Cancer therapeutics

1. A compound of formula (I):

wherein

R 1 is selected from H, C 1 -C 4 alkoxy, NR 4 R 5 , or R 6 , R 2 and R 3 are independently selected from H, unsubstituted C 1 -C 4 alkoxy, CO 2 H, NR 4 R 5 , or OR 6

wherein R 6 is a group of formula (II), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), or (IIIf):

and at least one of R 1 , R 2 and R 3 is not H;

R 4 and R 5 are each independently H or C 1 -C 3 alkyl, or together with the nitrogen carrying them form a pyrrolidine or a piperidine ring;

n ranges from 1-3;

x is 0, 1 or 2;

y is 0, 1 or 2;

Q is O or N—R 9 , and the sum of x+y≥1, or Q is a bond and the sum x+y≥2;

R 9 is C 1 -C 3 alkyl, benzyl, —C(O)phenyl, or a (CH 2 ) n R 11 , wherein R 11 is a group of formula (IVa), (IVb), (IVc), (IVd), (IVe), or (IVf)

R 7 and R 8 are each independently H, methyl or ethyl;

R 10 is H, methyl, ethyl, phenyl or CO 2 H; and

R 12 is H or (CH 2 ) n —CO 2 H;

or a pharmaceutically acceptable salt thereof.

2. A compound of claim 1 , wherein

R 1 is selected from H, methoxy, ethoxy, NR 4 R 5 , or OR 6 , R 2 and R 3 are independently selected from H, methoxy, ethoxy, CO 2 H, NR 4 R 5 , or OR 6 wherein R 6 is a group of formula (II) or a group of formula (IIIe), and at least one of R 1 , R 2 and R 3 is not H;

R 4 and R 5 are each independently methyl or ethyl, or together with the nitrogen carrying them form a pyrrolidine or a piperidine ring;

n ranges from 1-3;

x is 1 or 2;

y is 1 or 2;

Q is O or N—R 9 ;

R 9 is benzyl or (CH 2 ) n R 11 , wherein R 11 is a group of formula (IVd);

R 7 and R 8 are both H;

R 19 is methyl, phenyl or CO 2 H; and

R 12 is H or (CH 2 ) n —CO 2 H;

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 , wherein

R 1 is selected from H, methoxy, NR 4 R 5 , or OR 6 , and R 3 is selected from H, methoxy, CO 2 H, NR 4 R 5 , or OR 6 , wherein R 6 is a group of formula (II);

R 2 is H;

R 4 and R 5 are each independently methyl or ethyl, or together with the nitrogen carrying them form a pyrrolidine or a piperidine ring;

n is 2;

x is 1;

y is 1;

Q is O or N—R 9 ;

R 9 is benzyl;

R 7 and R 8 are both H; and

R 12 is H;

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 3 , wherein R 1 is H, OCH 3 or a group of formula (II), R 2 is H or OCH 3 , and R 3 is H, OCH 3 or a group of formula (II); at least one of R 1 , R 2 and R 3 is not H; and R 1 and R 3 are not both a group of formula (II).

5. A compound of claim 4 , wherein R 2 is H.

6. A compound of claim 5 , wherein R 1 is H or OCH 3 .

7. A compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

8. An acid addition salt of a compound of any one of claim 1 .

9. An acid addition salt of claim 8 , wherein the salt is a hydrochloride salt.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition of claim 10 , wherein the composition further comprises a solubilizing agent.

12. The pharmaceutical composition of claim 11 , wherein the solubilizing agent is a polyanionic variably substituted sulfobutyl ether of β-cyclodextrin.

13. A method of treating a RUNX-signaling-dependent cancer that expresses wild-type CBFβ in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 ; wherein the cancer is selected from the group consisting of a RUNX-signaling-dependent leukemia that expresses wild-type CBFβ, lung cancer, bladder cancer, ovarian cancer, uterine cancer, endometrial cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, cervical cancer, lymphoma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, salivary gland cancer, bone cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, skin cancer, melanoma, squamous cell carcinoma of the tongue, pleomorphic adenoma, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma, and adenocarcinoma, or mixtures thereof.

14. A method of treating a RUNX-signaling-dependent cancer that expresses wild-type CBFβ in a subject in need thereof, comprising administering to the subject the pharmaceutical composition of claim 10 ; wherein the cancer is selected from the group consisting of a RUNX-signaling-dependent leukemia that expresses wild-type CBFβ, lung cancer, bladder cancer, ovarian cancer, uterine cancer, endometrial cancer, breast cancer, liver cancer, pancreatic cancer, stomach cancer, cervical cancer, lymphoma, leukemia, acute myeloid leukemia, acute lymphocytic leukemia, salivary gland cancer, bone cancer, brain cancer, colon cancer, rectal cancer, colorectal cancer, kidney cancer, skin cancer, melanoma, squamous cell carcinoma of the tongue, pleomorphic adenoma, hepatocellular carcinoma, pancreatic cancer, squamous cell carcinoma, and adenocarcinoma, or mixtures thereof.

15. An acid addition salt of a compound of claim 7 .

16. An acid addition salt of claim 15 , wherein the salt is a hydrochloride salt.

17. A pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , wherein the composition further comprises a solubilizing agent.