Compounds and methods for inhibiting the interaction of BCL proteins with binding partners
The invention relates to isoxazolidine containing compounds that bind to bcl proteins and inhibit Bcl function. The compounds may be used for treating and modulating disorders associated with hyperproliferation, such as cancer.
1. A compound of formula 1:
or a pharmaceutically acceptable salt thereof;
wherein independently for each occurrence
m is 0, 1, 2, or 3;
n, o, and p are independently for each occurrence 1, 2, 3, 4, or 5;
R 1 is —OH, —OC(O)R 6 , —OC(O)N(R 6 )(R 7 ), or —N(R 6 )(R 7 );
R 2 is —OH, —OC(O)Me, —OCH 2 CO 2 H, —OCH 2 CO 2 Et, —N 3 , —N(R 8 )(R 9 ), —N(R)C(O)N(R 8 )(R 9 ), or —N(R)C(O)R 10 ; or has the formula 1b;
R 3 is alkyl, halide, alkoxy, (cycloalkyl)alkoxy, aralkyloxy, or —O(CH 2 ) 2 —N(R 15 )(R 16 );
R 4 is alkyl, alkoxy, hydroxyalkyl, alkoxyalkyl, halide, nitro, amino, acyl, amido, acylamino, aminoalkyl, acylaminoalkyl, acylaminoalkylamino, sulfonylaminoalkylamino, carboxylate, or —N═C(N(R) 2 ) 2 ;
R 5 is —OH or —N(R 17 )(R 18 );
R 6 and R 7 are independently for each occurrence H, alkyl, aralkyl, heteroaralkyl, or —[C(R 15 )(R 16 )] n —R 19 ;
R 8 and R 9 are independently for each occurrence H, alkyl, aralkyl, or heteroaralkyl;
R 10 is alkyl, haloalkyl, or —[C(R 15 )(R 16 )] o —COOR;
R, R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently for each occurrence H or alkyl;
R 17 and R 18 are independently for each occurrence H, alkyl, aralkyl, heteroaralkyl, alkoxy, or —[C(R 19 )(R 20 )] p —R 21 ;
R 19 and R 20 are independently for each occurrence H, hydroxy, alkyl, alkoxy, amino, aminoalkyl, acylamino, sulfonylamino, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroaralkyl;
R 21 is independently for each occurrence H, alkyl, aryl, heteroaryl, heterocyclyl, heterocyclylalkyl, alkoxy, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, amino, amido, or carboxyl;
R 22 independently for each occurrence is halide or alkyl;
R 23 is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, and haloalkyl;
R 24 is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, and haloalkyl; and
R 25 is selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, acyloxyalkyl, and haloalkyl.
2. The compound of claim 1 , wherein R 1 is selected from the group consisting of —OH, —OC(O)Me, —OC(O)(CH 2 ) 2 Ph, —OC(O)CH 2 CHMe 2 , —OC(O)NHMe, —OC(O)NMe 2 , —OC(O)NHCH 2 (4-(OH)-Ph), —OC(O)NHPh, —OC(O)NHCH 2 Ph, —OC(O)NH(CH 2 ) 4 Ph, —OC(O)NH(CH 2 ) 2 Ph, —OC(O)NH(CH 2 ) 2 Me, —OC(O)NH(CH 2 ) 2 NMe 2 , —OC(O)NH(CH 2 ) 2 NHC(O)Me, —OC(O)NH(CH 2 ) 2 CHMe 2 , —NHMe, —NH(CH 2 ) 2 Ph, —NHC(O)Me, and —NH(CH 2 ) 2 NMe 2 .
3. The compound of claim 1 , wherein R 1 is —OH.
4. The compound of claim 1 , wherein R 2 is —OH, —OC(O)Me, —OCH 2 CO 2 H, —OCH 2 CO 2 Et, —N 3 , —N═C(NMe 2 ) 2 , —NH 2 , —NMe 2 , —NHC(O)Me, —NHC(O)CF 3 , —NHC(O)Ph, —NHC(O)NHPh, —NHC(O)CH 2 CH 2 CO 2 H, —NHC(O)CH 2 CH 2 CO 2 Me, —NHCH 2 Ph, —NHCH 2 (4-pyridyl), —NHCH 2 (2-pyridyl), —NHCH 2 (4-(CO 2 H)Ph), —NHCH 2 (3-(CO 2 H)Ph), —NHEt, —NHCHMe 2 , —NHCH 2 CHMe 2 , —N(CH 2 CHMe 2 ) 2 , —NHCH 2 (cyclopropyl), or —NHC(O)CH 2 CH 2 NMe 2 .
5. The compound of claim 1 , wherein R 2 is —OH or —NH 2 .
6. The compound of claim 1 , wherein R 2 is —NH 2 .
7. The compound of claim 1 , wherein R 2 is —OH.
8. The compound of claim 1 , wherein R 3 is —OMe, —OEt, —OCH 2 (cyclopropyl), F, —O(CH 2 ) 2 NMe 2 , —O(CH 2 ) 2 (4-morpholino), —OCH 2 (4-(MeO)Ph), or —OCH 2 (2-pyridyl).
9. The compound of claim 1 , wherein R 3 is —OMe.
10. The compound of claim 1 , wherein R 4 is —NMe 2 , —NEt 2 , —NHEt, —NHCH 2 CHMe 2 , —N(Me)CH 2 CHMe 2 , —N(Me)CH 2 CH 2 NHC(O)Me, —N(Me)CH 2 CH 2 NHS(O) 2 Me, —N(Me)CH 2 CH 2 NHS(O) 2 CF 3 , —NHCH 2 CH 2 NMe 2 , —NHCH 2 CH 2 NMeCH 2 CH 2 Cl, —NHCH 2 CH 2 OH, —N(Me)CH 2 CH 2 OH, —N(CH 2 CH 2 OH) 2 , —N(Me)CH 2 CO 2 H, —N(Me)CH 2 C(O)NH 2 , —N(Me)CH 2 C(O)NHMe, —N(Me)CH 2 C(O)NMe 2 , —NHC(O)Me, —NHC(O)CHMe 2 , 1-pyrrolidinyl, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, (S)-2-(hydroxymethyl)-1-pyrrolidinyl, (R)-2-(C(O)NMe 2 )-1-pyrrolidinyl, (S)-2-(C(O)NMe 2 )-1-pyrrolidinyl, —NH 2 , —NO 2 , Br, Cl, F, —C(O)Me, —C(O)NMe 2 , —C(O)NH 2 , —CO 2 H, —CHO, —CH 2 OH, —CH(Me)OH, —CH 2 NH 2 , —CH 2 NHMe, —CH 2 NMe 2 , —CH 2 NHC(O)Me, —CF 3 , or tert-butyl.
11. The compound of claim 1 , wherein R 4 is amino.
12. The compound of claim 1 , wherein R 4 is —NMe 2 , —N(Me)CH 2 CH 2 OH, —N(Me)CH 2 C(O)NMe 2 , —N(Me)CH 2 C(O)NHMe, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, or (R)-2-(C(O)NMe 2 )-1-pyrrolidinyl.
13. The compound of claim 1 , wherein R 4 is —NMe 2 .
14. The compound of claim 1 , wherein R 22 is selected from the group consisting of F, Cl, and tert-butyl; and m is 0 or 1.
15. The compound of claim 1 , wherein R 22 is F; and m is 0 or 1.
16. The compound of claim 1 , wherein R 22 is selected from the group consisting of F, Cl, and tert-butyl; and m is 1.
17. The compound of claim 1 , wherein R 22 is F; and m is 1.
18. The compound of claim 1 , wherein R 23 is selected from the group consisting of methyl, hydroxymethyl, alkoxymethyl, acyloxymethyl, and halomethyl.
19. The compound of claim 1 , wherein R 24 is selected from the group consisting of methyl, hydroxymethyl, alkoxymethyl, acyloxymethyl, and halomethyl.
20. The compound of claim 1 , wherein R 23 is methyl.
21. The compound of claim 1 , wherein R 24 is methyl.
22. The compound of claim 1 , wherein R 23 is methyl; and R 24 is methyl.
23. The compound of claim 1 , wherein R 25 is selected from the group consisting of methyl, hydroxymethyl, alkoxymethyl, acyloxymethyl, and halomethyl.
24. The compound of claim 1 , wherein R 25 is methyl.
25. The compound of claim 1 , wherein R 23 is methyl; R 24 is methyl; and R 25 is methyl.
26. The compound of claim 1 , wherein R 1 is —OH; and R 2 is —OH or —NH 2 .
27. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; and R 3 is —OMe.
28. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; and R 4 is amino.
29. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; and R 4 is —NMe 2 , —N(Me)CH 2 CH 2 OH, —N(Me)CH 2 C(O)NMe 2 , —N(Me)CH 2 C(O)NHMe, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, or (R)-2-(C(O)NMe 2 )-1-pyrrolidinyl.
30. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; and R 4 is —NMe 2 .
31. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 23 is methyl; R 24 is methyl; and R 25 is methyl.
32. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; R 23 is methyl; R 24 is methyl; and R 25 is methyl.
33. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; R 4 is amino; R 23 is methyl; R 24 is methyl; and R 25 is methyl.
34. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; R 4 is —NMe 2 , —N(Me)CH 2 CH 2 OH, —N(Me)CH 2 C(O)NMe 2 , —N(Me)CH 2 C(O)NHMe, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, or (R)-2-(C(O)NMe 2 )-1-pyrrolidinyl; R 23 is methyl; R 24 is methyl; and R 25 is methyl.
35. The compound of claim 1 , wherein R 1 is —OH; R 2 is —OH or —NH 2 ; R 3 is —OMe; R 4 is —NMe 2 ; R 23 is methyl; R 24 is methyl; and R 25 is methyl.
36. A compound selected from the group consisting of:
37. A compound selected from the group consisting of: