heterocyclyl is optionally substituted with one or more independently selected R 4 substituents;

R 6 is H, halogen, C 1-3 alkyl, haloalkyl, hydroxyalkyl, or heteroalkyl;

each R 7 is independently halogen, CN, C 1-6 alkyl, haloalkyl, C 1-4 alkylene-N(R 5 ) 2 , hydroxyalkyl, heteroalkyl, C(O)heterocyclyl, N(R 5 ) 2 , NHC(O)heterocyclyl, OH, O(alkyl), ═O, cycloalkyl, or heterocyclyl; and

n is 1 or 2;

with the provisos that:

(1) if X is C(R 5 ) 2 , CR 5 OH, or O, then is a single bond; and

(2) if X is CR 5 , then is a double bond.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —O—.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein is a single bond; and X is C(R 5 ) 2 .

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein is a single bond; and X is O.

5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein is a double bond; and X is CR 5 .

6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is aryl, wherein the aryl is optionally substituted with one or more independently selected R 4 substituents.

7. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is optionally substituted with one or more independently selected R 4 substituents.

8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CN.

9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is —C(O)N(R 5 ) 2 .

10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C(O)R 5 .

11. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently H or halogen.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently H or F.

13. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein n is 1.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is —S—.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

16. A method for treating cancer in a patient, wherein the method comprises administering to the patient in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 15 ;

wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, head and neck cancer, liver cancer, lung cancer, lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and skin cancer.

17. The method of claim 16 , wherein the cancer is a polycomb repressive complex 2-associated cancer.

18. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.