Compounds having BET, estrogen receptor, and androgen receptor degradation activity and uses thereof
Compounds, pharmaceutical compositions containing such compounds, and their use in prevention and treatment of cancer and other related diseases and conditions are disclosed. In an embodiment, the disclosed compounds have the following Formula (I) and pharmaceutically acceptable salts thereof:
1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof:
wherein:
X 1 , X 2 , X 3 , X 4 , and X 5 are independently selected from C-Q, CH, and N;
R 1 , R 1′ and R 2 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 4 , wherein R 1 and R 1′ can be connected to form a 3 to 6 member heterocyclic or heteroaryl ring, and R 1 and R 2 can be connected to form a 5 to 7 member heterocyclic or heteroaryl ring;
Q is
p is 1;
L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from C(O), O, NR 3 , S, SO, SO 2 , C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ;
T is a targeting ligand;
R 3 is independently selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, and acyl, where acyl can contain C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, aryl and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ; and
each R 4 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxyl.
2. The compound according to claim 1 , wherein the compound is a compound of Formula (Ia):
wherein:
X 1 , X 2 , X 4 , and X 5 are independently selected from CH and N;
R 1 , R 1′ and R 2 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 4 , wherein R 1 and R 1′ can be connected to form a 3 to 6 member heterocyclic or heteroaryl ring, and R 1 and R 2 can be connected to form 5 to 7 member heterocyclic or heteroaryl ring;
Q is
L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from C(O), O, NR 3 , S, SO, SO 2 , C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ;
T is a targeting ligand;
R 3 is independently selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, and acyl, where acyl can contain C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, aryl and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ; and
each R 4 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxyl.
3. The compound according to claim 1 , wherein the compound is a compound of Formula (Ib):
wherein:
X 1 , X 3 , X 4 , and X 5 are independently selected from CH and N;
R 1 , R 1′ and R 2 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 4 , wherein R 1 and R 1′ can be connected to form a 3 to 6 member heterocyclic or heteroaryl ring, and R 1 and R 2 can be connected to form 5 to 7 member heterocyclic or heteroaryl ring;
Q is
L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from C(O), O, NR 3 , S, SO, SO 2 , C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ;
T is a targeting ligand;
R 3 is independently selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, and acyl, where acyl can contain C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, aryl and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ; and
each R 4 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxyl.
4. The compound according to claim 1 , wherein the compound is a compound of Formula (Ic):
wherein:
X 2 , X 3 , X 4 , and X 5 are independently selected from CH and N;
R 1 , R 1′ and R 2 are independently selected from H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 4 , wherein R 1 and R 1′ can be connected to form a 3 to 6 member heterocyclic or heteroaryl ring, and R 1 and R 2 can be connected to form 5 to 7 member heterocyclic or heteroaryl ring;
Q is
L is a linker of 1 to 22 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from C(O), O, NR 3 , S, SO, SO 2 , C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ;
T is a targeting ligand;
R 3 is independently selected from H, C 1 -C 6 alkyl, aryl, heteroaryl, and acyl, where acyl can contain C 1 -C 6 alkyl, C 1 -C 6 cycloalkyl, aryl and heteroaryl, each of which can be substituted with 0, 1, 2, or 3 R 4 ; and
each R 4 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxyl.
5. The compound according to claim 1 , wherein R 1 , R 1′ and R 2 are each independently selected from H, C, alkyl, C 3 cycloalkyl, halo, and hydroxy, each of which may be substituted with 0, 1, 2, or 3 R 4 .
6. The compound according to claim 1 , wherein X 1 is N and X 2 , X 3 , X 4 , and X 5 are C-Q or CH.
7. The compound according to claim 1 , wherein X 4 is N, and X 2 , X 3 , and X 5 are CH.
8. The compound according to claim 1 , wherein L is a linker of 1 to 16 carbon atoms in length, wherein one or more carbon atoms are each optionally and independently replaced by a group selected from C(O), O, NR 3 , S, SO, SO 2 , C 2 -alkenyl, C 2 -alkynyl, cycloalkyl, aryl, heterocycle, and heteroaryl, each of which is independently substituted with 0, 1, 2, or 3 R 4 .
9. The compound according to claim 1 , wherein L is a linker with one or more carbon atoms, wherein the one or more carbon atoms is each independently replaced by a group selected from C(O), O, NR 3 , C 2 -alkynyl, and heterocycle, each of which is independently substituted with 0, 1, 2, or 3 R 4 .
10. The compound according to claim 1 , wherein R 3 is independently selected from H and C 1 -C 6 alkyl.
11. The compound according to claim 1 , wherein L is selected from
12. The compound according to claim 1 , wherein L is
wherein n is 2 to 8.
13. The compound according to claim 1 , wherein the targeting ligand binds to a target protein selected from a protein containing a BET domain, an Estrogen Receptor (ER), and an Androgen Receptor (AR).
14. The compound according to claim 13 , wherein the targeting ligand is a compound of Formula (II):
wherein:
R 5 is selected from H, C 1 -C 6 alkyl, halo, hydroxy, and sulfhydryl, each of which is substituted with 0, 1, 2, or 3 R 8 ;
R 6 is selected from H, OH, C 1 -C 6 alkyl, and acyl, each of which is substituted with 0, 1, 2, or 3 R 8 ;
each R 8 is independently selected from C 1 -C 6 alkyl, halo, cyano, and hydroxy; and
wherein
is a bond to L.
15. The compound according to claim 13 , wherein the targeting ligand binds BRD2, BRD3, BRD4 or BRDT.
16. The compound according to claim 15 , wherein the targeting ligand is a compound of Formula (III):
wherein
is a bond to L.
17. The compound according to claim 13 , wherein the target protein is an androgen receptor.
18. The compound according to claim 17 , wherein the targeting ligand is a compound of Formula (IV):
wherein R 9 is selected from Cl, CH 3 , CF 3 , and OCH 3 , and
wherein
is a bond to L.
19. The compound according to claim 17 , wherein the targeting ligand is a compound of Formula (V):
wherein R 10 is selected from Cl, CH 3 , CF 3 , and OCH 3 ; and
wherein
is a bond to L.
20. The compound according to claim 17 , wherein the targeting ligand is a compound of Formula (VI):
wherein
is a bond to L.
21. The compound according to claim 17 , wherein the targeting ligand is a compound of Formula (VII):
wherein R 11 is selected from Cl, CH 3 , CF 3 , and OCH 3 ; and
wherein
is a bond to L.
22. The compound according to claim 1 , wherein the compound is selected from:
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(3-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(2-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-4-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(6-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(6-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(5-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(6-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
N-((1r,4r)-4-(3-chloro-4-cyanophenoxy)cyclohexyl)-6-(4-((4-(6-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-3-yl)piperazin-1-yl)methyl)piperidin-1-yl)pyridazine-3-carboxamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(3-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(5-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(2-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-4-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(6-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(6-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
(2S)—N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(2-(4-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)ethyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(3-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenoxy)propyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-(4-(3-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenoxy)propyl)piperazin-1-yl)phenoxy)-2-hydroxy-2-methylpropanamide;
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((4-(3-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenoxy)propyl)piperazin-1-yl)methyl)phenoxy)-2-hydroxy-2-methylpropanamide;
N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-((4-(3-(3-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenoxy)propyl)piperazin-1-yl)methyl)phenoxy)-2-hydroxy-2-methylpropanamide;
N-(4-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)benzyl)-5-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)pentanamide;
N-(4-(3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)benzyl)-5-(4-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)pentanamide;
N-(4-((S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)benzyl)-4-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)butanamide; and
N-(4-((S)-3-((4-cyano-3-(trifluoromethyl)phenyl)amino)-2-hydroxy-2-methyl-3-oxopropoxy)benzyl)-4-(4-(4-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)butanamide.
23. The compound according to claim 1 , wherein the compound is selected from:
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(2-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)ethyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(3-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)propyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(4-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)butyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(5-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)pentyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(6-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)hexyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(7-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)heptyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)octyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(9-(4-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)nonyl)acetamide;
11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(2-((2,6-dioxopiperidin-3-yl)(methyl)amino)-2-oxoethyl)phenyl)undecanamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)octyl)acetamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(7-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)piperazin-1-yl)heptyl)acetamide;
11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-((2S)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxopropan-2-yl)phenyl)undecanamide;
11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-((2R)-1-((2,6-dioxopiperidin-3-yl)amino)-1-oxopropan-2-yl)phenyl)undecanamide;
1-(3-(11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)undecanamido)phenyl)-N-(2,6-dioxopiperidin-3-yl)cyclopropane-1-carboxamide;
2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)-N-(8-(4-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)pyridin-2-yl)piperazin-1-yl)octyl)acetamide
2-(2-(4-(8-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)octyl)piperazin-1-yl)pyridin-4-yl)-N-(2,6-dioxopiperidin-3-yl)-N-methylacetamide;
11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)undecanamide;
6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)hexanamide;
6-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(3-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)hexanamide; and
11-(2-((S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamido)-N-(4-(2-((2,6-dioxopiperidin-3-yl)amino)-2-oxoethyl)phenyl)undecanamide.
24. The compound according to claim 1 , wherein the compound is selected from:
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(3-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(2-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-4-yl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(2-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-4-yl)acetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(4-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(6-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(6-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)acetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(4-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)acetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(4-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(6-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-3-yl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(5-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)pyridin-2-yl)-N-methylacetamide;
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(3-(4-((1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)methyl)piperazin-1-yl)phenyl)acetamide; and
(E)-N-(2,6-dioxopiperidin-3-yl)-2-(2-(4-(2-(1-(4-(1-(4-hydroxyphenyl)-2-phenylbut-1-en-1-yl)phenyl)piperidin-4-yl)ethyl)piperazin-1-yl)pyridin-4-yl)acetamide.
25. The compound according to claim 1 , wherein at least one of X 1 , X 2 , X 3 , X 4 , or X 5 is N, or R 1′ or R 1 is not H.
26. A pharmaceutical composition comprising the compound according to claim 1 and at least one additional component selected from pharmaceutically acceptable carriers, pharmaceutically acceptable vehicles, and pharmaceutically acceptable excipients.
27. A method of treating abnormal cellular proliferation, a tumor, cancer, an immune disorder, autoimmune disorder, arthritis, lupus, diabetes, cardiovascular disease, an infectious disease, sepsis, or an inflammatory condition in a subject in need thereof, comprising administering to said subject an effective amount of the compound according to claim 1 .
28. A method of treating abnormal cellular proliferation, a tumor, cancer, an immune disorder, autoimmune disorder, arthritis, lupus, diabetes, cardiovascular disease, an infectious disease, sepsis, or an inflammatory condition in a subject in need thereof, comprising administering to said subject an effective amount of the pharmaceutical composition of claim 26 .
29. The method of claim 27 , wherein the infectious disease is HIV, HBV, HCV, HSV, HPV, RSV, CMV, Ebola, Flavivirus, Pestivirus, Rotavirus, Influenza, Coronavirus, EBV, viral pneumonia, drug-resistant viruses, bird flu, RNA virus, DNA virus, adenovirus, poxvirus, meningitis, Picornavirus, Togavirus, Orthomyxovirus, Retrovirus, Hepadnovirus, Gram-negative bacteria, Gram-positive bacteria, Atypical bacteria, Staphylococcus, Streptococcus, E. coli, Salmonella, Helicobacter pylori , gonorrhea, Chlamydiaceae, Mycoplasmataceae, fungus, protozoa helminth, worms, or parasite.
30. The method according to claim 27 , wherein the cancer is selected from melanoma, breast cancer, prostate cancer, lung cancer, neuroblastoma, glioblastoma, hematologic malignancy, squamous-cell carcinoma, NUT carcinoma, basal cell carcinoma, adenocarcinoma, bladder cancer, bowel cancer, cervical cancer, colon cancer, esophageal cancer, head and neck cancer, kidney cancer, renal cell carcinoma, liver, hepatocellular carcinoma, ovarian cancer, pancreatic cancer, stomach cancer, sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcoma, peripheral neuroepithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, ganglioneuroma, ganglioglioma, medulloblastoma, pineal cell tumor, meningioma, meningeal sarcoma, neurofibroma, Schwannoma, uterine cancer, testicular cancer, thyroid cancer, carcinosarcoma, Wilms' tumor and teratocarcinoma.
31. The method according to claim 30 , wherein the hematologic malignancy is lymphoma, multiple myeloma, leukemia, myelodysplastic syndrome, or myeloproliferative neoplasms.
32. The method according to claim 31 , wherein the leukemia is acute myeloid leukemia, acute lymphoblastic leukemia, or chronic myeloid leukemia.
33. The method according to claim 31 , wherein the lymphoma is large B-cell lymphoma, peripheral T cell lymphoma, Burkitt's Lymphoma, or Hodgkin's lymphoma.
34. The method according to claim 30 , wherein the cancer is castrate-resistant prostate cancer, small cell lung cancer, non-small cell lung cancer, ER positive breast cancer, or triple negative breast cancer.
35. The method according to claim 27 , wherein the subject has been previously treated with an anti-cancer agent, and wherein the anti-cancer agent is exemestane, fulvestrant, enzalutamide, a γ-secretase inhibitor, RAF-inhibitor, an aromatase inhibitor, a selective estrogen modulator (SERM), a selective estrogen receptor down regulator (SERD), luteinizing hormone-releasing hormone superagonists, CYP17 inhibitor Abiraterone, or a small molecule antagonist that blocks the androgen/AR interaction.
36. A method of inhibiting cell growth, comprising contacting a cell with the compound according to claim 1 .