Substituted quinoline compounds and methods of use

1. A method of treating or lessening the severity of a proliferative disorder in a patient comprising administering to the patient a compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:

R 1 is hydroxy C 2-6 alkoxy; R 2 is H, alkoxy or hydroxyalkoxy; R 3 is H or F; R 4 is H, F, Cl,Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N,

wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.

2. The method according to claim 1 , wherein R 2 is H or methoxy; R 3 is H or F; and R 4 is H, F, Cl, Br, I, CN, C 1-3 haloalkyl, C 2-5 heterocyclyl, C 2-5 heterocyclyl C 1-3 alkyl, C 3-6 cycloalkyl, or C 3-6 cycloalkyl C 1-3 alkyl.

3. The method according to claim 1 , wherein R 2 is H or methoxy; R 3 is H or F; R 4 is H or F; and X is CH.

4. The method according to claim 1 , wherein R 2 is H; R 3 is H or F; R 4 is H; and X is CH.

5. The method of claim 1 , wherein the compound has one of the following structures:

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof.

6. A method of treating or lessening the severity of a proliferative disorder in a patient comprising administering to the patient a pharmaceutical composition comprising a compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:

R 1 is hydroxy C 2-6 alkoxy; R 2 is H, alkoxy or hydroxyalkoxy; R 3 is H or F; R 4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N,

wherein the proliferative disorder is metastatic cancer, colon cancer, gastric adenocarcinoma, bladder cancer, breast cancer, kidney cancer, liver cancer, lung cancer, thyroid cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, cancer of the CNS, glioblastoma, a myeloproliferative disorder, atherosclerosis or lung fibrosis.

7. The method according to claim 6 , wherein R 2 is H; R 3 is H or F; R 4 is H; and X is CH.

8. The method according to claim 6 , wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

9. The method according to claim 8 , wherein the pharmaceutical composition further comprises a therapeutic agent selected from a chemotherapeutic agent, an anti-proliferative agent, an agent for treating atherosclerosis, an agent for treating lung fibrosis, and combinations thereof.

10. The method according to claim 9 , wherein the additional therapeutic agent is adriamycin, rapamycin, temsirolimus, everolimus, ixabepilone, gemcitabin, cyclophosphamide, dexamethasone, etoposide, fluorouracil, afatinib, alisertib, amuvatinib, axitinib, bosutinib, brivanib, cabozantinib, cediranib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, danusertib, dovitinib, erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, motesanib, neratinib, niraparib, nilotinib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, trametinib, vandetanib, veliparib, vemurafenib, vismodegib, volasertib, an interferon, carboplatin, topotecan, taxol, vinblastine, vincristine, temozolomide, tositumomab, trabedectin, belimumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, tositumomab, trastuzumab or a combination thereof.

11. A method of inhibiting or modulating protein kinase activity in a biological sample comprising contacting a biological sample with a compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:

R 1 is hydroxy C 2-6 alkoxy; R 2 is H, alkoxy or hydroxyalkoxy; R 3 is H or F; R 4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N.

12. The method according to claim 11 , wherein R 2 is H; R 3 is H or F; R 4 is H; and X is CH.

13. The method of claim 11 , wherein the protein kinases are receptor tyrosine kinases.

14. The method of claim 13 , wherein the receptor tyrosine kinases are VEGFR, c-Met and/or Axl.

15. A method of inhibiting or modulating protein kinase activity in a biological sample comprising contacting a biological sample with a pharmaceutical composition comprising a compound of Formula (I):

or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, wherein:

R 1 is hydroxy C 2-6 alkoxy; R 2 is H, alkoxy or hydroxyalkoxy; R 3 is H or F; R 4 is H, F, Cl, Br, I, CN, alkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl; and X is CH or N.

16. The method according to claim 15 , wherein R 2 is H; R 3 is H or F; R 4 is H; and X is CH.

17. The method of claim 15 , wherein the protein kinases are receptor tyrosine kinases.

18. The method of claim 17 , wherein the receptor tyrosine kinases are VEGFR, c-Met and/or Axl.