Use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea and analogs for the treatment of cancers associated with genetic abnormalities in platelet derived growth factor receptor alpha

Abstract

Abstract The present disclosure relates to the use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2- oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea or 1-(5-(7-amino-1- ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea in the treatment of cancers. Specifically, the disclosure is directed to methods of inhibiting PDGFR kinases and treating cancers and disorders associated with inhibition of PDGFR kinases including lung adenocarcinoma, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytomas, sarcomas, gastrointestinal stromal tumors, malignant peripheral nerve sheath sarcoma, intimal sarcomas, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. Abstract The present disclosure relates to the use of 1-[4-bromo-5-[1-ethyl-7-(methylamino)-2- oxo-1,2-dihydro-1,6-naphthyridin-3-y1]-2-fluoropheny1]-3-phenylurea or 1-(5-(7-amino-1- ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-y1)-4-bromo-2-fluoropheny1)-3-phenylurea in the treatment of cancers. Specifically, the disclosure is directed to methods of inhibiting PDGFR kinases and treating cancers and disorders associated with inhibition of PDGFR kinases including lung adenocarcinoma, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytomas, sarcomas, gastrointestinal stromal tumors, malignant peripheral nerve sheath sarcoma, intimal sarcomas, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma. 20 24 20 55 05 02 A ug 2 02 4 A b s t r a c t 2 0 2 4 2 0 5 5 0 5 0 2 A u g 2 0 2 4

Claims

1. A method of treating or preventing a PDGFR kinase-mediated tumor growth or tumor progression comprising administering to a patient in need thereof an effective amount of 1-(4-bromo-5-[l-ethyl-7-(methylamino)-2-oxo-I,2-dihydro-l,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, or a pharmaceutically acceptable salt thereof.

2. The method of any one of claims 1, wherein tumor growth or tumor progression is caused by one or more of PDGFRa kinase overexpression, oncogenic PDGFRa missense mutations, oncogenic deletion PDGFRa mutations, oncogenic PDGFRa gene rearrangements leading to PDGFRa fusion proteins, PDGFRa intragenic in-frame deletions, or oncogenic PDGFRa gene amplification.

3. The method of claim I or 2, wherein tumor growth or tumor progression is caused by PDGFRa kinase overexpression.

4. The method of claim 1 or 2, wherein tumor growth or tumor progression is caused by oncogenic PDGFRa missense mutations or oncogenic deletion PDGFRa mutations.

5. The method of claim 1 or 2, wherein tumor growth or tumor progression is caused by oncogenic PDGFRa gene rearrangements leading to PDGFRa fusion proteins or PDGFRa intragenic in-frame deletions.

6. The method of claim 1 or 2, wherein tumor growth or tumor progression is caused by oncogenic PDGFRa gene amplification.

7. The method of any one of claims 1-6, wherein the tumor is lung adenocarcinoma, squamous cell lung cancer, glioblastoma, pediatric glioma, astrocytomas, sarcomas, gastrointestinal stromal tumors, malignant peripheral nerve sheath sarcoma, intimal sarcomas, hypereosinophilic syndrome, idiopathic hypereosinophilic syndrome, chronic eosinophilic leukemia, eosinophilia-associated acute myeloid leukemia, or lymphoblastic T-cell lymphoma.

8. The method of any one of claims 1-7, wherein the tumor is glioblastoma.

9. The method of any one of claims 1-7, wherein the tumor is gastrointestinal stromal tumors.2024205505   02 Aug 202410. The method of any one of claims 1-9, wherein l-[4-bromo-5-[l-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-l,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea, or a pharmaceutically acceptable salt thereof is administered as a single agent or in combination with other cancer targeted therapeutic agents, cancer-targeted biologicals, immune checkpoint inhibitors, or chemotherapeutic agents.

11. The method of claim 10, wherein the therapeutic agent is selected from cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-l-yl)methyl)-lH-imidazol-l-yl)methyl)benzonitrile hydrochloride, (R)-l-(( lH-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfony 1)-2,3,4,5-tetrahydro-1 H-benzo diazepine-7-carbonitrile, cetuximab, imatinib, interferon alfa-2b, Pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin -C, L-asparaginase, teniposide 17a-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17a-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thioTEPA, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin.

12. The method of claim 10, wherein the immune checkpoint inhibitor is selected from CTLA4 inhibitors ipilimumab and tremelimumab; PD1 inhibitors pembrolizumab, and2024205505   02 Aug 2024nivolumab; PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab (MEDI4736), avelumab, and monoclonal antibody PDR001; 4 - IBB ligand inhibitors urelumab and utomilumab PF05082566; OX40 agonist monoclonal antibody MEDI6469; glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor monoclonal antibody TRX518; CD27 inhibitor varblumab, TNFRSF25-TL1A inhibitors; CD40 agonist monoclonal antibody CP 870893; HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitors; LAG3 inhibitors monoclonal antibody BMS 986016; TIM3 inhibitors; Siglecs inhibitors; ICOS ligand agonists; B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors; HHLA2-TM1GD2 inhibitors; inhibitors of butyrophilins; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIRs inhibitor lirilumab; inhibitors of ILTs and LIRs; NKG2D and NKG2A inhibitor monalizumab IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-l,2,5-oxadiazole INCB024360; TGFp inhibitor galunisertib; Adenosine-CD39-CD73 inhibitors; CXCR4-CXCL12 inhibitors ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-l-amino-5-guanidino-l-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-] ,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H, 16H-pyrrolo[2,1 -p][ 1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontine-12-carboxamide BKT140; Phosphatidyl serine inhibitors bavituximab, SIRPA-CD47 inhibitor monoclonal antibody CC 90002; VEGF inhibitor bevacizumab, and or Neuropilin inhibitor monoclonal antibody MNRP1685A.

13. The method of claim 1 i, wherein the therapeutic agent is temozolomide14.    The method of claim 1, further comprising administering ionizing radiation.

15. The method of claim 1, further comprising administering temozolomide and ionizing radiation2024205505   02 Aug 202416. The method of claim 10, wherein the additional therapeutic agent is selected from AKT inhibitor, alkylating agent, all-trans retinoic acid, antiandrogen, azacitidine, BCL2 inhibitor, BCL-XL inhibitor, BCR-ABL inhibitor, BTK inhibitor, BTK / LCK / LYN inhibitor, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, CDK4 / 6 inhibitor, CDK9 inhibitor, CBP / p300 inhibitor, EGFR inhibitor, endothelin receptor antagonist, ERK inhibitor, famesyltransferase inhibitor, FLT3 inhibitor, glucocorticoid receptor agonist, HDM2 inhibitor, histone deacetylase inhibitor, IKKp inhibitor, immunomodulatory drug (IMiD), ingenoi, ionizing radiation, ITK inhibitor, JAK1 / JAK2 / JAK3 / TYK2 inhibitor, MEK inhibitor, midostaurin, MTOR inhibitor, PI3 kinase inhibitor, dual PI3 kinase / MTOR inhibitor, proteasome inhibitor, protein kinase C agonist, SUV39H1 inhibitor, TRAIL. VEGFR2 inhibitor, Wnt / P-catenin signaling inhibitor, decitabine, and anti-CD20 monoclonal antibody.

17. A method of inhibiting PDGFR kinase comprising administering to a patient in need thereof an effective amount of l-[4-bromo-5-[l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenyiurea, or a pharmaceutically acceptable salt thereof.

18. The method of claim 17, wherein the PDGFR kinase is PDGFRa or PDGFR^.

19. The method of claim 17, further comprising administering a cancer targeted therapeutic agent, cancer-targeted biological, immune checkpoint inhibitor, or chemotherapeutic agent.

20. The method of claim 19, wherein the therapeutic agent is selected from cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-l-yl)methyl)-lH-imidazol-i-yl)methyl)benzonitrile hydrochloride,    (R)-l-((lH-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzo diazepi ne-7-carbonitrile, cetuximab, imatinib, interferon alfa-2b, Pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, tri ethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxy coformy ci n, mitomycin -C, L-2024205505   02 Aug 2024asparaginase, teniposide 17a-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17a-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thioTEPA. altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin.

21. The method of claim 19, wherein the immune checkpoint inhibitor is selected from CTLA4 inhibitors ipilimumab and tremelimumab; PD1 inhibitors pembrolizumab, and nivolumab; PDLi inhibitors atezolizumab (formerly MPDL3280A), durvakimab (formerly MEDI4736), avelumab, and monoclonal antibody PDR001; 4-IBB ligand inhibitors urelumab and utomilumab (PF05082566); OX40 ligand agonist monoclonal antibody MEDI6469; glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor monoclonal antibody TRX518; CD27 inhibitor varlilumab; TNFRSF25-TL1A inhibitors; CD40 ligand agonist monoclonal antibody CP 870893, HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitors, LAG3 inhibitors monoclonal antibody BMS 986016; TIM3 inhibitors, Siglecs inhibitors; ICOS ligand agonists; B7--H3 inhibitor EnoblituzumabMGA271; B7--H4 inhibitors; VISTA inhibitors; HHL / X2-TMIGD2 inhibitors; inhibitors of butyrophili ns; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIRs inhibitor lirilumab; inhibitors of ILTs and LIRs, NKG2D and NKG2A inhibitor monalizumab IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSFIR inhibitors, emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino}-nitrosomethylidene]-4-(2-(sulfamoylamino)ethylamino]-l,2,5-oxadiazole INCB024360; TGFp inhibitor galunisertib; Adenosine-CD39-CD73 inhibitors, CXCR4-CXCL12 inhibitors ulocuplumab and (3 S,6S,9S, 12R, 17R,20S,23 S,26S,29S,34aS )-N-((S)-1-amino-5-guanidino-l-oxopentan-2-yl)-2024205505   02 Aug 202426,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-! ,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H, 16H-pyrrolo[2,1 -p][ 1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotriacontine-12-carboxamide BKT140, Phosphatidyl sen ne inhibitors bavituximab; S1RPA CD47 inhibitor monoclonal antibody CC 90002; VEGF inhibitors bevacizumab; and or neuropilin inhibitor monoclonal antibody MNRP1685A.

22. The method of claim 19, wherein the therapeutic agent is temozolomide.

23. The method of claim 16, further comprising administering ionizing radiation.24 The method of claim 16, further comprising administering temozolomide and ionizing radiation.

25. The method of claim 19, wherein the additional therapeutic agent is selected from AKT inhibitor, alkylating agent, all-trans retinoic acid, antiandrogen, azacitidine, BCL2 inhibitor, BCL-XL inhibitor, BCR-ABL inhibitor, BTK inhibitor, BTK / LCK / LYN inhibitor, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, CDK4 / 6 inhibitor, CDK9 inhibitor, CBP / p300 inhibitor, EGFR inhibitor, endothelin receptor antagonist, ERK inhibitor, famesyltransferase inhibitor, FLT3 inhibitor, glucocorticoid receptor agonist, HDM2 inhibitor, histone deacetylase inhibitor, IKKP inhibitor, immunomodulatory drug (IMiD), ingenol, ionizing radiation, ITK inhibitor, JAK1 / JAK2 / JAK3 / TYK2 inhibitor, MEK inhibitor, midostaurin, MTOR inhibitor, PI3 kinase inhibitor, dual PI3 kinase / MTOR inhibitor, proteasome inhibitor, protein kinase C agonist, SUV39H1 inhibitor, TRAIL, VEGFR2 inhibitor, WnVp-catenin signaling inhibitor, decitabine, and anti-CD20 monoclonal antibody.

26. A method of treating glioblastoma, comprising administering to a patient in need thereof an effective amount of l-[4-bromo-5-[l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl]-2-fluorophenyl]-3-phenylurea. or a pharmaceutically acceptable salt thereof.

27. The method of claim 26, further comprising administering a cancer targeted therapeutic agent, cancer-targeted biological, immune checkpoint inhibitor, or chemotherapeutic agent.2024205505   02 Aug 202428. The method of claim 27, wherein the therapeutic agent is selected from cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-l-yl)methyl)-lH-imidazol-I-yl)methyl)benzonitrile hydrochloride, (R)-]-((lH-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzo diazepine-7-carbonitrile, cetuximab, imatinib, interferon alfa-2b, Pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, tri ethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxy coformycin, mitomycin -C, L-asparaginase, teniposide 17a-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17a-hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine, procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxetan, arsenic trioxide, porfimer sodium, cetuximab, thioTEPA, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or valrubicin.

29. The method of claim 27, wherein the immune checkpoint inhibitor is selected from CTLA4 inhibitors ipilimumab and tremelimumab; PD1 inhibitors pembrolizumab, and nivolumab; PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab (formerly MEDI4736), avelumab, and monoclonal antibody PDR001, 4-IBB ligand inhibitors urelumab and utomilumab PF 05082566: OX40 ligand agonist monoclonal antibody MEDI6469; glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor monoclonal antibody2024205505   02 Aug 2024TRX518; CD27 inhibitor varlilumab; TNFRSF25 -TL1A inhibitors; CD40 ligand agonist monoclonal antibody CP 870893; HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitors; LAG3 inhibitors monoclonal antibody BMS 986016; TIM3 inhibitors, Siglecs inhibitors; ICOS ligand agonists, B7-H3 inhibitor EnoblituzumabMGA271; B7-H4 inhibitors, VISTA inhibitors, HHLA2-TM1GD2 inhibitors; inhibitors of butyrophilins; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIRs inhibitor lirilumab; inhibitors of ILTs and LlRs, NKG2D and NKG2A inhibitor monalizumab IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSF1R inhibitors emactuzumab, cabiralizumab, pexidartinib, ARRY382, and BLZ945; (DO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethylidene]-4-[2-(sulfamoylamino)ethylamino]-l,2,5-oxadiazoleINCB024360; TGFp inhibitor galunisertib; Adenosine-CD39-CD73 inhibitors, CXCR4-CXCL12 inhibitors ulocuplumab and (3S,6S,9S,12R,17R,20S,23S,26S,29S,34aS)-N-((S)-l-amino-5-guanidino-l-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-l,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-1H, 16H-pyrrolo[2,1 -p][ 1,2]dithia[5,8,11,14,17,20,23,26,29]nonaazacyclodotri aeon tine-12-carboxamide BKT140; Phosphatidylserine inhibitors bavituximab; SIRPA--CD47 inhibitor monoclonal antibody CC 90002; VEGF inhibitors bevacizumab; and or neuropilin inhibitor monoclonal antibody MNRP1685A.J30. The method of claim 28, wherein the therapeutic agent is temozolomide.

31. The method of claim 26, further comprising administering ionizing radiation32. The method of claim 26, further comprising administering temozolomide and ionizing radiation.

33. The method of claim 27, wherein the additional therapeutic agent is selected from AKT inhibitor, alkylating agent, all-trans retinoic acid, antiandrogen, azacitidine, BCL2 inhibitor, BCL-XL inhibitor, BCR-ABL inhibitor, BTK inhibitor, BTK / LCK / LYN inhibitor, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, CDK4 / 6 inhibitor, CDK9 inhibitor, CBP / p300 inhibitor, EGFR inhibitor, endothelin receptor antagonist, ERK inhibitor, farnesyltransferase inhibitor, FLT32024205505   02 Aug 2024inhibitor, glucocorticoid receptor agonist, HDM2 inhibitor, histone deacetylase inhibitor, IKKp inhibitor, immunomodulatory drug (IMiD), ingenol, ionizing radiation, ITK inhibitor, JAK1 / JAK2 / JAK3 / TYK2 inhibitor, MEK inhibitor, midostaurin, MTOR inhibitor, PI3 kinase inhibitor, dual PI3 kinase / MTOR inhibitor, proteasome inhibitor, protein kinase C agonist, SUV39H1 inhibitor, TRAIL, VEGFR2 inhibitor, Wnt / p-catenin signaling inhibitor, decitabine, and anti-CD20 monoclonal antibody.

34. A method of treating PDGFRa-mediated gastrointestinal stromal tumors, comprising administering to a patient in need thereof an effective amount of l-[4-bromo-5-[l-ethyl-7-(methylamino)-2-oxo-1,2-di hydro-1,6-naphthyridin-3-yl j-2-fluoropbenyl]-3-phenyl urea, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, further comprising administering a cancer targeted therapeutic agent, cancer-targeted biological, immune checkpoint inhibitor, or chemotherapeutic agent.

36. The method of claim 35, wherein the therapeutic agent is selected from cytotoxic agent, cisplatin, doxorubicin, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methotrexate, temozolomide, cyclophosphamide, lonafarib, tipifarnib, 4-((5-((4-(3-chlorophenyl)-3-oxopiperazin-l-yl)methyl)-lH-imidazol-I-yl)methyl)benzonitrile hydrochloride, (R)-1-(( 1 H-imidazol-5-yl)methyl)-3-benzyl-4-(thiophen-2-ylsulfonyl)-2,3,4,5-tetrahydro-1 H-benzo diazepine-7-carbonitrile, cetuximab, imatinib, interferon alfa-2b, Pegylated interferon alfa-2b, aromatase combinations, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, leucovorin, oxaliplatin, pentostatine, vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, mithramycin, deoxycoformycin, mitomycin -C, L-asparaginase, teniposide 17a-ethinyl estradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyltestosterone, prednisolone, triamcinolone, chlorotrianisene, 17a-hydroxyprogesterone, aminoglutethimide, estramustine. medroxyprogesterone acetate, leuprolide acetate, flutamide, toremifene citrate, goserelin acetate, carboplatin, hydroxyurea, amsacrine,2024205505   02 Aug 2024procarbazine, mitotane, mitoxantrone, levamisole, vinorelbine, anastrazole, letrozole, capecitabine, raloxifene, droloxafine, hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab tiuxeian, arsenic trioxide, porfimer sodium, cetuximab, thioTEPA, altretamine, fulvestrant, exemestane, rituximab, alemtuzumab, dexamethasone, bicalutamide, chlorambucil, or vahubicin.

37. The method of claim 35, wherein the immune checkpoint inhibitor is selected from CTLA4 inhibitors ipilimumab and tremelimumab; PD1 inhibitors pembrolizumab, and nivolumab; PDL1 inhibitors atezolizumab (formerly MPDL3280A), durvalumab MEDI4736, avelumab, and monoclonal antibody PDR001; 4 - IBB ligand inhibitors urelumab and utomilumab PF05082566; OX40 ligand agonist monoclonal antibody MEDI6469; glucocorticoid-induced tumor necrosis factor receptor (GITR) inhibitor monoclonal antibody TRX5I8; CD27 inhibitor varlilumab, TNFRSF25-TL1A inhibitors; CD40 ligand agonist monoclonal antibody CP870893; HVEM-LIGHT-LTA and HVEM-BTLA-CD160 inhibitors; LAG3 inhibitors monoclonal antibody BMS 986016; TIM3 inhibitors, Siglecs inhibitors; 1COS ligand agonists, B7-H3 inhibitor enoblituzumab MGA271; B7-H4 inhibitors; VISTA inhibitors, HHLA2TMIGD2 inhibitors; inhibitors of butyrophilins; BTNL2 inhibitors; CD244-CD48 inhibitors; inhibitors of TIGIT and PVR family members; KIRs inhibitor lirilumab; inhibitors of ILTs and LIRs, NKG2D and NKG2A inhibitor monalizumab IPH2201; inhibitors of MICA and MICB; CD244 inhibitors; CSFIR inhibitor emactuzumab, cabiralizumab, pexidartinib, AMG382, and BLZ945; IDO inhibitor (3E)-3-[(3-bromo-4-fluoroanilino)-nitrosomethy1idene]-4-[2-(sulfamoylamino)ethylamino]-l,2,5-oxadiazoleINCB024360; TGFP inhibitor galunisertib; Adenosine-CD39-CD73 inhibitors, CXCR4-CXCL12 inhibitors ulocuplumab and (3S,6S,9S,12R,l7R,20S,23S,26S,29S,34aS)-N-((S)-l-amino-5-guanidino-l-oxopentan-2-yl)-26,29-bis(4-aminobutyl)-17-((S)-2-((S)-2-((S)-2-(4-fluorobenzamido)-5-guanidinopentanamido)-5-guanidinopentanamido)-3-(naphthalen-2-yl)propanamido)-6-(3-guanidinopropyl)-3,20-bis(4-hydroxybenzyl)-l,4,7,10,18,21,24,27,30-nonaoxo-9,23-bis(3-ureidopropyl)triacontahydro-IH, 16H-pyrrolo[2, l-p][ 1,2]dithia[5,8,l 1,14,17,20,23,26,29]nonaazacyclodotriacontine-l2-carboxamide BKT140; Phosphatidyl serine inhibitors bavituximab; SIRPA - CD47 inhibitor2024205505   02 Aug 2024monoclonal antibody CC 90002, VEGF inhibitor bevacizumab; and or neuropilin inhibitor monoclonal antibody MNRP1685A.

38. The method of claim 36, wherein the therapeutic agent is temozolomide.

39. The method of claim 34, further comprising administering ionizing radiation.

40. The method of claim 34, further comprising administering temozolomide and ionizing radiation.

41. The method of claim 35, wherein the additional therapeutic agent is selected from AKT inhibitor, alkylating agent, all-trans retinoic acid, antiandrogen, azacitidine, BCL2 inhibitor, BCL-XL inhibitor, BCR-ABL inhibitor, BTK inhibitor, BTK / LCK / LYN inhibitor, CDK1 / 2 / 4 / 6 / 7 / 9 inhibitor, CDK4 / 6 inhibitor, CDK9 inhibitor, CBP / p300 inhibitor, EGFR inhibitor, endothelin receptor antagonist, ERK inhibitor, farnesyltransferase inhibitor, FLT3 inhibitor, glucocorticoid receptor agonist, HDM2 inhibitor, histone deacetylase inhibitor, IKKp inhibitor, immunomodulatory drug (IMiD), ingenol, ionizing radiation, ITK inhibitor, JAK1 / JAK2 / JAK3 / TYK2 inhibitor, MEK inhibitor, midostaurin, MTOR inhibitor, PI3 kinase inhibitor, dual PI3 kinase / MTOR inhibitor, proteasome inhibitor, protein kinase C agonist, SUV39H1 inhibitor, TRAIL, VEGFR2 inhibitor, Wnt / p-catenin signaling inhibitor, decitabine, and anti-CD20 monoclonal antibody.

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