Modulators of ATP-binding cassette transporters
The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator (“CFTR”), compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.
1. A compound having formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Ht is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, or N, wherein Ht is optionally substituted with w occurrences of —WR W , wherein w is 0-4;
R N is H or R;
R is hydrogen or C 1-6 aliphatic wherein up to two methylene units of R are optionally and independently replaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO 2 —, —OCO—, —NR′CO 2 —, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—, —SO, —SO 2 —, —NR′—, —SO 2 NR′—, NR′SO 2 —, or —NR′SO 2 NR′—;
ring A is a cyclopropyl ring, wherein ring A is optionally substituted with q occurrences of -QR Q ;
x is 2, wherein the two R x X form a fused benzodioxole ring;
q is 0-4;
each -Q-R Q , and —W—R w is independently R′;
R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z;
Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
R 8 is an amino protecting group.
2. The compound according to claim 1 , wherein R is hydrogen.
3. The compound according to claim 1 , wherein Ht is a 5-membered heteroaromatic ring containing 1-4 nitrogen atoms, wherein Ht is optionally substituted with up to three substituents.
4. The compound according to claim 3 , wherein Ht is selected from one of the following rings:
wherein each ring is linked to the remainder of the molecule through a carbon ring atom.
5. The compound according to claim 1 , having formula IIA:
wherein:
m is 0; and
Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, or N.
6. The compound according to claim 5 , wherein Ht 1 is selected from:
wherein each ring is linked to the remainder of the molecule through a carbon ring atom.
7. The compound according to claim 6 , wherein Ht 1 is selected from 1-d, 1-f, 1-j, or 1-l rings above.
8. The compound according to claim 7 , wherein Ht 1 is 1-d.
9. The compound according to claim 7 , wherein Ht 1 is 1-f.
10. The compound according to any one of claims 5 and 6 - 9 , wherein w is 1.
11. A compound having formula IIIB:
wherein:
m is 0;
Ar is phenyl or a six-membered heteroaromatic ring;
L is a bond, O, S, SO, SO 2 , C(O), NR′, C 1-4 aliphatic, or CHR L ;
or
R L is —OR′, —SR′, —SOR′, —SO 2 R′, or —N(R′) 2 ;
wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, or N, wherein ring A′ is optionally substituted with q occurrences of -QR Q ;
x is 0 wherein each -QR Q is independently R′;
q is 0-5;
R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z;
Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic;
R 8 is an amino protecting group;
X 9 is CH 2 or CF 2 ;
z is 0-5;
—ZR Z is independently R′; and
Ht 1 is a 5-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, S, or N.
12. The compound according to claim 11 , wherein Ht 1 is selected from:
wherein each ring is linked to the remainder of the molecule through a carbon ring atom.
13. The compound according to claim 11 , wherein Ht 1 is 1-d, 1-f, 1-j, or 1-l.
14. The compound according to claim 11 , wherein ring Ar is selected from:
15. The compound according to claim 11 , wherein said compound has formula IVB′:
wherein:
L is a bond, O, S, SO, SO 2 , C(O), NR′, C 1-4 aliphatic, or CHR L ;
or
R L is —OR′, —SR′, —SOR′, —SO 2 R′, or —N(R′) 2 ;
wherein ring A′ is a 3-7 membered monocyclic ring having 0-3 heteroatoms selected from O, S, or N, wherein ring A′ is optionally substituted with q occurrences of -QR Q ;
x is 0;
q is 0-5;
z is 0-5;
—ZR Z is independently R′;
R′ is independently R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic n -Y;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 NR 6 SO 2 R 5 , NR 5 SO 2 R 6 NR 5 SO 2 R 5 NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z;
Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
R 8 is an amino protecting group;
X 9 is CH 2 or CF 2 ;
X 1 is O, S, or NR;
R is hydrogen or C 1-4 aliphatic; and
each of X 2 and X 3 is independently selected from CH or N.
16. The compound according to claim 15 , having formula IVB-1′:
17. The compound according to claim 16 , wherein X 1 is S, X 2 is N, and X 3 is CH.
18. The compound according to claim 16 , wherein X 1 is S, X 2 and X 3 both are N.
19. The compound according to claim 16 , wherein X 1 is S, X 2 is CH, and X 3 is N.
20. The compound according to claim 16 , wherein X 1 is O, X 2 is N, and X 3 is CH.
21. The compound according to claim 16 , wherein X 1 is O, X 2 and X 3 both are N.
22. The compound according to claim 16 , wherein X 1 is O, X 2 is CH, and X 3 is N.
23. The compound according to claim 16 , wherein X 1 is NR, X 2 is N, and X 3 is CH.
24. The compound according to claim 16 , wherein R is hydrogen.
25. The compound according to claim 16 , wherein R is C 1-4 alkyl.
26. The compound according to claim 16 , wherein X 1 is NR, X 2 and X 3 both are N, wherein R is hydrogen or R is C 1-4 alkyl.
27. The compound according to claim 16 , wherein X 1 is NR, X 2 is CH, and X 3 is N, wherein R is hydrogen or C 1-4 alkyl.
28. The compound according to claim 15 , having formula IVB-2′:
29. The compound according to claim 28 , wherein X 1 is S, X 2 is N, and X 3 is CH.
30. The compound according to claim 28 , wherein X 1 is S, X 2 and X 3 both are N.
31. The compound according to claim 28 , wherein X 1 is S, X 2 is CH, and X 3 is N.
32. The compound according to claim 28 , wherein X 1 is O, X 2 is N, and X 3 is CH.
33. The compound according to claim 28 , wherein X 1 is O, X 2 and X 3 both are N.
34. The compound according to claim 28 , wherein X 1 is O, X 2 is CH, and X 3 is N.
35. The compound according to claim 28 , wherein X 1 is NR, X 2 is N, and X 3 is CH.
36. The compound according to claim 28 , wherein X 1 is NR, X 2 and X 3 both are N.
37. The compound according to claim 28 , wherein X 1 is NR, X 2 is CH, and X 3 is N.
38. The compound according to claim 15 , having formula IVB-3′:
39. The compound according to claim 38 , wherein X 1 is S, X 2 is N, and X 3 is CH.
40. The compound according to claim 38 , wherein X 1 is S, X 2 and X 3 both are N.
41. The compound according to claim 38 , wherein X 1 is S, X 2 is CH, and X 3 is N.
42. The compound according to claim 28 , wherein X 1 is O, X 2 is N, and X 3 is CH.
43. The compound according to claim 38 , wherein X 1 is O, X 2 and X 3 both are N.
44. The compound according to claim 38 , wherein X 1 is O, X 2 is CH, and X 3 is N.
45. The compound according to claim 38 , wherein X 1 is NR, X 2 is N, and X 3 is CH.
46. The compound according to claim 38 , wherein X 1 is NR, X 2 and X 3 both are N.
47. The compound according to claim 38 , wherein X 1 is NR, X 2 is CH, and X 3 is N.
48. The compound according to claim 15 , having formula IVA-4′ or formula IVB-4′:
49. The compound according to claim 48 , wherein X 1 is S, X 2 is N, and X 3 is CH.
50. The compound according to claim 48 , wherein X 1 is S, X 2 and X 3 both are N.
51. The compound according to claim 48 , wherein X 1 is S, X 2 is CH, and X 3 is N.
52. The compound according to claim 48 , wherein X 1 is O, X 2 is N, and X 3 is CH.
53. The compound according to claim 48 , wherein X 1 is O, X 2 and X 3 both are N.
54. The compound according to claim 48 , wherein X 1 is O, X 2 is CH, and X 3 is N.
55. The compound according to claim 48 , wherein X 1 is NR, X 2 is N, and X 3 is CH.
56. The compound according to claim 48 , wherein X 1 is NR, X 2 and X 3 both are N.
57. The compound according to claim 48 , wherein X 1 is NR, X 2 is CH, and X 3 is N.
58. A compound having formula IVA-5′ or formula IVA-6′:
wherein
x is 2, wherein the two R x X form a fused benzodioxole ring;
z is 0-5;
—ZR Z is independently R′;
R′ is R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z;
Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
R 8 is an amino protecting group;
X 1 is O, S, or NR;
R is hydrogen or C 1-4 aliphatic; and
each of X 2 and X 3 is independently selected from CH or N.
59. The compound according to claim 58 , wherein X 1 is S, X 2 is N, and X 3 is CH.
60. The compound according to claim 58 , wherein X 1 is S, X 2 and X 3 both are N.
61. The compound according to claim 58 , wherein X 1 is S, X 2 is CH, and X 3 is N.
62. The compound according to claim 58 , wherein X 1 is O, X 2 is N, and X 3 is CH.
63. The compound according to claim 58 , wherein X 1 is O, X 2 and X 3 both are N.
64. The compound according to claim 58 , wherein X 1 is O, X 2 is CH, and X 3 is N.
65. The compound according to claim 58 , wherein X 1 is NR, X 2 is N, and X 3 is CH.
66. The compound according to claim 58 , wherein X 1 is NR, X 2 and X 3 both are N.
67. The compound according to claim 58 , wherein X 1 is NR, X 2 is CH, and X 3 is N.
68. The compound according to claim 58 , wherein X 1 is S, X 2 is N, and X 3 is CH.
69. A compound having formula VA-1′, formula VA-2′, formula VA-3′, or formula VA-4′:
wherein:
x is 2, wherein the two R x X form a fused benzodioxole ring;
each of R C , R D , and R E is independently hydrogen or C 1-6 aliphatic optionally substituted with —OH, —O(C 1-4 aliphatic), —S(C 1-4 aliphatic), —CF 3 , —OCF 3 , —SCF 3 , halo, NH 2 , NHR, N(R) 2 , C(O)OH, C(O)O(C 1-4 aliphatic), NHC(O)(C 1-4 aliphatic), or a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C 1-4 aliphatic) p -Y;
p is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OR, SR, NH 2 , NHR, N(R) 2 , COOH, or COOR;
R is hydrogen or C 1-4 aliphatic;
R AA and R BB , taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C 1-4 aliphatic) p -Y;
p is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OR, SR, NH 2 , NHR, N(R) 2 , COOH, or COOR;
R is hydrogen or C 1-4 aliphatic
z is 0-5;
—ZR Z is independently R′;
R′ is R 1 , R 2 , R 3 , R 4 , or R 5 ;
R 1 is oxo, R 6 or ((C1-C4)aliphatic) n -Y;
n is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OH, NH 2 , NHR 6 , N(R 6 ) 2 , NR 6 R 8 , COOH, COOR 6 or OR 6 ; or
two R 1 on adjacent ring atoms, taken together, form 1,2-methylenedioxy or 1,2-ethylenedioxy;
R 2 is aliphatic, wherein each R 2 optionally comprises up to 2 substituents independently selected from R 1 , R 4 , or R 5 ;
R 3 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring optionally comprising up to 3 substituents, independently selected from R 1 , R 2 , R 4 or R 5 ;
R 4 is OR 5 , OR 6 , OC(O)R 6 , OC(O)R 5 , OC(O)OR 6 , OC(O)OR 5 , OC(O)N(R 6 ) 2 , OC(O)N(R 5 ) 2 , OC(O)N(R 6 R 5 ), SO 2 N(R 6 ) 2 , SO 2 N(R 5 ) 2 , SO 2 NR 5 R 6 , C(O)R 5 , C(O)OR 5 , C(O)R 6 , C(O)OR 6 , C(O)N(R 6 ) 2 , C(O)N(R 5 ) 2 , C(O)N(R 5 R 6 ), C(O)N(OR 6 )R 6 , C(O)N(OR 5 )R 6 , C(O)N(OR 6 )R 5 , C(O)N(OR 5 )R 5 , C(NOR 6 )R 6 , C(NOR 6 )R 5 , C(NOR 5 )R 6 , C(NOR 5 )R 5 , N(R 6 ) 2 , N(R 5 ) 2 , N(R 5 R 6 ), NR 5 C(O)R 5 , NR 6 C(O)R 6 , NR 6 C(O)R 5 , NR 5 C(O)R 6 , NR 6 C(O)OR 6 , NR 5 C(O)OR 6 , NR 6 C(O)OR 5 , NR 5 C(O)OR 5 , NR 6 C(O)N(R 6 ) 2 , NR 6 C(O)NR 5 R 6 , NR 6 C(O)N(R 5 ) 2 , NR 5 C(O)N(R 6 ) 2 , NR 5 C(O)NR 5 R 6 , NR 5 C(O)N(R 5 ) 2 , NR 6 SO 2 R 6 , NR 6 SO 2 R 5 , NR 5 SO 2 R 6 , NR 5 SO 2 R 5 , NR 6 SO 2 N(R 6 ) 2 , NR 6 SO 2 NR 5 R 6 , NR 6 SO 2 N(R 5 ) 2 , NR 5 SO 2 NR 5 R 6 , NR 5 SO 2 N(R 5 ) 2 , N(OR 6 )R 6 , N(OR 6 )R 5 , N(OR 5 )R 5 , or N(OR 5 )R 6 ;
R 5 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, optionally comprising up to 3 R 1 substituents;
R 6 is H or aliphatic, wherein R 6 optionally comprises a R 7 substituent;
R 7 is a cycloaliphatic, aryl, heterocyclic, or heteroaryl ring, and each R 7 optionally comprises up to 2 substituents independently chosen from H, (C1-C6)-straight or branched alkyl, (C 2-6 ) straight or branched alkenyl or alkynyl, 1,2-methylenedioxy, 1,2-ethylenedioxy, or (CH 2 ) n —Z;
Z is selected from halo, CN, NO 2 , CF 3 , OCF 3 , OH, S-aliphatic, S(O)-aliphatic, SO 2 -aliphatic, NH 2 , NH-aliphatic, N(aliphatic) 2 , N(aliphatic)R 8 , NHR 8 , COOH, C(O)O(-aliphatic), or O-aliphatic; and
R 8 is an amino protecting group.
70. The compound according to claim 69 , wherein R C is C 1-4 alkylidene optionally substituted with up to two substituents selected from —OH, —O(C 1-4 alkyl), NH(C 1-4 alkyl), or N(C 1-4 alkyl) 2 .
71. The compound according to claim 69 , wherein R C is C 1-4 alkylidene optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo, (C 1-4 aliphatic), (C 1-4 aliphatic)-Y, wherein Y is halo, —OH, or —O(C 1-4 alkyl).
72. The compound according to claim 69 , wherein R C is selected from —(CH 2 ) 2 -(4-hydroxy-1-piperidyl), —(CH 2 ) 3 -(4-hydroxy-1-piperidyl), —(CH 2 ) 4 -(4-hydroxy-1-piperidyl), ethylmethylamino-ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-methoxyethyl, isopropyl, (2-methoxymethyl-1-pyrrolidinyl)ethyl, tetrahydrofuran-2-ylmethyl, (pyrrolidin-2-one-5-yl)methyl, (pyrrolidin-1-yl)ethyl, dimethylaminoethyl, 1-piperidylethyl, allyl, n-propyl, diisopropylaminoethyl, and (N-morpholino)ethyl.
73. The compound of formula VA-1 according to claim 69 wherein:
a. z is 0-2 and ZR Z is selected from halo, OMe, OEt, CN, C(O)NH 2 , Me, Et, NH 2 , COOH, N(Me) 2 , or N(Et) 2 ; and
b. R C is —(CH 2 ) 2 -(4-hydroxy-1-piperidyl), —(CH 2 ) 3 -(4-hydroxy-1-piperidyl), —(CH 2 ) 4 -(4-hydroxy-1-piperidyl), (ethylmethylamino)ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-methoxyethyl, isopropyl, (2-methoxymethyl-1-pyrrolidinyl)ethyl, tetrahydrofuran-2-ylmethyl, (pyrrolidin-2-one-5-yl)methyl, (pyrrolidin-1-yl)ethyl, dimethylaminoethyl, 1-piperidylethyl, allyl, n-propyl, diisopropylaminoethyl, or (N-morpholino)ethyl.
74. The compound according to claim 69 , wherein R D is C 1-4 alkylidene optionally substituted with —OH, —O(C 1-4 alkyl), NH(C 1-4 alkyl), or N(C 1-4 alkyl) 2 .
75. The compound according to claim 69 , wherein R D is C 1-4 alkylidene optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo, (C 1-4 aliphatic), (C 1-4 aliphatic)-Y, wherein Y is halo, —OH, or —O(C 1-4 alkyl).
76. The compound according to claim 69 , wherein R D is selected from (N-morpholino)ethyl, (N-morpholino)propyl, dimethylaminoethyl, (N-piperidyl)ethyl, allyl, or diisopropylaminoethyl.
77. The compound of formula VA-2 according to claim 69 , wherein:
a. z is 0-2 and ZR Z is selected from halo, OMe, OEt, CN, C(O)NH 2 , Me, Et, NH 2 , COOH, N(Me) 2 , or N(Et) 2 ; and
b. R D is (N-morpholino)ethyl, (N-morpholino)propyl, dimethylaminoethyl, (N-piperidyl)ethyl, allyl, or diisopropylaminoethyl.
78. The compound of formula VA-3 according to claim 69 , wherein each of R AA and R BB is independently C 1-4 alkylidene optionally substituted with up to two substituents selected from —OH, —O(C 1-4 alkyl), NH(C 1-4 alkyl), or N(C 1-4 alkyl) 2 .
79. The compound according to claim 78 , wherein R AA and R BB is C 1-4 alkylidene optionally substituted with 5-6 membered heterocyclic ring containing up to 2 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo, (C 1-4 aliphatic), (C 1-4 aliphatic)-Y, wherein Y is halo, —OH, or —O(C 1-4 alkyl).
80. The compound according to claim 79 , wherein R AA and R BB is selected from Me, Et, propyl, butyl, allyl, hydroxyethyl, or dihydroxypropyl.
81. The compound according to claim 78 , wherein R AA and R BB , taken together with the nitrogen atom, is selected from:
wherein n= 0
82. The compound according to claim 69 , wherein R AB is selected from methoxymethyl, methoxyethyl, allyl, methyl, —OH, hydroxymethyl, hydroxyethyl, ethylenedioxy, COOH, or C(O)CH 3 .
83. The compound of formula VA-4 according to claim 69 , wherein R E is independently selected from hydrogen or C 1-6 aliphatic optionally substituted with —OH, —O(C 1-4 aliphatic), —S(C 1-4 aliphatic), —CF 3 , —OCF 3 , —SCF 3 , halo, NH 2 , NHR, N(R) 2 , C(O)OH, C(O)O(C 1-4 aliphatic), or NHC(O)(C 1-4 aliphatic).
84. The compound according to claim 83 , wherein R E is selected from —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, —(CH 2 ) 4 OH, —(CH 2 ) 2 NH 2 , —(CH 2 ) 2 NMe 2 , —(CH 2 ) 2 NEt 2 , —(CH 2 ) 2 NHC(O)Me, —(CH 2 )COOH, —(CH 2 ) 2 COOH, —(CH 2 )COOMe, —(CH 2 )CH(NH 2 )COOH, or —(CH 2 ) 2 CH(NH 2 )COOH.
85. The compound according to claim 15 , having formula VC-1′, formula VC-2′, formula VC-3′, of formula VC-4′:
wherein:
x is 0;
each of R C and R D is independently hydrogen or C 1-6 aliphatic optionally substituted with —O(C 1-4 aliphatic), —CF 3 , —OCF 3 , —SCF 3 , halo, NH 2 , NHR, N(R) 2 , or a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C 1-4 aliphatic) p -Y;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OR, SR, NH 2 , NHR, N(R) 2 , COOH, or COOR;
R is hydrogen or C 1-4 aliphatic;
R AA and R BB , taken together with the nitrogen atom, is a 3-7 membered heterocyclic ring containing up to 4 heteroatoms selected from O, N, or S, wherein said ring is optionally substituted with up to 2 substituents selected from oxo or (C 1-4 aliphatic) p -Y;
p is 0 or 1;
Y is halo, CN, NO 2 , CF 3 , OCF 3 , OR, SR, NH 2 , NHR, N(R) 2 , COOH, or COOR; and
R is hydrogen or C 1-4 aliphatic.
86. A pharmaceutical composition comprising:
(i) a compound according to any one of claims 1 , 11 , 58 , 68 and 77 ; and
(ii) a pharmaceutically acceptable carrier.