HCK inhibitors for the treatment of fibrosis and cancer
Compounds which are thiazole and triazole 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 6 , or S;
R 1 is selected from O or 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 or phenyl;
R 3 is selected from O, —OH, or —CN;
R 4 is selected from —C(═O)OR 5 , tetrazole, triazole, —CN, —C(═O) NH 2 , —BOR 7 OR 8 , or —BF 3 − ;
R 5 is selected from hydrogen or C 1 -C 6 alkyl;
R 6 is selected from hydrogen or C 1 -C 6 alkyl;
R 7 and R 8 are each independently selected from hydrogen or C 1 -C 6 alkyl or, together with the boron and the oxygens to which they are attached, form a 5- or 6-membered ring optionally substituted with C 1 -C 6 alkyl; and
independently in each instance 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 6 .
4. A compound according to claim 1 , wherein R 4 is-C(═O) OR 5 .
5. A compound according to claim 1 , wherein:
X is O or NH;
R 1 is selected from optionally substituted phenyl or O;
R 2 is selected from hydrogen or chloro;
R 3 is selected from O or CN;
R 4 is-C(═O) OR 5 ;
R 5 is ethyl; and
independently in each instance indicates a single bond or a double bond.
6. A compound according to claim 1 , wherein said compound is selected from:
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
8. A method for treating a disease or disorder in a patient, comprising administering to said patient an effective amount of a compound according to claim 1 , wherein said disease or disorder is selected from fibrosis or a fibrotic disease; a chronic kidney disease, renal fibrosis, or chronic renal allograft injury; solid malignancy or hematological malignancy; an autoimmune or inflammatory disease; or wherein the disease or disorder involves the dysregulation of hematopoietic cell kinase (HCK) signaling.
9. A method for inhibiting hematopoietic cell kinase (HCK) activation, said method comprising bringing hematopoietic cell kinase (HCK) into contact with a compound according to claim 1 .
10. A compound according to claim 3 , wherein R 6 is selected from hydrogen or methyl.
11. A compound according to claim 1 , wherein R 6 is hydrogen.
12. A compound according to claim 6 , wherein R 1 is unsubstituted phenyl and is a single bond.
13. A compound according to claim 1 , wherein R 1 is O and is a double bond.
14. A compound according to claim 1 , wherein R 2 is halogen.
15. A compound according to claim 1 , wherein R 2 is chloro.
16. A compound according to claim 1 , wherein R 2 is hydrogen.
17. A compound according to claim 1 , wherein R 3 is O and is a double bond.
18. A compound according to claim 1 , wherein R 3 is CN and is a single bond.
19. A method for treating a disease or disorder in a patient, comprising administering to said patient an effective amount of a compound according to claim 6 , wherein said disease or disorder is selected from fibrosis or a fibrotic disease; a chronic kidney disease, renal fibrosis, or chronic renal allograft injury; solid malignancy or hematological malignancy; an autoimmune or inflammatory disease; or wherein the disease or disorder involves the dysregulation of hematopoietic cell kinase (HCK) signaling.
20. A method for inhibiting hematopoietic cell kinase (HCK) activation, said method comprising bringing hematopoietic cell kinase (HCK) into contact with a compound according to claim 6 .