Therapeutically active compounds and their methods of use

1. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula (Ia) or a pharmaceutically acceptable salt or hydrate thereof, wherein:

ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, and wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH;

R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with —OH, —NH 2 , —CN, —O—C 1 -C 4 alkyl, —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;

R 2 and R 5 are each independently selected from —(C 1 -C 6 alkyl); —(C 2 -C 6 alkenyl) and —(C 2 -C 6 alkynyl), wherein any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl), —CO 2 H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H; and

R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl;

provided that

(i) when A is an optionally substituted pyridyl, then (A) N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHCH 2 CH 2 OH, and (B) when N(R 7 )C(R 4 )(R 5 )(R 6 ) is NHC(CH 3 ) 3 , then N(R 8 )C(R 1 )(R 2 )(R 3 ) is not NH—CH 2 CH 3 ;

(ii) when A is an optionally substituted heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, then N(R 7 )C(R 4 )(R 5 )(R 6 ) and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both N(CH 2 CH 3 ) 2 , NHCH 2 CH 2 -i-propyl, or NHCH 2 CH(CH 3 ) 2 ;

(iii) when A is optionally substituted 1-pyrazolyl, then neither N(R 7 )C(R 4 )(R 5 )(R 6 ) nor N(R 8 )C(R 1 )(R 2 )(R 3 ) is NHisopropyl, NHCH 2 CH 3 , or N(CH 2 CH 3 ) 2 ;

(iv) when A is an optionally substituted phenyl, then N(R 7 )C(R 4 )(R 5 )(R 6 ) is not the same as N(R 8 )C(R 1 )(R 2 )(R 3 );

(v) when A is substituted 1-pyrazolyl, then (A) N(R 7 )C(R 4 )(R 5 )(R 6 ); and N(R 8 )C(R 1 )(R 2 )(R 3 ) are not both NHC(CH 3 ) 3 .

2. The method of claim 1 , wherein ring A is a 6-member monocyclic heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl and wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH.

3. The method of claim 1 , wherein ring A is pyridinyl optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH.

4. The method of claim 1 , wherein ring A is pyridinyl optionally substituted with halo or —C 1 -C 4 haloalkyl.

5. The method of claim 1 , wherein ring A is phenyl or a 6-member monocyclic heteroaryl selected from pyridinyl, pyrimidinyl and pyrazinyl wherein said phenyl or 6-member monocyclic heteroaryl is optionally substituted with up to two substituents independently selected from halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH;

R 1 and R 4 are each independently selected from C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

R 3 and R 6 are both hydrogen;

R 2 and R 5 are each —(C 1 -C 6 alkyl);

wherein:

any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl), —CO 2 H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H; and

R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl.

6. The method of claim 1 , wherein the compound has formula (B), wherein:

X is N;

each X a is independently N or C—R 9a , provided that when one X a is N, then the other two X a are both C—R 9a ;

R 9 is selected from the group consisting of halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH;

each R 9a is independently selected from the group consisting of hydrogen, halo, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 1 -C 4 hydroxyalkyl, —NH—S(O) 2 —(C 1 -C 4 alkyl), —S(O) 2 NH(C 1 -C 4 alkyl), —CN, —S(O) 2 —(C 1 -C 4 alkyl), C 1 -C 4 alkoxy, —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —OH, —OCF 3 , —CN, —NH 2 , —C(O)NH 2 , —C(O)NH(C 1 -C 4 alkyl), —C(O)—N(C 1 -C 4 alkyl) 2 , and cyclopropyl optionally substituted with OH;

R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, —O—C 1 -C 4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with —OH, —NH 2 , —CN, —O—C 1 -C 4 alkyl, —NH(C 1 -C 4 alkyl), or —N(C 1 -C 4 alkyl) 2 ;

R 2 and R 5 are each independently selected from —(C 1 -C 6 alkyl); —(C 2 -C 6 alkenyl) and —(C 2 -C 6 alkynyl), wherein any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl), —CO 2 H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H; and

R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl.

7. The method of claim 6 , wherein:

R 1 and R 4 are each independently selected from C 1 -C 4 alkyl and C 1 -C 4 haloalkyl;

R 3 and R 6 are both hydrogen; and

R 2 and R 5 are each —(C 1 -C 6 alkyl);

wherein any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C 1 -C 4 alkyl), —CO 2 H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH 2 OH, CF 3 , —CH 2 F, —CH 2 Cl, C(O)CH 3 , C(O)CF 3 , CN, or CO 2 H; and

R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl.

8. The method of claim 6 , wherein each X a is C—R 9a .

9. The method of claim 8 , wherein each R 9a is H.

10. The method of claim 6 , wherein R 9 is selected from halo and —C 1 -C 4 haloalkyl.

11. The method of claim 6 , wherein R 9 is halo.

12. The method of claim 6 , wherein R 1 and R 4 are each independently selected from the group consisting of C 1 -C 4 alkyl and C 1 -C 4 haloalkyl, and R 2 and R 5 are each —(C 1 -C 6 alkyl).

13. The method of claim 6 , wherein R 7 and R 8 are both hydrogen.

14. The method of claim 1 , wherein the compound is selected from:

3

4

13

14

17

18

32

35

70

73

74

76

86

100

101

103

104

114

130

136

141

142

156

180

196

271

335

339

344

345

346

363

386

404

15. The method of claim 1 , wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.

16. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a compound having Formula:

or a pharmaceutically acceptable salt or hydrate thereof.

17. The method of claim 16 , wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.

18. The method of claim 16 , wherein the method further comprises administering a second therapeutic agent useful in the treatment of cancer.

19. A method for treating a glioma characterized by the presence of an isocitrate dehydrogenase 1 (IDH1) mutation comprising administering to a patient in need thereof a therapeutically effective amount of a pharmaceutical composition comprising

or a pharmaceutically acceptable salt or hydrate thereof and one or more pharmaceutically acceptable excipients.

20. The method of claim 19 , wherein the IDH1 mutation is an IDH1 R132H or R132C mutation.