Activators of executioner procaspases 3, 6 and 7
The present invention provides compounds as activators of procaspases 3, 6 and/or 7 and related derivatives, pharmaceutical compositions thereof, methods for their use, and methods for preparing these compounds. In one aspect, the compounds are useful for treating cancers and neoplastic diseases.
1. A compound of formula:
or a pharmaceutically acceptable salt thereof;
wherein
Q is —O—;
R 2 is independently selected from the group consisting of aryl-C 1-6 alkyl, —C 1-6 alkyl, —OC 1-6 alkyl, —OH, halo, aryl-C 1-6 alkyl-NH— and —NHC 1-6 alkyl;
wherein (1) is —H and R 3 is selected from the group consisting of
(a) imidazopyridinyl optionally substituted with from 1-3 R k members independently selected from the group consisting of aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O))NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members;
(b) pyridyl, isoxazolyl, pyrimidinyl, benzodioxanyl, or pyrazolyl; each independently optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, and S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members; and
(c) aryl optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR C , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, and S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members; or
(2) R 3 is —H and R 4 is benzoimidazolyl optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members; wherein R c and R d are each independently selected from the group consisting of —H, C 1-6 alkyl, —R e , —NHC 1-6 alkyl and —NH(C═O)R e , wherein R e is a heteroaryl or heterocyclyl having from 1-4 ring heteroatoms selected from O, N or S or an aryl, wherein the aryl or heteroaryl is further optionally substituted with from 1-3 R f selected from the group consisting of halo, haloalkyl, —OH, —OR g , —SR g , —CN, —NO 2 , NR g R g , oxo, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR g , S(O)C 1-4 alkyl and S(O) 2 C 1-4 alkyl, wherein R g is C 1-6 alkyl; and wherein each subscript n is independently an integer selected from 0, 1, 2, or 3;
wherein R c and R d are each independently selected from the group consisting of —H, C 1-6 alkyl, —R e , —NHC 1-6 alkyl and —NH(C═O)R e , wherein R e is a heteroaryl or heterocyclyl having from 1-4 ring heteroatoms selected from O, N or S or an aryl, wherein the aryl or heteroaryl is further optionally substituted with from 1-3 R f selected from the group consisting of halo, haloalkyl, —OH, —OR g , —SR g , —CN, —NO 2 , NR g R g , oxo, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR g , S(O)C 1-4 alkyl and S(O) 2 C 1-4 alkyl, wherein R g is C 1-6 alkyl; and wherein each subscript n is independently an integer selected from 0, 1, 2, or 3; and
the aliphatic portions of R 2 , R 3 , and R 4 are each optionally independently substituted with from 1 - 3 R h substituents selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-8 cycloalkyl or C 2-6 alkenyl is optionally substituted with C 1-6 haloalkyl, halo, OH, C 1-4 alkoxy, —NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , —CN, —N 3 , —O(C═O)C 1-4 alkyl, C 3-6 cycloalkyl, —NH 2 , —NHC(═O)C 1-4 alkyl, —C(═O)C 1-4 alkyl, OR c , SR c , CN, —NO 2 , NR c R d , C(═O)OC 1-4 alkyl, S(O)C 1-4 alkyl and S(O) 2 C 1-4 alkyl.
2. The compound of claim 1 , having formula If:
3. The compound of claim 2 , having formula Ib-3:
4. The compound of claim 1 , wherein R 2 is —OH or C 1-6 alkoxy.
5. The compound of claim 2 , wherein R 2 is —OH or C 1-6 alkoxy.
6. The compound of claim 3 , wherein R 2 is —OH or C 1-6 alkoxy.
7. The compound of claim 1 , wherein R h is selected from the group consisting of —CF 3 , CF 3 O, halo, OH, C 1-4 alkoxy, —NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , —CN, —N 3 , —O(C═O)C 1-4 alkyl, C 3-6 cycloalkyl, —NH 2 , —NHC(═O)C 1-4 alkyl, —C(═O)C 1-4 alkyl, —O(C 1-6 alkyl), —SH, —S(C 1-6 alkyl), —CN, —NO 2 , —N(C 1-6 alkyl) 2 , C(═O)OC 1-4 alkyl, S(O)C 1-4 alkyl and S(O) 2 C 1-4 alkyl.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
9. A method of activating executioner procaspase 3, 6 and/or 7, said method comprising: contacting a compound of claim 1 with executioner procaspase 3, 6 and/or 7 receptor under conditions sufficient to activate executioner procaspase 3, 6 and 7.
10. The compound of claim 1 , wherein R 4 is —H and R 3 is imidazopyridinyloptionally substituted with from 1-3 R k members independently selected from the group consisting of aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members.
11. The compound of claim 1 , wherein R 4 is —H and R 3 is pyridyl, isoxazolyl, pyrimidinyl, benzodioxanyl, or pyrazolyl; each independently optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, and S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members.
12. The compound of claim 1 , wherein R 4 is —H and R 3 is aryl optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, and S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5-or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members.
13. The compound of claim 1 , wherein R 4 is —H and R 3 is phenyl optionally substituted with from 1-3 R k members independently selected from the group consisting of C 1-4 alkyl, aryl-C 1-4 alkyl, halo, haloalkyl, —OR c , —SR c , —CN, —NO 2 , NR c R d , oxo, C 1-4 alkyl(C═O)NH—, haloalkoxy, —C(═O)C 1-4 alkyl, OC(═O)C 1-4 alkyl, —C(═O)OR c , S(O)C 1-4 alkyl, and S(O) 2 heterocycloalkyl and S(O) 2 C 1-4 alkyl, or optionally two adjacent R k substituents together with the atoms to which they are attached form an optionally substituted fused 5- or 6-membered heteroaryl or heterocycloalkyl ring having from 1-2 heteroatoms selected from O or N as ring members.
14. The compound of claim 1 , wherein R 4 is —H and R 3 is selected from the group consisting of
15. The compound of claim 1 , wherein R 3 is —H and R 4 is