Pyrimido-diazepinone kinase scaffold compounds and methods of treating DCLK1/2-mediated disorders
The present invention relates to use of pyrimido-diazepinone compounds that are able to modulate protein kinases such as doublecortin-like kinase (DCLK1) and doublecortin-like kinase 2 (DCLK2), which are members of serine/threonine-protein kinase family and Ca 2+ /calmodulin-dependent protein kinase class of enzymes, and the use of such compounds in the treatment of various diseases, disorders or conditions.
1. A method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of formula F-1:
or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is
R 2 is —CH 2 —CH 2 F, —CH 2 —CHF 2 , or —CH 2 —CF 3 ;
R 5 is hydrogen or methyl; and
R 6 is hydrogen or optionally substituted alkyl;
each R 7 is independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, alkoxy, NH(alkyl), NH(aryl), N(alkyl)(alkyl), or N(alkyl)(aryl), each of which may be optionally substituted; halo, nitro, or cyano; and
p is 0-4.
2. The method of claim 1 , wherein the compound is of formula F-1-a:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the subject is administered simultaneously or sequentially an additional therapeutic agent, wherein the additional therapeutic agent comprises an anti-inflammatory agent, which is azathioprine, cyclophosphamide, or sulfasalazine, or a chemotherapeutic agent, which is imatinib mesylate, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, an interferon, or a platinum derivative.
4. The method of claim 1 , wherein the subject is a human.
5. A compound of formula F-1:
or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is
R 2 is —CH 2 —CH 2 F, —CH 2 —CHF 2 , or —CH 2 —CF 3 ;
R 5 is hydrogen or methyl; and
R 6 is hydrogen or optionally substituted alkyl;
each R 7 is independently alkyl, alkenyl, aryl, arylalkyl, heteroaryl, heterocyclic, carbocyclic, alkoxy, NH(alkyl), NH(aryl), N(alkyl)(alkyl), or N(alkyl)(aryl), each of which may be optionally substituted; halo, nitro, or cyano; and
p is 0-4.
6. The compound of claim 5 , wherein the compound is of formula F-1-a:
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising the compound of claim 5 , or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
9. The compound of claim 5 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
10. A compound which is:
or a pharmaceutically acceptable salt thereof.
11. A method of treating pancreatic cancer in a subject, the method comprising administering to the subject a compound of claim 10 , or a pharmaceutically acceptable salt thereof.