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Title:
MORPHOLINO-SUBSTITUTED BICYCLOHETEROARYL COMPOUNDS AND THEIR USE AS ANTI CANCER AGENTS
Document Type and Number:
WIPO Patent Application WO/2008/075007
Kind Code:
A1
Abstract:
The present invention pertains generally to the field of therapeutic compounds, and mor specifically to certain morpholino-substituted bicydoheteroaryl compounds (referred to herein as MBHA compounds), of the following formula: and especially certain morpholino-substituted 7H- pyrrolo[2,3-dlpyrimidine and moφholino-substituted 1H-pyrazolo[3.4-b]pyridine compounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1, that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Inventors:
COLLINS, Ian (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
READER, John, Charles (Sareum Ltd, 2 Iconix ParkCambridge, Cambridgeshire CB22 3EG, GB)
CHEUNG, Kwai, Ming (The Institue of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
MATTHEWS, Thomas, Peter (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
PROISY, Nicolas (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
KLAIR, Sukhbinder, Singh (Sareum Ltd, 2 Iconix ParkCambridge, Cambridgeshire CB22 3EG, GB)
Application Number:
GB2007/004819
Publication Date:
June 26, 2008
Filing Date:
December 14, 2007
Export Citation:
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Assignee:
CANCER RESEARCH TECHNOLOGY LIMITED (Sardinia House, Sardinia StreetLondon, Greater London WC2A 3NL, GB)
COLLINS, Ian (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
READER, John, Charles (Sareum Ltd, 2 Iconix ParkCambridge, Cambridgeshire CB22 3EG, GB)
CHEUNG, Kwai, Ming (The Institue of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
MATTHEWS, Thomas, Peter (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
PROISY, Nicolas (The Institute of Cancer Research, 15 Cotswold RoadSutton, Surrey SM2 5NG, GB)
KLAIR, Sukhbinder, Singh (Sareum Ltd, 2 Iconix ParkCambridge, Cambridgeshire CB22 3EG, GB)
International Classes:
C07D471/04; A61K31/437; A61K31/519; A61K31/52; A61P29/00; A61P35/00; C07D473/34; C07D487/04
Domestic Patent References:
WO1999065909A1
Foreign References:
EP1277738A1
FR2880626A1
Attorney, Agent or Firm:
WYTENBURG, Wilhelmus et al. (Mewburn Ellis LLP, York House23 Kingsway,London, Greater London WC2B 6HP, GB)
Download PDF:
Claims:
CLAIMS

1. A compound selected from compounds of the following formula:

and pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof;

wherein:

R 1M is independently selected from:

-L M -NH 2 ;

-L M -NHR K ;

-L M -NR K 2 ;

-L M -OH; -L M -OR K ;

-COOH;

-COOR K ;

-CONH 2 ;

-CONHR K ; -CONR K 2 ;

-L M -COOH;

-L M -COOR K ;

-L M -CONH 2 ;

-L M -CONHR K ; -L M -CONR K 2 ; and

-L M -CN; wherein: each L M is independently C^alkylene; and each R κ is independently C 1-3 alkyl;

n is independently 0, 1 or 2;

each group R AM , if present, is independently C 1-3 alkyl or -CF 3 ;

X is independently N or C(R 2C );

if X is N, then the group -C(R 3C )=X- is independently: -C(Q A )=N- or -CH=N-; and

if X is C(R 2C ), then the group -C(R 3C )=X- is independently:

-CH=CH-, -C(Q A )=CH-, -C(Q A )=C(Q B )-, -CH=C(Q A )-, -C(Q B )=C(Q A )-,

-C(Q B )=CH-, or -CH=C(Q 8 )-;

Q A , if present, is independently selected from: -A A ;

-NR N1 -A B ;

-NR N2 -(CH 2 ) q1 -A c ;

-C(=O)-NR N3 -A D ;

-C(=O)-NR N4 -(CH 2 ) q2 -A E ; -C(=O)-NR N5 R N6 ;

-C(=O)-NR N1R R N2R ;

-C(=O)-OR E ;

_ G QA. wherein: A A is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

A B is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;

A G is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

A D is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

A E is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted; q1 is independently 1, 2, or 3; q2 is independently 1 , 2, or 3; R N1 is independently -H or C 1-3 alkyl; R N2 is independently -H or C 1-3 alkyl; R N3 is independently -H or C 1-3 alkyl; R N4 is independently -H or C 1-3 alkyl; each of R N5 and R N6 is independently -H 1 C 1-6 alkyl, or C 1-6 cycloalkyl;

R N1R and R N2R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non- aromatic heterocyclic ring is independently unsubstituted or substituted;

R E is independently -H or C 1-4 alkyl; and

G^ is independently halogen;

Q B , if present, is independently C 1-3 alkyl or -CF 3 ;

Y-Z is independently C(R 6C1 )=C(R 5C ), C(R 6C2 )=N, or N(R 6N )-C(=O);

R 5C , if present, is independently -H or C 1-3 alkyl;

R 6C1 , if present, is independently selected from:

-H; _ G β ci . -D 6C1 ;

-A F ;

-C(=O)NR N3R R N4R ; -C(=O)NR N7 -L 1 -J 1 ; -C(=O)NR N8 -B 6C1 ; -C(=O)NR N8 -A G ; and

-C(=O)NR N9 -(CH 2 ) q3 -A H ; wherein:

G 6C1 is independently halogen; D 6C1 is independently C 1-3 alkyl; A F is independently phenyl or C 5-6 heteroaryli and is independently unsubstituted or substituted;

R N3R and R N4R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non- aromatic heterocyclic ring is independently unsubstituted or substituted;

R N7 is independently -H or C 1-3 alkyl; either:

L 1 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and

J 1 is -H; or:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 1 is -H, -CN, -OH, -OR J1 , -NH 2 , -NHR J \ or -NR J1 2 ; each R J1 is independently C 1-3 alkyl; R m is independently -H or C 1-3 alkyl;

B 6C1 is independently C 5 . 7 cycloalkyl or Cs-yheterocyclyl, optionally substituted with one or more groups; A G is independently phenyl or C 5 - 6 heteroaryl, and is independently unsubstituted or substituted;

R N9 is independently -H or C 1-3 alkyl; q3 is independently 1 , 2, or 3; and

A H is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

R 6C2 , if present, is independently selected from: -H; p6C6. -D 6C6 ;

-A J ;

-C(=O)NR N5R R N6R ;

-C(=O)NR N10 -L 2 -J 2 ;

-C(=O)NR N11 -B 6G2 ; -C(=O)NR N11 -A K ; and

-C(=O)NR N12 -(CH 2 ) q4 -A L ; wherein:

G 6C2 is independently halogen;

D 6G2 is independently C 1-3 alkyl; A J is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

R N5R and R N6R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non- aromatic heterocyclic ring is independently unsubstituted or substituted;

R N1 ° is independently -H or C 1-3 alkyl; either:

L 2 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and

J 2 is -H; or:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 ; each R J2 is independently Ci -3 alkyl; R N11 is independently -H or C 1-3 alkyl;

B 602 is independently C 5 . 7 cycloalkyl or Cs^heterocyclyl, optionally substituted with one or more C^alkyl groups; A κ is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;

R N12 is independently -H or C 1-3 alkyl; q4 is independently 1 , 2, or 3; and

A L is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;

R 6N , if present, is independently selected from: -H; -A M ; -(CH 2 ) q5 -A N ; and

-L 3 -J 3 . wherein:

A M is independently phenyl or C g . 6 heteroaryl, and is independently unsubstituted or substituted; q5 is independently 1 , 2, or 3;

A N is independently phenyl or C 5 - 6 heteroaryl, and is independently unsubstituted or substituted; either:

L 3 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and J 3 is -H; or:

L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and

J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR J3 2 ; each R J3 is independently C t-3 alkyl.

2. A compound according to claim 1 , wherein R 1M is independently selected from:

-L M -NH 2 ;

-L M -NHR K ;

-L M -NR K 2 ; -COOH;

-COOR K ;

-CONH 2 ;

-CONHR K ;

-CONR K 2 ; -L M -COOH;

-L M -COOR K ;

-L M -CONH 2 ;

-L M -CONHR K ;

-L M -CONR K 2 ; and -L M -CN.

3. A compound according to claim 1 , wherein R 1M is independently selected from:

-L M -NH 2 ;

-L M -NHR K ; -L M -NR K 2 ;

-CONH 2 ;

-CONHR K ;

-CONR K 2 ;

-L M -CONH 2 ; -L M -CONHR K ; and

-L M -CONR K 2 .

4. A compound according to claim 1 , wherein R 1M is independently selected from:

-L M -NH 2 ; -L M -NHR K ; and

-l_ M -NR K 2 .

5. A compound according to claim 1 , wherein R 1M is independently selected from:

-CONH 2 ; -CONHR K ;

-CONR K 2 ;

-L M -CONH 2 ;

-L M -CONHR K ; and

-L M -CONR K 2 .

6. A compound according to claim 1 , wherein R 1M is independently selected from:

-(CH 2 )-NH 2 , -(CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 ;

-(CH 2 )-NHMe, -(CH 2 ) 2 -NHMe, -(CH 2 ) 3 -NHMe;

-(CH 2 )-NHEt, -(CH 2 ) 2 -NHEt, -(CH 2 ) 3 -NHEt; -(CH 2 )-NMe 2 , -(CH 2 ) 2 -NMe 2 , -(CH 2 ) 3 -NMe 2 ;

-(CH 2 )-NEt 2 , -(CH 2 ) 2 -NEt 2 , -(CH 2 ) 3 -NEt 2 ;

-(CH 2 )-OH, -(CH 2 ) 2 -OH, -(CHz) 3 -OH;

-(CHz)-OMe, -(CHz) 2 -OMe, -(CHz) 3 -OMe;

-(CH 2 )-OEt, -(CHz) 2 -OEt, -(CHz) 3 -OEt; -COOH;

-COOMe, -COOEt;

-CONH 2 ;

-CONHMe, -CONHEt;

-CONMe 2 , -CONEt 2 ; -(CHz)-COOH, -(CHz) 2 -COOH, -(CH 2 ) 3 -COOH;

-(CHz)-COOMe, -(CH 2 ) 2 -COOMe, -(CH 2 ) 3 -COOMe;

-(CH 2 )-COOEt, -(CHz) 2 -COOEt, -(CHz) 3 -COOEt;

-(CH 2 )-CONH 2 , -(CHs) 2 -CONH 2 , -(CHz) 3 -CONH 2 ;

-(CHz)-CONHMe, -(CHz) 2 -CONHMe, -(CH 2 ) 3 -CONHMe;

-(CH 2 )-CONHEt, -(CH 2 ) Z -CONHEt, -(CH 2 ) 3 -CONHEt;

-(CHz)-CONMe 2 , -(CH 2 ) 2 -CONMe 2 , -(CH 2 ) 3 -CONMe 2 ;

-(CH 2 )-CONEt 2 , -(CHz) 2 -CONEt 2 , -(CHz) 3 -CONEt 2 ;

-(CH 2 )-CN, -(CH 2 ) 2 -CN, and -(CH 2 J 3 -CN.

7. A compound according to claim 1 , wherein R 1M is independently selected from:

-(CH 2 )-NH 2 , -(CH 2 ) Z -NH 2 , -(CH 2 ) 3 -NH 2 ;

-(CH 2 )-NHMe, -(CH 2 ) 2 -NHMe, -(CH 2 ) 3 -NHMe;

-(CH 2 )-NHEt, -(CH 2 ) Z -NHEt, -(CHz) 3 -NHEt;

-(CH 2 )-NMe 2 , -(CH 2 ) Z -NMe 2 , -(CH 2 J 3 -NMe 2 ; -(CH 2 )-NEt 2 , -(CH 2 ) Z -NEt 2 , and -(CHz) 3 -NEt 2 .

8. A compound according to claim 1, wherein R 1M is independently selected from:

-(CHz)-NH 2 , -(CHz)-NHMe, -(CHz)-NHEt,

-(CHz)-NMe 2 , and -(CHz)-NEt 2 .

9. A compound according to claim 1, wherein R 1M is independently -(CHz)-NH 2 .

10. A compound according to any one of claims 1 to 9, wherein R 1M is attached at the 2- or 6-position of the morpholino group.

11. A compound according to any one of claims 1 to 9, wherein R 1M is attached at the 3- or 5-position of the morpholino group.

12. A compound according to any one of claims 1 to 11 , wherein each group R AM , if present, is independently Ci -3 alkyl.

13. A compound according to any one of claims 1 to 11 , wherein each group R AM , if present, is independently -Me, -Et, or -CF 3 .

14. A compound according to any one of claims 1 to 11 , wherein each group R AM , if present, is independently -Me.

15. A compound according to any one of claims 1 to 11 , wherein n is independently 0.

16. A compound according to any one of claims 1 to 15, wherein the ring carbon atom to which R 1M is attached is in the R-configuration.

17. A compound according to any one of claims 1 to 15, wherein the ring carbon atom to which R 1M is attached is in the S-configuration.

18. A compound according to any one of claims 1 to 17, wherein X is N.

19. A compound according to any one of claims 1 to 17, wherein X is C(R 2C ).

* * *

20. A compound according to any one of claims 1 to 17, wherein X is N and the group X=C(R 30 ) is -CH=N-.

21. A compound according to any one of claims 1 to 17, wherein X is N and the group X=C(R 30 ) is -C(Q A )=N-.

22. A compound according to any one of claims 1 to 17, wherein X is C(R 2C ) and the group X=C(R 3G ) is -CH=CH-, -C(Q A )=CH-, -C(Q A )=C(Q B )-, -CH=C(Q A )-, or

-C(Q B )=C(Q A )-.

23. A compound according to any one of claims 1 to 17, wherein X is C(R 2C ) and the group X=C(R 30 ) is -CH=CH-, -C(Q A )=CH-, or -C(Q A )=C(Q B )-.

24. A compound according to any one of claims 1 to 17, wherein X is C(R 2C ) and the group X=C(R 30 ) is -CH=CH-, -C(Q A )=CH-, or -CH=C(Q A )-.

25. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -CH=CH-, -CH=C(Q A )-, or -C(Q B )=C(Q A )-.

26. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -C(Q A )=CH- or -CH=C(Q A )-.

27. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -CH=CH-.

28. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -C(Q A )=CH-.

29. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -C(Q A )=C(Q B )-.

30. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -CH=C(Q A )-.

31. A compound according to any one of claims 1 to 17, wherein X is C(R 20 ) and the group X=C(R 30 ) is -C(Q B )=C(Q A )-.

* * *

32. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -A A .

33. A compound according to any one of claims 1 to 31, wherein Q A , if present, is independently -NR N1 2 .

34. A compound according to any one of claims 1 to ' 31 , wherein Q A , if present, is independently -NR N1 -A B .

35. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -NR N2 -(CH 2 ) q1 -A c .

36. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -C(=O)-NR N3 -A D .

37. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -C(=O)-NR N4 -(CH 2 ) q2 -A E .

38. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -C(=O)-NR N5 R N6 .

39. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -C(=O)-NR N1R R N2R .

40. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -C(=O)-OR E .

41. A compound according to any one of claims 1 to 31 , wherein Q A , if present, is independently -G*.

42. A compound according to any one of claims- 1 to 15, wherein Q A , if present, is independently -NH 2 , -NHPh, -NHCH 2 Ph, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, -C(=O)NH 2 , -C(O)NHMe, -C(=O)NHEt, -C(=O)-morpholino, -C(=O)NHPh, -Cl, -Br, or -Ph.

43. A compound according to any one of claims 1 to 42, wherein Q B , if present, is independently C 1-3 alkyl.

44. A compound according to any one of claims 1 to 42, wherein Q B , if present, is independently -Me, -Et, or -CF 3 .

45. A compound according to any one of claims 1 to 42, wherein Q B , if present, is independently -Me.

46. A compound according to any one of claims 1 to 45, wherein Y-Z is C(R 6C1 )=C(R 5C ).

47. A compound according to any one of claims 1 to 46, wherein R 5C , if present, is independently -H or -Me.

48. A compound according to any one of claims 1 to 46, wherein R 5C , if present, is independently -H.

49. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently selected from:

_ G 6C1. _ D 6C1. -A h ;

-C(=O)NR N3R R N4R ;

-C(=O)NR N7 -L 1 -J 1 ;

-C(=O)NR N8 -B 6C1 ;

-C(=O)NR N8 -A G ; and -C(=O)NR N9 -(CH 2 ) q3 -A H .

50. A compound according to any one of claims 1 to 48, wherein R 6C \ if present, is independently selected from:

-A F ; -C(=O)NR N3R R N4R ;

-C(=O)NR N7 -L 1 -J 1 ;

-C(=O)NR N8 -B 6C1 ;

-C(=O)NR N8 -A G ; and

51. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -H.

52. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -G 6C1 .

53. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -D 6C1 .

54. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -A F .

55. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -C(=O)NR N3R R N4R .

56. A compound according to any one of claims 1 to 48, wherein R 6G1 , if present, is independently -C(=O)NR N7 -L 1 -J 1 .

57. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -C(=O)NR N8 -B 6G1 .

58. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -C(=O)NR N8 -A G .

59. A compound according to any one of claims 1 to 48, wherein R 6C1 , if present, is independently -C(=O)NR N9 -(CH 2 ) q3 -A H .

60. A compound according to any one of claims 1 to 45, wherein Y-Z is C(R 6G2 )=N.

61. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -H.

62. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -G 602 .

63. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -D 6C2 .

64. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -A J .

65. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -C(=O)NR N5R R N6R .

66. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -C(=O)NR N10 -L 2 -J 2 .

67. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -C(=O)NR N11 -B 6C2 .

68. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -C(=O)NR N11 -A K .

69. A compound according to any one of claims 1 to 45 and 60, wherein R 6C2 , if present, is independently -C(=O)NR N12 -(CH 2 ) q4 -A L .

70. A compound according to any one of claims 1 to 45, wherein Y-Z is N(R 6N )-C(=O).

71. A compound according to any one of claims 1 to 45 and 70, wherein R 6N , if present, is independently -H.

72. A compound according to any one of claims 1 to 45 and 70, wherein R 6N , if present, is independently -A M .

73. A compound according to any one of claims 1 to 45 and 70, wherein R 6N , if present, is independently - (CH 2 ) q5 -A N .

74. A compound according to any one of claims 1 to 45 and 70, wherein R 6N , if present, is independently -L 3 -J 3 .

75. A compound according to any one of claims 1 to 74, wherein A A , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

76. A compound according to any one of claims 1 to 74, wherein A λ , if present, is independently selected from: phenyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, [1,3,4]oxadiazolyl, [1,2,4]oxadiazolyl, and pyridyl; and is independently unsubstituted or substituted.

77. A compound according to any one of claims 1 to 76, wherein A B , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl,

[1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

78. A compound according to any one of claims 1 to 76, wherein A B , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, or pyrimidinyl; and is independently unsubstituted or substituted.

79. A compound according to any one of claims 1 to 78, wherein A c , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

80. A compound according to any one of claims 1 to 78, wherein A c , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

81. A compound according to any one of claims 1 to 80, wherein A D , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

82. A compound according to any one of claims 1 to 80, wherein A D , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

83. A compound according to any one of claims 1 to 82, wherein A E , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl,

[1,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1,3,4]thiadiazolyl, [1,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

84. A compound according to any one of claims 1 to 82, wherein A E , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

* * *

85. A compound according to any one of claims 1 to 84, wherein A F , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

86. A compound according to any one of claims 1 to 84, wherein A F , if present, is independently selected from: phenyl, thienyl, pyrazolyl, [1 ,3,4]oxadiazolyl,

[1 ,2,4]oxadiazolyl, [1 ,2,3]triazolyl, [1,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

87. A compound according to any one of claims 1 to 84, wherein A F , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, [1 ,2,3]triazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

88. A compound according to any one of claims 1 to 84, wherein A F , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

89. A compound according to any one of claims 1 to 88, wherein A G , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl,

[1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

90. A compound according to any one of claims 1 to 88, wherein A G , if present, is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

91. A compound according to any one of claims 1 to 90, wherein A H , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

92. A compound according to any one of claims 1 to 90, wherein A H , if present, is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

93. A compound according to any one of claims 1 to 92, wherein A J , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

94. A compound according to any one of claims 1 to 92, wherein A J , if present, is independently selected from: phenyl, thienyl, pyrazolyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

95. A compound according to any one of claims 1 to 94, wherein A κ , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazoiyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

96. A compound according to any one of claims 1 to 94, wherein A κ , if present, is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

97. A compound according to any one of claims 1 to 96, wherein A L , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazoiyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

98. A compound according to any one of claims 1 to 96, wherein A L , if present, is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

99. A compound according to any one of claims 1 to 98, wherein A M , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazoiyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

100. A compound according to any one of claims 1 to 98, wherein A M , if present, is independently selected from: phenyl, thienyl, pyrazoiyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

101. A compound according to any one of claims 1 to 100, wherein A N , if present, is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

102. A compound according to any one of claims 1 to 100, wherein A N , if present, is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

103. A compound according to any one of claims 1 to 74, each of A F , A J , and A M , if present, is independently phenyl, pyridyl, [1 ,2,3]triazolyl, or pyrazolyl; and is independently unsubstituted or substituted.

104. A compound according to any one of claims 1 to 74, each of A F , A J , and A M , if present, is independently phenyl, pyridyl, or pyrazolyl; and is independently unsubstituted or substituted.

105. A compound according to any one of claims 1 to 74, each of A F , A J , and A M , if present, is independently phenyl; and is independently unsubstituted or substituted.

106. A compound according to any one of claims 1 to 74, each of A F , A J , and A M , if present, is independently pyridyl; and is independently unsubstituted or substituted.

107. A compound according to any one of claims 1 to 74, each of A F , A J , and A M , if present, is independently pyrazolyl; and is independently unsubstituted or substituted.

A compound according to any one of claims 1 to 107, wherein each of A A , A B , A c ,

A D , A E , A F , A G , A H , A J , A κ , A L , A M , and A N , if present, is independently unsubstituted or substituted with one or more substituents independently selected from: (H-1 ) -C(=O)OH;

(H-2) -C(=O)OR a ;

(H-3) -C(=O)NH 2 , -C(=O)NHR a , -C(=O)NR a R a , -C(=O)NR b R c ;

(H-4) -C(=O)R a ;

(H-5) -F, -Cl, -Br, -I; (H-6) -CN;

(H-7) -NO 2 ;

(H-8) -OH;

(H-9) -OR a ;

(H-IO) -SH; (H-11) -SR a ;

(H-12) -OC(=O)R a ;

(H-13) -OC(=O)NH 2 , -OC(=O)NHR a , -OC(=O)NR a R a , -OC(=O)NR b R c ;

(H-14) -NH 2 , -NHR a , -NR a R a , -NR b R c ;

(H-15) -NHC(=O)R a ; -NR a C(=O)R a ; (H-16) -NHC(=O)NH 2 , -NHC(=O)NHR a , -NHC(=O)NR a R a , -NHC(=O)NR b R c ,

-NR a C(=O)NH 2 , -NR a C(=O)NHR a , -NR a C(=O)NR a R a , -NR a C(=O)NR b R c ;

(H-17) -NHSO 2 R 3 , -NR 3 SO 2 R 3 ;

(H-18) -SO 2 R a ;

(H-19) -OSO 2 R a ; (H-20) -SO 2 NH 2 , -SO 2 NHR 3 , -SO 2 NR 3 R 3 , -SO 2 NR b R c ;

(H-21) =O;

(H-22) -CF 3 ; and

(H-23) -R d ;

wherein R d and each R a is independently selected from:

(C-1) C 1-7 alkyl;

(C-2) C 2-7 alkenyl;

(C-3) C 2-7 alkynyl;

(C-4) C 3-7 cycloalkyl; (C-5) C 3-7 cycloalkenyl;

(C-6) C 3-14 heterocyclyl,

(C-7) C 6- i 4 carboaryl,

(C-8) C 5-14 heteroaryl,

(C-9) C 3-7 cycloalkyl-C 1-3 alkylenyl, (C-10) C 3-14 heterocyclyl-C 1-3 alkylenyl,

(C-11) Ce-^carboaryl-d^alkylenyl, and

(C-12) Cs-^heteroaryl-C L salkylenyl;

wherein each C^alkyl, C 2-7 aIkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3 - 7 cycloalkenyl, C 3 . 14 heterocyclyl, C 6 .i 4 carboaryl, and C 5-14 heteroaryl is independently unsubstituted or substituted with one or more substituents selected from (H-1) through (H-22);

and wherein R b and R c taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.

109. A compound according to any one of claims 1 to 107, wherein each of A A , A B , A c ,

A°, A E , A F , A G , A H , A J , A κ , A L , A M , and A N , if present, is independently unsubstituted or substituted with one or more substituents independently selected from: (H'-2) -C(=O)OR a' ;

(H'-3) -C(=O)NH 2 , -C(=O)NHR a' , -C(=O)NR a R a' , -C(=O)NR b R c' ;

(H'-5) -F, -Cl, -Br, -I;

(H'-6) -CN;

(H'-8) -OH; (H'-9) -OR 3' ;

(H'-14) -NH 2 , -NHR 8' , -NR 8 R 3' , -NR b R c' ;

(H'-15) -NHC(=O)R a' ; -NR a' C(=O)R a' ;

(H'-17) -NHSO 2 R 8' , -NR a' SO 2 R 8' ;

(H'-18) -SO 2 R 8' ; (H'-20) -SO 2 NH 2 , -SO 2 NHR 3' , -SO 2 NR a' R a' , -SO 2 NR b R c' ;

(H'-22) -CF 3 ; and

(H'-23) -R d' ;

wherein R d' and each R 8' is independently selected from: (C'-1) C 1-7 alkyl;

(C-4) C 3-7 cycloalkyl;

(C'-6) C 3-14 heterocyclyl,

(C'-7) C 6-14 carboaryl,

(C'-8) C 5-14 heteroaryl, (C'-9) C 3-7 cycloalkyl-Ci -3 alkylenyl,

(C-IO) C 3-14 heterocyclyl-C 1-3 alkylenyl,

(C-11) C 6- i4carboaryl-Ci, 3 alkylenyl, and

(C-12) C 5- i 4 heteroaryl-C 1-3 alkylenyl;

wherein each C 1-7 alkyl, C 3-7 cycloalkyl, C 3-14 heterocyclyl, C 6- i 4 carboaryl, and

C 5-14 heteroaryl is independently unsubstituted or substituted with one or more

substituents selected from (H'-2), (H'-3), (H'-5), (H'-6), (H'-8), (H'-9), (H'-14), (H'- 15), (H'-17), (H'-18), (H'-20), and (H'-22).

and wherein R b' and R 0' taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.

110. A compound according to any one of claims 1 to 107, wherein each of A A , A B , A c , A D , A ε , A F , A G , A H , A J , A κ , A L , A M , and A N , if present, is independently unsubstituted or substituted with one or more substituents independently selected from:

C^alkyl;

-F, -Cl, -Br, -I,

-L 4 -CN;

-LλOH, -L 4 -OR e ; -L 4 -O-L 5 -OH, -L 4 -O-L 5 -OR e ;

-L 4 -C(=O)OR e ;

-L 4 -NH 2 , -L 4 -NHR e , -L 4 -NR e R e , -L 4 -NR f R 9 ;

-L 4 -NH-L 5 -NH 2 , -L 4 -NH-L 5 -NHR β , -L 4 -NH-L 5 -NR e R e , -L 4 -NH-L 5 -NR f R 9 ;

-L 4 -NR e -L 5 -NH 2 , -L 4 -NR e -L 5 -NHR e , -L 4 -NR e -L 5 -NR e R e , -L 4 -NR e -L 5 -NR f R 9 ; -L 4 -C(=O)NH 2 , -L 4 -C(=O)NHR e , -L 4 -C(=O)NR e R e , -L 4 -C(=O)NR f R 9 ;

-L 4 -S(=O) 2 NH 2 , -L 4 -S(=O) 2 NHR e , -L 4 -S(=O) 2 NR e R e , -L 4 -S(=O) 2 NR f R 9 ;

-L 4 -S(=O) 2 NH~L 5 -OH, -L 4 -S(=O) 2 NH-L 5 -OR e ; wherein: each L 4 is independently a covalent bond or C^alkylenyl; and each L 5 is independently C 2-4 alkylenyl; each R e is independently C 1-4 alkyl, -Ph, or -CH 2 Ph; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino,

N-(C 1-3 alkyl)-piperizino, or morpholino.

* * *

111. A pharmaceutical composition comprising a compound according to any one of claims 1 to 110, and a pharmaceutically acceptable carrier or diluent.

112. A method of preparing a pharmaceutical composition comprising the step of admixing a compound according to any one of claims 1 to 110, and a pharmaceutically acceptable carrier or diluent.

113. A compound according to any one of claims 1 to 110, for use in a method of treatment of the human or animal body by therapy.

114. A compound according to any one of claims 1 to 110, for use in a method of treatment of a disease or condition that is mediated by CHK1.

115. A compound according to any one of claims 1 to 110, for use in a method of treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.

116. A compound according to any one of claims 1 to 110, for use in a method of treatment of a proliferative condition.

117. A compound according to any one of claims 1 to 110, for use in a method of treatment of cancer.

118. A compound according to any one of claims 1 to 110, for use in a method of treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.

119. A compound according to any one of claims 113 to 118, wherein the method of treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation..

120. Use of a compound as defined in one of claims 1 to 110, in the manufacture of a medicament for the treatment of a disease or condition that is mediated by CHK1.

121. Use of a compound as defined in one of claims 1 to 110, in the manufacture of a medicament for the treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.

122. Use of a compound as defined in one of claims 1 to 110, in the manufacture of a medicament for the treatment of a proliferative condition.

123. Use of a compound as defined in one of claims 1 to 110, in the manufacture of a medicament for the treatment of cancer.

124. Use of a compound as defined in one of claims 1 to 110, in the manufacture of a medicament for the treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.

125. Use according to any one of claims 120 to 124, wherein the treatment further comprises treatment with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation..

126. A method for the treatment of a disease or condition that is mediated by CHK1 comprising administering to a subject in need of treatment a therapeutically- effective amount of a compound as defined in one of claims 1 to 110.

127. A method for the treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in one of claims 1 to 110.

128. A method for the treatment of a proliferative condition comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in one of claims 1 to 110.

129. A method for the treatment of cancer comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in one of claims 1 to 110.

130. A method for the treatment of lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound as defined in one of claims 1 to 110.

131. A method according to any one of claims 126 to 130, wherein the treatment further comprises administering to a subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation..

* * *

132. A method of inhibiting CHK1 kinase function, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound as defined in one of claims 1 to 110.

133. A method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound as defined in one of claims 1 to 110.

134. A method of inhibiting cell proliferation, inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound as defined in one of claims 1 to 110.

Description:

MORPHOLINO-SUBSTITUTED BICYCLOHETEROARYL COMPOUNDS AND THEIR USE AS ANTI CANCER AGENTS

RELATED APPLICATIONS

This application is related to: United Kingdom patent application number 0625633.3 filed 21 December 2006 and United States patent application number 60/876,137 filed 21 December 2006; the contents of each of which are incorporated herein by reference in their entirety.

TECHNICAL FIELD

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain morpholino-substituted bicycloheteroaryl compounds (referred to herein as MBHA compounds), and especially certain morpholino-substituted 7H- pyrrolo[2,3-d]pyrimidine and morpholino-substituted 1 H-pyrazolo[3,4-b]pyridine compounds, which, inter alia, inhibit Checkpoint Kinase 1 (CHK1 ) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK1 kinase function, and in the treatment of diseases and conditions that are mediated by CHK1 , that are ameliorated by the inhibition of CHK1 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

BACKGROUND

A number of patents and publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

Throughout this specification, including the claims which follow, unless the context requires otherwise, the word "comprise," and variations such as "comprises" and "comprising," will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

Ranges are often expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by the use of the antecedent "about," it will be understood that the particular value forms another embodiment.

This disclosure includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.

Checkpoint Kinase 1 (CHKD

Progression through the cell division cycle is a tightly regulated process and is monitored at several positions known as cell cycle checkpoints (see, e.g., Weinert and Hartwell,

1989; Bartek and Lukas, 2003). These checkpoints are found in all four stages of the cell cycle; G1 , S (DNA replication), G2 and M (Mitosis) and they ensure that key events which control the fidelity of DNA replication and cell division are completed correctly. Cell cycle checkpoints are activated by a number of stimuli, including DNA damage and DNA errors caused by defective replication. When this occurs, the cell cycle will arrest, allowing time for either DNA repair to occur or, if the damage is too severe, for activation of cellular processes leading to controlled cell death.

All cancers, by definition, have some form of aberrant cell division cycle. Frequently, the cancer cells possess one or more defective cell cycle checkpoints, or harbour defects in a particular DNA repair pathway. These cells are therefore often more dependent on the remaining cell cycle checkpoints and repair pathways, compared to non-cancerous cells (where all checkpoints and DNA repair pathways are intact). The response of cancer cells to DNA damage is frequently a critical determinant of whether they continue to proliferate or activate cell death processes and die. For example, tumour cells that contain a mutant form(s) of the tumour suppressor p53 are defective in the G1 DNA damage checkpoint. Thus inhibitors of the G2 or S-phase checkpoints are expected to further impair the ability of the tumour cell to repair damaged DNA.

Many known cancer treatments cause DNA damage by either physically modifying the cell's DNA or disrupting vital cellular processes that can affect the fidelity of DNA

replication and cell division, such as DNA metabolism, DNA synthesis, DNA transcription and microtubule spindle formation. Such treatments include for example, radiotherapy, which causes DNA strand breaks, and a variety of chemotherapeutic agents including topoisomerase inhibitors, antimetabolites, DNA-alkylating agents, and platinum- containing cytotoxic drugs. A significant limitation to these genotoxic treatments is drug resistance. One of the most important mechanisms leading to this resistance is attributed to activation of cell cycle checkpoints, giving the tumour cell time to repair damaged DNA. By abrogating a particular cell cycle checkpoint, or inhibiting a particular form of DNA repair, it may therefore be possible to circumvent tumour cell resistance to the genotoxic agents and augment tumour cell death induced by DNA damage, thus increasing the therapeutic index of these cancer treatments.

CHK1 is a serine/threonine kinase involved in regulating cell cycle checkpoint signals that are activated in response to DNA damage and errors in DNA caused by defective replication (see, e.g., Bartek and Lukas, 2003). CHK1 transduces these signals through phosphorylation of substrates involved in a number of cellular activities including cell cycle arrest and DNA repair. Two key substrates of CHK1 are the Cdc25A and Cdc25C phosphatases that dephosphorylate CDK1 leading to its activation, which is a requirement for exit from G2 into mitosis (M phase) (see, e.g., Sanchez et al., 1997). Phosphorylation of Cdc25C and the related Cdc25A by CHK1 blocks their ability to activate CDK1 , thus preventing the cell from exiting G2 into M phase. The role of CHK1 in the DNA damage-induced G2 cell cycle checkpoint has been demonstrated in a number of studies where CHK1 function has been knocked out (see, e.g., Liu et al., 2000; Zhao et a/., 2002; Zachos et al., 2003).

The reliance of the DNA damage-induced G2 checkpoint upon CHK1 provides one example of a therapeutic strategy for cancer treatment, involving targeted inhibition of CHK1. Upon DNA damage, the p53 tumour suppressor protein is stabilised and activated to give a p53-dependent G1 arrest, leading to apoptosis or DNA repair (Balaint and Vousden, 2001 ). Over half of all cancers are functionally defective for p53, which can make them resistant to genotoxic cancer treatments such as ionising radiation (IR) and certain forms of chemotherapy (see, e.g., Greenblatt et al., 1994; Carson and Lois, 1995). These p53 deficient cells fail to arrest at the G1 checkpoint or undergo apoptosis or DNA repair, and consequently may be more reliant on the G2 checkpoint for viability and replication fidelity. Therefore abrogation of the G2 checkpoint through inhibition of the CHK1 kinase function may selectively sensitise p53 deficient cancer cells to genotoxic cancer therapies, and this has been demonstrated (see, e.g., Wang et al., 1996; Dixon and Norbury, 2002).

In addition, CHK1 has also been shown to be involved in S phase cell cycle checkpoints and DNA repair by homologous recombination. Thus, inhibition of CHK1 kinase in those

- A -

cancers that are reliant on these processes after DNA damage, may provide additional therapeutic strategies for the treatment of cancers using CHK1 inhibitors (see, e.g., Sorensen et al., 2005). Recent data using CHK1 selective siRNA supports the selective inhibition of CHK1 as a relevant therapeutic approach, and suggests that combined inhibition with certain other checkpoint kinases provides no additional benefit and may be non-productive (see, e.g., Xiao et al., 2006). Small-molecule selective inhibitors of CHK1 kinase function from various chemical classes have been described (see, e.g., Tao and Lin, 2006).

SUMMARY OF THE INVENTION

One aspect of the invention pertains to certain morpholino-substituted bicycloheteroaryl compounds compounds (referred to herein as MBHA compounds), as described herein.

Another aspect of the invention pertains to a composition (e.g., a pharmaceutical composition) comprising an MBHA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the invention pertains to method of preparing a composition (e.g., a pharmaceutical composition) comprising the step of admixing an MBHA compound, as described herein, and a pharmaceutically acceptable carrier or diluent.

Another aspect of the present invention pertains to a method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of an MBHA compound, as described herein.

In one embodiment, the method further comprises contacting the cells with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo; comprising contacting cells (or the cell) with an effective amount of an MBHA compound, as described herein.

In one embodiment, the method further comprises contacting the cells with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to a method for treatment comprising administering to a subject in need of treatment a therapeutically-effective amount of an MBHA compound, as described herein, preferably in the form of a pharmaceutical composition.

In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA

damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to an MBHA compound as described herein for use in a method of treatment of the human or animal body by therapy.

In one embodiment, the method of treatment comprises treatment with both (i) the MBHA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to use of a MHBA compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the treatment comprises treatment with both (i) a medicament comprising the MBHA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

In one embodiment, the treatment is treatment of a disease or condition that is mediated by CHKL

In one embodiment, the treatment is treatment of a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.

In one embodiment, the treatment is treatment of a proliferative condition.

In one embodiment, the treatment is treatment of cancer.

In one embodiment, the treatment is treatment of a hyperproliferative skin disorder, for example, psoriasis, actinic keratosis, and/or non-melanoma skin cancer.

In one embodiment, the treatment is treatment of a disease or condition that is characterised by inappropriate, excessive, and/or undesirable angiogenesis, for example, macular degeneration, cancer (solid tumours), psoriasis, and obesity.

In one embodiment, the treatment is treatment of an inflammatory disease.

In one embodiment, the treatment is treatment a disease or disorder associated with heart remodelling, myocyte hypertrophy of the heart, impaired contractility of the heart, pump failure of the heart, pathologic cardiac hypertrophy, and/or heart failure.

Another aspect of the present invention pertains to a kit comprising (a) an MBHA compound, as described herein, preferably provided as a pharmaceutical composition and in a suitable container and/or with suitable packaging; and (b) instructions for use, for example, written instructions on how to administer the compound.

In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.

Another aspect of the present invention pertains to an MBHA compound obtainable by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to an MBHA compound obtained by a method of synthesis as described herein, or a method comprising a method of synthesis as described herein.

Another aspect of the present invention pertains to novel intermediates, as described herein, which are suitable for use in the methods of synthesis described herein.

Another aspect of the present invention pertains to the use of such novel intermediates, as described herein, in the methods of synthesis described herein.

As will be appreciated by one of skill in the art, features and preferred embodiments of one aspect of the invention will also pertain to other aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds

One aspect of the present invention pertains to compounds selected from compounds of the following formula:

and pharmaceutically acceptable salts, solvates, chemically protected forms, and prodrugs thereof; wherein X, Y, Z, R 3C , R AM , n, and R 1M are as defined herein.

For convenience, the compounds may be described as having three core rings: a 6-membered Ring A fused to a 5-membered Ring B (and forming an bicyclic fused ring system), with a morpholino ring (denoted Ring C) linked to a ring carbon atom of Ring A, as illustrated below:

Note that the "lower" ring nitrogen atom in Ring B (adjacent to Z) is unsubstituted. Without wishing to be bound by any particular theory, the inventors believe that the absence of a substituent at this position contributes significantly to the compounds' activity.

For the avoidance of doubt, it is not intended that Ring A be fused to any other rings, other than Ring B; and it is not intended that Ring B be fused to any other rings, other than Ring A.

For the avoidance of doubt, it is not intended that Ring C be linked to Ring A, other than by the single covalent bond shown; it is not intended that Ring C be linked to Ring B; and it is not intended that Ring C be fused to any other rings.

The Bicvclic Fused Ring System

The group X is independently N or C(R ).

In one embodiment, X is N, as in, for example:

In one embodiment, X is C(R ), as in, for example:

The group Y-Z is independently C(R 6O1 )=C(R 5L ), C(R bϋ2 )=N, or N(R bN )-C(=O).

For the avoidance of doubt, it is intended that "Y-Z is C(R 6C1 )=C(R 5C )" means that Y is C(R 6G1 ) and Z is C(R 5C ). Similarly, it is intended that "Y-Z is C(R 6C2 )=N" means that Y is C(R 602 ) and Z is N. Finally, it is intended that "Y-Z is N(R 6N )-C(=O)" means that Y is N(R 6N ) and Z is C(=O).

In one embodiment, Y-Z is C(R 6C1 )=C(R 5C ), as in, for example:

7H-pyrrolo[2,3-d]pyrimidines 1 H-pyrrolo[2,3-b]pyridines

In one embodiment, Y-Z is C(R 6C2 )=N, as in, for example:

1 H-pyrazolo[3,4-d]pyrimiclines 1 H-pyrazolo[3,4-b]pyridines

In one embodiment, Y-Z is N(R )-C(=O), as in, for example:

7,9-dihydro-purin-8-ones 1,3-dihydro-imidazo[4,5-b]pyridin-2-ones

In one preferred embodiment, X is N and Y-Z is C(R 6C1 )=C(R 5C ), as in, for example ("7H-pyrrolo[2,3-d]pyrimidines"):

7H-pyrrolo[2,3-d]pyrimidines

In one preferred embodiment, X is C(R 2C ) and Y-Z is C(R 6C2 )=N, as in, for example ("1 H-pyrazolo[3,4-b]pyridines"):

1 H-pyrazolo[3,4-b]pyridines

Tautomers of the Bicyclic Fused Ring System

Note that the bicyclic fused ring system of the compounds described herein may exist in different tautomeric forms, to various extents, when the 5-membered Ring B contains an NH group. See, for example, Comprehensive Heterocyclic Chemistry Il (A. R. Katritzky, C. W. Rees & E. F. V. Scriven Eds; 1st Edition, Pergamon, 1996). For the avoidance of doubt, it is intended that, unless specifically indicated otherwise, a reference to any one tautomer is intended to be a reference to all tautomers. For example, a reference to the compound labelled "Tautomer 1" below is intended to be a reference to that compound and all tautomers thereof, including, for example, Tautomers 2, 3 and 4.

Tautomer 1 Tautomer 2 Tautomer 3 Tautomer 4

The Morpholino Group

The compounds bear a morpholino group, as shown below, attached via its nitrogen ring atom to the bicyclic fused ring system:

The morpholino group bears at least one substituent, R 1M .

Without wishing to be bound by any particular theory, the inventors believe that the presence of a R 1M substituent contributes significantly to the compounds' activity.

In one embodiment, R 1M is attached at the 2- or 6-position of the morpholino group. In one embodiment, R 1M is attached at the 3- or 5-position of the morpholino group.

Chirality

At least the ring carbon atom to which the group R 1M is attached is a chiral centre, and therefore the compounds are expected to be optically active. Some examples of the stereoisomers are shown below.

If one or more additional subsitutents, R AM , are present, then the ring carbon atoms to which they are attached will also be chiral centres. Some examples of the stereoisomers are shown below.

The chiral centre, or each chiral centre, if more than one is present, is independently in the R-configuration or the S-configuration.

If no configuration is indicated, then both configurations are encompassed.

In one embodiment, the ring carbon atom to which the group R 1M is attached is in the R- configuration.

In one embodiment, the ring carbon atom to which the group R 1M is attached is in the S- configuration.

The Morpholino Substituent. R 1M

The group R 1M is independently selected from:

-L M -NH 2 ;

-L M -NHR K ;

-L M -NR K 2 ; -L M -OH;

-L M -OR K ;

-COOH;

-COOR K ;

-CONH 2 ;

-CONHR K ; -CONR K 2 ; -L M -COOH; -L M -COOR K ; -L M -CONH 2 ;

-L M -CONHR K ; -L M -CONR K 2 ; and -L M -CN; wherein: each L M is independently d. 3 alkylene; and . each R κ is independently C 1-3 alkyl.

In one embodiment, R 1M is independently selected from:

-L M -NH 2 ; -L M -NHR K ;

-L M -NR K 2 ;

-COOH;

-COOR K ;

-CONH 2 ; -CONHR K ;

-CONR K 2 ;

-iλCOOH;

-L M -COOR K ;

-L M -CONH 2 ; -L M -CONHR K ;

-L M -CONR K 2 ; and

-L M -CN.

In one embodiment, R 1M is independently selected from: -L M -NH 2 ;

-L M -NHR K ;

-L M -NR K 2 ;

-CONH 2 ;

-CONHR K ; -CONR K 2 ;

-L M -CONH 2 ;

-L M -CONHR K ; and

-L M -CONR K 2 .

In one embodiment, R 1M is independently selected from: -L M -NH 2 ;

-L M -NHR K ; and -L M -NR K 2 .

In one embodiment, R 1M is independently selected from: -CONH 2 ;

-CONHR K ; -CONR K 2 ; -L M -CONH 2 ; -L M -CONHR K ; and -L M -CONR K 2 .

In one embodiment, R 1M is independently selected from: -L M -CN.

In one embodiment, R 1M is independently selected from: -L M -OH; or -L M -OR K .

In one embodiment, each L M is independently -(CH 2 )-, -(CH 2 ) 2 -, or -(CH 2 ) 3 -. In one embodiment, each L M is independently -(CH 2 )-. In one embodiment, each L M is independently -(CH 2 ) 2 . In one embodiment, each L M is independently -(CH 2 ) 3 -.

In one embodiment, each R κ is independently -Me or Et.

In one embodiment, R 1M is independently selected from:

-(CH 2 J-NH 2 , -(CH 2 ) 2 -NH 2 , -(CH 2 ) 3 -NH 2 ;

-(CH 2 )-NHMe, -(CH 2 ) 2 -NHMe, -(CH 2 ) 3 -NHMe;

-(CHa)-NHEt, -(CHz) 2 -NHEt, -(CH 2 J 3 -NHEt; -(CH 2 )-NMe 2 , -(CH 2 ) 2 -NMe 2 , -(CH 2 ) 3 -NMe 2 ;

-(CHa)-NEt 2 , -(CHa) 2 -NEt 2 , -(CH 2 J 3 -NEt 2 ;

-(CHa)-OH, -(CHz) 2 -OH, -(CH 2 ) 3 -OH;

-(CHa)-OMe 1 -(CH 2 ) 2 -OMe, -(CH 2 ) 3 -OMe;

-(CHa)-OEt 1 -(CH 2 ) 2 -OEt, -(CHa) 3 -OEt; -COOH;

-COOMe, -COOEt;

-CONH 2 ;

-CONHMe, -CONHEt;

-CONMe 2 , -CONEt 2 ; -(CH 2 )-COOH, -(CHa) 2 -COOH, -(CH 2 ) 3 -COOH;

-(CH 2 )-COOMe, -(CHa) 2 -COOMe, -(CHa) 3 -COOMe;

-(CH 2 )-COOEt, -(CH 2 ) 2 -COOEt, -(CH 2 ) 3 -COOEt; -(CH 2 )-CONH 2 , -(CH 2 ) 2 -CONH 2 , -(CH 2 ) 3 -CONH 2 ; -(CH 2 )-CONHMe, -(CH 2 )JrCONHMe 1 -(CH 2 ) 3 -CONHMe; -(CH 2 )-CONHEt, -(CH 2 ) 2 -CONHEt, -(CH 2 ) 3 -CONHEt; -(CH 2 )-CONMe 2 , -(CH 2 ) 2 -CONMe 2 , -(CH 2 ) 3 -CONMe 2 ;

-(CHa)-CONEt 2 , -(CH 2 ) 2 -CONEt 2 , -(CH 2 ) 3 -CONEt 2 ; -(CH 2 )-CN, -(CHa) 2 -CN, and -(CH 2 J 3 -CN.

In one embodiment, R 1M is independently selected from: -(CH 2 )-NH 2 , -(CHa) 2 -NH 2 , -(CHa) 3 -NH 2 ;

-(CHa)-NHMe, -(CH 2 ) 2 -NHMe, -(CHa) 3 -NHMe;

-(CHa)-NHEt, -(CHa) 2 -NHEt, -(CHa) 3 -NHEt;

-(CHa)-NMe 2 , -(CHa) 2 -NMe 2 , -(CHz) 3 -NMe 2 ;

-(CHa)-NEt 2 , -(CHa) 2 -NEt 2 , and -(CHa) 3 -NEt 2 .

In one embodiment, R 1M is independently selected from:

-(CHa)-NH 2 ,

-(CHa)-NHMe,

-(CHa)-NHEt, -(CHa)-NMe 2 , and

-(CHa)-NEt 2 .

In one embodiment, R 1M is independently -(CH 2 )-NH 2 .

In one embodiment, R 1M is -(CH 2 ) P -NH 2 (wherein p is independently 1, 2, or 3); R 1M is attached at the 2- or 6-position; and n is O, as in, for example, the following group:

In one embodiment, R 1M is -CH 2 -NH 2 ; R 1M is attached at the 2- or 6-position; and n is O, as in, for example, the following group:

The Optional Additional Morpholino Substitueπts, R AM

The morpholino group optionally bears 1 or 2 additional subsitutents, R AM .

Thus, n is independently 0, 1 or 2.

In one embodiment, n is independently 0. In one embodiment, n is independently 1. In one embodiment, n is independently 2.

An additional subsitutent, R AM , if present, may be attached at the same position as the group R 1M , or at a different position than the group R 1M .

In one embodiment, an additional subsitutent, R AM , is attached at the same position as the group R 1M , as in, for example:

In one embodiment, any additional subsitutents, R AM , are attached at different positions than the group R 1M (i.e., are not attached at the same position as the group R 1M ), as in, for example:

Each group R AM , if present, is independently C^alkyl or -CF 3 . In one embodiment, each R AM , if present, is independently C 1-3 alkyl. In one embodiment, each R AM , if present, is independently -Me, -Et, or -CF 3 . In one embodiment, each R AM , if present, is independently -Me.

In one embodiment, the morpholino group is selected from the following groups (wherein n is 1 or 2, each R AM is -Me):

In one embodiment, the morphoino group is selected from the following groups (wherein n is 1 or 2, each R AM is -Me, and R 1M is -CH 2 -NH 2 ):

The Substituents R 2C and R 3C

If X is N, then the group -C(R 3C )=X- is -C(R 3C )=N- (shown below) and is independently: -C(Q A )=N- (denoted "N1") or -CH=N- (denoted "N2") (both shown below)

and if X is C(R 2C ), then the group -C(R 3C )=X- is -C(R 3C )=C(R 2C )- (shown below) and is independently:

-CH=CH- (denoted "C1")

-C(Q A )=CH- (denoted "C2"),

-C(Q A )=C(Q B )- (denoted "C3"),

-CH=C(Q A )- (denoted "C4"),

-C(Q B )=C(Q A )- (denoted "C5"),

-C(Q 8 )=CH- (denoted "C6"), or

-CH=C(Q 6 )- (denoted "C7")

(all shown below).

In one embodiment, X is N and X=C(R 3C ) is N1 or N2. In one embodiment, X is N and X=C(R 30 ) is N1. In one embodiment, X is N and X=C(R 3C ) is N2.

In one embodiment, X is C(R 2G ) and X= =C(R 3G ) is C1 , C2, C3, C4, C5, C6, or C7. In one embodiment, X is C(R 2C ) and X= =C(R 30 ) is C1 , C2, C3, C4, or C5. In one embodiment, X is C(R 2C ) and X= :C(R 3G ) is C1 , C2, or C3. In one embodiment, X is C(R 2C ) and X= :C(R 3G ) is C1 , C2, or C4. In one embodiment, X is C(R 2C ) and X= =C(R 3C ) is C1, C4, or C5. In one embodiment, X is C(R 2C ) and X= :C(R 3C ) is C2 or C4. In one embodiment, X is C(R 2C ) and X= :C(R 3C ) is C1. In one embodiment, X is C(R 20 ) and X= ^C(R 30 ) is C2. In one embodiment, X is C(R 20 ) and X= ■C(R 3C ) is C3. In one embodiment, X is C(R 2C ) and X= :C(R 3C ) is C4. In one embodiment, X is C(R 2C ) and X= C(R 3C ) is C5. In one embodiment, X is C(R 20 ) and X= : C(R 3G ) is C6. In one embodiment, X is C(R 20 ) and X= C(R 30 ) is C7.

The Group Q A

The group Q A is independently selected from: -A A ; -NR N1 2 ; -NR N1 -A B ; -NR N2 -(CH 2 ) q1 -A°; -C(=O)-NR N3 -A D ; -C(=O)-NR N4 -(CH 2 ) q2 -A E ; -C(=O)-NR N5 R N6 ; -C(=O)-NR N1R R N2R ; -C(=O)-OR E ;

_ G QA. wherein:

A A is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;

A B is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

A c is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

A D is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted; A E is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted; q1 is independently 1 , 2, or 3; q2 is independently 1 , 2, or 3;

R N1 is independently -H or C 1-3 alkyl; R N2 is independently -H or C 1-3 alkyl;

R N3 is independently -H or C 1-3 alkyl;

R N4 is independently -H or C 1-3 alkyi; each of R N5 and R m is independently -H, C 1-6 alkyl, or C 1-6 cycloalkyl;

R N1R and R N2R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;

R ε is independently -H or C 1-4 alkyl; and

G 0 ^ is independently halogen.

(Note that if the non-aromatic heterocyclic ring has exactly one ring heteroatom, then that ring heteroatom is the nitrogen atom to which R N1 R and R N2R are attached. If the non- aromatic heterocyclic ring has exactly two ring heteroatoms, then one ring heteroatom is the nitrogen atom to which R N1R and R N2R are attached, and the other ring heteroatom is independently selected from nitrogen, oxygen, and sulfur.)

In one embodiment, Q A is independently -A A .

In one embodiment, Q A is independently -NR N1 2 . In one embodiment, Q A is independently -NH 2 .

In one embodiment, Q A is independently -NR N1 -A B .

In one embodiment, R N1 is independently -H or -Me. In one embodiment, R N1 is independently -H.

In one embodiment, Q A is independently -NR N2 -(CH 2 ) q1 -A c .

In one embodiment, R N2 is independently -H or -Me. In one embodiment, R N2 is independently -H.

In one embodiment, q1 is independently 1 or 2. In one embodiment, q1 is independently 1.

In one embodiment, Q A is independently -C(=O)-NR N3 -A D .

In one embodiment, R m is independently -H or -Me. In one embodiment, R m is independently -H.

In one embodiment, Q A is independently -C(=O)-NR N4 -(CH 2 ) q2 -A E .

In one embodiment, R N4 is independently -H or -Me. In one embodiment, R N4 is independently -H.

In one embodiment, q2 is independently 1 or 2. In one embodiment, q2 is independently 1.

In one embodiment, Q A is independently -C(=O)-NR N5 R N6 .

In one embodiment, R N5 is independently -H or C 1-3 alkyl; and R N6 is independently -H, C 1 . 6 alkyl, or Ci-βcycloalkyl.

In one embodiment, each of R N5 and R m is independently -H or C-, -6 alkyl. In one embodiment, each of R N5 and R N6 is independently -H or Ci -3 alkyl.

In one embodiment, Q A is independently -C(=O)-NR N1R R N2R .

In one embodiment, -NR N1R R N2R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

azetidino pyrrolidino imidazolidino pyrazolidino

piperidino piperizino morpholino azepino 1 ,4-diazepino

In one embodiment, -NR N1R R N2R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, Q A is independently -C(=O)-OR E .

In one embodiment, R E is independently C 1-4 alkyl. In one embodiment, R E is independently -H, -Me, -Et, -nPr, or -iPr. In one embodiment, R E is independently -Me, -Et, -nPr, or -iPr. In one embodiment, R ε is independently -Me or -Et.

In one embodiment, Q A is independently -G 0 ^.

In one embodiment, G^ is independently -F, -Cl, -Br 1 or -I. ' In one embodiment, G™ is independently -Cl, -Br, or -I.

In one embodiment, G 0 ^ is independently -Cl or -Br.

In one embodiment, G 0 ^ is independently -Cl. In one embodiment, G^ is independently -Br.

In one embodiment, Q A is independently -NH 2 , -NHPh, -NHCH 2 Ph, -C(=O)OH, -C(=O)OMe, -C(=O)OEt, -C(=O)NH 2 , -C(=O)NHMe, -C(=O)NHEt, -C(=O)-morpholino, - C(=O)NHPh, -Cl, -Br, or -Ph.

In one embodiment, Q A is independently selected from those groups exemplified for Q A under the heading "Some Preferred Embodiments."

The Group Q B

The group Q B , if present, is independently C^alkyl or -CF 3 .

In one embodiment, Q B , if present, is independently C^alkyl.

In one embodiment, Q B , if present, is independently -Me, -Et, or -CF 3 .

In one embodiment, Q B , if present, is independently -Me.

The Substituent R 5C

The substituent R 5C is present when Y-Z is C(R 6C1 )=C(R 5C ).

The substituent R 5G , if present, is independently -H or C 1-3 alkyl. In one embodiment, R 5G , if present, is independently -H or -Me. In one embodiment, R 5G , if present, is independently -H.

In one embodiment, Y-Z is C(R 6C1 )=CH, as in, for example:

The Substituent R 6C1

The substituent R 6C1 is present when Y-Z is C(R 6C1 )=C(R 5C ).

The substituent R 6G1 is independently selected from: -H;

-G 6G1 ;

_ D 6C1.

-A F ; -C(=O)NR N3R R N4R ;

-C(=O)NR N7 -L 1 -J 1 ;

-C(=O)NR N8 -B 6G1 ;

-C(=O)NR N8 -A G ; and

-C(=O)NR N9 -(CH 2 ) q3 -A H ; wherein:

G 6C1 is independently halogen;

D 6G1 is independently Ci -3 alkyl;

A F is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted; R N3R and R N4R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and

having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;

R N7 is independently -H or C 1-3 alkyl; either:

L 1 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and

J 1 is -H; or:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and

J 1 is -H, -CN, -OH, ~OR J1 , -NH 2 , -NHR J1 , or -NR Ji 2 ; each R J1 is independently C 1-3 alkyl;

R Na is independently -H or C-|. 3 alkyl; B 6C1 is independently C 5-7 cycloalkyl or C 5- rheterocyclyl, optionally substituted with one or more C 1-3 alkyl groups;

A G is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

R N9 is independently -H or C 1-3 alkyl; q3 is independently 1 , 2, or 3; and

A H is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, R 6C1 is independently selected from: -G 6C1 ;

_ D 6C1.

-A F ;

-C(=O)NR N3R R N4R ; -C(=O)NR N7 -L 1 -J 1 ; -C(=O)NR N8 -B 6C1 ;

-C(=O)NR N8 -A G ; and -C(=O)NR N9 -(CH 2 ) q3 -A H .

In one embodiment, R 6C1 is independently selected from: -A F ;

-C(=O)NR N3R R N4R ;

-C(=O)NR N7 -L 1 -J 1 ;

-C(=O)NR N8 -B 6C1 ;

-C(=O)NR N8 -A G ; and -C(=O)NR N9 -(CH 2 ) q3 -A H .

In one embodiment, R 6C1 is independently -H.

In one embodiment, R 6C1 is independently -G 6C1 .

In one embodiment, G 6C1 is independently -F, -Cl, -Br, or -I. In one embodiment, G 6G1 is independently -Cl, -Br, or -I. In one embodiment, G 6C1 is independently -Cl or -Br. In one embodiment, G 6C1 is independently -Cl. In one embodiment, G 6C1 is independently -Br.

In one embodiment, R 6C1 is independently -D 6C1 .

In one embodiment, D 6C1 is independently -Me, -Et, -nPr, or -iPr.

In one embodiment, R 6C1 is independently -A F .

In one embodiment, R 6C1 is independently -C(=O)NR N3R R N4R .

In one embodiment, -NR N3R R N4R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, -NR N3R R N4R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, R 6C1 is independently -C(=O)NR N7 -L 1 -J 1 .

In one embodiment, R N7 is independently -H or -Me. In one embodiment, R N7 is independently -H.

In one embodiment:

L 1 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or - CH 2 CH 2 CH 2 -, and J 1 is -H.

In one embodiment:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and J 1 is -CN.

In one embodiment:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 1 is -OH or -OR J1 .

In one embodiment:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 1 Js -NH 2 , -NHR J1 , or -NR J1 2 .

In one embodiment: L 1 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 - > and

J 1 is -H.

In one embodiment:

L 1 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and J 1 is -H, -CN 1 -OH, -OR J1 , -NH 2 , -NHR J1 , or -NR J1 2 .

In one embodiment:

L 1 is -CH 2 CH 2 CH 2 -, and

J 1 is -H, -CN, -OH, -OR J1 , -NH 2 , -NHR J1 , or -NR J1 2 .

In one embodiment, each R J1 is independently -Me or -Et.

In one embodiment, the group -L 1 -J 1 is independently selected from: -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ; -(CH 2 ) J rCN 1 -(CHz) 3 -CN;

-(CHz) 2 -OH, -(CH 2 ) 3 -OH; -(CHz) 2 -OMe, -(CHz) 3 -OMe; -(CHz) 2 -OEt, -(CHs) 3 -OEt; -(CHz) 2 -NH 2 , -(CHa) 3 -NH 2 ; -(CHz) 2 -NHMe, -(CH 2 ) 3 -NHMe; -(CHz) 2 -NHEt, -(CHz) 3 -NHEt; -(CH 2 ) Z -NMe 2 , -(CH 2 ) 3 -NMe 2 ; -(CHz) 2 -NEt 2 , and -(CH 2 )^NEt 2 .

In one embodiment, R 6G1 is independently -C(=O)NR N8 -B 6C1 .

In one embodiment, R N8 is independently -H or -Me. In one embodiment, R N8 is independently -H.

In one embodiment, B 6C1 is independently cylcopentyl, cyclohexyl, cylcoheptyl, pyrrolidine, imidazolidinyl, pyrazolidinyl, piperidinyl, piperizinyl, morpholinyl, azepinyl, or

diazepinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 a!kyl groups, e.g., -Me).

In one embodiment, B 6C1 is independently cyclohexyl, piperidinyl, piperizinyl, or morpholinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, R 6C1 is independently -C(=O)NR N8 -A G .

In one embodiment, R NS is independently -H or -Me. In one embodiment, R N8 is independently -H.

In one embodiment, R 6C1 is independently -C(=O)NR N9 -(CH 2 ) q3 -A H .

In one embodiment, R N9 is independently -H or -Me. In one embodiment, R N9 is independently -H.

In one embodiment, q3 is independently 1 or 2. In one embodiment, q3 is independently 1.

In one embodiment, R 6C1 is independently selected from those groups exemplified for R 6G1 and R 6C2 under the heading "Some Preferred Embodiments."

In one embodiment, R 6C1 is independently selected from those groups exemplified for R 6C1 under the heading "Some Preferred Embodiments."

The Substituent R 6C2

The substituent R 6C2 is present when Y-Z is C(R 6C2 )=N.

The substituent R 6C2 is independently selected from: -H;

-A J ;

-C(=O)NR N5R R N6R ;

-C(=0)NR N10 -L 2 -J 2 ;

-C(=O)NR N11 -B 6C2 ;

-C(=O)NR N11 -A K ; and -C(=O)NR N12 -(CH 2 ) q4 -A L ;

wherein:

G 6C2 is independently halogen;

D 6C2 is independently C 1-3 alkyl;

A J is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted;

R N5R and R N6R , taken together with the nitrogen atom to which they are attached, independently form a non-aromatic heterocyclic ring having from 4 to 7 ring atoms, and having exactly one ring heteroatom, wherein said one ring heteroatom is nitrogen, or having exactly two ring heteroatoms, wherein one of said two ring heteroatoms is nitrogen and the other of said two ring heteroatoms is independently selected from nitrogen, oxygen, and sulfur; and wherein said non-aromatic heterocyclic ring is independently unsubstituted or substituted;

R N1 ° is independently -H or C 1-3 alkyl; either: L 2 is -CH 2 -, -CH(CH 3 )- or -C(CH 3 ) 2 -, and

J 2 is -H; or:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and

J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 ; each R J2 is independently C 1-3 alkyl;

R N11 is independently -H or C 1-3 alkyl;

B 6C2 is independently C 5-7 cycloalkyl or C 5-7 heterocyclyl, optionally substituted with one or more C 1-3 alkyl groups;

A κ is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted;

R N12 is independently -H or C 1-3 alkyl; q4 is independently 1 , 2, or 3;. and

A L is independently phenyl or C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, R 6C2 is independently -H.

In one embodiment, R 6C2 is independently -G 6C2 .

In one embodiment, G 6C2 is independently -F, -Cl, -Br, or -I.

In one embodiment, G 6C2 is independently -Cl, -Br, or -I.

In one embodiment, G 6C2 is independently -Cl or -Br.

In one embodiment, G 6C2 is independently -Cl.

In one embodiment, G 6C2 is independently -Br.

In one embodiment, R 6C2 is independently -D 6C2 .

In one embodiment, D 6C2 is independently -Me, -Et, -nPr, or -iPr.

In one embodiment, R 6C2 is independently -A J .

In one embodiment, R 6C2 is independently -C(=O)NR N5R R N6R .

In one embodiment, -NR N5R R N6R is independently selected from: azetidino, pyrrolidino, imidazolidino, pyrazolidino, piperidino, piperizino, morpholino, azepino, and diazepino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, -NR N5R R N6R is independently selected from: pyrrolidino, piperidino, piperizino, and morpholino; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, R 6C2 is independently -C(=0)NR N10 -L 2 -J 2 .

In one embodiment, R N1 ° is independently -H or -Me. In one embodiment, R N1 ° is independently -H.

In one embodiment:

L 2 is -CH 2 -, -CH(CH 3 )-, -C(CH 3 J 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 2 is -H.

In one embodiment:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and

J 2 is -CN.

In one embodiment:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and

J 2 is -OH or -OR J2 .

In one embodiment:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, Or -CH 2 CH 2 CH 2 -, and J 2 is -NH 2 , -NHR J2 , or -NR J2 2 .

In one embodiment: L 2 is -CH 2 -, -CH(CH 3 )- or -C(CHg) 2 -, and

J 2 is -H.

In one embodiment:

L 2 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and

J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 .

In one embodiment:

L 2 is -CH 2 CH 2 CH 2 -, and

J 2 is -H, -CN, -OH, -OR J2 , -NH 2 , -NHR J2 , or -NR J2 2 .

In one embodiment, each R J2 is independently -Me or -Et.

In one embodiment, the group -L 2 -J 2 is independently selected from:

-CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 J

-(CH 2 ) Z -CN, -(CHz) 3 -CN; -(CHz) 2 -OH, -(CH 2 ) 3 -OH;

-(CHz) 2 -OMe, -(CHz) 3 -OMe;

-(CHz) 2 -OEt, -(CHa) 3 -OEt;

-(CHz) 2 -NH 2 , -(CH 2 ) 3 -NH 2 ;

-(CHz) 2 -NHMe, -(CH 2 ) 3 -NHMe; -(CH 2 J 2 -NHEt, -(CHz) 3 -NHEt;

-(CHz) 2 -NMe 2 , -(CH 2 ) 3 -NMe 2 ;

-(CHz) 2 -NEt 2 , and -(CH 2 ) 3 -NEt 2 .

In one embodiment, R 6C2 is independently -C(=O)NR N11 -B 6C2 .

In one embodiment, R N11 is independently -H or -Me. In one embodiment, R N11 is independently -H.

In one embodiment, B 6C2 is independently cylcopentyl, cyclohexyl, cylcoheptyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperizinyl, morpholinyl, azepinyl, or diazepinyl; and is independently unsubstituted or substituted (e.g., with one or more C^alkyl groups, e.g., -Me).

In one embodiment, B 602 is independently cyclohexyl, piperidinyl, piperizinyl, or morpholinyl; and is independently unsubstituted or substituted (e.g., with one or more C 1-3 alkyl groups, e.g., -Me).

In one embodiment, R 6C2 is independently -C(=O)NR N11 -A K .

In one embodiment, R N11 is independently -H or -Me. In one embodiment, R N11 is independently -H.

In one embodiment, R 6C2 is independently -C(=O)NR N12 -(CH 2 ) q4 -A L .

In one embodiment, R N12 is independently -H or -Me. In one embodiment, R N12 is independently -H.

In one embodiment, q4 is independently 1 or 2. In one embodiment, q4 is independently 1.

In one embodiment, R 6C2 is independently selected from those groups exemplified for R 6C1 and R 6C2 under the heading "Some Preferred Embodiments."

In one embodiment, R 6C2 is independently selected from those groups exemplified for R 602 under the heading "Some Preferred Embodiments."

The Substituent R m

The substituent R 6N is present when Y-Z is N(R 6N )-C(=O).

The substituent R 6N is independently selected from:

-H;

-A M ;

-(CH 2 ) q5 -A N ; and

-L 3 -J 3 . wherein:

A M is independently phenyl or C 5 - 6 heteroaryl, and is independently unsubstituted or substituted; q5 is independently 1 , 2, or 3;

A N is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted; either:

L 3 is -CH 2 -, -CH(CH 3 )- or -C(CHg) 2 -, and

J 3 is -H; or: L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and

J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR J3 2 ; each R J3 is independently C 1-3 alkyl.

In one embodiment, R 6N is independently selected from: -A M ;

-(CH 2 ) q5 -A N ; and

-L 3 -J 3 .

In one embodiment, R 6N is independently -H.

In one embodiment, R 6N is independently -A M .

In one embodiment, R 6N is independently -(CH 2 )q 5 -A N .

In one embodiment, q5 is independently 1 or 2. In one embodiment, q5 is independently 1.

In one embodiment, R 6N is independently -L 3 -J 3 .

In one embodiment: L 3 is -CH 2 -, -CH(CH 3 )-, -C(CHs) 2 -, -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or

-CH 2 CH 2 CH 2 -, and J 3 is -H.

In one embodiment: L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and

J 3 is -CN.

In one embodiment:

L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and J 3 is -OH or -OR J3 .

In one embodiment:

L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, or -CH 2 CH 2 CH 2 -, and

J 3 Js -NH 2 , -NHR J3 , or -NR J3 2 .

In one embodiment:

L 3 is -CH 2 -, -CH(CH 3 )- or -C(CHs) 2 -, and

J 3 is -H.

In one embodiment:

L 3 is -CH 2 CH 2 -, -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, and J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR j3 2 .

In one embodiment: L 3 is -CH 2 CH 2 CH 2 -, and

J 3 is -H, -CN, -OH, -OR J3 , -NH 2 , -NHR J3 , or -NR J3 2 .

In one embodiment, each R J3 is independently -Me or -Et.

In one embodiment, the group -L 3 -J 3 is independently selected from: -CH 3 , -CH 2 CH 3 , -CH 2 CH Z CH 3 ;

-(CHz) 2 -CN, -(CHz) 3 -CN;

-(CHz) 2 -OH, -(CHz) 3 -OH;

-(CHz) 2 -OMe, -(CHz) 3 -OMe;

-(CHz) 2 -OEt, -(CH 2 ) 3 -OEt; -(CHz) 2 -NH 21 -(CHz) 3 -NH 2 ;

-(CHz) 2 -NHMe, -(CH 2 ) 3 -NHMe;

-(CH 2 ) Z -NHEt, -(CHz) 3 -NHEt;

-(CHs) 2 -NMe 2 , -(CH 2 ) 3 -NMe 2 ;

-(CH 2 ) Z -NEt 2 , and -(CHz) 3 -NEt 2 .

The Groups A A . A B , A c , A D , A E . A F , A G , A H , A J , A κ , A L , A M , and A N

As discussed above, each of the groups A A , A B , A c , A D , A E , A F , A G , A H , A J , A κ , A L , A M , and A N , if present, is independently phenyl or C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, the or each C 5 . 6 heteroaryl is independently selected from: furanyl (C 5 ), thienyl (C 5 ), pyrrolyl (C 5 ), imidazolyl (C 5 ), pyrazolyl (C 5 ), oxazolyl (C 5 ), isoxazolyi (C 5 ), thiazolyl (C 5 ), isothiazolyl (C 5 ), furazanyl (C 5 ), [1 ,3,4]oxadiazolyl (C 5 ), [1 ,2,4]oxadiazolyl (C 5 ), [1 ,2,5]thiadiazolyl (C 5 ), [1 ,3,4]thiadiazolyl (C 5 ), [1 ,2,4]thiadiazolyl (C 5 ), [1 ,2,3]triazolyl (C 5 ), [1 ,2,4]triazolyl (C 5 ), pyridyl (C 6 ), pyrazinyl (C 6 ), pyrimidinyl (C 6 ), and pyridazinyl (C 6 ).

furan thiophene pyrrole imidazole pyrazole oxazole

isoxazole thiazole isothiazole

furazan [1 ,3,4]oxadiazole [1 ,2,4]oxadiazole

[1 ,2,5]thiadiazole [1,3 ,4]thiadiazole [1 ,2,4]thiadiazole

[ 1 ,2,3]triazole [1,2,4]triazol€

V V V" pyridine p Uyrazine pyrimidine pyridazine-

For example, in one embodiment, A A is independently selected from: phenyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1,2,5]thiadiazolyl, [1 ,3,4]thiadiazolyl, [1 ,2,4]thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

In one embodiment, the or each C 5-6 heteroaryl is independently selected from: thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl; and is independently unsubstituted or substituted.

In one embodiment, A A is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A A is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A A is independently selected from: phenyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, [1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, and pyridyl; and is independently unsubstituted or substituted.

In one embodiment, A A is independently thienyl, and is independently unsubstituted or substituted.

In one embodiment, A B is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A B is independently C 5 - 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A B is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, or pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A c is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A c is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A c is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A D is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A D is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A D is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A E is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A E is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A E is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A F is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A F is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A F is independently selected from: phenyl, thienyl, pyrazolyl,

[1 ,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A F is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, [1 ,2,3]triazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A F is independently selected from: phenyl, pyridyl, pyrazolyl, [1 ,2,3]triazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A F is independently selected from: phenyl, thienyl, pyridyl, pyrazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A F is independently selected from: phenyl, pyridyl, pyrazolyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A G is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A G is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A G is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A H is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A H is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A H is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A J is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A J is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A J is independently selected from: phenyl, thienyl, pyrazolyl, [1,3,4]oxadiazolyl, [1 ,2,4]oxadiazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A κ is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A κ is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A κ is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A L is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A L is independently C 5 _ 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A L is independently selected from: phenyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, A M is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A M is independently C 5-6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A M is independently selected from: phenyl, thienyl, pyrazolyl, [1 ,2,3]triazolyl, [1 ,2,4]triazolyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted.

In one embodiment, A N is independently phenyl, and is independently unsubstituted or substituted.

In one embodiment, A N is independently C 5 . 6 heteroaryl, and is independently unsubstituted or substituted.

In one embodiment, A N is independently selected from: phenyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; and is independently unsubstituted or substituted; and is independently unsubstituted or substituted.

In one embodiment, each of A F , A J , and A M is independently phenyl, pyridyl, [1 ,2,3]triazolyl, or pyrazolyl; and is independently unsubstituted or substituted.

In one embodiment, each of A F , A J , and A M is independently phenyl, pyridyl, or pyrazolyl; and is independently unsubstituted or substituted.

In one embodiment, each of A F , A J , and A M is independently the following group, wherein R f is independently a substituent as defined under the heading Optional Substituents on Phenyl and Cs-eHeteroaryl":

In one embodiment, each of A F , A J , and A M is independently selected from the following groups, wherein R f is independently a substituent as defined under the heading "Optional Substituents on Phenyl and C 5 . 6 Heteroaryl":

In one embodiment, each of A F , A J , and A M is independently selected from the following groups, wherein R f is independently a substituent as defined under the heading "Optional Substituents on Phenyl and C 5 . 6 Heteroaryl":

Optional Substituents on Phenyl and Cg^Heteroaryl

As discussed above, certain groups (e.g., A A , A B , A c , A D , A E , A F , A G , A H , A J , A κ , A L , A M , and A N ) are, for example, phenyl or C 5 . 6 heteroaryl, and are unsubstituted or substituted, for example, substituted with one or more (e.g., 1 , 2, etc.) substituents.

Substituents, if present, may be on a ring carbon atom or a ring heteroatom. For example, when a C 5 . 6 heteroaryl group includes -NH- in the aromatic ring (e.g., as in pyrrolyl, imidazolyl, pyrazolyl), this group may be N-substituted, for example N-(C 1-3 alkyl)- substituted, for example N-(methyl)-substituted, as in, for example, N-methyl-pyrazolyl.

In one embodiment, each substituent (e.g., each optional substituent on A λ , A B , A c , A D ,

A E , A F , A G , A H , A J , A κ , A L , A M , and/or A N ) is independently selected from:

(H-I ) -C(O)OH;

(H-2) -C(O)OR 3 ; (H-3) -C(O)NH 2 , -C(=O)NHR a , -C(=O)NR a R a , -C(=O)NR b R c ;

(H-4) -C(=0)R a ;

(H-5) -F, -Cl, -Br, -I;

(H-6) -CN;

(H-7) -NO 2 ; (H-8) -0H;

(H-9) -0R a ;

(H-I O) -SH;

(H-11) -SR a ;

(H-12) -OC(=O)R a ; (H-13) -OC(O)NH 2 , -OC(=O)NHR a , -0C(=0)NR a R a , -0C(=0)NR b R c ;

(H-14) -NH 2 , -NHR a , -NR 3 R 3 , -NR b R c ;

(H-15) -NHC(=O)R a ; -NR a C(=0)R a ;

(H-16) -NHC(=O)NH 2 , -NHC(=O)NHR a , -NHC(O)NR 9 R 3 , -NHC(=O)NR b R c ,

-NR 3 C(O)NH 2 , -NR a C(=0)NHR a , -NR a C(=0)NR a R a , -NR a C(=0)NR b R c ; (H-17) -NHSO 2 R 3 , -NR 3 SO 2 R 3 ;

(H-18) -SO 2 R 3 ;

(H-19) -OSO 2 R a ;

(H-20) -SO 2 NH 2 , -SO 2 NHR 3 , -SO 2 NR 3 R 3 , -SO 2 NR b R c ;

(H-21) O; . (H-22) -CF 3 ; and

(H-23) -R d ;

wherein R d and each R a is independently selected from:

(C-I J C^alkyl; (C-2) C 2-7 alkenyl;

(C-3) C 2-7 alkynyl;

(C-4) C 3-7 cycloalkyl;

(C-5) C 3 . 7 cycloalkenyl;

(C-6) C 3- i 4 heterocyclyl, (C-7) Cβ-ucarboaryl,

(C-8) C 5-14 heteroaryl,

(C-9) C 3 . 7 cycloalkyl-C 1-3 alkylenyl, (C-10) C 3 . 14 heterocyclyl-C 1-3 alkyleny!, (C-1 1 ) C 6-14 carboaryl-C 1-3 alkylenyl, and (C-12) C^heteroaryl-C^alkylenyl;

wherein each Ci -7 alkyl, C 2-7 alkenyl, C 2-7 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, C 3- 14 heterocyclyl, C 6-14 carboaryl, and C 5- i 4 heteroaryl is independently unsubstituted or substituted with one or more (e.g., 1 , 2, etc.) substituents selected from (H-1) through (H- 22);

and wherein R b and R c taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.

In one embodiment, each substituent (e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A κ , A L , A M , and/or A N ) is independently selected from:

(H'-2) -C(=O)OR a> ;

(H'-3) -C(=O)NH 2 , -C(=O)NHR a' , -C(=O)NR a' R a' , -C(=O)NR b R c' ;

(H'-5) -F, -Cl, -Br, -I;

(H'-6) -CN; (H'-8) -OH;

(H'-9) -OR a' ;

(H'-14) -NH 2 , -NHR a' , -NR 3 R 3' , -NR b R c' ;

(H'-15) -NHC(=O)R a' ; -NR a' C(=O)R 3' ;

(H'-17) -NHSO 2 R 3' , -NR a' SO 2 R a' ; (H'-18) -SO 2 R a' ;

(H'-20) -SO 2 NH 2 , -SO 2 NHR 3' , -SO 2 NR a' R a' , -SO 2 NR b R c' ;

(H'-22) -CF 3 ; and

(H'-23) -R d' ;

wherein R d' and each R a' is independently selected from:

(C-1) C 1-7 alkyl;

(C'-4) C 3-7 cycloalkyl;

(C-6) C^heterocyclyl,

(C'-7) C 6- i 4 carboaryl, (C-8) C 5-14 heteroaryl,

(C'-9) C3.7cycloalkyl-C 1-3 alkylenyl,

(C-10) C 3-14 heterocyclyl-C 1-3 alkylenyl,

(C-11 ) Ce-ucarboaryl-Ci-salkylenyl, and

(C-12) C 5 -i 4 heteroaryl-C 1-3 alkylenyl;

wherein each C 1-7 alkyl, C 3-7 cycloalkyl, C 3 . 14 heterocyclyl, C 6- i 4 carboaryl, and C 5- i 4 heteroaryl is independently unsubstituted or substituted with one or more (e.g., 1 , 2, etc.) substituents selected from (H'-2), (H'-3), (H'-5), (H'-6), (H'-8), (H'-9), (H'-14), (H'-15), (H'-17), (H'-18), (H"-20), and (H'-22).

and wherein R b' and R 0' taken together with the nitrogen atom to which they are attached form a ring having from 3 to 7 ring atoms.

In one embodiment, each substituent (e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A κ , A L , A M , and/or A N ) is independently selected from:

C-,. 4 alkyl;

-F, -Cl, -Br, -I;

-L 4 -CN;

-L 4 -OH, -L 4 -OR e ; -L 4 -O-L 5 -OH, -L 4 -O-L 5 -OR e ;

-L 4 -C(=O)OR e ;

-L 4 -NH 2 , -L 4 -NHR e , -L 4 -NR e R e , -L 4 -NR f R 9 ;

-L 4 -NH-L 5 -NH 2 , -L 4 -NH-L 5 -NHR e , -L 4 -NH-L 5 -NR e R θ , -L 4 -NH-L 5 -NR f R 9 ;

-L 4 -NR e -L 5 -NH 2 , -L 4 -NR e -L 5 -NHR e , -L 4 -NR e -L 5 -NR e R e , -L 4 -NR θ -L 5 -NR f R 9 ; -L 4 -C(=O)NH 2 , -L 4 -C(=O)NHR e , -L 4 -C(=O)NR e R e , -L 4 -C(=O)NR f R 9 ;

-L 4 -S(=O) 2 NH 2 , -L 4 -S(=O) 2 NHR e , -L 4 -S(=O) 2 NR e R e , -L 4 -S(=O) 2 NR f R 9 ;

-L 4 -S(=O) 2 NH-L 5 -OH, -L 4 -S(=O) 2 NH-L 5 -OR e ; wherein: each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2 . 4 alkylenyl; each R e is independently C 1-4 alkyl, -Ph, Or -CH 2 Ph; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(C 1-3 alkyl)-piperizino, or morpholino.

In one embodiment, each substituent (e.g., each optional substituent on A A , A B , A c , A D , A E , A F , A G , A H , A J , A κ , A L , A M , and/or A N ) is independently selected from:

C 1-4 alkyl;

-L 4 -CN;

-L 4 -OH, -L 4 -OR e ; -L 4 -O-L 5 -OH, -L 4 -O-L 5 -OR e ;

-L 4 -NH 2 , -L 4 -NHR e , -L 4 -NR e R e , -L 4 -NR f R 9 ;

-L 4 -NH-L 5 -NH 2 , -L 4 -NH-L 5 -NHR e , -L 4 -NH-L 5 -NR e R e , -L 4 -NH-L 5 -NR f R 9 ;

-L 4 -NR e -L 5 -NH 2 , -L 4 -NR e -L 5 -NHR θ , -L 4 -NR e -L 5 -NR e R e , -L 4 -NR e -L 5 -NR f R 9 ;

-L 4 -C(=O)NH 2 , -L 4 -C(=O)NHR e , -L 4 -C(=O)NR e R θ , -L 4 -C(=O)NR f R 9 ; -L 4 -S(=O) 2 NH 2 , -L 4 -S(=O) 2 NHR β , -L 4 -S(=O) 2 NR θ R e , -L 4 -S(=O) 2 NR f R 9 ;

-L 4 -S(=O) 2 NH-L 5 -OH, -L 4 -S(=O) 2 NH-L 5 -OR e ;

wherein: each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2-4 alkylenyl; each R e is independently C 1-4 alkyl, -Ph, or -CH 2 Ph; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino,

N-(Ci -3 alkyl)-piperizino, or morpholino.

In one embodiment: each L 4 is independently a covalent bond or C 1-4 alkylenyl; and each L 5 is independently C 2-4 alkylenyl; each R e is independently Ci. 4 alkyl; and each NR f R 9 is independently pyrrolidino, piperidino, piperizino,

N-(C 1-3 alkyl)-piperizino, or morpholino.

In one embodiment: each L 4 is independently a covalent bond, -CH 2 -, -CH 2 CH 2 -, Or -CH 2 CH 2 CH 2 -; each L 5 is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; each R e is independently -Me, -Et, -Ph, or -CH 2 Ph. each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(C 1-3 alkyl)-piperizino, or morpholino.

In one embodiment: each L 4 is independently a covalent bond, -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -; each L 5 is independently -CH 2 CH 2 - or -CH 2 CH 2 CH 2 -; each R e is independently -Me or -Et. each NR f R 9 is independently pyrrolidino, piperidino, piperizino, N-(Ci -3 alkyl)-piperizino, or morpholino.

In one embodiment, the substituents are independently selected from those substituents exemplified under the heading "Some Preferred Embodiments."

Optional Substituents on the Non-Aromatic Heterocyclic Ring

As discussed above, certain groups (e.g., -NR N1R R N2R , -NR N3R R N4R , -NR N5R R N6R ) may be, for example, a non-aromatic heterocyclic ring (as defined herein), and are unsubstituted or substituted, for example, substituted with one or more (e.g., 1 , 2, etc.) substituents.

Substituents, if present, may be on a ring carbon atom or a ring heteroatom. For example, when a non-aromatic heterocyclic ring includes -NH- (e.g., as in imidazolidino, pyrazolidino, piperidino, diazepino), this group may be N-substituted, for example N-(Ci-

3 alkyl)-substituted, for example N-(methyl)-substituted, as in, for example, N-methyl- piperidino.

In one embodiment, the substituents (e.g., optional substituents on -NR N1R R N2R , -NR N3R R N4R , -NR N5R R N6R ) are as defined for substituents under the heading Optional Substituents on Phenyl and C 5 - 6 Heteroaryl".

In one embodiment, the substituents (e.g., optional substituents on -NR N1R R N2R , -NR N3R R N4R , -NR N5R R N6R ) are independently selected from those substituents exemplified under the heading "Some Preferred Embodiments."

Combinations

Each and every plausible and compatible combination of the embodiments described herein is explicitly disclosed herein, as if each such combination was individually and specifically recited.

For example, in one embodiment, X is N; Y-Z is C(R 6C1 )=C(R 5C ), R 5C is -H; n is 0; and R 1M is attached at the 2- or 6-position, as in, for example:

For example, in one embodiment, X is N; Y-Z is C(R 6C1 )=C(R 5C ), R 5C is -H; n is 0; and R 1M s -CH 2 -NH 2 and is attached at the 2- or 6-position, as in, for example:

For example, in one embodiment, X is N; R 3C is -H; Y-Z is C(R 6C1 )=C(R 5C ), R 5C is -H; n is 0; and R 1M is -CH 2 -NH 2 and is attached at the 2- or 6-position, as in, for example:

For example, in one embodiment, X is C(R 2C ); Y-Z is C(R 6C2 )=N; one of R 2C and R 3G is Q A , and the other is -H; n is 0; and R 1M is attached at the 2- or 6-position, as in, for example:

For example, in one embodiment, X is C(R 2G ); Y-Z is C(R 6C2 )=N; one of R 2G and R 3C is Q A , and the other is -H; n is 0; and R 1M is -CH 2 -NH 2 and is attached at the 2- or 6-position, as in, for example:

For example, in one embodiment, X is C(R 2C ); Y-Z is C(R 6C2 )=N; R 2C is -H; R 3C is -H; n is 0; and R 1M is -CH 2 -NH 2 and is attached at the 2- or 6-position, as in, for example:

Molecular Weight

In one embodiment, the compound has a molecular weight of 250 to 1200.

In one embodiment, the bottom of range is 275; 300; 325; 350; 375; 400. In one embodiment, the top of range is 1100; 1000, 900, 800, 700. In one embodiment, the range is 300 to 700.

Some Preferred Embodiments

Examples of some preferred compounds where X is N and Y-Z is C(R 6C1 )=C(R 5C ) ("7H-pyrrolo[2,3-d]pyrimidines") include the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

Examples of some preferred compounds where X is C(R 2C ) and Y-Z is C(R 6C2 )=N ("H-pyrazolo[3,4-b]pyridines") include the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

Examples of some preferred compounds where X is N and Y-Z is N(R 6N )-C(=O) ("7,9-dihydro-purin-8-ones"), include the following compound, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

Examples of some preferred compounds where X is C(R 2C ) and Y-Z is N(R 6N )-C(=O) ("1 ,3-dihydro-imidazo[4,5-b]pyridin-2-ones") include the following compounds, and pharmaceutically acceptable salts, solvates, amides, esters, ethers, N-oxides, chemically protected forms, and prodrugs thereof.

Chemical Definitions

The term "alkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of a saturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified).

In one embodiment, each C 1-7 alkyl is independently selected from: -Me, -Et, -nPr, -iPr, - nBu, -iBu, -sBu, -tBu, n-pentyl, i-pentyl, neo-pentyl, n-hexyl, n-heptyl; and is

independently unsubstituted or substituted. In one embodiment, each C-ι -7 alkyl is independently unsubstitued.

The term "alkylenyl," as used herein, pertains to a divalent bidentate moiety obtained by removing two hydrogen atoms from one carbon atom or two different carbon atoms of a saturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified).

In one embodiment, each C 1-7 alkylenyl is independently selected from: -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )-, -CH(CH 2 CH 3 )-, -CH(CH 3 )CH 2 -,

-CH 2 CH(CH 3 )-, -CH(CH 3 )CH 2 CH 2 -, and -CH 2 CH 2 CH(CH 3 )-, and is independently unsubstituted or substituted. In one embodiment, each C 1-7 alkylenyl is independently unsubstitued.

The term "alkenyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an unsaturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified) and having one or more (e.g., 1 , 2, etc.) carbon-carbon double bonds.

In one embodiment, each C 2-7 a!kenyl is independently selected from: -CH=CH 2 , -CH=CH- CH 3 , -CH-CH=CH 2 , -C(CHs)=CH 2 , and butenyl (C 4 ); and is independently unsubstituted or substituted. In one embodiment, each C 2-7 alkenyl is independently unsubstitued.

The term "alkynyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a carbon atom of an unsaturated aliphatic hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified) and having one or more (e.g., 1 , 2, etc.) carbon-carbon triple bonds.

In one embodiment, each C 2-7 alkynyl is independently selected from: -C=CH and -CH 2 -C=CH; and is independently unsubstituted or substituted. In one embodiment, each C 2-7 alkynyl is independently unsubstitued.

The term "cycloalkyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring carbon atom of a saturated hydrocarbon compound having at least one carbocyclic ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified).

In one embodiment, each C 3-7 cycloalkyl is independently selected from: cyclopropyl (C 3 ), cyclobutyl (C 4 ), cyclopentyl (C 5 ), cyclohexyl (C 6 ), cycloheptyl (C 7 ), methylcyclopropyl (C 4 ), dimethylcyclopropyl (C 5 ), methylcyclobutyl (C 5 ), dimethylcyclobutyl (C 6 ),

methylcyclopentyl (C 6 ), dimethylcyclopentyl (C 7 ), methylcyclohexyl (C 7 ); and is independently unsubstituted or substituted. In one embodiment, each C 3-7 cycloalkyl is independently unsubstitued.

The term "cycloalkenyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a ring carbon atom of an unsaturated hydrocarbon compound having at least one carbocyclic ring that has at least one carbon-carbon double bond as part of that ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified).

In one embodiment, each C 3-7 cycloalkenyl is independently selected from: cyclopropenyl (C 3 ), cyclobutenyl (C 4 ), cyclopentenyl (C 5 ), cyclohexenyl (C 6 ), methylcyclopropenyl (C 4 ), dimethylcyclopropenyl (C 5 ), methylcyclobutenyl (C 5 ), dimethylcyclobutenyl (C 6 ), methylcyclopentenyl (C 6 ), dimethylcyclopentenyl (C 7 ), methylcyclohexenyl (C 7 ); and is independently unsubstituted or substituted. In one embodiment, each C 3-7 cycloalkenyl is independently unsubstitued.

The term "heterocyclyl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from a non-aromatic ring atom of a compound having at least one non-aromatic heterocyclic ring, and having from 3 to 20 carbon atoms (unless otherwise specified), including from 3 to 20 ring atoms (unless otherwise specified), of which from 1 to 10 are ring heteroatoms (unless otherwise specified). Preferably, each ring of the compound has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. Preferably, the ring heteroatoms are selected from N, O, and S.

In this context, the prefixes (e.g., C 3- i 4 , C 3-7 , C 5-6 , etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 5-6 heterocyclyl," as used herein, pertains to a heterocyclyl group having 5 or 6 ring atoms.

In one embodiment, each C 3- i 4 heterocyclyl is independently selected from: C 3 heterocyclyl groups including: Ni : aziridinyl (C 3 ); O 1 : oxiranyl (C 3 ); and S 1 : thiiranyl (C 3 );

C 4 heterocyclyl groups including: N 1 : azetidinyl (C 4 ); O 1 : oxetanyl (C 4 ); and S 1 : thietanyl (C 4 ); C 5 heterocyclyl groups including:

N 1 : pyrrolidinyl (C 5 ), pyrrolinyl (C 5 ), 2H-pyrrolyl or 3H-pyrrolyl (C 5 );

O 1 : tetrahydrofuranyl (C 5 ), dihydrofuranyl (C 5 );

S 1 : tetrahydrothienyl (C 5 );

O 2 : dioxolanyl (C 5 );

N 2 : imidazolinyl (C 5 ), pyrazoϋnyl (C 5 ); N 1 O 1 : tetrahydrooxazolyl (C 5 ), dihydrooxazolyl (C 5 ), tetrahydroisoxazolyl (C 5 ), dihydroisoxazolyl (C 5 );

N 1 S 1 : thiazolinyl (C 5 ), thiazolidinyl (C 5 ); and

O 1 S 1 : oxathiolyl (C 5 ); C 6 heterocyclyl groups including: N 1 : piperidinyl (C 6 ), dihydropyridinyl (C 6 ), tetrahydrøpyridinyl (C 6 );

O 1 : tetrahydropyranyl (C 6 ), dihydropyranyl (C 6 ), pyrany! (C 6 );

Si : tetrahydrothiopyranyl (C 6 );

O 2 : dioxanyl (C 6 );

O 3 : trioxanyl (C 6 ); N 2 : piperazinyl (C 6 );

N 1 O 1 : morpholinyl (C 6 ), tetrahydrooxazinyl (C 6 ), dihydrooxazinyl (C 6 ), oxazinyl (C 6 );

N 1 S 1 : thiomorpholinyl (C 6 );

N 2 O 1 : oxadiazinyl (C 6 ); O 1 S 1 : oxathianyl (thioxanyl) (C 6 ); and,

NiO 1 S 1 : oxathiazinyl (C 6 ); and Cyheterocyclyl groups including:

Ni: azepinyl (C 7 );

O 1 : oxepinyl (C 7 ); S 1 : thiepanyl (C 7 ); and

O 2 : dioxepanyl (C 7 ).

The term "aryl," as used herein, pertains to a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety has from 3 to 20 ring atoms (unless otherwise specified). Preferably, each ring has from 5 to 7 ring atoms, of which from 0 to 4 are ring heteroatoms.

The ring atoms may be all carbon atoms, as in "carboaryl" groups. Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroaryl" groups. Preferably, the ring heteroatoms are selected from N, O, and S.

In this context, the prefixes (e.g., C 3 . 14l C 5-7 , C 5-6 , etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C 5-6 heteroaryl," as used herein, pertains to a heteroaryl group having 5 or 6 ring atoms, including at least one heteroatom.

In one embodiment, each C 6- i 4 carboaryl is independently selected from: phenyl (C 6 ), indanyl (C 9 ), indenyl (C 9 ), isoindenyl (C 9 ), naphthyl (Ci 0 ), azulenyl (C 10 ), tetralinyl (1 ,2,3,4-tetrahydronaphthalene) (C 10 ), acenaphthenyl (C 12 ), fluorenyl (C 13 ), phenalenyl (C 13 ), anthracenyl (C 14 ), and phenanthreny! (C 14 ).

In one embodiment, each C 5-14 heteroaryl is independently selected from: C 5 heteroaryl groups including: N 1 : pyrrolyl (C 5 ); O 1 : furanyl (C 5 ); Sv thienyl (C 5 );

NiO 1 : oxazolyl (C 5 ), isoxazolyl (C 5 ); N 2 O 1 : oxadiazolyl (C 5 ); N 3 O 1 : oxatriazolyl (C 5 ); NiS 1 : thiazolyl (C 5 ), isothiazolyl (C 5 ); N 2 : imidazolyl (C 5 ), pyrazolyl (C 5 );

N 3 : triazolyl (C 5 ); and, N 4 : tetrazolyl (C 5 ); Ceheteroaryl groups including:

N 1 : pyridinyl (C 6 ); N 1 O 1 : isoxazinyl (C 6 );

N 2 : pyridazinyl (C 6 ), pyrimidinyl (C 6 ), pyrazinyl (C 6 ); N 3 : triazinyl (C 6 ); and, Cgheteroaryl groups including:

N 1 : indolyl (C 9 ), isoindolyl (C 9 ), indolizinyl (C 9 ), indolinyl (C 9 ), isoindolinyl (C 9 ); O 1 : benzofuranyl (C 9 ), isobenzofuranyl (C 9 );

S 1 : benzothiofuranyl (Cg); N 2 : benzimidazolyl (C 9 ), indazolyl (C 9 ); N 1 O 1 : benzoxazolyl (C 9 ), benzisoxazolyl (C 9 ). N 1 Si: benzothiazolyl (C 9 ); O 2 : benzodioxolyl (C 9 );

N 2 O 1 : benzofurazanyl (C 9 ); N 2 Si: benzothiadiazoly! (C 9 ); N 3 : benzotriazolyl (C 9 ); and N 4 : purinyl (C 9 ); C 10 heteroaryl groups including:

O 1 : chromenyl (C 10 ), isochromenyl (C 10 ), chromanyl (C 10 ), isochromanyl (C 10 ); O 2 : benzodioxanyl (C 10 );

N 1 : quinolinyl (Ci 0 ), isoquinolinyl (N-i), quinolizinyl (N 1 ); N 1 Oi: benzoxazinyl (Ci 0 ); N 2 : benzodiazinyl (Ci 0 ), pyridopyridinyl (Ci 0 ), quinoxalinyl (Ci 0 ), quinazolinyl (Ci 0 ), cinnolinyl (C 10 ), phthalazinyl C 10 ), naphthyridinyl (Ci 0 ); and

N 4 : pteridinyl (C 10 ); C-nheteroaryl groups (with 2 fused rings) including:

N 2 : benzodiazepinyl (Cn);

C 13 heteroaryl groups (with 3 fused rings) including: N 1 : carbazolyl (C 13 );

O 1 : dibenzofuranyl (C 13 );

S 1 : dibenzothiophenyl (C 13 ); and

N 2 : carbolinyl (C 13 ), pyridoindolyl (C 13 ); and C 14 heteroaryl groups (with 3 fused rings) including: N 1 : acridinyl (C 14 ), phenanthridine (C 14 );

O 1 : xanthenyl (C 14 );

S 1 : thioxanthenyl (Ci 4 );

N 2 : phenazinyl (C 14 ), phenanthroline (C 14 ), phenazine (C 14 );

N 1 O-,: phenoxazinyl (C 14 )' N 1 S 1 : phenothiazinyl (C 14 );

O 2 : oxanthrenyl (C 14 );

O 1 S 1 : phenoxathiin (C 14 );

S 2 : thianthrene (C 14 ).

Substantially Purified Forms

Another aspect of the present invention pertains to compounds, as described herein, in substantially purified form and/or in a form substantially free from contaminants.

In one embodiment, the substantially purified form is at least 50% by weight, e.g., at least 60% by weight, e.g., at least 70% by weight, e.g., at least 80% by weight, e.g., at least 90% by weight, e.g., at least 95% by weight, e.g., at least 97% by weight, e.g., at least 98% by weight, e.g., at least 99% by weight.

Unless specified, the substantially purified form refers to the compound in any stereoisomeric or enantiomeric form. For example, in one embodiment, the substantially purified form refers to a mixture of stereoisomers, i.e., purified with respect to other compounds. In one embodiment, the substantially purified form refers to one stereoisomer, e.g., optically pure stereoisomer. In one embodiment, the substantially purified form refers to a mixture of enantiomers. In one embodiment, the substantially purified form refers to an equimolar mixture of enantiomers (i.e., a racemic mixture, a racemate). In one embodiment, the substantially purified form refers to one enantiomer, e.g., optically pure enantiomer.

In one embodiment, the contaminants represent no more than 50% by weight, e.g., no more than 40% by weight, e.g., no more than 30% by weight, e.g., no more than 20% by

weight, e.g., no more than 10% by weight, e.g., no more than 5% by weight, e.g., no more than 3% by weight, e.g., no more than 2% by weight, e.g., no more than 1% by weight.

Unless specified, the contaminants refer to other compounds, that is, other than stereoisomers or enantiomers. In one embodiment, the contaminants refer to other compounds and other stereoisomers. In one embodiment, the contaminants refer to other compounds and the other enantiomer.

In one embodiment, the substantially purified form is at least 60% optically pure (i.e., 60% of the compound, on a molar basis, is the desired stereoisomer or enantiomer, and 40% is the undesired stereoisomer or enantiomer), e.g., at least 70% optically pure, e.g., at least 80% optically pure, e.g., at least 90% optically pure, e.g., at least 95% optically pure, e.g., at least 97% optically pure, e.g., at least 98% optically pure, e.g., at least 99% optically pure.

Isomers

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH 3 , is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hydroxyazo, and nitro/aci-nitro.

keto enol enol ate

Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C, and 14 C; O may be in any isotopic form, including 16 O and 18 O; and the like.

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.

Salts

It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et a/., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL Vol. 66, pp. 1-19.

For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO " ), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al +3 . Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R 2 + , NHR 3 + , NR 4 + ). Examples of some suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine. An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .

If the compound is cationic, or has a functional group which may be cationic (e.g., -NH 2 may be -NH 3 + ), then a salt may be formed with a suitable anion. Examples of suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids: hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and phosphorous.

Examples of suitable organic anions include, but are not limited to, those derived from the following organic acids: 2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic, camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic, ethanesuifonic, fumaric, glucheptonic, gluconic, glutamic, glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic, lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic, oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic, phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic, sulfanilic, tartaric, toluenesulfonic, trifluoroacetic, and valeric. Examples of suitable polymeric organic anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.

Unless otherwise specified, a reference to a particular compound also includes salt forms thereof.

Solvates

It may be convenient or desirable to prepare, purify, and/or handle a corresponding solvate of the compound. The term "solvate" is used herein in the conventional sense to refer to a complex of solute (e.g., compound, salt of compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc.

Unless otherwise specified, a reference to a particular compound also includes solvate forms thereof.

Chemically Protected Forms

It may be convenient or desirable to prepare, purify, and/or handle the compound in a chemically protected form. The term "chemically protected form" is used herein in the conventional chemical sense and pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions under specified conditions (e.g., pH, temperature, radiation, solvent, and the like). In practice, well known chemical methods are employed to reversibly render unreactive a functional group, which otherwise would be reactive, under specified conditions. In a chemically protected form, one or more reactive functional groups are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group). By protecting a reactive functional group, reactions involving other unprotected reactive functional groups can be performed, without affecting the protected group; the protecting group may be removed, usually in a subsequent step, without substantially affecting the remainder of the molecule. See, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).

Unless otherwise specified, a reference to a particular compound also includes chemically protected forms thereof.

A wide variety of such "protecting," "blocking," or "masking" methods are widely used and well known in organic synthesis. For example, a compound which has two nonequivalent reactive functional groups, both of which would be reactive under specified conditions, may be derivatized to render one of the functional groups "protected," and therefore unreactive, under the specified conditions; so protected, the compound may be used as a reactant which has effectively only one reactive functional group. After the desired reaction (involving the other functional group) is complete, the protected group may be "deprotected" to return it to its original functionality.

For example, a hydroxy group may be protected as an ether (-OR) or an ester (-OC(=O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (-OC(=O)CH 3| -OAc).

For example, an aldehyde or ketone group may be protected as an acetal (R-CH(OR) 2 ) or ketal (R 2 C(OR) 2 ), respectively, in which the carbonyl group (>C=O) is converted to a diether (>C(OR) 2 ), by reaction with, for example, a primary alcohol. The aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide (-NRCO-R) or a urethane (-NRCO-OR), for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH-Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (-NHCO-OC(CHs) 2 C 6 H 4 C 6 H 5 , -NH-Bpoc), as a 9- fluorenylmethoxy amide (-NH-Fmoc), as a 6-nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-Alloc), as a 2(-phenylsulphonyl)ethyloxy amide (-NH-Psec); or, in suitable cases (e.g., cyclic amines), as a nitroxide radical (>N-O»).

For example, a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g., a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a

C 1-7 trihaloalkyl ester); a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-20 aryl-C 1-7 alkyl ester (e.g., a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.

For example, a thiol group may be protected as a thioether (-SR), for example, as: a benzyl thioether; an acetamidomethyl ether (-S-CH 2 NHC(=O)CH 3 ).

Prodruqs

It may be convenient or desirable to prepare, purify, and/or handle the compound in the form of a prodrug. The term "prodrug," as used herein, pertains to a compound which, when metabolised (e.g., in vivo), yields the desired compound. Typically, the prodrug is inactive, or less active than the compound, but may provide advantageous handling, administration, or metabolic properties.

Unless otherwise specified, a reference to a particular compound also includes prodrugs thereof.

For example, some prodrugs are esters of the compound (e.g., a physiologically acceptable metabolically labile ester). During metabolism, the ester group (-C(=O)OR) is cleaved to yield the active drug. Such esters may be formed by esterification, for example, of any of the carboxylic acid groups (-C(=O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the compound, or a compound which, upon further chemical reaction, yields the compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.

Chemical Synthesis

Several methods for the chemical synthesis of compounds of the present invention are described herein. These and/or other well known methods may be modified and/or adapted in known ways in order to facilitate the synthesis of additional compounds within the scope of the present invention.

Uses

The compounds described herein are useful, for example, in the treatment of diseases and conditions that are ameliorated by the inhibition of CHK1 kinase function, such as, for example, proliferative conditions, cancer, etc.

Use in Methods of Inhibiting CHK1

One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function, in vitro or in vivo, comprising contacting the cell with an effective amount of a compound, as described herein.

One aspect of the present invention pertains to a method of inhibiting CHK1 kinase function in a cell, in vitro or in vivo, comprising contacting the ceil with an effective amount of a compound, as described herein.

In one embodiment, the method further comprises contacting the cells with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Suitable assays for determining CHK1 kinase function inhibition are described herein and/or are known in the art.

Use in Methods of Inhibiting Cell Proliferation, Etc.

The compounds described herein, e.g., (a) regulate (e.g., inhibit) cell proliferation; (b) inhibit cell cycle progression; (c) promote apoptosis; or (d) a combination of one or more of these.

One aspect of the present invention pertains to a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), inhibiting cell cycle progression, promoting apoptosis, or a combination of one or more these, in vitro or in vivo, comprising contacting cells (or the cell) with an effective amount of a compound, as described herein.

In one embodiment, the method is a method of regulating (e.g., inhibiting) cell proliferation (e.g., proliferation of a cell), in vitro or in vivo, comprising contacting cells (or the cell) with an effective amount of a compound, as described herein.

In one embodiment, the method further comprises contacting the cells with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

In one embodiment, the method is performed in vitro. In one embodiment, the method is performed in vivo.

In one embodiment, the compound is provided in the form of a pharmaceutically acceptable composition.

Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, and skin.

One of ordinary skill in the art is readily able to determine whether or not a candidate compound regulates (e.g., inhibits) cell proliferation, etc. For example, assays which may conveniently be used to assess the activity offered by a particular compound are described herein.

For example, a sample of cells (e.g., from a tumour) may be grown in vitro and a compound brought into contact with said cells, and the effect of the compound on those cells observed. As an example of "effect," the morphological status of the cells (e.g., alive or dead, etc.) may be determined. Where the compound is found to exert an influence on the cells, this may be used as a prognostic or diagnostic marker of the efficacy of the compound in methods of treating a patient carrying cells of the same cellular type.

Use in Methods of Therapy

Another aspect of the present invention pertains to a compound as described herein for use in a method of treatment of the human or animal body by therapy.

In one embodiment, the method of treatment comprises treatment with both (i) the MBHA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, for use in a method of treatment of the human or animal body by therapy, wherein the method of treatment comprises treatment with both (i) an MBHA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.

Use in the Manufacture of Medicaments

Another aspect of the present invention pertains to use of a compound, as described herein, in the manufacture of a medicament for use in treatment.

In one embodiment, the medicament comprises the compound, as described herein.

In one embodiment, the treatment comprises treatment with both (i) a medicament comprising the MBHA compound and (ii) one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Another aspect of the present invention pertains to use of (a) a DNA topoisomerase I or Il inhibitor, (b) a DNA damaging agent, (c) an antimetabolite or TS inhibitor, or (d) a microtubule targeted agent, as described herein, in the manufacture of a medicament for use in a treatment, wherein the treatment comprises treatment with both (i) an MBHA compound, as described herein, and (a) the DNA topoisomerase I or Il inhibitor, (b) the DNA damaging agent, (c) the antimetabolite or TS inhibitor, or (d) the microtubule targeted agent.

Methods of Treatment

Another aspect of the present invention pertains to a method of treatment comprising administering to a patient in need of treatment a therapeutically effective amount of a compound as described herein, preferably in the form of a pharmaceutical composition.

In one embodiment, the method further comprises administering to the subject one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

Conditions Treated - Conditions Mediated by CH K1

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of a disease or condition that is mediated by CHK1.

Conditions Treated - Conditions Ameliorated by the Inhibition of CHK1 Kinase Function

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a disease or condition that is ameliorated by the inhibition of CHK1 kinase function.

Conditions Treated - Proliferative Conditions and Cancer

In one embodiment (e.g., of use in methods of therapy, of use in the manufacture of medicaments, of methods of treatment), the treatment is treatment of: a proliferative condition.

The term "proliferative condition," as used herein, pertains to an unwanted or uncontrolled cellular proliferation of excessive or abnormal cells which is undesired, such as, neoplastic or hyperplastic growth.

In one embodiment, the treatment is treatment of: a proliferative condition characterised by benign, pre-malignant, or malignant cellular proliferation, including but not limited to, neoplasms, hyperplasias, and tumours (e.g., histocytoma, glioma, astrocyoma, osteoma), cancers (see below), psoriasis, bone diseases, fibroproliferative disorders (e.g., of connective tissues), pulmonary fibrosis, atherosclerosis, smooth muscle cell proliferation in the blood vessels, such as stenosis or restenosis following angioplasty.

In one embodiment, the treatment is treatment of: cancer.

In one embodiment, the treatment is treatment of: p53 negative cancer.

In one embodiment, the treatment is treatment of: lung cancer, small cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, stomach cancer, bowel cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, breast cancer, ovarian cancer, endometrial cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, renal cell carcinoma, bladder cancer, pancreatic cancer, brain cancer, glioma, sarcoma, osteosarcoma, bone cancer, nasopharyngeal cancer (e.g., head cancer, neck cancer), skin cancer, squamous cancer, Kaposi's sarcoma, melanoma, malignant melanoma, lymphoma, or leukemia.

In one embodiment, the treatment is treatment of: a carcinoma, for example a carcinoma of the bladder, breast, colon (e.g., colorectal carcinomas such as colon adenocarcinoma and colon adenoma), kidney, epidermal, liver, lung (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g., exocrine pancreatic carcinoma), stomach, cervix, thyroid, prostate, skin (e.g., squamous cell carcinoma); a hematopoietic tumour of lymphoid lineage, for example leukemia, acute lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non- Hodgkin's lymphoma, hairy cell lymphoma, or Burkett's lymphoma; a hematopoietic tumor of myeloid lineage, for example acute and chronic myelogenous leukemias, myelodysplasia syndrome, or promyelocytic leukemia; a tumour of mesenchymal origin, for example fibrosarcoma or habdomyosarcoma; a tumor of the central or peripheral nervous system, for example astrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma; teratocarcinoma; osteosarcoma; xenoderoma pigmentoum; keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma.

In one embodiment, the treatment is treatment of solid tumour cancer.

In one embodiment, the treatment is treatment of: lung cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or glioma.

The anti-cancer effect may arise through one or more mechanisms, including but not limited to, the regulation of cell proliferation, the inhibition of cell cycle progression, the inhibition of angiogenesis (the formation of new blood vessels), the inhibition of metastasis (the spread of a tumour from its origin), the inhibition of invasion (the spread of tumour cells into neighbouring normal structures), or the promotion of apoptosis (programmed cell death). The compounds of the present invention may be used in the treatment of the cancers described herein, independent of the mechanisms discussed herein.

Treatment

The term "treatment," as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviatiation of symptoms of the condition, amelioration of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the condition, but who are at risk of developing the condition, is encompassed by the term "treatment."

For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

The term "therapeuticaϋy-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.

Combination Therapies

The term "treatment" includes combination treatments and therapies, in which two or more treatments or therapies are combined, for example, sequentially or simultaneously. For example, the compounds described herein may also be used in combination therapies, e.g., in conjunction with other agents, for example, cytotoxic agents, anticancer

agents, etc. Examples of treatments and therapies include, but are not limited to, chemotherapy (the administration of active agents, including, e.g., drugs, antibodies (e.g., as in immunotherapy), prodrugs (e.g., as in photodynamic therapy, GDEPT, ADEPT, etc.); surgery; radiation therapy; photodynamic therapy; gene therapy; and controlled diets.

For example, it may be beneficial to combine treatment with a compound as described herein with one or more other (e.g., 1, 2, 3, 4) agents or therapies that regulates cell growth or survival or differentiation via a different mechanism, thus treating several characteristic features of cancer development.

One aspect of the present invention pertains to a compound as described herein, in combination with one or more additional therapeutic agents, as described below.

The particular combination would be at the discretion of the physician who would select dosages using his common general knowledge and dosing regimens known to a skilled practitioner.

The agents (i.e., the compound described herein, plus one or more other agents) may be administered simultaneously or sequentially, and may be administered in individually varying dose schedules and via different routes. For example, when administered sequentially, the agents can be administered at closely spaced intervals (e.g., over a period of 5-10 minutes) or at longer intervals (e.g., 1 , 2, 3, 4 or more hours apart, or even longer periods apart where required), the precise dosage regimen being commensurate with the properties of the therapeutic agent(s).

The agents (i.e., the compound described here, plus one or more other agents) may be formulated together in a single dosage form, or alternatively, the individual agents may be formulated separately and presented together in the form of a kit, optionally with instructions for their use.

Combination Therapies Employing DNA Damaging Agents

As discussed herein, in some embodiments, the MBHA compound is employed in combination with (e.g., in conjunction with) with one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

When both an MBHA compound and one or more other agents are employed, they may be used (e.g., contacted, administered, etc.) in any order. Furthermore, they may be

used (e.g., contacted, administered, etc.) together, as part of a single formulation, or separately, as separate formulations.

For example, in regard to methods of treatment employing both an MBHA compound and one or more other agents, treatment with (e.g., administration of) the MBHA compound may be prior to, concurrent with, or may follow, treatment with (e.g., administration of) the one or more other agents, or a combination thereof.

In one embodiment, treatment with (e.g., administration of) the MBHA compound is concurrent with, or follows, treatment with (e.g., administration of) the one or more other agents.

In one embodiment, the one or more other agents is a DNA topoisomerase I or Il inhibitor; for example, Etoposide, Toptecan, Camptothecin, Irinotecan, SN-38, Doxorubicin, Daunorubicin.

In one embodiment, the one or more other agents is a DNA damaging agent; for example, alkylating agents, platinating agents, or compounds that generate free radicals; for example, Temozolomide, Cisplatin, Carboplatin, Mitomycin C, Cyclophosphamide, BCNU, CCNU, Bleomycin.

In one embodiment, the one or more other agents is an antimetabolite or TS inhibitor; for example, 5-fluorouracil, hydroxyurea, Gemcitabine, Arabinosylcytosine, Fludarabine, Tomudex, ZD9331.

In one embodiment, the one or more other agents is a microtubule targeted agent; for example, Paclitaxel, Docetaxel, Vincristine, Vinblastine.

In one embodiment, the one or more other agents is ionising radiation (e.g., as part of radiotherapy).

Other Uses

The compounds described herein may also be used as cell culture additives to inhibit CHK1 kinase function, e.g., to inhibit cell proliferation, etc.

The compounds described herein may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.

The compounds described herein may also be used as a standard, for example, in an assay, in order to identify other compounds, other CHK1 kinase function inhibitors, other anti-proliferative agents, other anti-cancer agents, etc.

Kits

One aspect of the invention pertains to a kit comprising (a) a compound as described herein, or a composition comprising a compound as described herein, e.g., preferably provided in a suitable container and/or with suitable packaging; and (b) instructions for use, e.g., written instructions on how to administer the compound or composition.

In one embodiment, the kit further comprises one or more other agents selected from: (a) a DNA topoisomerase I or Il inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; and (d) a microtubule targeted agent.

The written instructions may also include a list of indications for which the active ingredient is a suitable treatment.

Routes of Administration

The compound or pharmaceutical composition comprising the compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or topically (i.e., at the site of desired action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eyedrops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.

The Subject/Patient

The subject/patient may be a chordate, a vertebrate, a mammal, a placental mammal, a marsupial (e.g., kangaroo, wombat), a rodent (e.g., a guinea pig, a hamster, a rat, a mouse), murine (e.g., a mouse), a lagomorph (e.g., a rabbit), avian (e.g., a bird), canine (e.g., a dog), feline (e.g., a cat), equine (e.g., a horse), porcine (e.g., a pig), ovine (e.g., a

sheep), bovine (e.g., a cow), a primate, simian (e.g., a monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutang, gibbon), or a human.

Furthermore, the subject/patient may be any of its forms of development, for example, a foetus.

In one preferred embodiment, the subject/patient is a human.

Formulations

While it is possible for the compound to be administered alone, it is preferable to present it as a pharmaceutical formulation (e.g., composition, preparation, medicament) comprising at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, including, but not limited to, pharmaceutically acceptable carriers, diluents, excipients, adjuvants, fillers, buffers, preservatives, anti-oxidants, lubricants, stabilisers, solubilisers, surfactants (e.g., wetting agents), masking agents, colouring agents, flavouring agents, and sweetening agents. The formulation may further comprise other active agents, for example, other therapeutic or prophylactic agents.

Thus, the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one compound, as described herein, together with one or more other pharmaceutically acceptable ingredients well known to those skilled in the art, e.g., carriers, diluents, excipients, etc. If formulated as discrete units (e.g., tablets, etc.), each unit contains a predetermined amount (dosage) of the compound.

The term "pharmaceutically acceptable," as used herein, pertains to compounds, ingredients, materials, compositions, dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of the subject in question (e.g., human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, diluent, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

Suitable carriers, diluents, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences. 18th edition, Mack Publishing Company, Easton, Pa., 1990; and Handbook of Pharmaceutical Excipients, 2nd edition, . 1994.

The formulations may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the compound with a carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound with carriers (e.g., liquid carriers, finely divided solid carrier, etc.), and then shaping the product, if necessary.

The formulation may be prepared to provide for rapid or slow release; immediate, delayed, timed, or sustained release; or a combination thereof.

Formulations may suitably be in the form of liquids, solutions (e.g., aqueous, nonaqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, mouthwashes, drops, tablets (including, e.g., coated tablets), granules, powders, losenges, pastilles, capsules (including, e.g., hard and soft gelatin capsules), cachets, pills, ampoules, boluses, suppositories, pessaries, tinctures, gels, pastes, ointments, creams, lotions, oils, foams, sprays, mists, or aerosols.

Formulations may suitably be provided as a patch, adhesive plaster, bandage, dressing, or the like which is impregnated with one or more compounds and optionally one or more other pharmaceutically acceptable ingredients, including, for example, penetration, permeation, and absorption enhancers. Formulations may also suitably be provided in the form of a depot or reservoir.

The compound may be dissolved in, suspended in, or admixed with one or more other pharmaceutically acceptable ingredients. The compound may be presented in a liposome or other microparticulate which is designed to target the compound, for example, to blood components or one or more organs.

Formulations suitable for oral administration (e.g., by ingestion) include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil-in-water, water-in-oil), elixirs, syrups, electuaries, tablets, granules, powders, capsules, cachets, pills, ampoules, boluses.

Formulations suitable for buccal administration include mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs. Losenges typically comprise the compound in a flavored basis, usually sucrose and acacia or tragacanth.

Pastilles typically comprise the compound in an inert matrix, such as gelatin and glycerin, or sucrose and acacia. Mouthwashes typically comprise the compound in a suitable liquid carrier.

Formulations suitable for sublingual administration include tablets, losenges, pastilles, capsules, and pills.

Formulations suitable for oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions (e.g., oil- in-water, water-in-oil), mouthwashes, losenges, pastilles, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for non-oral transmucosal administration include liquids, solutions (e.g., aqueous, non-aqueous), suspensions (e.g., aqueous, non-aqueous), emulsions

(e.g., oil-in-water, water-in-oil), suppositories, pessaries, gels, pastes, ointments, creams, lotions, oils, as well as patches, adhesive plasters, depots, and reservoirs.

Formulations suitable for transdermal administration include gels, pastes, ointments, creams, lotions, and oils, as well as patches, adhesive plasters, bandages, dressings, depots, and reservoirs.

Tablets may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g., povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g., lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, silica); disintegrants (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose); surface-active or dispersing or wetting agents (e.g., sodium lauryl sulfate); preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid); flavours, flavour enhancing agents, and sweeteners. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with a coating, for example, to affect release, for example an enteric coating, to provide release in parts of the gut other than the stomach.

Ointments are typically prepared from the compound and a paraffinic or a water-miscible ointment base.

Creams are typically prepared from the compound and an oil-in-water cream base. If desired, the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxy! groups such

as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.

Emulsions are typically prepared from the compound and an oily phase, which may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax, and the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low. Thus the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.

Formulations suitable for intranasal administration, where the carrier is a liquid, include, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser, include aqueous or oily solutions of the compound.

Formulations suitable for intranasal administration, where the carrier is a solid, include, for example, those presented as a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.

Formulations suitable for pulmonary administration (e.g., by inhalation or insufflation therapy) include those presented as an aerosol spray from a pressurised pack, with the

use of a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.

Formulations suitable for ocular administration include eye drops wherein the compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the compound.

Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, for example, cocoa butter or a salicylate; or as a solution or suspension for treatment by enema.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the compound, such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration (e.g., by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g., solutions, suspensions), in which the compound is dissolved, suspended, or otherwise provided (e.g., in a liposome or other microparticulate). Such liquids may additional contain other pharmaceutically acceptable ingredients, such as anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, suspending agents, thickening agents, and solutes which render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended recipient. Examples of excipients include, for example, water, alcohols, polyols, glycerol, vegetable oils, and the like. Examples of suitable isotonic carriers for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection. Typically, the concentration of the compound in the liquid is from about 1 ng/ml to about 10 μg/ml, for example from about 10 ng/ml to about 1 μg/ml. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.

Dosage

It will be appreciated by one of skill in the art that appropriate dosages of the compounds, and compositions comprising the compounds, can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects. The selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular

compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health, and prior medical history of the patient. The amount of compound and route of administration will ultimately be at the discretion of the physician, veterinarian, or clinician, although generally the dosage will be selected to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.

Administration can be effected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell(s) being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician, veterinarian, or clinician.

In general, a suitable dose of the compound is in the range of about 10 μg to about 250 mg (more typically about 100 μg to about 25 mg) per kilogram body weight of the subject per day. Where the compound is a salt, an ester, an amide, a prodrug, or the like, the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.

EXAMPLES

The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein.

Chemical Synthesis

Liquid Chromatography - Mass spectrometry (LC-MS) Methods

LC-MS (1) analyses were performed on a Micromass ZQ mass spectrometer / Waters Alliance 2795 HT HPLC with a Phenomenex Gemini 5 μm, C18, 30 mm x 4.6 mm i.d. column at a temperature of 35°C and a flow rate of 2 mL/minute using the following solvent gradient:

Solvent A: 0.1% Ammonia in acetonitrile.

Solvent B: 0.1% Ammonia, 5% acetonitrile and 0.063% ammonium formate in water. 0.00 - 4.25 minutes: 5% A / 95% B to 95% A / 5% B. 4.25 - 5.80 minutes: 95% A / 5% B.

5.80 - 5.90 minutes: 95% A / 5% B to 5% A / 95% B. 5.90 - 7.00 minutes: 5% A / 95% B.

UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 80-1000 amu.

LC-MS (2) analyses were performed on a Micromass LCT / Waters Alliance 2795 HPLC system with a Discovery 5 μm, C18, 50 mm x 4.6 mm or 30 mm x 4.6 mm i.d. column from Supelco at a temperature of 22°C and a flow rate of 1 mL/minute using the following solvent gradient:

Solvent A: Methanol.

Solvent B: 0.1 % Formic acid in water . 0.0 - 0.3 minutes: 10% A/ 90% B.

0.3 - 0.6 minutes: 10% A/ 90% B to 20% A/ 80% B.

0.6 - 4.5 minutes: 20% A/ 80% B to 90% A/ 10% B.

4.5 - 5.4 minutes: 90% A/ 10% B.

5.4 - 5.7 minutes: 90% A/ 10% B to 10% A/ 90%.B. 5.7 - 6.0 minutes: 10% A / 90% B.

UV detection was at 254 nm and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 50-1000 amu.

Synthesis 1-1 -A ferf-Butyl (4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholin-2-yl)methylcar bamate

Triethylamine (0.10 mL, 0.75 mmol) was added to 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (50 mg, 0.33 mmol) and ferf-butyl morpholin-2-ylmethylcarbamate (74 mg, 0.34 mmol) in 1-butanol (1.4 mL), and the mixture was stirred at 100 0 C overnight. After cooling, the volatiles were evaporated and the residue was purified by column chromatography, eluting with a gradient of MeOH in dichloromethane, to yield the title compound as a yellow solid (72 mg, 66%). LC-MS (2) R, 3.06 min; m/z (ESI) 334 [MH + ].

Svnthesis 1-1 -B (4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)morpholin-2-yl)methanami ne

A solution of 4 M HCI in dioxane (1 mL) was added to fe/ϊ-butyl (4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)morpholin-2-yl)methylcarbamate (36 mg, 0.11 mmol) in dioxane (1 mL) and the solution was stirred overnight at room temperature. The volatiles were evaporated and the residue was purified by column chromatography and preparative TLC, eluting with 20% MeOH, 1 % triethylamine in dichloromethane, to yield the title compound as a white powder (17 mg, 68%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.93-3.09 (3H, m), 3.31-3.38 (1H, m), 3.72-3.78 (2H, m), 4.08-4.12 (1 H, m), 4.53-4.56 (1 H, m), 4.64-4.67 (1H 1 m), 6.66 (1 H, d, J = 3.5 Hz), 7.17 (1H, d, J = 3.5 Hz), 8.18 (1H, s) ;LC-MS (2) R t 0.56 min; m/z (ESI) 234 [MH + ].

Synthesis 2-1 -A

5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine

A suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.49 g, 3.2 mmol) and N-bromosuccinimide (0.68 g, 3.8 mmol) in dry dichloromethane (20 mL) was stirred at room temperature for 2.5 hours. The suspension was diluted with methanol and evaporated onto silica. The crude product was purified using flash column chromatography, eluting with 2:1 hexanes-ethyl acetate, to yield the title compound as an off-white solid (0.613 g, 2.64 mmol, 83%).

1 H NMR (500 MHz, CD 3 OD) δ 7.64 (1 H, s), 8.56 (1 H, s); LC-MS (2) R 1 3.34 min; m/z (ESI) 236, 234, 232 [MH + ].

Synthesis 2-1 -B 5-Bromo-4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyr rolo[2,3-d]pyrimidine

Sodium hydride (0.1O g, 55% suspension in oil, 2.4 mmol) was added to a stirred solution of 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.508 g, 2.18 mmol) in dry tetrahydrofuran (10 ml_) at room temperature under nitrogen. After 19 hours, the solution was quenched with water (50 mL) and extracted with ethyl acetate (50 ml_). The extract was washed with brine (20 mL), dried (Na 2 SO 4 ), and evaporated onto silica gel. The crude product was purified using flash column chromatography, eluting with 3:1 hexanes- ethyl acetate, to yield the title compound as a pink solid (0.331 g, 0.913 mmol, 42%).

1 H NMR (500 MHz, CD 3 OD) δ -0.03 (9H, s), 0.94 (2H, dd, J = 7,7 Hz), 3.55 (2H, dd, J = 7, 7 Hz), 5.64 (2H, s), 7.45 (1 H, s), 8.67 (1 H, s); LC-MS (2) R, 4.34 min; m/z (ESI) 366, 364, 362 [MH + ].

Synthesis 2-1 -C tert-Butyl (4-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3-d]pyrimidin-4- yl)morpholin-2-yl)methylcarbamate

A solution of ferf-butyl morpholin-2-ylmethylcarbamate (0.075 g, 0.35 mmol), 5-bromo-4- chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d ]pyrimidine (0.12 g, 0.33 mmol) and triethylamine (0.13 mL, 0.75 mmol) in n-butanol (1.5 mL) was heated at 100 0 C in a microwave reactor for 1 hour. The solution was concentrated onto silica gel. The crude product was purified using flash column chromatography, eluting with 2:1 hexanes-ethyl acetate, to yield the title compound as a viscous oil (0.122 g, 0.225 mmol, 68%).

1 H NMR (500 MHz, CDCI 3 ) δ -0.03 (9H, s), 0.93 (2H, dd, J = 7,7 Hz), 1.27 (9H, s), 2.95 (1H, dd, J = 7, 7 Hz), 3.21-3.23 (2H, m), 3.40-3.45 (1H, m), 3.56 (2H, dd, J = 7, 7 Hz), 3.85-3.90 (2H, m), 4.02-4.16 (2H, m), 4.90-4.95 (1H, m), 5.58 (2H, s), 7.28 (1 H, s), 8.43 (1H, s); LC-MS (2) R 1 4.30 min; m/z (ESI) 544, 542 [MH + ].

Synthesis 2-1 -D

(4-(5-Phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)morpholin-2- yl)methanamine

A mixture of ferf-butyi (4-(5-bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[ 2,3- d]pyrimidin-4-yl)morpholin-2-yl)methylcarbamate (0.085 g, 0.157 mmol), Pd(PPh 3 ) 4 (18 mg, 10 mol%), benzeneboronic acid (0.040 g, 0.31 mmol) and aqueous sodium carbonate (2 M, 0.30 mL, 0.60 mmol) in DMF (2 ml_) was heated to 150 0 C in a microwave reactor for 1 hour. The mixture was partitioned between water (20 mL) and ethyl acetate (2 x 20 mL). The combined organic layers were washed with water (20 mL), brine (5 mL), dried (Na 2 SO 4 ), filtered, and concentrated. Preparative TLC, eluting with 2:1 hexanes- ethyl acetate, gave crude ferf-butyl (4-(5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H- pyrrolo[2,3-d]pyrimidin-4-yl)morpholin-2-yl)methylcarbamate as a colourless oil (0.166 g; LC-MS R t 4.43 min;m/z (ESI) 540 [MH + ]). The crude material was dissolved in DMF (2 mL) and tetra-N-butylammonium fluoride (1 M in THF, 0.25 mL, 0.25 mmol) and ethylenediamine (0.01 mL, 0.16 mmol) were added. The solution was stirred at 60 0 C under nitrogen for 4 hours. Further TBAF (1 M in THF, 0.25 mL, 0.25 mmol) was added and stirring was continued for an additional 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined extracts were washed with brine (10 mL), dried (Na 2 SO 4 ), filtered, and concentrated. The residue was dissolved in methanol (2 mL) and 4 M HCI-dioxane (1 mL) was added. After 24 hours at room temperature, the solvent was evaporated and the residue was purified on SCX-II acidic resin (2 g) eluting with methanol and then 2M ammonia-methanol. The basic fractions were combined. Preparative TLC, eluting with 1% ammonia - 9% methanol - dichloromethane, gave the title compound as a white powder (0.023 g, 0.0743 mmol, 47%).

1 H NMR (500 MHz, CDCI 3 ) δ 2.44 (1 H, dd, J = 13, 4 Hz), 2.51-2.60 (2H, m), 2.87 (1 H, ddd, J = 13, 13, 3), 3.38-3.51 (2H, m), 3.68-3.77 (3H, m), 7.30 (1 H, s), 7.36 (1 H, t, J = 7 Hz), 7.47 (2H, dd, J = 7 Hz), 7.53 (2H, d, J = 7 Hz), 8.33 (1 H 1 s); LC-MS (2) R 1 2.16 min; m/z (ESI) 310 [MH + ].

The following compounds were prepared using methods analogous to those described above, replacing phenylboronic acid with the appropriately substituted (hetero)arylboronate reagents in Synthesis 2-1 -D.

Synthesis 3-1 -A terf-Butyl (4-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl) morpholin-2-yl)methylcarbamate

A solution of terf-butyl morpholin-2-ylmethylcarbamate (0.03 g, 0.18 mmol), 4-chloro-7H- pyrrolo[2,3-d]pyrimidin-2-amine (0.0385 g, 0.18 mmol) and triethylamine (0.1 mL, 0.72 mmol) in n-butanol (1.0 mL) was heated at 100 0 C in a microwave reactor for 60 minutes. The solvent was evaporated and the residue was purified by preparative TLC, eluting with 5:1 EtOAc-MeOH, to give the title compound as a yellow oil (0.011 g, 0.032 mmol, 18%).

1 H NMR (500 MHz, CD 3 OD) δ 1.45 (9H, s), 2.90 (1 H, dd, J = 10.7, 13 Hz), 3.20-3.30 (3H, m), 3.55-3.62 (1 H, m), 3.62-3.68 (1 H, m), 3.95-4.02 (1 H, m), 4.48 (1 H, d, J = 13.6 Hz), 4.56 (1 H, d, J = 13.6 Hz), 6.40 (1 H, d, J = 3.8 Hz), 6.80 (1 H, d, J = 3.8 Hz); LC-MS (2) R, 2.56 min; m/z (ESI) 349 [MH + ].

Synthesis 3-1 -B 4-(2-(Aminomethyl)morpholino)-7H-pyrrolo[2,3-d]pyrimidin-2-a mine

fe/f-Butyl (4-(2-amino-7H-pyrrolo[2,3-d]pyrimiclin-4-yl)morpholin-2-yl) methylcarbamate (0.01 g, 0.03 mmol) was dissolved in methanol (3 mL) and 4 M HCI-dioxane (2 mL) was added. After 16 hours at room temperature, the solvent was evaporated and the residue was purified on SCX-II acidic resin (2 g) eluting with methanol then 2M ammonia- methanol. Evaporation of the combined basic fractions gave the title compound as a yellow powder (0.005 g, 0.02 mmol, 67%).

1 H NMR (500 MHz, CD 3 OD) δ 2.80 (1 H, dd, J = 7.5, 13 Hz), 2.83 (1 H, dd, J = 4, 13 Hz), 2.90 (1H, dd, J = 10, 13 Hz), 3.20-3.25 (1H, m), 3.55-3.62 (1 H, m), 3.65-3.74 (1H, m), 4.00-4.05 (1 H, m), 4.48 (1 H, d, J = 13.6 Hz), 4.60 (1 H, d, J = 13.6 Hz), 6.44 (1 H, d, J = 3.6 Hz), 6.78 (1H, d, J = 3.6 Hz); LC-MS (2) R ( 0.44 min; m/z (ESI) 249 [MH + ].

Synthesis 4-1 -A

Ethyl 4-(2-((te/f-butoxycarbonylamino)methyl)morpholino)-1H-pyrazo lo[3,4-b]pyridine-5- carboxylate bocv

A solution of tert-buty] morpholin-2-ylrnethylcarbamate (0.134 g, 0.62 mmol), ethyl 4-chloro-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.142 g, 0.63 mmol) (Hoehn et al., 1973) and triethylamine (0.26 mL, 1.87 mmol) in n-butanol (2.5 mL) was heated at 12O 0 C in a microwave reactor for 60 minutes. When cooled, the yellow solids were collected by filtration, redissolved in ethyl acetate (15 mL) and washed with brine (10 mL) and water (10 mL). The organic extract was evaporated to give the title compound as a yellow solid (0.11 g, 0.27 mmol, 44%).

1 H NMR (500 MHz, d 6 -DMSO) δ 1.30 (3H, t, J = 7.5 Hz) 1 1.40 (9H, s), 2.95-3.20 (4H, m), 3.54 (1 H, d, J =13 Hz), 3.60-3.75 (3H, m), 3.94 (1 H, d, J = 11.5 Hz) 1 4.25 (2H, q, J = 7.5 Hz), 7.00 (1H, s, broad), 8.24 (1H, s), 8.52 (1H, s); LC-MS (2) R, 4.12 min; m/z (ESI) 406 [MH + ].

Synthesis 4-1 -B Ethyl 4-(2-(aminomethyl)morphoiino)-1H-pyrazolo[3,4-b]pyridine-5-c arboxylate boc

Ethyl 4-(2-((tert-butoxycarbonylamino)methyl)morpholino)-1 H-pyrazolo[3,4-b]pyridine-5- carboxylate (0.028 g, 0.07 mmol) was dissolved in methanol (3 rtiL) and TFA (2 mL) was added. After being refluxed for 16 hours, the solvents were evaporated and the residue was purified on SCX-II acidic resin (2 g) eluting with methanol then 2 M ammonia- methanol. After the basic fractions were combined and evaporated, the title compound was obtained as a yellow oil (0.020 g, 0.065 mmol, 93%).

1 H NMR (500 MHz, CD 3 OD) δ 1.40 (3H, t, J = 7.5 Hz), 2.75-2.90 (2H, m), 3.25 (1 H, dd, J = 10, 12.5 Hz), 3.45-3.55 (1 H, m), 3.65 (1H, d, J = 12.5 Hz), 3.75 (1 H, d, J = 11.5 Hz), 3.84-3.90 (2H, m), 4.05 (1 H, d, J = 11 Hz), 4.30 (2H, q, J = 7.5 Hz), 8.28 (1 H, s), 8.65 (1 H, s); LC-MS (2) R 1 1.22 min; m/z (ESI) 306 [MH + ].

Synthesis 5-1 -A N-Benzyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine

Chlorotitanium triisopropoxide (0.28 mL, 1.3 mmol) was added to a suspension of 6-chloro-7deazaguanine (0.10 mg, 0.59 mmol) and benzaldehyde (0.057 g, 0.53 mmol) in a mixture of anhydrous THF (0.75 mL) and dichloromethane (0.75 mL) under argon. The reactants initially dissolved to form an orange solution, followed by formation of a white precipitate. After stirring for 5 minutes, freshly ground sodium triacetoxyborohydride (0.507 g, 2.65 mmol) was added in portions followed by acetic acid (3 drops). The inert atmosphere was reintroduced and the suspension was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane (15 mL) and water (15 mL) and vigorously shaken. The dichloromethane layer was separated using a Radleys Phase Extraction Column before being dried (MgSO 4 ) and concentrated to give crude title compound as a tan coloured powder (0.119 g).

1 H NMR (500 MHz, Ci 6 -DMSO) δ 4.51 (2H, d, J = 4.5 Hz), 6.26 (1 H, dd, J = 3.5, 1.5 Hz), 7.07 (1 H, dd, J = 3.5, 2.0 Hz), 7.18-7.22 (1 H, m), 7.27-7.33 (4H, m), 7.61 (1 H, broad s), 11.55 (1H, broad s); LC-MS (2) R t 4.92 min; m/z (ESI) 259 [MH + ].

Synthesis 5-1 -B terf-Butyl (4-(2-(benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl) morpholin-2-yl)methylcarbamate

Triethylamine (0.14 ml_, 1.0 mmol) was added to N-benzyl-4-chloro-7H-pyrrolo[2,3- d]pyrimidin-2-amine (0.110 g, 0.43 mmol) and ferf-butyl morpholin-2-ylmethylcarbamate (0.097 mg, 0.45 mmol) in butan-1-ol (1.8 ml_) and the mixture was heated overnight at 100 0 C. The mixture was cooled and concentrated. Preparative TLC, eluting with 10% methanol-dichloromethane, gave the title compound (0.061 g, 0.138 mmol, 32%).

1 H NMR (500 MHz, d 6 -DMSO) δ 1.39 (9H, s), 2.79 (1 H, dd, J = 13.0, 10.5 Hz), 2.99-3.09 (3H, m), 3.40-3.53 (2H, m), 3.88-3.92 (1H, m), 4.47-4.63 (4H, m), 6.33 (1H, dd, J = 4.0, 2.0 Hz), 6.56 (1 H, broad t, J = 6.5 Hz), 6.73 (1 H, dd, J = 2.5, 2.0 Hz), 6.96 (1H, broad t, J = 5.5 Hz), 7.17 (1 H, t, J = 7.5 Hz), 7.26 (2H, dd, J = 7.5, 7.5 Hz), 7.32 (2H, d, J = 7.5 Hz), 10.94 (1H, broad s); LC-MS (2) R 1 3.60 min; m/z (ESI) 440 [MH + ].

Synthesis 5-1 -C 4-(2-(Aminomethyl)morpholino)-N-benzyl-7H-pyrrolo[2,3-d]pyri midin-2-amine

ferf-Butyl-(4-(2-(benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-4- yl)morpholin-2- yl)methylcarbamate (30 mg, 0.068 mmol) was dissolved in a mixture of methanol (1 mL) and 4 M HCI in 1 ,4-dioxane (1 mL) and stirred overnight at room temperature. The volatiles were removed by evaporation. The residue was dissolved in methanol and purified by ion exchange on isolute SCX-II acidic resin (2 g), eluting with 1 M ammonia- methanol, to give the title compound as a brown powder (0.17 g, 50 mmol, 73%).

1 H NMR (500 MHz, Ci 6 -MeOH) δ 2.68-2.75 (2H, m), 2.83 (1 H, dd, J = 13, 10 Hz), 3.14- 3.20 (1 H, m), 3.45-3.50 (1 H, m), 3.58-3.63 (1 H, m), 3.94-3.97 (1 H, m), 4.43 (1H, broad d, J = 13 Hz), 4.49 (1 H, dt, J = 13, 2 Hz), 4.56 (2H, s), 6.40 (1H, d, J = 4 Hz), 6.76 (1H, d, J = 4 Hz), 7.18 (1H, t, J = 7.5 Hz), 7.27 (2H, dd, J = 7.5, 7.5 Hz), 7.34 (2H, d, J = 7.5 Hz); LC-MS (2) R t 1.70 min; m/z (ESI) 339 [MH + ].

Synthesis 6-1 -A

Ethyl 3-bromo-4-(2-((tenf-butoxycarbonylamino)methyi)morpholino)- 1 H-pyrazolo[3,4-b]pyridine-5-carboxylate

N-Bromosuccinimide (0.044 g, 0.25 mmol) was added in portions at room temperature to a solution of ethyl 4-(2-((ferf-butoxycarbonylamino)methyl)-morpholino)-1 H-pyrazolo[3,4- b]pyridine-5-carboxylate (0.083 g, 0.20 mmol) in DMF (2 ml_). After stirring for 2 hours, saturated brine was added and the precipitate was collected by filtration, washed with water, and dried, to yield the title compound as a pale yellow powder (0.076 g, 77%).

1 H NMR (500 MHz, d 4 -MeOD) δ 1.46 (12H, m), 3.05-3.13 (1 H, m), 3.13-3.29 (3H, m), 3.39-3.48 (1 H, m), 3.55-3.62 (1 H, m), 3.95-4.00 (2H, m), 4.02-4.07 (1 H, m), 4.44 (2H, q, J = 7.5 Hz), 8.53 (1H, s); LC-MS R 1 4.83 min; m/z (ESI) 484, 486 [MH + ].

Synthesis 6-1 -B Ethyl 4-(2-(aminomethyl)morpholino)-3-bromo-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate

Ethyl 3-bromo-4-(2-((terf-butoxycarbonylamino)methyl)morpholino)-1 H-pyrazolo[3,4- b]pyridine-5-carboxylate (5 mg, 0.01 mmol) was dissolved in ethanol (1 mL) and BF 3 etherate (1 mL) was added. After stirring at room temperature for 16 hours, the solvents were evaporated and the residue was purified on SCX-II acidic resin (2 g) elutiήg with methanol then 2 M ammonia-methanol. The basic fractions were combined and evaporated to yield the title compound as a white solid (1 mg, 25%).

1 H NMR (500 MHz, Ci 4 -MeOD) δ 1.43 (3H, t, J = 7.5 Hz), 2.92-3.00 (1H, m), 3.05-3.17 (2H, m), 3.24-3.33 (2H, m), 3.44-3.57 (2H, m), 4.05-4.08 (1H, m), 4.22-4.31 (1H, m), 4.44 (2H, q, J = 7.5 Hz), 8.57 (1H, s); LC-MS R, 2.24 min; m/z (ESI) 384, 386 [MH + ].

Synthesis 7-1 -A

Ethyl 4-(2-((tert-butoxycarbonylamino)methyl)morpholino)-3-(3-cyan ophenyl)-1 H- pyrazolo[3,4-b]pyridine-5-carboxylate boc

A mixture of ethyl 3-bromo-4-(2-((tert-butoxycarbonylamino)methyl)-morpholino)- 1H- pyrazolo[3,4-b]pyridine-5-carboxylate (14 mg, 0.029 mmol), PdCI 2 (CIpPf)-CH 2 CI 2 (18 mg, 10 mol%), 3-cyanophenylboronic acid (9 mg, 0.06 mmol) and sodium carbonate (8 mg, 0.075 mmol) in DME (2 ml_) and water (0.5 mL) was heated to 140 0 C in a microwave reactor for 2 hours. The mixture was partitioned between brine (10 mL) and ethyl acetate (2 x 8 mL). The combined organic layers were washed with brine (10 mL), water (10 mL), dried (Na 2 SO 4 ), filtered, and concentrated. Preparative TLC, eluting with 1 :2 hexane- ethyl acetate, gave the title compound as a light yellow oil (7 mg, 48%).

1 H NMR (500 MHz, d 4 -MeOD) δ 1.44 (3H, t, J = 7.5 Hz), 1.46 (9H, s), 2.86-3.05 (4H, m), 3.06-3.26 (4H, m), 3.57-3.65 (1H, m), 4.45 (2H, q, J = 7.5 Hz), 7.75 (1 H, dd, J = 7.5, 7.5 Hz), 7.87 (1H, d, J = 7.5 Hz), 8.01 (1H, d, J = 7.5 Hz), 8.08 (1 H, s), 8.55 (1H, s); LC-MS R, 4.74 min; m/z (ESI) 507 [MH + ].

Synthesis 7-1 -B

Ethyl 4-(2-(aminomethyl)morpholino)-3-(3-cyanophenyl)-1H-pyrazolo[ 3,4-b]pyridine-5- carboxylate boc

Ethyl 4-(2-((fe/f-butoxycarbonylamino)methyl)morpholino)-3-(3-cyan ophenyl)-1 H- pyrazolo[3,4-b]pyridine-5-carboxylate (2 mg, 0.004 mmol) was dissolved in methanol (2 mL) and TFA (1 mL) was added. After being refluxed at 80°C for 16 hours, the solvents were evaporated and the residue was purified on SCX-II acidic resin (2 g) eluting with methanol then 2 M ammonia-methanol. The basic fractions were combined and

concentrated. The crude oil was purified by preparative TLC, eluting with EtOAc, to give the title compound as a yellow oil (1 mg, 62%).

1 H NMR (500 MHz, d 4 -MeOD) δ 1.43 (3H, t, J = 7.5 Hz), 2.46-2.51 (2H, m), 2.85-2.91 (1 H, m), 2.97-3.05 (2H, m), 3.08-3.25 (3H, m), 3.62-3.67 (1 H, m), 4.44 (2H, q, J = 7.5 Hz), 7.75 (1 H, dd, J = 7.5, 7.5 Hz), 7.90 (1 H, d, J = 7.5 Hz), 8.00 (1 H, d, J = 7.5 Hz), 8.08 (1 H, s), 8.56 (1 H, s); LC-MS R 1 2.56 min; m/z (ESI) 407 [MH + ].

The following compound was prepared using methods analogous to those described above, replacing 3-cyanophenylboronic acid with the appropriately substituted

(hetero)arylboronate reagent in Synthesis 7-1 -A.

Synthesis 8-1 -A

4-Chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid

n-BuLi (4 mL, 1.5M, 6 mmol) was added to a solution of 5-bromo-4-chloro-7H-pyrrolo[2,3- d]pyrimidine (0.95 g, 4.09 mmol) in THF (15 mL) at -78°C. The mixture was stirred at - 78°C for 1 hour followed by addition of solid CO 2 . The resulting suspension was stirred at -78 0 C for 2 hours, and then warmed gradually to room temperature. 1 M HCI was added until the solution became acidic and the precipitate was collected by filtration, washed with water, and dried, to give the title compound as a white solid (0.53 g, 66%).

1 H NMR (500 MHz 1 d e -DMSO ) δ 8.30 (1H, s), 8.66 (1 H, s); LC-MS R 4 2.63 min; m/z (ESI) 198 [MH + ].

Svnthesis 8-1 -B f-Butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamido)piperi dine-1-carboxylate

A solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (18 mg, 0.09 mmol), HATU (45 mg, 0.12 mmol), and diisopropylethylamine (80 μl_, 0.46 mmol) in DMF (1 mL) was stirred at room temperature for 30 minutes. ferf-Butyl 3-aminopiperidine-1- carboxylate hydrochloride (28 mg, 0.12 mmol) in DMF (0.5 mL) was added and the resulting solution was stirred for 16 hours. The mixture was diluted with brine and extracted with ethyl acetate. The combined organic layers were washed sequentially with NaHCO 3 solution, citric acid, and brine, then dried (Na 2 SO 4 ), filtered, and concentrated. Purification by preparative TLC, eluting with ethyl acetate, gave the title compound as a light yellow oil (10 mg, 29%).

1 H NMR (500 MHz, CD 3 OD) δ 1.47 (9H, s), 1.49-1.69 (2H, m), 1.71-1.84 (1 H, m), 2.02- 2.11 (1 H, m), 3.13-3.27 (1 H, m), 3.54-3.68 (1 H, m), 3.86-3.96 (2H, m), 4.00-4.09 (1 H, m), 7.92 (1 H, s), 8.61 (1 H, s); LC-MS R t 4.29 min; m/z (ESI) 380 [MH + ].

Synthesis 8-1 -C te/f-Butyl 3-(4-(2-((f-butoxycarbonylamino)methyl)morpholino)-7H-pyrrol o[2,3- d]pyrimidine-5-carboxamido)piperidine-1-carboxylate boc

A solution of fe/t-butyl 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carboxamido)piperi dine- 1-carboxylate (10 mg, 0.026 mmol), fe/f-butyl morpholin-2-ylmethylcarbamate (8 mg, 0.037 mmol) and triethylamine (11 μL, 0.08 mmol) in n-butanol (0.5 mL) was heated at 120°C in a microwave reactor for 15 minutes. The solution was concentrated and purified by preparative TLC, eluting with ethyl acetate, to give the title compound as a viscous oil (7.5 mg, 51%).

1 H NMR (500 MHz, CD 3 OD) δ 1.45 (9H, s), 1.47 (9H, s), 1.55-1.69 (2H, m), 1.75-1.86 (1 H, m), 2.05-2.15 (1 H, m), 2.86-3.00 (3H, m), 3.15-3.26 (3H, m), 3.67-4.00 (7H, m), 4.04-4.10 (1 H, m), 7.65 (1 H, s), 8.30 (1 H, s); LC-MS R t 4.66 min; m/z (ESI) 560 [MH + ].

Svnthesis 8-1-D 4-(2-(Aminomethyl)morpholino)-N-(piperidin-3-yl)-7H-pyrrolo[ 2,3-d]pyrimidine-5- carboxamide

terf-Butyl 3-(4-(2-((tert-butoxycarbonylamino)methyl)morpholino)-7H-pyr rolo[2,3- d]pyrimidine-5-carboxamido)piperidine-1-carboxylate (7.5 mg, 0.013 mmoi) was dissolved in methanol (1 mL) and 4 M HCI-dioxane (1 mL) was added. After stirring for 16 hours at room temperature, the solvent was evaporated and the residue was purified on SCX-II acidic resin (2 g), eluting with methanol and then 2 M ammonia-methanol. The combined basic fractions were concentrated to give the title compound as a yellow oil (3.7 mg, 77%).

1 H NMR (500 MHz, CD 3 OD) δ 1.51-1.72 (2H, m), 1.76-1.87 (1 H, m), 2.00-2.13 (1 H, m), 2.51-2.67 (2H, m), 2.72-2.85 (2H, m), 2.89-3.02 (2H, m), 3.14-3.26 (2H, m), 3.67-3.86 (2H, m), 3.91-4.00 (3H, m), 4.02-4.14 (1H, m), 7.63 (1H, s), 8.30 (1H, s); LC-MS R 1 0.56 min; m/z (ESI) 360 [MH + ].

Synthesis 9-1 -A

4-(2-((tert-Butoxycarbonylamino)methyl)morpholino)-1H-pyr azolo[3,4-b]pyridine-5- carboxylic acid

2 M NaOH solution (1 mL) was added to ethyl.4-(2-((tert- butoxycarbonylamino)methyl)morpholino)-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate (50 mg, 0.12 mmol) in EtOH (1 mL) and the mixture was refluxed overnight. Upon cooling the solution was diluted with water (2 mL), acidified to pH 5 using 10% aqueous citric acid, and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine, dried (MgSO 4 ), filtered, and evaporated to give crude title compound as a white powder which was used without further purification (14 mg, 30%). LC-MS (2) Rt 3.12 min;m/z (ESI) 378 [MH + ].

Svπthesis 9-1-B 4-(2-(Aminomethyl)morpholino)-N-ethyl-1 H-pyrazolo[3,4-b]pyridine-5-carboxamide

4-(2-((ferf-Butoxycarbonylamino)methyl)morpholino)-1 H-pyrazo!o[3,4-b]pyridine-5- carboxylic acid (14 mg, 0.037 mmol) and o-(7-azabenzotriazol-1-yl)-N,N,N\N'- tetramethyluronium hexafluorophosphate (18 mg, 0.048 mmol) were dissolved in anhydrous DMF and diisopropylethylamine (0.026 ml_, 0.148 mmol) was added. After stirring for 5 minutes under a nitrogen atmosphere, 2 M ethylamine in THF (0.024 ml, 0.048 mmol) was added via syringe and the solution was stirred at room temperature overnight. The reaction mixture was diluted with MeOH and loaded onto a 2 g lsolute

SCX-II acidic resin column. The column was washed with fresh MeOH and then with 1 M NH 3 in MeOH to elute the crude product. After the volatiles were removed in vacuo, the crude material was purified by preparative TLC, eluting with 10% MeOH in dichloromethane to yield tert-hutyi (4-(5-(ethylcarbamoyl)-1 H-pyrazolo[3,4-b]pyridin-4- yl)morpholin-2-yl)methylcarbamate as on off-white powder (10 mg, 67%); LC-MS R t 2.91 min;m/z (ESI) 405 [MH + ].

The material was dissolved in dioxane (0.25 mL), 4 M HCI in dioxane (0.25 mL, 1.0 mmol) was added, and the solution was stirred overnight at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and purified using a 2 g lsolute SCX Il acidic resin column, washing with MeOH, and eluting the product with 1 M NH 3 in MeOH to afford the title compound as a colourless crystalline solid (7 mg, 92%).

1 H NMR (500 MHz, d 4 -MeOH) δ 1.26 (3H, t, J = 7.5 Hz), 2.75-2.83 (2H, m), 3.20 (1 H, dd, J = 12.5, 10.5 Hz), 3.40-3.49 (3H 1 m), 3.71-3.80 (3H, m), 3.85 (1 H, dt,.J = 2.5, 11.5 Hz), 4.03-4.061 (1 H, m), 8.26 (1H, s), 8.29 (1H, s); LC-MS (2) R 4 0.56 min; m/z 305 (ESI) [MH + ].

The following compounds were prepared using methods analogous to those described above, replacing ethylamine with the appropriate amine reagents in synthesis 9-1-B.

Synthesis 10-1 -A tert-Butyl (4-(5-bromo-1 H-pyrazolo[3,4-t>]pyridin-4-yl) morpholin-2-yl)methylcarbamate

5-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4(7H)- one (100 mg, 0.30 mmol) was suspended in phosphorous oxychloride (2.5 mL, 26.8 mmol) and heated for 3 hours at 110 0 C. After cooling, the volatiles were evaportated and the remaining syrup was poured on to ice-water and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were washed with brine, dried (Na 2 SO 4 ), filtered, and concentrated to give a crude mixture containing 5-bromo-4-chloro-1H-pyrazolo[3,4-b]pyridine as the major component (LC-MS R t 4.43 min;m/z (ESI) 232/234 [MH + ]).

The dried crude material was dissolved in warmed 1-butanol (1.9 mL) before terf-butyl morpho!in-2-ylmethy!carbamate (98 mg, 0.45 mmol) and triethylamine (0.14 mL, 0.99 mmol) were added. The reaction mixture was heated at 100 0 C overnight, then cooled and concentrated. Preparative TLC, eluting with 5% MeOH in dichloromethane, gave the

title compound as a yellow powder (66mg, 53%). LC-MS (2) R 1 4.60 nnin; m/z (ESI) 412/414 [MH + ].

Synthesis 10-1 -B (4-(5-Bromo-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl)methanamine

To fert-butyl (4-(5-bromo-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl) methylcarbamate (33 mg, 0.08 mmol) in dioxane (0.5 ml_) was added 4 M HCI in dioxane (0.5 ml_, 2.0 mmol) and the solution was stirred overnight at room temperature. The volatiles were removed in vacuo and the residue was taken up in MeOH and purified using a 2 g lsolute SCX Il acidic resin column, washing with MeOH and eluting the crude product with 1 M NH 3 in MeOH. Preparative TLC, eluting with 20% MeOH, 1% triethylamine in dochloromethane, gave the title compound as an off-white powder (2 mg, 8%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.85-2.93 (2H, m), 3.20 (1H, dt, J = 2.0, 10.0 Hz), 3.41- 3.46 (1 H, m), 3.81-3.86 (2H, m), 3.89-3.94 (2H, m), 4.10-4.13 (1 H, m); LC-MS (2) R t 1.63 min; m/z (ESI) 312/314 [MH + ].

Synthesis 11-1 -A 5-Bromo-4-chloro-1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine

5-Bromo-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4(7H)- one (200 mg, 0.60 mmol) was suspended in phosphorous oxychloride (5 mL, 53.6 mmol) and heated for 18 hours at 60 0 C. Upon cooling, the volatiles were removed in vacuo and the remaining syrup was poured into ice-water and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine, dried (Na 2 SO 4 ), and concentrated to give the title compound as an off-white powder (166 mg, 79%).

1 H NMR (500 MHz, d 4 -MeOH) δ 3.70 (3H, s), 5.61 (2H, s), 6.86 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 8.29 (1 H, s), 8.79 (1 H, s); LC-MS (2) R t 5.70 min;m/z (ESI) 352, 354 [MH + ].

Synthesis 11-1 -B tert-Butyl (4-(5-bromo-1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-

2-yl)methylcarbamate

5-Bromo-4-chloro-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyrid ine (100 mg, 0.28 mmol) was dissolved in warmed 1-butanol (1.2 ml_) before terf-butyl morpholin-2- ylmethylcarbamate (135 mg, 0.62 mmol) and triethylamine (0.18 mL, 1.31 mmol) were added. The reaction mixture was heated at 16O 0 C for 3 hours in a microwave reactor. Upon cooling, the solvent was removed in vacuo and the crude product was purified by column chromatography using a gradient of ethyl acetate in hexanes to give the title compound as a white powder (74 mg, 49%).

1 H NMR (500 MHz, d 4 -MeOH) δ 1.45 (9H, s), 3.11-3.15 (1 H, m), 3.19-3.27 (2H, m), 3.36- 3.41 (1H, m), 3.52-3.59 (1H, m), 3.73 (3H, s), 3.77-3.94 (3H, m), 4.03-4.05 (1H, m), 5.54 (2H, s), 6.82 (2H, d, J = 8.5 Hz), 7.22 (2H, d, J = 8.5 Hz), 8.24 (1 H, s), 8.42 (1 H, s); LC- MS (2) R t 5.49 min; m/z (ESI) 532, 534 [MH + ].

Synthesis 11-1 -C (4-(5-Phenyl-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl)methanamine

ferf-Butyl (4-(5-bromo-1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2- yl)methylcarbamate (50 mg, 0.094 mmol) in warmed acetonitrile (1.7 mL) was added to benzeneboronic acid (23 mg, 0.19 mmol), sodium carbonate (25 mg, 0.24 mmol), and [1 ,1'-bis(diphenylphosphino)ferrocene]-dichloro palladium ll.dichloromethane complex (7 mg, 10mol%), followed by water (0.35 mL). Nitrogen gas was bubbled through the stirred solution for 5 minutes before the mixture was heated at 140°C for 30 minutes in a microwave reactor. Upon cooling, the volatiles were removed and the residue was

purified by preparative TLC, eluting with 60% ethyl acetate in hexane, to give the title compound as a white powder (31 mg, 62%). LC-MS (2) R, 5.47 min; m/z (ESI) 530 [MH + ].

fe / f-Butyl (4-(1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4 -y!)morpholin-2- yl)methylcarbamate (31 mg, 0.059 mmol) was dissolved in TFA (1 mL) and stirred at 4O 0 C overnight. Upon cooling, the TFA was removed in vacuo. The residue was taken up in methanol and loaded onto a 2 g lsolute SCX-II acidic resin column which was washed with MeOH and eluted with 1 M NH 3 in MeOH. The crude product was further purified by preparative TLC, eluting with 20% MeOH, 1% triethylamine in dichloromethane, to give the title compound as a white powder (4.5 mg, 25%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.89-2.95 (2H, m), 3.05 (1 H, dd, J = 10.0, 12.0 Hz), 3.20- 3.26 (1 H, m), 3.47-3.49 (1H, m), 3.60-3.65 (2H, m), 3.74-3.79 (1 H, m), 3.86-3.89 (1 H, m), 7.37-7.41 (1H, m), 7.51 (2H, t, J = 7.5 Hz), 7.56 (2H, dd, J = 1.5, 7.5 Hz) 1 8.14 (1H, s), 8.32 (1H, s) ; LC-MS (2) R, 0.67 min; m/z (ESI) 310 [MH + ].

The following compounds were synthesised by an analogous route to Synthesis 11-1 using the appropriate (hetero)arylboronic acid or ester in Synthesis 11-1 -C.

Synthesis 12-1 (4-(3-Bromo-5-phenyl-1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl)methanamine

λ/-Bromosuccinimide (10 mg, 0.058 mmol) was added to (4-(5-phenyl-1tf-pyrazolo[3,4- b]pyridin-4-yl)morpholin-2-yl)methanamine, prepared as described in Synthesis 11-1 , (15 mg, 0.048 mmol) in DMF (0.5 ml_) and the reaction was stirred at rt for 16 hours. Further λ/-bromosuccinimide (5 mg, 0.029 mmol) was added and reaction was stirred for

2 hours before being diluted with MeOH and added to a conditioned 2 g lsolute SCX-II acidic resin column. This was washed with fresh MeOH followed by 0.1 M NH 3 in MeOH, before the basic products were eluted with 1 M NH 3 in MeOH. The crude product was purified by preparative TLC, eluting with 10% MeOH in dichloromethane, to give the title compound as a white powder (3 mg, 16%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.54-2.65 (2H, m), 2.71 (1 H 1 dd, J = 4.0, 14.0 Hz), 2.78- 2.83 (1 H, m), 3.02-3.05 (1 H, m), 3.33-3.36 (1 H, m), 3.78-3.82 (1 H, m), 3.86-3.91 (1 H, m), 3.93-3.99 (1 H, m), 7.33-7.36 (2H, m), 7.43-7.51 (3H, m), 8.19 (1H, s); LC-MS (2) R 1 2.61 min; m/z (ESI) 388/390 [MH + ].

Synthesis 13-1 (4-(1 H-Pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl)methanamine

Crude (4-(1 H-pyrazolo[3,4-b]pyridin-4-yl)morpholin-2-yl)methanamine was isolated as a by-product from Synthesis 11-9. Preparative TLC, eluting with 10% MeOH, 1% ammonia solution (0.88 s.g.) in dichloromethane, gave the title compound as a clear glass (3.3 mg, 19%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.87-2.91 (1 H, m), 2.97-3.03 (2H, m), 3.27-3.30 (1 H, m), 3.75-3.81 (1 H, m), 3.82-3.87 (1 H, m), 4.04-4.16 (3H, m), 6.52 (1 H, d, J = 5.5 Hz), 8.14 (1 H, d, J = 5.5 Hz), 8.25 (1 H, s); LC-MS (2) R 1 0.52 min; m/z (ESI) 234 [MH + ].

Synthesis 14-1 -A (S)-2-Cloro-N-(2,3-dihydroxypropyl)acetamide

Triethylamine (4.0 mL, 28.9 mmol) was added at -10 0 C to a solution of (S)-3-amino-1 ,2- propanediol (2.2 g, 24.1 mmol) in a mixture of MeCN/MeOH (80 mL/13 mL). Chloroacetyl chloride (2.1 mL, 26.5 mmol) was added dropwise under nitrogen at -10 0 C over 30 minutes. The reaction mixture was allowed to warm to room temperature and was stirred for 16 hours. The mixture was concentrated and purified by flash chromatography on

silica gel, eluting with MeOH-EtOAc (8:92), to give the title compound as a white solid (3.63 g, 90%).

1 H NMR (500 MHz, (CD 3 ) 2 SO) 2.97-3.02 (1 H, m), 3.23-3.33 (3H, m), 3.47-3.53 (2H, m), 4.07 (1 H, s), 4.53 (1 H, t, J = 5.6), 4.79 (1 H, d, J = 5.0), 9.10 (1 H, s).

Synthesis 14-1 -B (S)-6-(Hydroxymethyl)morpholin-3-one

(S)-2-chloro-N-(2,3-dihydroxypropyl)acetamide (4.77 g, 28.45 mmol) in terf-amyl alcohol (70 mL) was added under nitrogen to a stirred solution of potassium terf-butoxide (3.59 g, 21.4 mmol) in terf-amyl alcohol (25 mL) at room temperature over 2 hours. After 1 hour, MeOH (12 mL) and water (0.7 mL) were added and the reaction mixture was stirred for a 20 minutes. The mixture was concentrated and purified by flash chromatography on silica gel, eluting with MeOH-EtOAc (20:80), to provide the title compound as a white solid (1.26 g, 45%).

1 H NMR (500 MHz, (CD 3 ) 2 SO) 3.05-3.09 (1 H, m), 3.15-3.19 (1 H, m), 3.38-3.50 (2H, m), 3.62-3.66 (1H, m), 4.04 (2H, AB, J = 16.4), 4.83 (1 H, t, J = 5.7), 7.90 (1H, s).

Synthesis 14-1 -C (S)-Morpholin-2-ylmethanol

A solution of Red-AI, (bis(2 methoxyethoxy)aluminum hydride, (65 wt% in toluene 0.46 mL, 1.52 mmol) was slowly added over 1 hour under nitrogen at 0 0 C to a suspension of (S)-6-(hydroxymethyl)morpholin-3-one (0.050 g, 0.38 mmol) in anhydrous THF (2 mL).

The reaction mixture was stirred for 16 hours at room temperature and then cooled to 0 0 C before the addition of water (0.5 mL) followed by potassium hydroxide solution (4M,

1 mL). The resulting precipitate was filtered through Celite and rinsed with dichloromethane. The filtrate was concentrated under vacuum and purified by flash chromatography on silica gel, eluting with MeOH-CHCI 3 (25:75), to provide the title compound as a pale yellow oil (0.015 g, 33%).

1 H NMR (500 MHz, (CD 3 ) 2 CO) 2.45-2.50 (1 H, m), 2.70-2.72 (2H, m), 2.87-2.90 (1 H, m), 3.16 (1 H, s), 3.38-3.51 (4H, m), 3.73 (1 H, dt, J = 10.7, 2.5).

Synthesis 14-1 -D (S)-Ethyl 4-(2-(hydroxymethyl)morpholino)-1H-pyrazolo[3,4-b]pyridine-5 -carboxylate

A solution of ethyl 4-chloro-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.031 g, 0.13 mmol) and (S)-morpholin-2-ylmethanol (0.015 g, 0.13 mmol) in n-butanol (1.5 mL) was heated at 120 0 C for 60 minutes in a microwave reactor. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate- hexane (1:9), to give the title compound as a colourless solid (0.027 g, 64%).

1 H NMR (500 MHz, (CD 3 J 2 SO) 1.37 (3H, t, J = 6.9), 3.27-3.32 (2H, m), 3.48-3.54 (1 H, m), 3.59-3.73 (2H, m), 3.82-3.87 (2H, m), 3.92-4.02 (2H, m), 4.32-4.38 (2H, m), 8.28 (1 H, s), 8.63 (1 H, s), 12.70 (1 H, s); LC-MS (2) R t 2.35 min; m/z (ESI) 307 [MH + ].

The following compound was prepared using methods analogous to those described above, replacing (S)-3-amino-1,2-propanediol with (R)-3-amino-1 ,2- propanediol in Synthesis 14-1 -A.

Synthesis 15-1 -A (f?)-2-(Methoxymethyl)morpholine

A solution of (R)-(~) glycidylmethylether (0.800 g, 10.66 mmol) in methanol (11 mL) was added dropwise to a solution of 2-aminoethanesulfonic acid (6.440 g, 53.3 mmol) in 40% aqueous sodium hydroxide (11 mL) at 5O 0 C. After stirring for 75 minutes, further 40% aqueous sodium hydroxide (19 mL) was added and the reaction mixture was stirred for 20 hours at 5O 0 C. The solution was cooled to room temperature and diluted with water (76 mL). The aqueous phase was extracted with ethyl acetate (3 x 75 mL). The combined organic phases were dried (Na 2 SO 4 ). The solvent was removed in vacuo and

the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate-hexane (2:8), to give the title compound as a colourless oil (0.121 g, 10%).

1 H NMR (500 MHz 1 (CD 3 ) 2 CO) 2.47 (1 H, dd, J = 10.4, 1.9), 2.70-2.72 (1H, m), 2.84 (1 H 1 dd, J = 11.9, 2.2), 3.22-3.25 (2H, m), 3.27 (3H, s), 3.29-3.34 (4H, m), 3.45-3.53 (2H, m), 3.73 (1H, dt, J = 11.0, 2.5).

Synthesis 15-1 -B (R)-ethyl 4-(2-(methoxymethyl)morpholino)-1H-pyrazolo[3,4-b]pyridine-5 -carboxylate

A solution of ethyl 4-chloro-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.050 g, 0.22 mmol) and (R)-2-(methoxymethyl)morpholine (0.029 g, 0.13 mmol) in n-butanol (1.0 mL) was heated at 120 0 C for 60 minutes in a microwave reactor. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate-hexane (1 :9), to give the title compound as a colourless solid (0.033 g, 46%).

1 H NMR (500 MHz, (CD 3 ) 2 CO) 1.37 (3H, t, J = 6.9), 3.23-3.28 (1H, m), 3.37 (3H, s), 3.43- 3.46 (1H, m), 3.52-3.56 (2H, m), 3.67-3.72 (1H, m), 3.81-3.86 (2H, m), 3.92-4.02 (2H, m), 4.34-4.37 (2H, m), 8.28 (1 H, s), 8.63 (1 H, s), 12.70 (1 H, s); LC-MS (2) R, 3.05 min; m/z (ESI) 321 [MH + ].

The following compound was prepared using methods analogous to those described above, replacing (ft)-(-) glycidylmethylether with (S)-(-) glycidylmethylether in

Synthesis 15-1 -A.

Synthesis 16-1 -A

(S)-Ethyl 4-(2-(hydroxymethyl)morpholino)-1-(4-methoxybenzyl)-1H-pyraz olo[3,4- b]pyιϊdine-5-carboxylate

A solution of ethyl ethyl 4-chloro-1-(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine-5- carboxylate (0.622 g, 1.80 mmol) and (S)-morpholin-2-ylmethanol (prepared as described in Synthesis 14-1 -C) (0.212 g, 1.80 mmol) in n-butanol (5.5 ml.) was heated at 12O 0 C for 60 minutes in a microwave reactor. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with methanol- dichloromethane (1 :20), to give the title compound as a yellow solid (0.746 g, 96%).

LC-MS (2) R t 4.63 min; m/z (ESI) 427 [MH + ].

Synthesis 17-1 -A

(S)-Ethyl 1 -(4-methoxybenzyl)-4-(2-(tosyloxymethyl)morpholino)-1 H-pyrazolo[3,4- b]pyridine-5-carboxylate

Tosyl chloride (0.179 g, 0.94 mmol) was added to an ice-cooled solution of (S)-ethyl 4-(2- (hydroxymethyl)morpholino)-1-(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine-5- carboxylate (prepared as described in Synthesis 16-1 -A) (0.262 g, 0.62 mmol), triethylamine (0.726 ml, 1.24 mmol) and DMAD (0.007 g, 0.06 mmol) in dichloromethane (4 ml_). The reaction mixture was stirred at room temperature for 4 hours, then diluted with water (4 mL) and washed with an aqueous HCI solution (0.2 M, 8 mL). The organic phase was dried (MgSO 4 ) and the solvent was removed in vacuo. The crude mixture was purified by flash column chromatography on silica, eluting with ethyl acetate-hexane (1:1), to give the title compound as a colourless solid (0.316 g, 87%).

LC-MS (2) R t 5.38 min; m/z (ESI) 381 [MH + ].

Synthesis 17-1 -B

('S)-Ethyl 4-(2-(cyanomethyl)morpholino)-1-(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine-

5-carboxylate

A solution of (S)-ethyl 1-(4-methoxybenzyl)-4-(2-(tosyloxymethyl)morpholino)-1H- pyrazolo[3,4-b]pyridine-5-carboxylate (0.050 g, 0.08 mmol) and sodium cyanide (0.012 mg, 0.25 mmol) in DMSO (0.5 mL), was heated at 80 0 C for 60 minutes in a microwave reactor. The crude reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were dried (MgSO 4 ) and the solvent was removed in vacuo. The crude mixture was purified by flash column chromatography on silica, eluting with ethyl acetate-hexane (1 :1), to give the title compound as a colourless solid (0.022 g, 58%).

LC-MS (2) R t 4.76 min; m/z (ESI) 436 [MH + ].

Synthesis 17-1 -C (S)-Ethyl 4-(2-(cyanomethyl)morpholino)-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate

A solution of (S)-ethyl 4-(2-(cyanomethyl)morpholino)-1-(4-methoxybenzyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxylate (0.017 g, 0.04 mmol), anisole (0.1 mL) and sulfuric acid (cat.) in trifluoroacetic acid (0.2 mL) was stirred at room temperature for 90 minutes. The reaction mixture was poured into an ice-cooled solution of aqueous sodium carbonate (1 mL) and stirred for 2 hours at 0 0 C. The aqueous solution was extracted with ethyl acetate (2 x 3 mL). The combined organic phases were washed with water (5 mL), brine (5 mL) and dried (MgSO 4 ). The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer silica chromatography, eluting with ethyl actetate-hexane (1 :1), to give the title compound as a white solid (0.004 g, 32%).

1 H NMR (500 MHz, CDCI 3 ) 1.42 (3H, t, J = 7.1), 2.67 (2H, dd, J = 5.7, 3.8), 3.29 (1 H 1 dd, J = 12.6, 10.0), 3.62 (1 H, td, J = 12.6, 3.1 ), 3.77 (2H, d, J = 12.6), 3.98 (1H, td, J = 11.3,

2.5), 4.11-4.24 (2H, m), 4.41 (2H, q, J = 7.0), 8.17 (1 H, s), 8.95 (1 H, s); LC-MS (2) R t 3.09 min; m/z (ESI) 316 [MH + ].

Synthesis 18-1 -A

CS)-Ethyl 4-(2-(cyanomethyl)morpholino)-1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine-

5-carboxyiate

The title compound was repared using the methods described in Syntheses 16-1 -A, 16-1 -B and 17-1 -B, replacing (S)-morpholin-2-ylmethanol with (R)-morpholin-2-ylmethanol in Synthesis 16-1 -A.

LC-MS (2) R 1 4.79 min; m/z (ESI) 436 [MH + ].

Synthesis 18-1 -B

(S)-Ethyl 4-(2-(2-aminoethyl)morpholino)-1 -(4-methoxybenzyl)-1 H- pyrazolo[3,4-b]pyridine-5-carboxylate

A solution of (S)-ethyl 4-(2-(cyanomethyl)morpholino)-1-(4-methoxybenzyl)-1H- pyrazolo[3,4-b]pyridine-5-carboxylate (0.123 g, 0.28 mmol) and Raney Nickel (1 g) in ethanol-acetic acid (10:1 , 2.2 mL), was stirred at room temperature for 6 hours. The crude mixture was filtered through celite and concentrated in vacuo. Flash chromatography on silica, eluting with methanol-dichloromethane (1 :9), gave the title compound as a yellow solid (0.040 g, 32%).

LC-MS (2) R t 3.01 min; m/z (ESI) 440 [MH + ].

Synthesis 18-1 -C (S)-Ethyl 4-(2-(2-aminoethyl)morpholino)-1H-pyrazolo[3,4-b]pyridine-5- carboxylate

A solution of (S)-ethyl 4-(2-(2-aminoethyl)morpholino)-1-(4-methoxybenzyl)-1 H- pyrazolo[3,4-b]pyridine-5-carboxylate (0.034 g, 0.07 mmol), anisole (0.2 ml_) and sulfuric acid (cat.) in trifluoroacetic acid (0.4 ml_) was stirred at room temperature for 90 minutes. The reaction mixture was poured into an ice-cooled solution of aqueous sodium carbonate (2 mL) and stirred for 2 hours at 0 0 C. The aqueous solution was extracted with ethyl acetate (2 x 6 mL). The combined organic phases were washed with water (5 mL), brine (10 mL) and dried (MgSO 4 ). The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer silica chromatography, eluting with methanol-dichloromethane (1:9), to give the title compound as a white solid (0.012 g, 48%).

1 H NMR (500 MHz, CDCI 3 ) 1.43 (3H, t, J = 7.1), 1.63-1.83 (2H, m), 2.89-2.98 (2H 1 m), 3.22 (1 H, dd, J = 12.9, 10.4), 3.53-3.59 (1 H, m), 3.74 (1 H, td, J = 12.6, 1.9), 3.88-3.98 (2H, m), 4.03-4.06 (1 H, m), 4.39 (2H, q, J = 7.1 ), 8.19 (1 H, s), 8.88 (1 H, s); LC-MS (2) R t 1.43 min; m/z (ESI) 320 [MH + ].

Synthesis 19-1 -A 1 -(4-Methoxybenzyl)-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-4-ol

A solution of 4-hydroxy-1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (118 mg, 0.39 mmol), HATU (165 mg, 0.43 mmol), DIPEA (0.18 mL) and N'-hydroxyacetimidamide (35.5 mg, 0.48 mmol) in DMF (1.5 mL) was heated at 50 0 C in a microwave reactor for 1 hour, then at 15O 0 C for 15 minutes. The mixture was partitioned between brine (10 mL) and ethyl acetate (2 x 8 mL). The combined organic layers were washed with brine (10 mL), saturated citric acid (10 mL), water (10 mL), then dried (Na 2 SO 4 ), filtered and concentrated. The yellow solids (60 mg) obtained were used in the next step without further purification.

LC-MS (2) Rt 4.68 min; m/z (ESI) 338 [MH + ].

Synthesis 19-1 -B 5-(4-Chioro1 -(4-methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridin-5-yl)-3-methyl-1 ,2,4- oxadiazole

B

Crude 1 -(4-methoxybenzyl)-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-pyrazolo[3,4-b]pyridin-4- ol (60 mg) was dissolved in POCI 3 (2.5 mL) and the solution was stirred at 60 0 C for 1 hour. After cooling, the volatiles were evaporated and the residue was purified by preparative TLC, eluting with EtOAc / n-hexane (1 : 1 ), R f = 0.62, to yield 5-(4-chloro-1 -(4- methoxybenzyl)-1 H-pyrazolo[3,4-b]pyridin-5-yl)-3-methyl-1 ,2,4-oxadiazole as a yellow oil (24 mg, 17%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.48 (3H, s), 3.70 (3H, s), 5.67 (2H, s), 6.90 (2H, d, J = 9.0 Hz), 7.24 (2H, d, J = 9.0 Hz), 8.52 (1H, s), 9.20 (1 H, s); LC-MS (2) R, 5.38 min; m/z (ESI) 356 [MH + ].

Synthesis 19-1 -C terf-Butyl (4-(1-(4-methoxybenzyl)-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-pyrazolo[3,4- b]pyridin-4-yl)morpholin-2-yl)methylcarbamate

A solution of terf-butyl morpholin-2-ylmethylcarbamate (12 mg, 0.055 mmol), 5-(4-chloro- 1-(4-methoxybenzyl)-1 H~pyrazolo[3,4-b]pyridin-5-yl)-3-methyl-1 ,2,4-oxadiazole (20 mg, 0.056 mmol) and triethylamine (0.023 mL, 0.165 mmol) in EtOH (3 mL) was heated at 120 0 C in a microwave reactor for 1 hour. The solution was concentrated and the crude product was purified by preparative TLC, EtOAc / n-hexane (1 :1), R f = 0.12, to yield the title compound as a yellow oil (7 mg, 23%).

1 H NMR (500 MHz, d 4 -MeOH) δ 1.50 (9H, s), 2.53 (3H, s), 3.17-3.27 (3H, m), 3.45-3.54 (2H 1 m), 3.65-3.74 (1H, m), 3.80 (3H, s), 3.81-3.95 (2H, m), 4.00-4.05 (1 H, m), 5.62 (2H, s), 6.88 (2H, d, J = 9.0 Hz), 7.30 (2H, d, J = 9.0 Hz), 8.38 (1 H, s), 8.80 (1 H, s); LC-MS (2) Rt 5.22 min; m/z (ESI) 536 [MH + ].

Synthesis 19-1 -D

(4-(5-(3-Methyl-1 ,2,4-oxadiazol-5-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl)morpholi n-2- yl)methanamine

fe/f-Butyl (4-(1 -(4-methoxybenzyl)-5-(3-methyl-1 ,2,4-oxadiazol-5-yl)-1 H-pyrazolo[3,4- b]pyridin-4-yl)morpholin-2-yl)methylcarbamate (7 mg, 0.013 mmol) was dissolved in methanol (3 mL) and TFA (1.5 mL) was added. After stirring at 40 0 C for 16 hours, the solvents were evaporated and the residue was purified on SCX-II acidic resin (500 mg), eluting with methanol then 2 M ammonia-methanol. The basic fractions were combined and concentrated, and the crude was purified by preparative TLC to give the title compound as yellow oil (1.5 mg, 36%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.45 (3H, s), 2.80-2.95 (2H, m), 3.20-3.30 (1 H, m), 3.45- 3.55 (2H, m), 3.65-3.70 (1 H, m), 3.90-4.00 (2H, m), 4.02-4.10 (1H, m), 8.39 (1 H, s), 8.75 (1 H, s); LC-MS (2) R { 1.73 min; m/z (ESI) 316 [MH + ].

Synthesis 20-1 -A 6-Chloro-7H-purin-8(9H)-one

N Xr NH2

A mixture of 4-chloropyrimidine-2,3-diamine (36 mg, 0.25 mmol) and di(/V-succinimidyl)carbonate (128 mg, 0.50 mmol) in acetonitrile (10 mL) was refluxed for 16 hours. The solids formed were collected, washed with acetonitrile (2 x 5 mL) and dried, to give the title compound as a light yellow powder (33 mg, 78%).

1 H NMR (500 MHz, d e -DMSO) δ 8.35 (1 H, s), 11.90 (2H, s, broad); LC-MS (2) R 1 1.96 min; m/z (ESI) 171 [MH + ].

Synthesis 20-1 -B terf-Butyl (4-(8-oxo-8,9-dihydro-7H-purin-6-yl)morpholin-2-yl)methylcar bamate

A solution of terf-butyl morpholin-2-ylmethylcarbamate (13 mg, 0.06 mmol), 6-chloro-7H- purin-8(9H)-one (10 mg, 0.059 mmol) and triethylamine (0.025 ml_, 0.18 mmol) in n-BuOH (0.6 mL) was heated at 150 0 C in a microwave reactor for 3 hours. n-BuOH was evaporated and ether (3 mL) was added. Crude title compound (22 mg) was collected by filtration, dried and used in the next step without further purification.

LC-MS (2) R t 3.95 min; m/z (ESI) 351 [MH + ].

Synthesis 20-1 -C 6-(2-(Aminomethyl)morpholino)-7H-purin-8(9H)-one

Crude terf-butyl (4-(2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin~7-yl)morpholin-2- yl)methylcarbamate (22 mg) was dissolved in methanol (4 mL) and 4M HCI/dioxane (1 mL) was added. After stirring at room temperature for 16 hours, the solvents were evaporated and the residue was purified on SCX-II acidic resin (2 g), eluting with methanol then 2 M ammonia-methanol. The basic fractions were combined and concentrated, to give the title compound as yellow oil (10 mg, 68%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.80-2.92 (2H, m), 3.10-3.20 (1 H, m), 3.42-3.50 (1 H, m), 3.57-3.65 (2H, m), 3.68-3.78 (1 H, m), 3.82-3.92 (1 H, m), 4.00-4.04 (1 H, m), 8.13 (1 H, s); LC-MS (2) R 1 0.72 min; m/z (ESI) 251 [MH + ].

Synthesis 21-1 -A te/t-Butyl (4-(2-amino-5-chloro-3-nitropyridin-4-yl)morpholin-2-yl)meth ylcarbamate

A solution of morpholin-2-ylmethyl-carbamic acid tert-butyl ester (0.155 g, 0.72 mmol) and 2-amino-4,5 dichloro-3-nitropyridine (0.150 g, 0.72 mmol) in n-butanol (2.2 mL) was heated at 120°C for 90 minutes in a microwave reactor. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate-petroleum ether (1:1), to give the title compound as a yellow solid (0.237 g, 84%).

LC-MS (2) -R, 4.66 min; m/z (ESI) 288 [MH + ].

Synthesis 21-1 -B ferf-Butyl (4-(2,3-diamino-5-chloropyridin-4-yl)morpholin-2-yl)methylca rbamate

Ammonium formate (0.188 g, 2.30 mmol) was added to a suspension of Pd/C (0.028 g), fe/t-butyl (4-(2-amino-5-chloro-3-nitropyridin-4-yl)morpholin-2-yl)meth ylcarbamate (0.100 g, 0.27 mmol) in ethanol (3.7 ml_). The reaction mixture was stirred for 90 minutes, filtered over celite and concentrated. The resulting brown oil was dissolved in ethyl acetate (25 mL) and washed sequentially with water (25 mL) and NaHCO 3 aq

(25 mL). The organic phase was dried (MgSO 4 ) and the solvent was removed in vacuo to give the title compound as a colorless oil (0.091 g, 99%).

LC-MS (2) Rt 3.00 min; m/z (ESI) 302 [(M - f-But)H * ].

Synthesis 21-1 -C fe/t-Butyl (4-(6-chloro-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl )morpholin-2- yl)methylcarbamate

Triethylamine (0.052 mL, 0.38 mmol) and trisphosgene (0.062 g, 0.20 mmol) were added sequentially to a solution of ferf-butyl (4-(2,3-diamino-5-chloropyridin-4-yl)morpholin-2- yl)methylcarbamate (0.067 g, 0.19 mmol) in THF (1.8 mL) at 0 0 C. The reaction mixture was stirred for 15 minutes at O 0 C and 16 hours at room temperature. The reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried (MgSO 4 ) and the solvent was removed in vacuo. The crude mixture was purified by flash chromatography on silica, eluting with ethyl acetate, to give the title compound as a yellow solid (0.048 g, 65%).

LC-MS (2) R, 4.53 min; m/z (ESI) 284 [(M - BoC)H + ].

Synthesis 21-1-D 7-(2-(Aminomethyl)morpholino)-6-chloro-1 H-imidazo[4,5-b]pyridin-2(3H)-one

A solution of tert-butyl (4-(6-chloro-2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-7- yl)morpholin-2-yl)methylcarbamate (0.030 g, 0.08 mmol) in trifluoroacetic acid (0.8 mL) was stirred at room temperature for 90 minutes. The solvent was removed in vacuo and the crude mixture was purified by preparative thin layer chromatography on silica, eluting with methanol-dichloromethane (1 :9) to give the title compound as a yellow solid (0.010 g, 45%).

1 H NMR (500 MHz, MeOD) 3.02 (1 H, dd, J = 13.2, 8.7), 3.12-3.22 (2H, m), 3.31-3.35 (2H, m), 3.34 (1 H, s), 3.36-3.43 (2H, m), 3.88 (1 H, td, J = 11.0, 2.5), 3.97 (1 H, m), 4.06 (1 H, m), 7.90 (1H 1 s); LC-MS (2) R 1 1.61 min; m/z (ESI) 284 [MH + ].

Synthesis 22-1 -A

2-((4-(2-Amino-3-nitropyridin-4-yl)morpholin-2-yl)methyl) isoindoline-1 ,3-dione

A solution of 2-(morpholin-2-ylmethyl)isoindoline-1 ,3-dione (20.5 mg, 0.083 mmol), 4-chloro-3-nitropyridin-2-amine (14.5 mg, 0.084 mmol) and triethylamine (25 μl_, 0.25 mmol) in EtOH (0.8 mL) was heated at 140 0 C in a microwave reactor for 30 minutes. The solids were collected by filtration, washed with EtOH and dried to give the title compound as a bright yellow powder (20 mg, 62%).

1 H NMR (500 MHz, d 6 -DMSO) δ 2.82-2.92 (1H, m), 2.96-3.08 (1H, m), 3.08-3.15 (1H, m), 3.30-3.38 (1 H, m), 3.48-3.56 (1 H, m), 3.60-3.67 (1 H, m), 3.70-3.79 (1 H, m), 3.79-3.88

(1H, m), 4.00-4.10 (1H, m), 6.32 (1H, d, J = 6.8 Hz), 6.89 (2H, s), 7.80-7.93 (4H+1H, m); LC-MS (2) R t 2.42 min; m/z (ESI) 384 [MH + ].

Synthesis 22-1 -B

2-((4-(2,3-Diaminopyridin-4-yl)morpholin-2-yl)methyl)isoi ndoline-1 ,3-dione

A solution of 2-((4-(2-amino-3-nitropyridin-4-yl)morpholin-2-yl)methyl)-is oindoline-1,3- dione (30 mg, 0.078 mmol) and SnCI 2 .2H 2 O (53 mg, 0.23 mmol) in EtOH (1.5 ml.) was heated at 80°C in a microwave reactor for 1 hour. Solvents were removed by evaporation and the residue was purified on SCX-II acidic resin (2 g), eluting with methanol then 2 M ammonia-methanol. The basic fractions were combined and concnetrated, to give the title compound as a yellow oil (17 mg, 67%).

1 H NMR (500 MHz, d 4 -MeOH) δ 2.60-2.70 (1 H, m), 2.85-2.90 (1 H, m), 3.10-3.18 (2H, m), 3.48-3.53 (1 H, m), 3.70-3.77 (1 H, m), 3.95-4.02 (2H, m), 4.05-4.10 (1 H, m), 6.64 (1H, d, J = 6.8 Hz), 7.37 (1 H, d, J = 6.8 Hz), 7.80-7.90 (4H, m); LC-MS (2) R t 2.31 min; m/z (ESI) 354 [MH + ].

Synthesis 22-1 -C

2-((4-(2-Oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-7-yl)morpholin-2-yl)methyl)isoindoli ne-

1 ,3-dione

A mixture of 2-((4-(2,3-diaminopyridin-4-yl)morpholin-2-yl)methyl)isoindo line-1 ,3-dione (37 mg, 0.104 mmol) and di(λ/-succinimidyl)carbonate (53 mg, 0.21 mmol) in acetonitrile (3 mL) was heated at 130 0 C in a microwave reactor for 1 hour. The solvents were evaporated and MeOH (2 mL) was added. The resulting solid was collected by filtration to give the title compound as a white powder (4 mg, 10%).

1 H NMR (500 MHz, d 6 -DMSO) δ 2.52-2.56 (1H, m), 2.78-2.86 (1H, m), 3.48-3.55 (1H, m), 3.58-3.70 (2H, m), 3.72-3.80 (1 H, m), 3.88-3.94 (2H, m), 4.02-4.08 (1H 1 m), 6.52 (1H, d, J = 7.0 Hz), 7.74 (1H, d, J = 7.0 Hz), 7.82-7.92 (4H, m), 10.84 (1H 1 s), 11.10 (1H, s); LC- MS (2) R t 3.57 min; m/z (ESI) 380 [MH + ].

Synthesis 22-1 -D 7-(2-(Aminomethyl)morpholino)-1H-imidazo[4,5-b]pyridin-2(3H) -one

2-((4-(2-Oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)mo rpholin-2-yl)methyl)isoindoline- 1 ,3-dione (4 mg, 0.0105 mmol) was suspended in MeOH (2 niL) and hydrazine hydrate (0.5 mL) was added. The resulting solution was stirred at rt for 16 hours. The volatiles were removed by evaporation and the residue was purified on SCX-II acidic resin (500 mg), eluting with methanol then 2 M ammonia-methanol. The basic fractions were combined and concentrated to give the title compound as a yellow oil (1 mg, 38%). The oil was dissolved in TFA/MeOH (0.05 mL/0.5 mL) and stirred for 15 minutes. The solution was concentrated to obtain the trifluoroacetate salt as yellow oil.

1 H NMR (500 MHz, CF 3 COOD) δ 3.80-3.94 (3H, m), 4.00-4.18 (3H, m), 4.35-4.48 (2H, m), 4.52-4.62 (1 H, m), 7.45 (1 H, d, J = 7.5 Hz), 8.44 (1 H, d, J = 7.5 Hz); LC-MS (2) R 1 0.63 min; m/z (ESI) 250 [MH + ].

Synthesis 23-1 -A terf-Butyl (4-(2-oxo-6-phenyl-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-7-yl)morpholin-2- yl)methylcarbamate

A solution of terf-butyl (4-(6-chloro-2-oxo-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-7- yl)morpholin-2-yl)methylcarbamate (prepared as described in Synthesis 21-1 -C) (0.023 g, 0.06 mmol ), phenyl borononic acid (0.014 g, 0.11 mmol), sodium carbonate (0.015 g, 0.14 mmol) and Bedford catalyst (0.001 g, 0.01 mmol) in a mixture of acetronitrile-water (4:1 , 0.6 mL) was heated at 150 0 C in a microwave reactor for 30 minutes. The crude reaction mixture was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2 M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo. Preparative TLC, eluting with methanol-dichloromethane (1:9), gave the title compound as a yellow solid (20 mg, 80%).

LC-MS (2) R, 4.77 min; m/z (ESI) 426 [MH + ].

Synthesis 23-1 -B 7-(2-(Aminomethyl)morpholino)-6-phenyl-1H-imidazo[4,5-b]pyri din-2(3H)-one

A solution of ferf-butyl (4-(2-oxo-6-phenyl-2,3-dihydro-1 H-imidazo[4,5-b]pyridin-7- yl)morpholin-2-yl)methylcarbamate (0.020 g, 0.04 mmoi) in trifluoroacetic acid (0.5 mL) was stirred at room temperature for 90 minutes. Solvent was removed in vacuo and the crude reaction mixture was purified by ion exchange on SCX-II acidic resin (500 mg) eluting with methanol, then 2 M ammonia-methanol. The basic fractions were combined and the solvent was removed in vacuo to give the title compound as a yellow solid (0.01O g, 75%).

1 H NMR (500 MHz 1 MeOD) 2.82-2.98 (1 H, m), 3.06-3.24 (2H, m), 3.31-3.33 (2H, m), 3.36 (1 H, s), 3.54-3.81 (3H, m), 7.37-7.51 (5H, m), 7.72 (1 H, s); LC-MS (2) R 4 2.12 min; m/z (ESI) 326 [MH + ].

Biological Methods

Measurement of Inhibition of CHK1 Kinase Function

CHK1 kinase function was measured in a DELFIA® assay in order to monitor phosphorylation of a CDC25C peptide using a specific phospho antibody.

The enzyme reaction was carried out in polypropylene plates (Greiner) using a reaction mix (25 μL) containing enzyme and peptide mix (CHK1 , 1 nM; Biotin-

KKKVSRSGLYRSPSMPENLNRPR, 1 μM or 15 μL), ATP (30 μM or 5 μL) and either DMSO (2.5%) or test compound (5 μL) diluted to a give a range of concentrations (from 0 to 100 μM in 2.5% DMSO, final concentrations) in assay buffer (40 mM Tris, 40 mM NaCI, 2 mM MgCI 2 , 1 mM DTT and 0.1% Tween 20). The reaction mixture was incubated for 30 minutes at room temperature and then stopped by the addition of buffer (125 μL) containing 40 mM EDTA, 0.05% Tween 20, 0.1% BSA in TBS (10x concentrate, Sigma). An aliquot (100 μL) of the stopped reaction mixture was transferred to a black neutravidin- coated plate (Perbio) and incubated for 1 hour on a shaker (Titertek, Flow Laboratories) at room temperature. The plates were washed four times with wash buffer (25 mM Tris (pH 8), 150 mM NaCI, and 0.1% Tween 20) (WellWash4, Thermo Life Sciences) and incubated for 1 hour as before with an antibody mixture (100 μL) consisting of anti-

phospho CDC25C (1.25 nM, #9528, Cell Signalling Technology) and europium-labelled anti-rabbit IgG (0.3 μg/mL, AD0105, PerkinElmer Life Sciences) diluted in DELFIA assay buffer (PerkinElmer Life Sciences). The plates were washed a further four times with wash buffer before the addition of enhancement solution (100 μL/well, PerkinElmer Life Sciences). The plate was read on a Victor 2 1420 multilabel counter (Perkin Elmer Life Sciences) using a time-resolved measurement mode reading fluorescence at 615 nm.

Measurement of Cytotoxicity

HT29 colon carcinoma cells are obtained from ATCC (Rockville, MD, USA). Cells are grown in DMEM supplemented with 10% foetal calf serum and containing L-glutamine 5 mM, glucose, penicillin, and streptomycin. Cells are grown at 37°C in a dry 5% CO 2 atmosphere. Cytotoxicity assays are carried out in 96-well plates using quadruplicate wells for each dose. Cells are seeded at 1.6 x 10 3 per well in 160 μL medium and are allowed to attach for 36 hours prior to treatment. Test compounds are dissolved in

DMSO at 10 mM and serially diluted in culture medium to 5 x final concentration prior to addition in a volume of 40 μl per well. Cells are left for 4 doublings (96 hours) in the presence of the test compounds and then fixed in 10% TCA for 30 minutes, washed in water, and dried. The fixed cells are stained with Sulfurhodamine B (SRB, 0.4% in 1% acetic acid, Sigma, Dorset, UK) for 30 minutes, washed in 1% acetic acid, and dried.

SRB is resolubilised in 10 mM Tris base and the OD is measured at 490 nm. Results are expressed relative to untreated controls and the concentration of compound required to inhibit growth by 50% (SRB IC 50 ) is calculated.

Mitosis Inhibition Assay (MIA)

Checkpoint abrogation by CHK1 kinase function inhibitors in combination with genotoxic agents is assessed using a europium based ELISA assay designed to quantify the number of cells trapped in mitosis after treatment with a genotoxic agent (to induce G2 arrest) followed by a test compound in combination with nocodazole to abrogate this arrest.

HT29 cells are seeded at 10 4 cells per well into 96 well plates in a volume of 160 μL and left to attach for 36 hours. Etoposide (10 mM stock in DMSO) is diluted in medium to 250 μM and then 40 μL is added to appropriate wells to give a final concentration of 50 μM and incubated for 1 hour. This treatment has previously been optimised to induce a G2 arrest in 80% of cells 16 hours following treatment. After genotoxic drug exposure, the medium is removed and replaced with fresh medium (160 μL). Cells are either untreated (untreated control or etoposide pre-treatment alone), exposed to nocodazole following etoposide pre-treatment or nocodazole alone (100 ng/mL final concentration), or exposed to increasing concentrations of test compound (200 μM - 0.01 nM final concentration) in

combination with nocodazole (100 ng/mL final concentration). Test compounds are added in 40 μl_ using quadruplicate wells for each dose. After 21 hours exposure, the medium is removed and cells are fixed in 4% formaldehyde in phosphate buffered saline (PBS, pH 7.4, pre-cooled to 4°C) for 30 minutes at 4 0 C, followed by 100% methanol (pre- cooled to -20 0 C) for 10 minutes at ambient temperature. Wells are washed with PBS and blocked with 5% dried milk (Marvel) in Tris-buffered saline (TBS, pH 7.4) at 37 0 C for 30 minutes. Each well is washed three times with water containing 0.1% tween 20. Primary antibody (MPM-2, Upstate cat# 05-368, 1 μg/mL in 5% milk in TBS) is added to each well and incubated overnight with shaking at 4°C. Primary antibody is removed and wells are washed with water containing 0.1% Tween 20. The secondary antibody (europium labelled anti-mouse, Perkin-Elmer cat# AD0124, 333 ng/mL in assay buffer Perkin-Elmer cat# 1244-111) is added to each well and incubated at 37°C for 1 hour. Each well is washed with water 0.1% containing tween 20 and treated with enhancement solution (Perkin-Elmer cat# 1244-105). Europium emissions are counted on a Wallac, Victor 2 counter (Perkin-Elmer, Bucks UK). Appropriate controls are included and results are expressed as the concentration of test compound required to allow 50% of cells to enter mitosis (MIA IC 50 ).

Biological Data

Biological data were obtained using the CHK1 kinase function inhibition assay described above for the following 31 compounds: X-1 through X-23 and Y- 1 through Y-9.

For the CHK1 kinase function inhibition assay, the IC50 (μM) values are as follows: at least 5 of these compounds have an IC50 of 1 μM or less. at least 18 of these compounds have an IC50 of 10 μM or less.

Biological data were obtained using the CHK1 kinase function inhibition assay described above for the following compounds: X-1 through X-25, Y- 1 through Y-35, Z-1 , and W-1 through W-3.

The following compounds have an IC50 value of less than 10 μM: X-1 , X-10, X-13, X-14, X-2, X-20, X-24, X-3, X-4, X-5, X-6, X-7, X-8, Y-1, Y-10, Y-11, Y-12, Y-13, Y-14, Y-15, Y-16, Y-17, Y-18, Y-19, Y-2, Y-20, Y-21, Y-22, Y-23, Y-24, Y-25, Y-26, Y-27, Y-28, Y-29, Y-3, Y-30, Y-31 , Y-33, Y-34, Y-35, Y-7, Y-8, Y-9, W-1.

The following compounds have an IC50 value of at least 10 μM and less than 50μM: W-2, W-3, X-11, X-15, X-16, X-18, X-25, X-9, Y-32, Y-4, Y-6, Z-1.

Compound X-1 , has an IC50 value of 6.4 μM. Compound Y-1 , has an IC50 value of 1.2 μM.

Compound Z-1 , has an IC50 value of 16 μM. Compound W-2, has an IC50 value of 5.8 μM.

One compound, X-1 , has an IC50 value of 6.4 μM. This is a factor of ~4 better than the corresponding compound which lacks a morpholino subsitutent, as shown below.

Biological data were also obtained using the MIA cellular assay described above for the following 2 compounds: Y- 1 and Y-8. The results are summarised in the following table.

The foregoing has described the principles, preferred embodiments, and modes of operation of the present invention. However, the invention should not be construed as limited to the particular embodiments discussed. Instead, the above-described embodiments should be regarded as illustrative rather than restrictive, and it should be appreciated that variations may be made in those embodiments by workers skilled in the art without departing from the scope of the present invention.

REFERENCES

A number of patents and publications are cited above in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Full citations for these references are provided below. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

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