4-amino pyrimidine compounds for the treatment of cancer

1 . A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by Formula I,

Wherein:

L is a linker selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynlene, each of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, halogen, wherein two or more C 1-6 alkyl substituents optionally link up to form a 3-6 membered ring;

M is selected from the group consisting of OR a , C(O)R b , 3-6 membered cycloalkylnone, 4-6 membered lactam, and 4-6 membered lactone;

R a is selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 1-4 alkylene-(OC 2-4 alkylene) p -OC 1-4 alkyl;

R b is selected from the group consisting of haloC 1-4 alkyl, C 1-4 alkylene-OH, NR c R d ;

R c is H or C 1-4 alkyl;

R d is OH, OC 1-6 alkyl, OC 1-4 alkyleneC 6-10 aryl, OC 1-4 alkyleneC 5-10 heteroaryl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the C 6-10 aryl or C 5- 10heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, and N(R e ) 2 ;

each R e is independently H or C 1-4 alkyl;

each R 1 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

each R 2 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

m and n are each an integer ranging from 0 to 4; and p is an integer ranging from 1 to 20,

provided the compound is not

2 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein M is OH, L is optionally substituted C 2-4 alkylene.

3 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein M is OH, and L is C 2-4 alkylene substituted with haloC 1-6 alkyl.

4 . The compound or the pharmaceutically acceptable salt thereof of claim 3 , wherein the haloC 1-6 alkyl is CF 3 .

5 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein M is OH, and L is C 3-6 alkylene wherein two substituents of the C 3-6 alkylene link up to form a 3-5 membered carbocyclic ring.

6 . The compound or the pharmaceutically acceptable salt thereof of claim 5 , wherein the two substituents of the C 3-6 alkylene link up to form a 3 membered carbocyclic ring.

7 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein L is C 2-6 alkylene, wherein M is selected from the group consisting of OR a , and R a is C(O)C 1-6 alkyl.

8 . The compound or the pharmaceutically acceptable salt thereof of claim 7 , wherein R a is C(O) tert butyl.

9 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein L is C 2-6 alkylene, wherein M is selected from the group consisting of OR a , and R a is C(O C 1-4 alkylene-(OC 2-4 alkylene) p -OC 1-4 alkyl.

10 . The compound or the pharmaceutically acceptable salt thereof of claim 9 , wherein p is 1-3.

11 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein L is C 2-6 alkylene, M is C(O)R b , and R b is selected from the group consisting of haloC 1-4 alkyl, C 1-4 alkylene-OH, and NR c R d .

12 . The compound or the pharmaceutically acceptable salt thereof of claim 11 , wherein R c is H or C 1-4 alkyl, and R d is OH or OC 1-2 alkyleneC 6 aryl.

13 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein L is C 2-6 alkylene, and M is selected from the group consisting of 3-6 membered cycloalkylnone, 4-6 membered lactam, and 4-6 membered lactone.

14 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of

15 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

16 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

17 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

18 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

19 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

20 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is

21 . A pharmaceutical formulation comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof of claim 1 and a pharmaceutically acceptable carrier.

22 . A method of treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disease is diffuse intrinsic pontine glioma (DIPG),

wherein the compound is represented by Formula I,

Wherein:

L is a linker selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynlene, each of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, halogen, wherein two or more C 1-6 alkyl substituents optionally link up to form a 3-6 membered ring;

M is selected from the group consisting of OR a , C(O)R b , 3-6 membered cycloalkylnone, 4-6 membered lactam, and 4-6 membered lactone;

R a is selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl, C (O) C 1-6 alkyl, C(O)C 1-4 alkylene-(OC 2-4 alkylene) p -OC 1-4 alkyl;

R b is selected from the group consisting of haloC 1-4 alkyl, C 1-4 alkylene-OH, NR c R d ;

R c is H or C 1-4 alkyl;

R d is OH, OC 1-6 alkyl, OC 1-4 alkyleneC 6-10 aryl, OC 1-4 alkyleneC 5-10 heteroaryl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the C 6-10 aryl or C 5-10 heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, and N(R e ) 2 ;

each R e is independently H or C 1-4 alkyl;

each R 1 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

each R 2 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

m and n are each an integer ranging from 0 to 4; and p is an integer ranging from 1 to 20,

provided the compound is not

23 . A method of treating a disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of glioblastomas, diffuse intrinsic pontine glioma (DIPG), ependymoma, T-cell acute lymphoblastic leukemia, acute myeloid leukemia, diffuse large B-cell lymphoma, neuroblastoma, prostate cancer, gastric cancer, multiple myeloma, rheumatoid arthritis, other arthritis, and bone metastases,

wherein the compound is represented by Formula I,

Wherein:

L is a linker selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynlene, each of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, halogen, wherein two or more C 1-6 alkyl substituents optionally link up to form a 3-6 membered ring;

M is selected from the group consisting of OR a , C(O)R b , 3-6 membered cycloalkylnone, 4-6 membered lactam, and 4-6 membered lactone;

R a is selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl, C (O) C 1-6 alkyl, C(O)C 1-4 alkylene-(OC 2-4 alkylene) p -OC 1-4 alkyl;

R b is selected from the group consisting of haloC 1-4 alkyl, C 1-4 alkylene-OH, NR c R d ;

R c is H or C 1-4 alkyl;

R d is OH, OC 1-6 alkyl, OC 1-4 alkyleneC 6-10 aryl, OC 1-4 alkyleneC 5-10 heteroaryl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the C 6-10 aryl or C 5-10 heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, and N(R e ) 2 ;

each R e is independently H or C 1-4 alkyl;

each R 1 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

each R 2 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

m and n are each an integer ranging from 0 to 4; and p is an integer ranging from 1 to 20,

provided the compound is not

wherein the subjected has been determined to have a mutation selected from the group consisting of mutation of H3K27M, mutation of TP53 (H3.3 and H3.1 K27M-mutant DIPG), and mutation of ACVR1 (H3.1 K27M-mutant DIPG).

24 . A method of inhibiting JMJD3 histone H3K27 demethylase, comprising contacting the JMJD3 histone H3K27 demethylase a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof

wherein the compound is represented by Formula I,

Wherein:

L is a linker selected from the group consisting of C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynlene, each of which is optionally substituted with one or more substituents selected from C 1-6 alkyl, haloC 1-6 alkyl, halogen, wherein two or more C 1-6 alkyl substituents optionally link up to form a 3-6 membered ring;

M is selected from the group consisting of OR a , C(O)R b , 3-6 membered cycloalkylnone, 4-6 membered lactam, and 4-6 membered lactone;

R a is selected from the group consisting of H, C 1-6 alkyl, haloC 1-6 alkyl, C(O)C 1-6 alkyl, C(O)C 1-4 alkylene-(OC 2-4 alkylene) p -OC 1-4 alkyl;

R b is selected from the group consisting of haloC 1-4 alkyl, C 1-4 alkylene-OH, NR c R d ;

R c is H or C 1-4 alkyl;

R d is OH, OC 1-6 alkyl, OC 1-4 alkyleneC 6-10 aryl, OC 1-4 alkyleneC 5-10 heteroaryl, C 6-10 aryl, or C 5-10 heteroaryl, wherein the C 6-10 aryl or C 5-10 heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, and N(R e ) 2 ;

each R e is independently H or C 1-4 alkyl;

each R 1 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

each R 2 is independently selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, carboxamide, amido and N(R e ) 2 ;

m and n are each an integer ranging from 0 to 4; and p is an integer ranging from 1 to 20,

provided the compound is not

25 . The compound or the pharmaceutically acceptable salt thereof of claim 1 , wherein

R d is OC 1-6 alkyl, OC 1-4 alkyleneC 6-10 aryl, OC 1-4 alkyleneC 5-10 heteroaryl, C 6-10 aryl, or C 5 -10heteroaryl, wherein the C 6-10 aryl or C 5 -10heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halogen, acyl, CN, haloalkyl, hydroxyl, C 1-6 alkyl, OC 1-6 alkyl, hydroxyC 1-6 alkyl, and N(R e ) 2 .

26 . The method of claim 22 , wherein the compound is