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US 2022/0177464 A1Published application
Hck inhibitors for the treatment of fibrosis and cancer
AssigneeIcahn School of Medicine at Mount Sinai
InventorsBarbara MURPHY, Bhaskar DAS, Chengguo WEI, Li LI
Life of this patent
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Abstract
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.
Claims29
A compound of formula I:
- wherein
- X is selected from O, NR6, or S;
- R1 is selected from O or phenyl optionally substituted with one or more substituents selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 fluoroalkyl and halogen;
- R2 is selected from halogen, hydrogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 fluoroalkyl or phenyl;
- R3 is selected from O, —OH, or —CN;
- R4 is selected from —C(═O)OR5, tetrazole, triazole, —CN, —C(═O)NH2, —BOR7OR8, or —BF3−;
- R5 is selected from hydrogen or C1-C6 alkyl;
- R6 is selected from hydrogen or C1-C6 alkyl;
- R7 and R8 are each independently selected from hydrogen or C1-C6 alkyl or, together with the boron and the oxygens to which they are attached, form a 5- or 6-membered ring optionally substituted with C1-C6 alkyl;
- and
- independently in each instance indicates a single bond or a double bond.
8 more elements
4-13. (canceled)
15-16. (canceled)
A compound of formula II:
- wherein
- independently in each instance indicates a single bond or a double bond;
- R11 is hydrogen or C1-C6 alkyl;
- R12 is hydrogen or C1-C6 alkyl or, when is a double bond, is absent;
- R13 is selected from hydrogen or —CR14R15R16;
- or
- P R11 and R13 form a 5- to 7-membered heterocyclic or heteroaryl ring, substituted with R16;
- R14 is hydrogen or, when is a double bond, is absent;
- R15 is selected from hydrogen, cyano, C1-C6 haloalkyl, —C(═O)O(C1-C6 alkyl), or —C(═O)NH2, or, when R11 and R13 form a ring, is absent;
- R16 is a phenyl ring, optionally substituted with 1, 2, or 3 instances of R17;
- R17 is selected independently in each instance from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —BOR18OR19, —BF3−, —CN, —C(═O)NH2, —C(═O)OR17a, tetrazole, triazole, or —NO2;
- R17a is selected from hydrogen or C1-C6 alkyl;
- R18 and R19 are each independently selected from hydrogen or C1-C6 alkyl or, together with the boron and the oxygens to which they are attached, form a 5- or 6-membered ring optionally substituted with C1-C6 alkyl;
- and
- R20 is selected from hydrogen, C1-C6 alkyl, a 5- or 6-membered heteroaryl optionally substituted with C1-C6 alkyl, or phenyl optionally substituted independently in each instance with one or more of halogen, C1-C6 alkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, C1-C3 haloalkyl, a heterocycle, —CN, and —C(═O)NH2.
12 more elements
(canceled)
(canceled)
26-31. (canceled)
A compound of formula III:
- wherein
- R21 is hydrogen or C1-C6 alkyl;
- independently in each instance indicates a single bond or a double bond;
- R22 is cyano when is a single bond, or is selected from ═O or ═N—OH when is a double bond;
- R23 is absent or is selected from —CH═CH— or a 5- or 6-membered heteroaryl;
- R24 is a phenyl ring, optionally substituted with 1, 2, or 3 instances of R25;
- R25 is selected independently in each instance from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, —BOR26OR27, —BF3−, —CN, —C(═O)NH2, —C(═O)OR27a, tetrazole, triazole, —NO2, guanidine, and an amidoxime;
- R26 and R27 are each selected from hydrogen or C1-C6 alkyl or, together with the boron and the oxygens to which they are attached, form a 5- or 6-membered ring optionally substituted with one or more C1-C6 alkyl groups;
- and
- R27a is selected from hydrogen or C1-C6 alkyl.
7 more elements
34-35. (canceled)
37-45. (canceled)
49-55. (canceled)
57-58. (canceled)
Dependencies are inferred from the claim text.