IAP inhibitors
Smac mimetics that inhibit IAPs.
1. A compound of Formula I:
wherein
Z 1 and Z 2 are each independently CH or N;
R 1 is H or optionally substituted hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R 2 and R 2 ′ are each independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl, or when R 2 ′ is H then R 2 and R 1 can together form an aziridine or azetidine ring;
R 3 and R 4 are each independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or, R 3 and R 4 are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
R 5 and R 6 are each independently H or optionally substituted hydroxy, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 5 and R 6 are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
M is a bond, optionally substituted alkylene group of 1 to 5 carbon atoms, optionally substituted with a lower alkyl; or M and G together form a bond;
G is a bond, a heteroatom, —S(O) n —, —NR 8 —, —NCOR 8 —, or —NS(O) n R 8 —, where R 8 is selected from the group consisting of lower alkyl, optionally-substituted lower alkyl and C 3-8 cycloalkyl; or M and G together form a bond;
R 7 is a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl, each substituted with -L1-R 10 and each cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is optionally further substituted;
L1 is a covalent bond or C 1-6 alkylene, alkenylene, or alkynylene;
R 10 is an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or R 10 is heteroaryl with at least one N atom in the ring;
each n can be the same or different and is 0, 1, or 2;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein when Z 1 is N and Z 2 is CH, then at least one of the following is true:
(i) R 5 and R 6 together are not both carbon atoms linked by a single covalent bond;
(ii) R 5 and R 6 are both carbon atoms linked by a single covalent bond and R 5 is disubstituted;
(iii) R 5 and R 6 are both carbon atoms linked by a single covalent bond and R 6 is mono- or disubstituted;
(iv) R 5 and R 6 are both carbon atoms linked by a single covalent bond and R 3 and R 4 are both carbon atoms linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
M is optionally-substituted C 1 -C 5 alkylene, optionally substituted with a lower alkyl;
G is a bond;
R 7 is aryl or heteroaryl, each substituted with -L1-R10 and each aryl or heteroaryl is optionally further substituted;
L 1 is a covalent bond or C 1 -C 4 alkylene, alkenylene, or alkynylene;
R 10 is a tetrahydrofuranyl or tetrahydropyranyl moiety each of which is optionally substituted with hydroxy, lower alkyl, lower alkoxy, or optionally-substituted lower alkoxy selected from the group consisting of arylalkyloxy, alkylcarbonyloxy, arylcarbonyloxy, and acetyloxy; or, R 10 is an optionally-substituted nitrogen-containing 5- to 7-membered heteroaryl or heterocycloalkyl group and (i) R3 and R4 are covalently linked, (ii) R5 and R6 are covalently linked or (iii) both R3 and R4 are covalently linked, and R5 and R6 are covalently linked.
4. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein
M is C 1 -C 3 alkylene, but not alkenylene or alkynylene, optionally-substituted with lower alkyl;
L 1 is a single covalent bond;
R 10 is tetrahydrofuranyl or tetrahydropyranyl substituted with at least one hydroxy or acetyloxy group.
5. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein
M is C 1 -C 3 alkylene, but not alkenylene or alkynylene, optionally-substituted with lower alkyl;
L 1 is a single covalent bond;
R 10 is a 5- to 7-membered heteroaryl or heterocycloalkyl group having a single nitrogen atom in the ring and no additional heteroatoms.
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 1 is H, methyl, allyl, propargyl, ethyl, cycloalkyl, hydroxyethyl or cyclo alkylmethyl.
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 2 and R 2 ′ are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, hydroxyethyl, fluoroethyl, and cycloalkyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are independently H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally-substituted with hydroxyl, mercapto, sulfonyl, alkylsulfonyl, halogen, pseudohalogen, amino, carboxyl, alkyl, haloalky, pseudohaloalkyl, alkoxy, or alkylthio, or R 3 and R 4 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R 5 and R 6 are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 5 and R 6 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 is H, methyl, allyl, propargyl, ethyl, cycloalkyl, hydroxyethyl or cycloalkylmethyl;
R 2 and R 2 ′ are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, hydroxyethyl, fluoroethyl, and cycloalkyl;
R 3 and R 4 are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 3 and R 4 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O;
R 5 and R 6 are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 5 and R 6 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O;
M is C 1 -C 3 alkylene optionally-substituted with lower alkyl.
11. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
R 1 is H, methyl, allyl, propargyl, ethyl, cycloalkyl, hydroxyethyl or cycloalkylmethyl;
R 2 and R 2 ′ are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, hydroxyethyl, fluoroethyl, and cycloalkyl;
R 3 and R 4 are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O;
R 5 and R 6 are independently H or optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 5 and R 6 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
M is C 1 -C 3 alkylene optionally-substituted with lower alkyl.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein
R 7 is IIa or IIb:
L 1 is a single covalent bond
X is —N—, —C═C(R 16 )—, —N═C— or —C(O)N—;
Y is —C—, —N—, or —N + —; such that,
When Y is —C— then R 9 , R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when X is —N— or —C(O)—N—, -L 1 -R 10 is bound to the —N— atom; and, when X is —C═C(R 16 )— or —N═C—, -L 1 -R 10 is bound to the —C═ atom; and
When Y is —N— or —N + —, then R 11 is absent or —O − , and R 9 , R 12 , R 13 , R 14 , R 15 , and R 16 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime; provided that when X is —N— or —C(O)—N—, -L 1 -R 10 is bound to the —N— atom; and, when X is —C═C(R 16 )— or —N═C—, -L 1 -R 10 is bound to the —C═ atom.
13. The compound of claim 1 or a pharmaceutically acceptable salt thereof having the formula (III):
wherein
Y is —C—, —N—, or —N + —; such that,
A is a single or double bond;
When A is a single bond and Y is —C— then R 9 a, R 9 b, R 11 , R 12 , R 13 , R 14 , and R 17 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime;
When A is a single bond and Y is —N— or —N + —, then R 11 is absent or —O − , and R 9 a, R 9 b, R 12 , R 13 , R 14 , and R 17 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime;
When A is a double bond and Y is —C— then R 9 b and R 17 are absent; and R 9 a, R 11 , R 12 , R 13 , and R 14 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime;
When A is a double bond and Y is —N— or —N + —, then R 9 b and R 17 are absent; and R 11 is absent or —O − , and R 9 a, R 12 , R 13 , and R 14 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, or carboxylate, sulfonate, sulfone, imine, or oxime.
14. The compound of claim 12 or a pharmaceutically acceptable salt thereof wherein
R 7 is IIa or IIb;
X is —N—;
Y is —C—, —N—, or —N + —; such that
When Y is —C—, then R 9 , R 11 , R 12 , R 13 , R 14 and R 15 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy or heteroaryloxy;
When Y is —N—, then R 11 is absent, and R 9 , R 12 , R 13 , R 14 and R 15 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy or heteroaryloxy;
When Y is —N + —, then R 11 is —O − , and R 9 , R 12 , R 13 , R 14 and R 15 are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxyl, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy or heteroaryloxy;
R 3 is methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally-substituted with hydroxyl, mercapto, halogen, pseudohalogen, amino, carboxyl, alkyl, haloalkyl, pseudohaloalkyl, alkoxy, or alkylthio;
R 2 is —H, methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, and cycloalkyl;
R 2 ′ is H;
R 1 is selected from H, methyl, allyl, propargyl, ethyl, cycloalkyl, or cycloalkylmethyl;
Z 1 is nitrogen;
Z 2 is —CH—;
R 4 is —H and R 5 and R 6 are both carbon atoms and together form C 2 -C 4 alkylene; or, R 3 and R 4 are both carbon atoms and together form C 2 -C 4 alkylene; or, both R 5 and R 6 together and R 3 and R 4 together both form C 2 -C 4 alkylene groups;
L 1 is a covalent bond.
15. The compound of claim 14 or a pharmaceutically acceptable salt thereof wherein
R 9 , R 11 , R 12 , R 13 , R 14 and R 15 are, independently, —H, -halogen, or optionally-substituted lower alkyl;
R 3 is optionally-substituted lower alkyl, C 3 -C 8 cycloalkyl, or heterocycloalkyl wherein the optional substituents are hydroxy, lower alkoxy, or lower alkyl;
R 2 is optionally-substituted lower alkyl, C 3 -C 8 cycloalkyl, or heterocycloalkyl wherein the optional substituents are hydroxy, lower alkoxy, or lower alkyl;
R 2 ′ is H;
R 1 is —H or lower alkyl;
R 5 and R 6 are both carbon atoms and are linked by a covalent bond;
R 4 is —H;
Z 2 is —CH—;
R 10 is tetrahydropyran, tetrahydrofuran, D- or L-fucose, D- or L-xylose, D- or L-galactose, or D- or L-glucose, pyrrolidine, piperidine, perhydroazapine, pyridine, pyrimidine, or pyrazine.
16. The compound of claim 1 selected from the group consisting of Compounds A through U and Compounds HH through SS, as follows, or a pharmaceutically acceptable salt thereof:
Com-
pound
R1
R2
R3
R18
R9
R13
R12
R11
R10
A
Me
Me
tBu
H
4-F-
H
F
H
D-xylose
phenyl
B
Me
Me
iPr
H
4-F-
H
F
H
D-xylose
phenyl
C
Me
Me
tBu
H
4-F-
H
F
Me
L-fucose
phenyl
D
Me
Me
iPr
H
H
H
H
Me
L-fucose
E
Me
Me
iPr
H
H
H
H
H
D-xylose
F
Me
Me
tBu
H
H
H
F
H
L-fucose
G
Me
Me
cHex
H
H
H
F
H
L-fucose
H
Me
Me
iPr
H
H
H
F
H
L-fucose
I
Me
Me
iPr
H
H
H
F
H
D-xylose
J
Me
Me
iPr
H
H
H
F
H
D-
glucose
K
Me
Me
iPr
H
H
H
F
H
D-
galactose
L
Me
Me
iPr
H
H
H
F
H
D-
galactose
tetra
acetate
M
Me
Me
cHex
H
H
H
F
H
D-xylose
N
Me
Me
tBu
H
H
H
F
H
D-xylose
O
Me
Me
R-(Me)
H
4-F-
H
F
H
L-fucose
CHOMe
phenyl
P
Me
Me
R-(Me)
S-
4-F-
Me
H
H
L-fucose
CHOMe
OH
phenyl
Q
Me
Me
tert-
S-
4-F-
Me
H
H
L-fucose
Butyl
OH
phenyl
R
Me
Me
R-(Me)
H
4-F-
Me
H
H
L-fucose
CHOMe
phenyl
S
Me
Me
tert-
H
4-F-
Me
H
H
L-fucose
Butyl
phenyl
T
Me
Me
tert-
S-
4-F-
H
F
H
L-fucose
Butyl
OH
phenyl
U
Me
Me
R-(Me)
S-
4-F-
H
F
H
L-fucose
CHOMe
OH
phenyl
Compound
R1
R2
R3
R18
HH
Me
Me
tBu
H
II
Me
Me
R-(Me)CHOMe
H
JJ
Me
Et
R-(Me)CHOMe
H
KK
Me
cyclo-propyl
R-(Me)CHOMe
H
LL
Me
Me
tBu
S-OH
MM
Et
Me
tBu
S-OH
NN
Me
CH 2 OH
tBu
S-OH
OO
Me
cyclo-propyl
tBu
S-OH
PP
Me
Me
R-(Me)CHOMe
S-OH
Et
Me
R-(Me)CHOMe
S-OH
RR
Me
Et
R-(Me)CHOMe
S-OH
SS
Me
cyclo-propyl
R-(Me)CHOMe
S-OH.
17. A compound having Formula IV, or a pharmaceutically acceptable salt thereof:
wherein
Z 1 a, Z 2 a, Z 1 b, and Z 2 b are independently CH or N;
R 1 a and R 1 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; and when R 2 a′ is H then R 2 a and R 1 a can together form an aziridine or azetidine ring and when R 2 b′ is H then R 2 b and R 1 b can together form an aziridine or azetidine ring;
R 2 a, and R 2 b are independently H or optionally substituted alkyl, cycloalkyl, or heterocycloalkyl; or when R 2 a′ is H then R 2 a and R 1 a can together form an aziridine or azetidine ring and when R 2 b′ is H then R 2 b and R 1 b can together form an aziridine or azetidine ring;
R 3 a, R 3 b, R 4 a and R 4 b are independently H or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or, R 4 a and R 3 a, or R 4 b and R 3 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
R 5 a, R 6 a, R 5 b, and R 6 b are independently H or optionally substituted hydroxyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or R 5 a and R 6 a or R 5 b and R 6 b, or both, are carbon atoms linked by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
n can be the same or different in each usage and is 0, 1, or 2;
Xa is —O—, —N(La—R 10 a)—, —S—, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—O—, —C(O)—N(La—R 10 a)—, —N═C(La—R 10 a)-;
Xb is —O—, —N(Lb-R 10 b)—, —S—, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—O—, —C(O)—N(Lb-R 10 b)—, —N═C(Lb-R 10 b)-, provided that if Xb is —O—, —S—, or —C(O)—O—, then Xa is —N(La—R 10 a)—, optionally-substituted —C(La—R 10 a)=CH—, —C(O)—N(La—R 10 a)—, or —N═C(La—R 10 a)-, and if Xa is —O—, —S—, or —C(O)—O—, then Xb is —N(Lb-R 10 b)—, optionally-substituted —C(Lb-R 10 b)=CH—, —C(O)—N(Lb-R 10 b)—, or —N═C(Lb-R 10 b)-;
La and Lb are independently a covalent bond or C 1 -C 4 alkylene, alkenylene, or alkynylene;
R 10 a and R 10 b are independently an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or heteroaryl with at least one N atom in the ring provided that one but not both of R 10 a and R 10 b can be —H or absent;
Wa and Wb are together a Linker and
Ya and Yb are independently —C—, —N—, or —N+-; such that,
(a) when Ya or Yb is —C— then R 11 a, R 11 b, R 12 a, R 12 b, R 13 a, R 13 b, R 14 a and R 14 b respectively are independently —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime;
(b) when Ya or Yb is —N— then R 11 a, and R 11 b respectively are absent, and R 12 a, R 12 b, R 13 a, R 13 b, R 14 a and R 14 b respectively are independently —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime and
(c) when Ya or Yb is —N+-, then R 11 a and R 11 b respectively are —O − and R 12 a, R 12 b, R 13 a, R 13 b, R 14 a, and R 14 b are, independently, —H, halogen, or optionally substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, polyalkylether, amino, alkylamino, dialkylamino, alkoxyalkyl, sulfonate, aryloxy, heteroaryloxy, acyl, acetyl, carboxylate, sulfonate, sulfone, imine, or oxime.
18. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein when Z 1 a is N and Z 2 a is CH, and Z 1 b is N and Z 2 b is CH, then at least one of the following is true:
(i) R 5 a and R 6 a are not both carbon atoms linked by a single covalent bond;
(ii) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 6 a is disubstituted;
(iii) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 6 a is mono- or disubstituted;
(iv) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R 3 a and R 4 a are both carbon atoms linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O;
(v) R 5 a and R 6 a are both carbon atoms linked by a single covalent bond and R2a is not H.
19. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein R 3 a, R 4 a, R 3 b, and R 4 b are independently selected from H, methyl, ethyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, optionally-substituted with hydroxyl, mercapto, sulfonyl, alkylsulfonyl, halogen, pseudohalogen, amino, carboxyl, alkyl, haloalky, pseudohaloalkyl, alkoxy, or alkylthio.
20. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein R 2 a and R 2 b are independently selected from —H, methyl, fluoromethyl, difluoromethyl, ethyl, fluoroethyl, hydroxyethyl, and cycloalkyl.
21. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein R 1 a and R 1 b are independently selected from H, methyl, allyl, propargyl, ethyl, hydroxyethyl, cycloalkyl, or cycloalkylmethyl.
22. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein R 3 a, R 4 a, R 3 b, and R 4 b are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy.
23. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein R 5 a and R 6 a, and R 5 b and R 6 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
24. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein Z 1 a and Z 1 b are both N and Z 2 a and Z 2 b are both C and wherein R 3 a and R 4 a, and R 3 b and R 4 b, are each carbon and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 8 carbon atoms where one to three carbon atoms can be replaced by N, O, S(O) n , or C═O.
25. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein Wa and Wb together are a covalent bond or optionally substituted alkylene, cycloalkyl, or aryl, of 2 to 20 carbon atoms where one or more carbon atoms can be replaced with N, O, or S(O) n ; and Xa and Xb are independently —O—, —S—, or —C(O)—O—.
26. The compound of claim 17 or a pharmaceutically acceptable salt thereof wherein one of R 10 a and R 10 b is —H or is absent.
27. A compound selected from the group consisting of Compounds V through Z and AA through GG, as follows, or a pharmaceutically acceptable salt thereof:
Compound
R1
R2
R3
R18
R13
R12
R10
V
Me
Me
iPr
H
H
F
L-fucose
W
H
H
iPr
H
H
F
L-fucose
X
H
H
iPr
H
H
F
D-xylose
Y
Me
Me
iPr
H
H
F
D-xylose
Z
Me
Me
R-(Me)CHOMe
H
F
H
D-galactose
AA
Me
Me
iPr
H
F
H
D-galactose
BB
Me
Me
R-(Me)CHOMe
H
F
H
D-glucose
CC
Me
Me
iPr
H
F
H
D-glucose
DD
Me
Me
iPr
H
F
H
L-fucose
EE
Me
Me
R-(Me)CHOMe
H
H
F
L-fucose
FF
Me
Me
R-(Me)CHOMe
S-OH
H
F
L-fucose
GG
Me
Me
R-(Me)CHOMe
S-OH
H
F
L-fucose.
28. The compound of claim 1 or a pharmaceutically acceptable salt thereof having the formula
wherein R 1 , R 2 , and R 3 are independently lower alkyl, lower alkoxy, lower alkanol, or C 3 -C 6 cycloalkyl; R 18 is H or OH; R 9 is H or phenyl optionally substituted with halogen; R 11 , R 12 , and R 13 are independently H or halogen and R 10 is an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or R 10 is heteroaryl with at least one N atom in the ring.
29. The compound of claim 17 or a pharmaceutically acceptable salt thereof having the formula
wherein R 1 , R 2 , and R 3 are independently lower alkyl, lower alkoxy, lower alkanol, or C 3 -C 6 cycloalkyl; R 18 is H or OH; R 11 , R 12 , and R 13 are independently H or halogen and R 10 is an optionally substituted 5-, 6-, or 7-membered heterocycloalkyl with at least one N or O atom in the ring or R 10 is heteroaryl with at least one N atom in the ring.
30. A method for inducing apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to induce apoptosis in the cell.
31. The method of claim 30 , wherein said cell is neoplastic.
32. The method of claim 30 , wherein said cell overexpresses an inhibitor of caspase.
33. The method of claim 32 , wherein the inhibitor inhibits activation or activity of one or more of a caspase selected from caspase-3, caspase-7 and caspase-9.
34. A method of stimulating apoptosis in a cell comprising contacting the cell with a compound of claim 1 in an amount sufficient to stimulate apoptosis in the cell.
35. The method of claim 34 , wherein said cell is a cancer cell.
36. A method of enhancing apoptosis of pathogenic cells in vivo in an individual comprising administering to the individual a therapeutically effective amount of a compound of claim 1 .
37. The method of claim 36 further comprising administering a second therapy selected from radiation, chemotherapy, immunotherapy, photodynamic therapy and combinations thereof.
38. A pharmaceutical composition comprising: a compound selected from a compound of claim 1 and a pharmaceutically acceptable excipient.
39. The composition of claim 38 further comprising a second chemotherapeutic agent.
40. The composition of claim 39 , wherein said second chemotherapeutic agent is selected from altretamine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphomide, dacarbazine, hexamethylmelamine, ifosfamide, lomustine, melphalan, mechlorethamine, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, uramustine, docetaxel, etoposide, irinotecan, paclitaxel, tenisopide, topotecan, vincristine, vinblastine, vindesine, vinorelbine, bleomycin, dactinomycin, daunorubicin, epirubicin, hydroxyurea, idarubicin, mitomycin, mitoxantrone, plicamycin, azathioprine, capecitabine, cladribine, cytarabine, fludarabine, fluorouracil, floxuridine, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemeterxed, pentostatin, thioguanine, camptothecan, irinotecan, topotecan, BNP 1350, SN 38,9-amino-camptothecan, lurtotecan, gimatecan, diflomotecan, an anthracycline, anthraquinone, podophyllotoxin, doxorubicin, epirubicin, idarubicin, nemorubicin, mitoxantrone, loxoxantrone, etoposide, teniposide and combinations thereof.
41. The composition of claim 39 , wherein said second chemotherapeutic agent is selected from alkylating agents, plant alkaloids, antitumor antibiotics, antimetabolites, topoisomerase inhibitors and combinations thereof.
42. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein
R 1 is H, methyl, allyl, propargyl, ethyl, cycloalkyl, hydroxyethyl or cycloalkylmethyl;
R 2 and R 2 ′ are independently H, methyl, fluoromethyl, difluoromethyl, ethyl, hydroxyethyl, fluoroethyl, and cycloalkyl;
R 3 and R 4 are independently optionally substituted lower alkyl or C 3 -C 8 cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 3 and R 4 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O;
R 5 and R 6 are independently optionally substituted lower alkyl or C 3 -C s cycloalkyl wherein the optional substituents are hydroxy or lower alkoxy, or R 5 and R 6 are carbon atoms and are linked by a covalent bond or by an optionally-substituted alkylene or alkenylene group of 1 to 3 carbon atoms of which 1 or more atoms can be replaced by N, O, S(O) n , or C═O;
M is C 1 -C 3 alkylene optionally-substituted with lower alkyl.