STAT3 inhibitors and their anticancer use
View Patent ↗In one aspect, the invention relates to substituted 6-amino-5,8-dioxo-5,8-dihydronaphthalene-1-sulfonamide analogs and derivatives thereof, substituted 4-amino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide analogs and derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound having a structure represented by a formula:
wherein R 1 is selected from hydrogen and C1-C3 alkyl;
wherein Q 1 is —NR 2a R 2b and wherein Q 2 is O; or wherein Q 1 and Q 2 are together N;
wherein each of R 2a and R 2b , when present, is independently selected from hydrogen and C1-C3 alkyl;
wherein Q 3 is selected from —(C1-C6)-Ar 1 , Ar 1 , —(C1-C6)-Cy 1 , and Cy 1 ;
wherein Ar 1 , when present, is selected from phenyl, naphthyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b ;
wherein n is 0, 1, or 2;
wherein each R 3 , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;
wherein each of R 4a and R 4b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;
wherein each of R 5a and R 5b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and —(C═O)NR 6a R 6b ;
wherein each of R 6a and R 6b , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each Ar 2 , when present, is independently selected from is phenyl and monocyclic heteroaryl; and wherein Ar2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
wherein each Cy 2 , when present, is independently selected from C3-C8 cycloalkyl and C2-C7 heterocycloalkyl; and wherein Cy 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R7, —(C═O)OR7, —(C═O)NR 8a R 8b , —(C═O)-(C1-C6 alkyl)Ar3, —(C═O)—O—(C1-C6 alkyl)Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)Ar 3 ;
wherein each R 7 , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein each of R 8a and R 8b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein each Ar 3 , when present, is independently selected from phenyl and monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein Cy 1 , when present, is selected from C3-C8 cycloalkyl and C2-C7 heterocycloalkyl; and wherein Cy 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b ;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Q 1 is —NH 2 .
3. The compound of claim 1 , wherein Q 1 is —NHCH 3 .
4. The compound of claim 1 , wherein Q 3 is Ar 1 .
5. The compound of claim 1 , wherein Q 3 is —(C1-C6)-Ar 1 .
6. The compound of claim 1 , wherein Ar 1 , when present, is phenyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .
7. The compound of claim 1 , wherein Ar 1 , when present, is phenyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .
8. The compound of claim 1 , wherein Ar 1 , when present, is pyridinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .
9. The compound of claim 1 , wherein Cy 2 , when present, is a C2-C7 heterocycloalkyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .
10. The compound of claim 1 , wherein Cy 2 , when present, is piperidinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .
11. The compound of claim 1 , wherein Cy 2 , when present, is morpholinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .
12. The compound of claim 1 , wherein Cy 2 is unsubstituted.
13. The compound of claim 1 , wherein R 1 is hydrogen.
14. The compound of claim 1 , wherein R 1 is selected from hydrogen and methyl.
15. The compound of claim 1 , having a structure represented by a formula:
16. The compound of claim 1 , having a structure represented by a formula:
17. The compound of claim 1 , having a structure represented by a formula:
18. The compound of claim 1 , having a structure represented by a formula:
19. The compound of claim 1 , having a structure represented by a formula:
wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e is independently selected from hydrogen, halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b , provided that at least two of R 10a , R 10b , R 10c , R 10d , and R 10e are hydrogen.
20. The compound of claim 1 , having a structure represented by a formula:
wherein each of R 10a , R 10b , R 10c , R 10d , and R 10e independently selected from hydrogen, halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , (C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b , provided that at least two of R 10a , R 10b , R 10c , R 10d , and R 10e are hydrogen.
21. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. A method for the amelioration of breast cancer in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.
23. The method of claim 22 , wherein the compound exhibits inhibition of STAT3 activity with an IC 50 of less than 5 μM.
24. The method of claim 22 , wherein the compound exhibits inhibition of STAT3 activity with an IC 50 of less than 1 μM.