HCK inhibitors for the treatment of fibrosis and cancer
Compounds which are oxadiazaborole derivatives are disclosed, including compounds of the following genus: The compounds are inhibitors of hematopoietic cell kinase (HCK) and exhibit anti-fibrotic and anti-proliferative effects. They are useful in the treatment of a variety of disorders, including a fibrosis or a fibrotic disease, such as renal fibrosis.
1. A compound of formula I:
wherein
X is selected from O, NR 3 , and S;
R 1 is selected from O and phenyl optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 fluoroalkyl, and halogen;
R 2 is selected from halogen, hydrogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 fluoroalkyl, and phenyl;
R 3 is selected from hydrogen and C 1 -C 6 alkyl;
Ar is selected from phenyl, a 5-membered heteroaryl, and a 6-membered heteroaryl, wherein said phenyl, 5-membered heteroaryl, or 6-membered heteroaryl is optionally substituted with amino, cyano, halogen, hydroxy, —C(O)NH 2 , —C(═O)OR 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4 is selected from hydrogen and C 1 -C 6 alkyl; and
indicates a single bond or a double bond.
2. A compound according to claim 1 , wherein X is O.
3. A compound according to claim 1 , wherein X is NR 3 .
4. A compound according to claim 1 , wherein R 1 is optionally substituted phenyl and is a single bond.
5. A compound according to claim 1 , wherein R 1 is O and is a double bond.
6. A compound according to claim 1 , wherein R 2 is halogen.
7. A compound according to claim 1 , wherein R 2 is hydrogen.
8. A compound according to claim 1 , wherein Ar is optionally substituted phenyl.
9. A compound according to claim 1 , wherein Ar is an optionally substituted 5-membered heteroaryl.
10. A compound according to claim 1 , wherein Ar is an optionally substituted 6-membered heteroaryl.
11. A compound according to claim 1 , wherein:
X is O;
R 1 is optionally substituted phenyl;
R 2 is chloro; and
indicates a single bond.
12. A compound according to claim 1 , wherein said compound is selected from:
13. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
14. A method for treating fibrosis or a fibrotic disease in a patient, comprising administering to said patient an effective amount of a compound according to claim 1 .
15. The method according to claim 14 , wherein said fibrosis or fibrotic disease is selected from renal fibrosis; pulmonary fibrosis; cystic fibrosis; cirrhosis; fibrosis of the heart; mediastinal fibrosis; retroperitoneal cavity fibrosis; bone marrow fibrosis; hypertrophic scars; keloids; scleroderma; systemic sclerosis; crohn's disease; peyronie's disease; lupus nephritis; folic acid nephropathy; and fibrosis induced by radiation, infection, chemotherapeutic drugs, surgery, burns, and inhalation.
16. A method for treating a chronic kidney disease, renal fibrosis, or chronic renal allograft injury in a patient, comprising administering to said patient an effective amount of a compound according to claim 1 .
17. A method for treating a disease or disorder in a patient chosen from solid malignancy and hematological malignancy, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 .
18. The method according to claim 17 , wherein the disease or disorder is breast cancer, colon cancer, rectal cancer, stomach cancer, chronic myeloid leukemia, acute lymphoblastic leukemia, a myelodysplastic syndrome, multiple myeloma or a lymphoma.
19. A method for treating a disease or disorder in a patient chosen from an autoimmune or inflammatory disease associated with hematopoietic cell kinase (HCK) signaling, the method comprising administering to the patient a therapeutically effective amount of a compound according to claim 1 .
20. A method for inhibiting hematopoietic cell kinase (HCK) activation in vitro, said method comprising bringing hematopoietic cell kinase (HCK) into contact with a compound according to claim 1 .