Bicyclic heterocycles as FGFR inhibitors
The present invention relates to bicyclic heterocycles, and pharmaceutical compositions of the same, that are inhibitors of one or more FGFR enzymes and are useful in the treatment of FGFR-associated diseases such as cancer.
1. A method of inhibiting or ameliorating cancer in a patient, comprising administering to said patient a therapeutically effective amount of 2′-(2,6-difluoro-3,5-dimethoxyphenyl)-6′-[(2-morpholin-4-ylethyl)amino]-1′,2′-dihydro-3′H-spiro[cyclopropane-1,4′-[2,7]naphthyridin]-3′-one, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent, wherein the cancer is associated with abnormal expression or activity of FGFR enzymes or FGFR ligands, and wherein the cancer is selected from kidney cancer, gastric cancer, esophageal cancer, lung cancer, breast cancer, bladder cancer, head and neck cancer, ovarian cancer, cervical cancer, glioblastoma, and endometrial cancer.
2. The method of claim 1 , wherein said cancer is kidney cancer.
3. The method of claim 1 , wherein said cancer is gastric cancer.
4. The method of claim 1 , wherein said cancer is esophageal cancer.
5. The method of claim 1 , wherein said cancer is lung cancer.
6. The method of claim 1 , wherein said cancer is breast cancer.
7. The method of claim 1 , wherein said cancer is bladder cancer.
8. The method of claim 1 , wherein said cancer is head and neck cancer.
9. The method of claim 1 , wherein said cancer is ovarian cancer.
10. The method of claim 1 , wherein said cancer is glioblastoma.
11. The method of claim 1 , wherein said additional therapeutic agent is an anti-hormonal agent.
12. The method of claim 1 , wherein said additional therapeutic agent is selected from inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, or Flt-3 and against cancer-associated fusion protein kinases.
13. The method of claim 1 , wherein said additional therapeutic agent is an agent against the PI3 kinase.
14. The method of claim 1 , wherein said additional therapeutic agent is an inhibitor of mTOR.
15. The method of claim 1 , wherein said additional therapeutic agent is an alkylating agent.
16. The method of claim 1 , wherein said additional therapeutic agent is a platinum-based doublet.
17. The method of claim 16 , wherein the platinum-based doublet is selected from cisplatin plus gemcitabine, carboplatin plus gemcitabine, cisplatin plus docetaxel, carboplatin plus docetaxel, cisplatin plus paclitaxel, carboplatin plus paclitaxel, cisplatin plus pemetrexed, carboplatin plus pemetrexed, and gemcitabine plus paclitaxel bound particles.
18. The method of claim 1 , wherein said additional therapeutic agent is an antimetabolite.
19. The method of claim 1 , wherein said additional therapeutic agent is a cytotoxic agent.
20. The method of claim 1 , wherein said additional therapeutic agent is an immunotherapy drug.
21. The method of claim 20 , wherein the immunotherapy drug is selected from interferon alpha, interleukin 2, and tumor necrosis factor (TNF).
22. The method of claim 1 , wherein said additional therapeutic agent is an antibody therapeutic to costimulatory molecules.
23. The method of claim 1 , wherein said additional therapeutic agent is an anti-cancer vaccine.
24. The method of claim 1 , wherein said additional therapeutic agent is selected from vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons, etoposide, and teniposide.
25. The method of claim 1 , wherein said cancer is cervical cancer.
26. The method of claim 1 , wherein said cancer is endometrial cancer.