Methods of treating pancreatic cancer

Abstract

The present disclosure relates to methods of treating pancreatic cancer. In particular, methods of treating pancreatic cancer and limiting overexpression of oncogenes, activating tumor suppressor genes, or modulating signaling proteins in a patient are described, comprising administering a compound and a pharmaceutical combination as described herein.

Description

[0001] This application is a divisional application of the invention patent application filed on June 13, 2017, with application number 201780049675.7 and entitled "Method for Treating Pancreatic Cancer".

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 349,217, filed June 13, 2016, entitled “Method for Treating Pancreatic Cancer,” pursuant to 35 USC § 119(e), the entire contents of which are incorporated herein by reference.

[0003] field This disclosure describes methods for treating pancreatic cancer in patients and limiting the overexpression of oncogenes, activating tumor suppressor genes, or regulating signal transduction proteins, including administration of CCR2 chemokine inhibitor compounds and drug combinations as described herein.

[0004] background Cancer is a major health problem worldwide. Despite advances in cancer detection and treatment, there are currently no vaccines or other universally successful preventative and / or treatment methods.

[0005] Current treatments, often based on chemotherapy or a combination of surgery and radiation, continue to prove inappropriate in many patients.

[0006] The pancreas, located in the upper abdomen behind the peritoneum, is closely associated with many major structures, including the portal vein, stomach, duodenum, common bile duct, and superior mesenteric artery.

[0007] Pancreatic cancer is the fifth leading cause of cancer death in the United States. It is more common in men, with the highest risk among men aged 60 to 70. As the tumor grows, symptoms arise from its infiltration into surrounding structures, leading to pain, nausea, vomiting, weight loss, and jaundice. The latter condition presents with symptoms in less than half of patients.

[0008] Once tumor infiltration occurs, other structures such as the portal vein will be affected, thus ruling out curative resection of the pancreas.

[0009] Effective treatment for pancreatic cancer is often delayed by months. This delay has profound implications because 60% of patients have already been diagnosed with metastasis to the liver or lymph nodes, and this factor reduces the prospect of long-term survival. Furthermore, pancreatic cancer is asymptomatic in its early stages. The most common symptoms in later stages are weight loss, abdominal pain, and jaundice. Weight loss, the cause of which is not fully understood, is often significant. Jaundice occurs if the cancer obstructs the common bile duct. By the time it is identified as malignant, it has usually spread (metastasized) to other parts of the body. The median survival from diagnosis is only 6 months.

[0010] Current treatments for this common and refractory disease include surgery and / or chemotherapy. Tumors often cannot be removed surgically because they have invaded vital, inaccessible structures or because they have spread to distant sites.

[0011] Therefore, there is a need in this field to improve the treatment of primary and metastatic pancreatic cancer.

[0012] Attached Figure Figure 1 This indicates the average plasma concentration of compound Ib after intravenous administration in dogs.

[0013] Figure 2 This indicates the mean plasma concentration of compound Ib after oral administration in dogs.

[0014] Overview This disclosure provides compounds that regulate CCR2 chemokine ligand activity and can be used in methods for treating pancreatic cancer. Therefore, the compounds disclosed herein are compounds that regulate at least one function or characteristic of mammalian CCR2 protein, such as human CCR2.

[0015] Therefore, this disclosure describes methods for treating patients with pancreatic cancer, including administering combinations of compounds and drugs as described herein. Methods for limiting the overexpression of oncogenes, activating tumor suppressor genes, and regulating signal transduction proteins are also described, comprising administering an effective amount of any of the compounds or drug combinations as described herein to a patient in need of them.

[0016] One embodiment of this disclosure includes a method of treating a patient with pancreatic cancer, comprising administering an effective amount of a compound of formula I to the patient in need of it: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A 2 and A 3 Each is either -CH- or -N-, where A1 A 2 Or A 3 At least one of them is -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula Ib: Or a pharmaceutically acceptable salt thereof. In one embodiment, the pancreatic cancer is stage I, II, III, or IV pancreatic cancer. In one embodiment, the treatment provides one or more of the following: reduction of tumor size, inhibition or reduction of tumor growth, no new tumor formation, reduction of new tumor formation, increased survival or progression-free survival, no metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improvement of appetite, improvement of digestion, reduction of gallbladder size, and reduction of the incidence of blood clots. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieves slower disease progression. In one embodiment, the patient has one or more of the following: pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreatic progenitor cell carcinoma, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of formula I is provided as an orally administered pharmaceutical composition. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the method includes administering one or more additional therapeutic compounds to a patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine Emetine, Trimethoprim, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Alireta-Retinoic Acid, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0017] One implementation includes a method for treating a patient with pancreatic cancer, comprising administering an effective amount of a compound of formula Ib to the patient in need: Or a pharmaceutically acceptable salt thereof. In one embodiment, the pancreatic cancer is stage I, II, III, or IV pancreatic cancer. In one embodiment, the treatment provides one or more of the following: reduction of tumor size, inhibition or reduction of tumor growth, no new tumor formation, reduction of new tumor formation, increased survival or progression-free survival, no metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improvement of appetite, improvement of digestion, reduction of gallbladder size, and reduction of the incidence of blood clots. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieves slower disease progression. In one embodiment, the patient has pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreatic progenitor cell carcinoma, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of formula Ib is provided as a pharmaceutical composition for oral administration. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the effective amount is 50 mg to 300 mg. In one embodiment, the effective amount is 150 mg. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y)clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0018] One embodiment of this disclosure includes a pharmaceutical combination comprising a compound of formula I: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; A 1 A 2 and A 3 Each is either -CH- or -N-, where A 1, A 2 Some A 3At least one of them is -N-; and one or more other therapeutic compounds. In one embodiment, the one or more other therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, poly-ADP Ribose polymerase inhibitors, poly-ADP-ribose polymerase 1 inhibitors, poly-ADP-ribose polymerase 2 inhibitors, poly-ADP-ribose polymerase 3 inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors. Agents, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, Notch-2 receptor antagonists, Notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM-CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors Hedgehog protein inhibitors; Smoothened receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, novaCaps, trametinib, Atu-027, sonidiazole, GRASPA, tramedersen, nastorazepide, Vaccell, and ozogluconate. Voramab, Istiratumab, Refumetinib, Regorafenib, Lapatinib, Selmetinib, Lucapaib, Pelareorrhep, Taretosumab, Pegylated Hyaluronidase, Varlitinib, Aglatimagenebesadenovec, GBS-01, GI-4000, WF-10, Galunisertib, Afatinib, RX-0201, FG-3019, Pertuzumab, DCVax-Direct, Selinexor, Glucophosphamide, Virulina, Yttrium (90Y) clivatuzumabtetraxetan, bromudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin calcium, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel. In one embodiment, the combination comprises a fixed-dose combination or fractional doses. In one embodiment, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, the combination is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula 1b: Or its pharmaceutically acceptable salt.

[0019] One implementation method includes a method for limiting the overexpression of oncogenes, activating tumor suppressor genes, or regulating signal transduction proteins, comprising administering an effective amount of a compound of formula I to a patient in need of it: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A 2 and A 3 Each is either -CH- or -N-, where A 1 A 2 Or A 3 At least one of them is -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A3 The compound is -N-. In one embodiment, the compound is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula 1b: Or a pharmaceutically acceptable salt thereof. In one embodiment, overexpression of oncogenes, inactivation of tumor suppressor genes, or dysregulation of various signaling proteins leads to a diagnosis of pancreatic cancer in the patient. In one embodiment, the patient has been diagnosed with pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, squamous pancreatic cancer, pancreatic progenitor cell cancer, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, pancreatic ductal adenocarcinoma, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of Formula I is provided as a pharmaceutical composition for oral administration. In one embodiment, a patient achieves a complete response. In one embodiment, a patient achieves a partial response. In one embodiment, a patient achieves stable disease. In one embodiment, a patient achieves slower disease progression. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the method comprises administering one or more additional therapeutic compounds to a patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidylate synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0020] One implementation includes a method for controlling adenocarcinoma in a patient, comprising administering an effective amount of a compound of formula I to the patient in need: Formula I Or a pharmaceutically acceptable salt thereof. In one embodiment, R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A 2 and A 3Each is either -CH- or -N-, where A 1 A 2 Or A 3 At least one of them is -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is... Or a pharmaceutically acceptable salt thereof. In one embodiment, the adenocarcinoma is pancreatic adenocarcinoma. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieves slower disease progression. In one embodiment, the patient achieves clinical benefit. In one embodiment, the clinical benefit is one or more of the following: reduced tumor size, inhibition or reduction of tumor growth, delay of disease progression time, no new tumors or lesions, reduction of new tumor formation, increased survival or progression-free survival, no metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improvement of appetite, improvement of digestion, reduction of gallbladder size, and reduction of blood clot incidence. In one embodiment, the compound of formula I is provided as an orally administered pharmaceutical composition. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the effective amount is from 50 mg to 300 mg. In one embodiment, the effective amount is 150 mg. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCGLiver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutacil, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephostine, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, Fluorouracil, Fludarabine Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Tiimomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon α-2a, Interferon α-2b, Irinotecan, Lenalidomide, Letrozole, Leucovorin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, Mitomycin C, Mitotan, Mitoxantrone, Nandrolone, Nerapine, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Parib Fumin, pamidronate, pegaspargase, pegaspargase, pemetrexed disodium, pentostatin, piperobromane, procamycin, porphyrin sodium, procarbazine, quinacrine, raburicase, rituximab, nostolinib, saxaglastine, sorafenib, streptozotocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testosterone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tosimomab, trastuzumab, retinoic acid, ATRA, uramustine, pentorubicin, vinblastine The compounds include alkaloids, vincristine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvastatinab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, one or more of the additional therapeutic compounds are FOLFIRINOX. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0021] Detailed Explanation This disclosure relates to methods of treating a patient with pancreatic cancer by administering a combination of compounds and drugs as described herein. Methods for limiting the overexpression of oncogenes, activating tumor suppressor genes, or regulating signal transduction proteins are also described, including administering an effective amount of any of the compounds or drug combinations as described herein to a patient in need of such treatment. Therefore, this disclosure describes compounds that regulate at least one function or characteristic of mammalian CCR2 protein, such as human CCR2.

[0022] Abbreviations and Definitions The following definitions are intended to clarify, but not limit, the terms defined. If a particular term used herein is not specifically defined, it should not be considered undefined. Rather, it is used by those skilled in the art within its acceptable meaning.

[0023] "alkyl" itself, or as part of another substituent, refers to a hydrocarbon group that can be straight-chain, cyclic, branched, or a combination thereof, having a specified number of carbon atoms (i.e., C40, C50, C6 ... 1-8 (Represents one to eight carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, cyclohexyl, cyclopentyl, (cyclohexyl)methyl, cyclopropylmethyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc.

[0024] "Alkoxy" refers to -O-alkyl. Examples of alkoxy groups include methoxy, ethoxy, and n-propoxy.

[0025] "Clinical benefit" is a phrase used by physicians and / or clinicians treating cancer. The term includes any understood or perceived benefit experienced by the patient during treatment. As used herein, the term includes, but is not limited to, one or more clinical benefits, which are one or more of the following: reduced tumor size, inhibition or reduction of tumor growth, delay of disease progression time, absence of new tumors or lesions, reduction of new tumor formation, increased survival or progression-free survival, absence of metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improved appetite, improved digestion, reduction of gallbladder size, and reduction of the incidence of blood clots.

[0026] "Complete response" refers to a response that leads to the complete eradication of non-invasive or invasive cancer.

[0027] "FOLFIRINOX" refers to a chemotherapy regimen used to treat advanced pancreatic cancer. It consists of the following four drugs: a) FOL-leucovorin (formyltetrahydrofolate), a vitamin B derivative, which regulates / enhances / reduces the side effects of fluorouracil; b) F-fluorouracil (5-FU), a pyrimidine analog and antimetabolite that incorporates into DNA molecules and inhibits DNA synthesis; c) IRIN-irinotecan (Camptosar), a topoisomerase inhibitor that prevents DNA unwinding and replication; and d) OX-Oxaliplatin (Eloxatin), a platinum-based antitumor agent that inhibits DNA repair and / or DNA synthesis.

[0028] "Halogen" or "halogen" itself or as part of a substituent refers to a chlorine, bromine, iodine, or fluorine atom.

[0029] "Haloalkyl" as a substituted alkyl group refers to monohaloalkyl or polyhaloalkyl, which is most commonly substituted with 1-3 halogen atoms. Examples include 1-chloroethyl, 3-bromopropyl, trifluoromethyl, etc.

[0030] "Heteroatoms" refers to oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0031] "Partial response" refers to a response that results in a reduction of at least 30% in tumor size compared to baseline (i.e., before the application of the compound).

[0032] A "pharmaceutically acceptable" carrier, diluent, or excipient is a carrier, diluent, or excipient that is compatible with other components of the formulation and is harmless to its recipient.

[0033] "Pharmaceutically acceptable salt" means a salt that is acceptable for administration to a patient (e.g., a mammal) (e.g., a salt that has acceptable mammalian safety for a given dosage regimen). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the specific substituents found on the compounds described herein. When the compounds of this disclosure contain relatively acidic functional groups, a base addition salt can be obtained by contacting such a compound in its neutral form with a sufficient amount of the desired base (pure or in a suitable inert solvent). Salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese sulfide, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include the following: primary amines, secondary amines, tertiary amines, and quaternary amines, including substituted amines, cyclic amines, and naturally occurring amines, such as arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds in their neutral form with a sufficient amount of the desired acid (pure or in a suitable inert solvent). Salts derived from pharmaceutically acceptable acids include acetates, ascorbic acid salts, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethanesulfonates, fumarates, gluconates, glucuronates, glutamates, hippurates, hydrobromide salts, hydrochlorides, hydroxyethylsulfonates, lactates, lacturonic acid, maleates, malates, mandelates, methanesulfonates, mucilages, naphthalenesulfonates, nicotinates, nitrates, dihydroxynaphthaleneate, pantothenates, phosphates, succinates, sulfates, tartrates, and p-toluenesulfonates.

[0034] This also includes salts of amino acids, such as arginine salts, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM et al., “Pharmaceutical Salts”, J. PharmaceuticalScience, 1977, 66:1-19). Certain specific compounds disclosed herein contain both basic and acidic functional groups, which allow the compounds to be converted into base or acid addition salts.

[0035] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties, such as solubility in polar solvents, but in other respects is equivalent to the parent form of the compound for the purposes of this disclosure.

[0036] "Disease progression" refers to an increase of at least 20% in tumor size or spread since the start of treatment.

[0037] "Its salt" refers to a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation, or a compound formed by a base that is protonated with an anti-counterion. Preferably, the salt is a pharmaceutically acceptable salt, although this is not necessary for the salt of intermediate compounds that are not intended to be administered to a patient.

[0038] In addition to the salt form, this disclosure also provides compounds in prodrug form. The prodrugs of the compounds described herein are those compounds that are readily subjected to chemical changes under physiological conditions to provide the compounds of this disclosure. Furthermore, prodrugs can be converted into the compounds of this disclosure in an in vitro environment by chemical or biochemical methods. For example, when a prodrug is placed in a transdermal patch reservoir, it can be slowly converted into the compounds of this disclosure using suitable enzymes or chemical reagents.

[0039] "Stable condition" refers to cancer whose extent or severity neither increases nor decreases.

[0040] "Therapeutic effective dose" refers to the amount that is sufficient to achieve therapeutic effect when administered to a patient in need of treatment.

[0041] As used herein, “treating” means treating a patient’s disease or medical condition (e.g., viral, bacterial, or fungal infection or other infectious disease, as well as autoimmune or inflammatory conditions), said patient being, for example, a mammal (particularly a human or pet), which includes improving the disease or medical condition, i.e., eliminating or causing the remission of the patient’s disease or medical condition; suppressing the disease or medical condition, i.e., slowing or preventing the progression of the patient’s disease or medical condition; or alleviating the symptoms of the patient’s disease or medical condition.

[0042] Some compounds of this disclosure may exist in both solvated and hydrated forms, including hydrated forms. Generally, both solvated and hydrated forms are intended to be included within the scope of this disclosure. Some compounds of this disclosure may exist in a variety of crystalline or amorphous forms (i.e., as polymorphs). Generally, all physical forms are equivalent for the purposes contemplated in this disclosure and are intended to fall within the scope of this disclosure.

[0043] It will be apparent to those skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, and all such tautomeric forms of compounds are within the scope of this disclosure. Certain compounds of this disclosure have asymmetric carbon atoms (optical centers) or double bonds; racemic mixtures, diastereomers, geometric isomers, and single isomers (e.g., isolated enantiomers) are all intended to be included within the scope of this disclosure. The compounds of this disclosure may also contain non-natural proportions of atomic isotopes at one or more atoms constituting such compounds. Non-natural proportions of isotopes can be defined as ranging from amounts found in nature to amounts consisting of 100% of the atoms in discussion. For example, compounds may be doped with radioactive isotopes, such as tritium (…). 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C), or non-radioactive isotopes, such as deuterium (C), 2 H) or carbon-13 ( 13 (c) Such isotopic variations can provide additional utility for those described elsewhere in this application. For example, isotopic variants of the compounds of the present invention may be found to have additional utility, including but not limited to, as diagnostic and / or imaging agents, or as therapeutic agents for cytotoxicity / radiotoxicity. Additionally, isotopic variants of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics, which may contribute to enhanced safety, tolerability, or efficacy during treatment. All isotopic variations of the compounds of the present invention, regardless of radioactivity, are intended to be included within the scope of this disclosure.

[0044] Compounds that regulate CCR2 activity This disclosure provides compounds for regulating CCR2 activity. Chemokine receptors are intact membrane proteins that interact with extracellular ligands (e.g., chemokines) and mediate cellular responses to the ligands, such as chemotaxis, increased intracellular calcium ion concentration, etc. Therefore, regulating chemokine receptor function, for example, by interfering with chemokine receptor-ligand interactions, will modulate chemokine receptor-mediated responses and treat or prevent chemokine receptor-mediated conditions or diseases. Regulation of chemokine receptor function includes both induction and inhibition of function. The type of regulation achieved will depend on the characteristics of the compound, i.e., antagonist or complete, partial, or inverse agonist.

[0045] Without being bound by any particular theory, the compounds provided herein are believed to interfere with the interaction between chemokine receptors and one or more homologous ligands. In particular, these compounds are believed to interfere with the interaction between CCR2 and CCR2 ligands (e.g., MCP-1). Compounds contemplated in this disclosure include, but are not limited to, the exemplary compounds and their salts provided herein.

[0046] The compounds disclosed herein are believed to interfere with inappropriate T-cell transport by specifically modulating or inhibiting chemokine receptor function. Compounds contemplated in this disclosure include, but are not limited to, the exemplary compounds and their salts provided herein.

[0047] compound One embodiment of this disclosure includes a compound of formula I, or a salt thereof: Formula I R 1 Halogen or C 1-6 alkyl; R 2 Selected from groups including: hydrogen, halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 Selected from groups including: hydrogen, halogens, or C. 1-6 alkyl; R 4 If present, it is selected from the group containing: hydrogen, halogen, or C. 1-6 alkyl; Each R 5 If it exists, it is independently selected from the group containing the following: C 1-6 Alkyl, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A 2 and A 3 Each is either -CH- or -N-, where A 1 A 2 Or A 3 At least one of them is -N-.

[0048] Since any composition described herein defines any atom as nitrogen, that is, for A 1 A 2 and A 3 Those skilled in the art will understand that the nitrogen atom will retain its aromaticity. Nothing in this disclosure should be interpreted otherwise.

[0049] In one implementation, R 1 R2 is a halogen or methyl group; R2 is a halogen or C group. 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N; A2 For -CH; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from the following formula or a salt thereof: and .

[0050] In another embodiment, the compound is a compound of formula 1b or a salt thereof.

[0051] Composition.

[0052] Pharmaceutically acceptable compositions may be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment or drops), buccally, or as a mouth or nasal spray.

[0053] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to one or more active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water, or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0054] Injectable formulations can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques, such as sterile injectable aqueous or oily suspensions. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable media and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid can be incorporated into the injectable product. Injectable formulations can be sterilized, for example, by filtration through a bacterial trap filter or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0055] To prolong the effects of the disclosed compounds, it is generally necessary to slow the absorption of compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound then depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the parenteral administration of the compound can be achieved by dissolving or suspending the compound in an oily medium. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. The rate of compound release can be controlled depending on the ratio of compound to polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable reservoir formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0056] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds of this disclosure with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity and releases the active compound.

[0057] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silica, (b) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (c) humectants such as glycerin, (d) disintegrants such as agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate, (e) solution blockers such as paraffin, (f) absorption enhancers such as quaternary ammonium compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) absorbents such as kaolin and bentonite, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0058] Excipients such as lactose or toffee and high molecular weight polyethylene glycol can also be used as fillers in soft and hard-filled gelatin capsules. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They may optionally contain light-blocking agents and may also be compositions that release one or more active ingredients, either alone or preferably in a portion of the intestine, optionally in a delayed manner. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Excipients such as lactose or toffee and high molecular weight polyethylene glycol can also be used as fillers in soft and hard-filled gelatin capsules.

[0059] The compounds disclosed herein or their pharmaceutically acceptable salts can be formulated using nanotechnology. Nanoparticles are attractive for medical purposes due to their unique characteristics, such as their higher surface-to-mass ratio than other particles, their quantum properties, and their ability to adsorb and carry other compounds. Nanoparticles can have sizes below 0.1 μm or 100 nm. Alternatively, pharmaceutical compositions can contain relatively large (size >100 nm) nanoparticles, as needed to load a sufficient amount of drug onto the particles. Furthermore, for drug delivery, not only can engineered particles be used as carriers, but the drug itself can also be formulated at the nanoscale and then used as its own carrier. The composition of engineered nanoparticles can vary. The source material can be biologically derived, such as phospholipids, lipids, lactic acid, dextran, chitosan, or have more chemical characteristics, such as various polymers, carbon, silica, and metals. Especially in the field of polymer-derived engineered nanoparticles, the chemical composition offers a wide range of possibilities. See, for example, Martins et al. Nanoparticle Drug Delivery Systems: Recent Patents and Applications in Nanomedicine, Recent Patents on Nanomedicine, 2013, 3(2), pp 1 - 14.

[0060] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may also be in a microencapsulated form having one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells, such as enteric coatings, release-controlled coatings, and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, or starch. Conventionally, such dosage forms may also contain substances other than inert diluents, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage forms may also contain buffers. They may optionally contain light-blocking agents and may also be compositions that release one or more active ingredients, either alone or preferably in a delayed manner, only in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0061] Dosage forms for topical or transdermal application of the compounds of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer under aseptic conditions, as needed. Ophthalmic preparations, ear drops, and eye drops are also contemplated to fall within the scope of this disclosure. Additionally, transdermal patches are contemplated for use, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0062] Treatment One embodiment of this disclosure includes a method for treating a patient with pancreatic cancer, comprising administering an effective amount of any of the compounds described herein to a patient in need of it. In one embodiment, the pancreatic cancer is stage I, II, III, or IV pancreatic cancer. In one embodiment, the treatment provides one or more of the following: reduction in tumor size, inhibition or reduction of tumor growth, no new tumor formation, reduction of new tumor formation, increased survival or progression-free survival, absence of metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improvement of appetite, improvement of digestion, reduction of gallbladder size, and reduction of the incidence of blood clots. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieves slower disease progression. In one embodiment, the patient has one or more of the following: pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreatic progenitor cell carcinoma, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of formula I is provided as an orally administered pharmaceutical composition. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine Emetine, Trimethoprim, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Alireta-Retinoic Acid, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0063] One embodiment of this disclosure includes a method of treating a patient with pancreatic cancer, comprising administering an effective amount of a compound of formula Ib to the patient in need of it: .

[0064] In one implementation, the pancreatic cancer is stage I, II, III, or IV pancreatic cancer. In one implementation, the treatment provides one or more of the following: reducing tumor size, inhibiting or reducing tumor growth, preventing new tumor formation, reducing new tumor formation, increasing survival or progression-free survival, preventing metastasis, increasing treatment options, delaying the time from surgery to recurrence, reducing jaundice, inhibiting spread to the liver, reducing pain, improving appetite, improving digestion, reducing gallbladder size, and reducing the incidence of blood clots. In one implementation, the patient achieves a complete response. In one implementation, the patient achieves a partial response. In one implementation, the patient achieves stable disease. In one implementation, the patient achieves slower disease progression. In one embodiment, the patient has one or more of the following: pancreatic adenocarcinoma, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, unresectable pancreatic cancer, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreatic progenitor cells, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of formula Ib is provided as an orally administered pharmaceutical composition. In one embodiment, the compound is administered once daily. In one embodiment, the compound of formula Ib is administered twice daily. In one embodiment, the effective amount is 50 mg to 300 mg. In one embodiment, the effective amount is 150 mg. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one aspect of this embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0065] One embodiment of this disclosure includes a pharmaceutical combination comprising a compound of formula 1: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; A 1 A 2 and A 3 Each is either -CH- or -N-, where A 1, A 2 Some A 3At least one of them is -N-; and one or more additional therapeutic compounds. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ogovanumab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximab, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia + Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCGLiver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutacil, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephostine, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, Fluorouracil, Fludarabine Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Tiimomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon α-2a, Interferon α-2b, Irinotecan, Lenalidomide, Letrozole, Leucovorin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, Mitomycin C, Mitotan, Mitoxantrone, Nandrolone, Nerapine, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Parib Fumin, pamidronate, pegaspargase, pegaspargase, pemetrexed disodium, pentostatin, piperobromane, procamycin, porphyrin sodium, procarbazine, quinacrine, raburicase, rituximab, nostolinib, saxaglastine, sorafenib, streptozotocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testosterone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tosimomab, trastuzumab, retinoic acid, ATRA, uramustine, pentorubicin, vinblastine The compounds include alkaloids, vincristine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvamarab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, one or more of the additional therapeutic compounds are FOLFIRINOX. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and nab-paclitaxel. In one embodiment, the combination comprises a fixed-dose combination or fractional doses. In one aspect of this implementation plan, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from the following formula or a salt thereof: and .

[0066] In one embodiment, the compound is a compound of formula Ib: .

[0067] In one embodiment, the method includes administering a combination of drugs containing any of the compounds described herein.

[0068] One embodiment of this disclosure includes methods for restricting the overexpression of oncogenes, activating tumor suppressor genes, or regulating signal transduction proteins, comprising administering an effective amount of a compound of formula I to a patient in need of it: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 alkyl; Each R 5 Independently for C 1-6 Alkyl, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A2 and A 3 Each is either -CH- or -N-, where A 1 A 2 Or A 3 At least one of them is -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula Ib: Or a pharmaceutically acceptable salt thereof. In one aspect of this embodiment, overexpression of oncogenes, inactivation of tumor suppressor genes, or dysregulation of various signaling proteins leads to a diagnosis of pancreatic cancer in the patient. In one embodiment, the patient has been diagnosed with pancreatic adenocarcinoma, unresectable pancreatic cancer, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, squamous pancreatic cancer, pancreatic progenitor cell cancer, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, pancreatic ductal adenocarcinoma, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor. In one embodiment, the compound of formula I is provided as a pharmaceutical composition for oral administration. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieved slower disease progression. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCG Liver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutamol, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dextromethorphan, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide Glycosides, Exemestane, Filgrastim, Fluorouracil, Fludarabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Teimimonab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, MitomycinC. Mitotan, Mitoxantrone, Nandrolone, Nerapin, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Palivmin, Pamidronate, Pegaspargase, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenyl, Pucarimycin, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinotinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Vinegar Formic acid, ATRA, uramustine, penoxuridine, vincristine, vinblastine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvalbumin, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, the one or more additional therapeutic compounds are FOLFIRINOX. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, the one or more additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0069] One embodiment of this disclosure includes a method for controlling adenocarcinoma in a patient, comprising administering an effective amount of a compound of formula I to the patient in need: Formula I Or a pharmaceutically acceptable salt thereof, wherein R 1 Halogen or C 1-6 Alkyl; R 2 For hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy or -CN; R 3 It is hydrogen, halogen or C 1-6 Alkyl; R 4 It is hydrogen, halogen or C 1-6 Alkyl; each R 5 Independently for C 1-6 Alkyl group, -OH, or -NH2; n is 0, 1, 2, or 3; and A 1 A 2 and A 3Each is either -CH- or -N-, where A 1 A 2 Or A 3 At least one of them is -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 Halogen or C 1-6 Halogenated alkyl; R 3 Halogen or C 1-6 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 For -N-. In one implementation, R 1 It is a halogen or methyl group; R 2 C 1-3 Halogenated alkyl; R 3 Halogen or C 1-3 Alkyl; R 4 It is hydrogen; n is 0; A 1 For -CH- or -N-; A 2 For -CH-; and A 3 The compound is -N-. In one embodiment, the compound is selected from: and Or a pharmaceutically acceptable salt thereof. In one embodiment, the compound is a compound of formula Ib: Or a pharmaceutically acceptable salt thereof. In one embodiment, the adenocarcinoma is pancreatic adenocarcinoma. In one embodiment, the patient achieves a complete response. In one embodiment, the patient achieves a partial response. In one embodiment, the patient achieves stable disease. In one embodiment, the patient achieves slower disease progression. In one embodiment, the patient achieves clinical benefit. In one embodiment, the clinical benefit is one or more of the following: reduced tumor size, inhibition or reduction of tumor growth, delay of disease progression time, no new tumors or lesions, reduction of new tumor formation, increased survival or progression-free survival, no metastasis, increased treatment options, delay of time from surgery to recurrence, reduction of jaundice, inhibition of spread to the liver, reduction of pain, improvement of appetite, improvement of digestion, reduction of gallbladder size, and reduction of blood clot incidence. In one embodiment, the compound of formula I is provided as an orally administered pharmaceutical composition. In one embodiment, the compound is administered once daily. In one embodiment, the compound is administered twice daily. In one embodiment, the effective amount is from 50 mg to 300 mg. In one embodiment, the effective amount is 150 mg. In one embodiment, the method further includes administering one or more additional therapeutic compounds to the patient. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, polyADP-ribose polymerase inhibitors, polyADP-ribose polymerase 1 inhibitors, polyADP-ribose polymerase 2 inhibitors, and polyADP-ribose polymerase...3. Inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, notch-2 receptor antagonists, notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM -CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, hedgehog protein inhibitors; smoothed receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, RasGTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators. In one embodiment, the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidiazole, GRASPA, trabedersen, nastorazepide, Vaccell, ozovozab, istiramumab, remetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, varlitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-0201, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia +Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCGLiver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutacil, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Doxorubicin (neutral), Doxorubicin Hydrochloride, Drotahistamine Propionate, Epirubicin, Ephostine, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, Fluorouracil, Fludarabine Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Tiimomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon α-2a, Interferon α-2b, Irinotecan, Lenalidomide, Letrozole, Leucovorin, Leuprorelin Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, Mitomycin C, Mitotan, Mitoxantrone, Nandrolone, Nerapine, Nofetumab, Olepiridone, Interleukin, Oxaliplatin, Paclitaxel, Parib Fumin, pamidronate, pegaspargase, pegaspargase, pemetrexed disodium, pentostatin, piperobromane, procamycin, porphyrin sodium, procarbazine, quinacrine, raburicase, rituximab, nostolinib, saxaglastine, sorafenib, streptozotocin, sunitinib maleate, talc, tamoxifen, temozolomide, teniposide, VM-26, testosterone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tosimomab, trastuzumab, retinoic acid, ATRA, uramustine, pentorubicin, vinblastine The compounds include alkaloids, vincristine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvastatinab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003. In one embodiment, one or more of the additional therapeutic compounds are FOLFIRINOX. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and paclitaxel. In one embodiment, one or more of the additional therapeutic compounds are gemcitabine and nab-paclitaxel.

[0070] Dosing regimen This document provides dosing regimens for the treatment of pancreatic cancer, comprising administering a compound of formula I, Ia, Ib, or Ic in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 6, 12, 24, or 48 weeks. In some embodiments, the dosing regimen comprises administering a compound of formula I, Ia, Ib, or Ic in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 12 weeks. In some embodiments, the dosing regimen comprises administering a compound of formula Ib in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 6, 12, 24, or 48 weeks. In some embodiments, the dosing regimen comprises administering a compound of formula Ib in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 12 weeks. In some embodiments, the dosing regimen comprises administering a compound of formula Ib in combination with Folfirinox for 12 weeks.

[0071] This document provides dosing regimens for the treatment of pancreatic cancer, comprising administering a compound of formula I, Ia, Ib, or Ic in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 6, 12, 24, or 48 weeks, followed by administration of fluorouracil (5-FU) alone or a compound of formula I, Ia, Ib, or Ic alone. In some embodiments, the dosing regimen comprises administering a compound of formula I, Ia, Ib, or Ic in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 12 weeks, followed by administration of fluorouracil (5-FU) alone or a compound of formula I, Ia, Ib, or Ic alone. In some embodiments, the dosing regimen comprises administering a compound of formula Ib in combination with Folfirinox or gemcitabine and paclitaxel or gemcitabine and nab-paclitaxel for 12 weeks, followed by administration of fluorouracil (5-FU) alone or a compound of formula Ib alone. In some implementations, the dosing regimen includes administration of a compound of formula Ib in combination with Folfirinox for up to 12 weeks, followed by administration of fluorouracil (5-FU) alone or a compound of formula Ib alone.

[0072] Example 1 - Treatment Method Fifty-four patients aged 18 years and older participated in an open-label phase 1-b interventional study to evaluate the safety and efficacy of compound Ib in patients with pancreatic adenocarcinoma who were also receiving FOLFIRINOX chemotherapy. Dosage consisted of 150 mg oral tablets administered once or twice daily for at least 12 weeks.

[0073] Inclusion criteria include: • Unresectable pancreatic adenocarcinoma, with or without metastasis, confirmed by histology or cytology. • Eastern Cooperative Oncology Group (ECOG) activity status score ≤2 • Life expectancy ≥ 12 weeks • Radiographically measurable diseases, according to RECIST 1.1 • Use appropriate contraception (as described in the agreement). • Able to provide written informed consent and comply with research requirements.

[0074] Exclusion criteria include: • Received other cancer treatments or investigational drugs within 4 weeks prior to screening. • Women who are pregnant or breastfeeding • Major surgery within 4 weeks of the first dose of the study drug • Liver, kidney, or bone marrow insufficiency within 2 weeks of the first dose • Serious complications, altered medical condition, or any uncontrolled medical condition. • Screen for any infection within the past 4 weeks that requires antibiotic or antiviral treatment. • Known active HIV, HBV, or HCV infection • Do not swallow tablets • Any medical condition or disease that the researcher believes could place a subject at an unacceptable risk of participating in the study.

[0075] Example 2 - Pharmacokinetic parameters of compounds Ib and PF-04136309 in Sprague-Dawley rats Compounds Ib and PF-04136309 in aqueous hydroxypropyl methylcellulose were administered intravenously at 0.5 mg / kg and orally at 2 mg / kg. Blood samples were collected at predetermined time points after each administration, and the corresponding plasma concentrations of compounds Ib and PF-04136309 were analyzed using LC-MS / MS. Plasma concentration-time curves were constructed, and the corresponding pharmacokinetic parameters were obtained using non-compartmental analysis.

[0076] For intravenous administration, blood (0.2 mL) was collected via jugular vein or cardiac puncture (for endpoint only) before administration, and at 2, 5, 10, 15, and 30 minutes, and 1, 2, 4, 6, and 8 hours after administration; and for oral administration, blood was collected via jugular vein or cardiac puncture (for endpoint only). Blood samples were collected into frozen polypropylene tubes containing sodium EDTA as an anticoagulant, and plasma was collected by centrifugation (Eppendorf Centrifuge 5417R) at 10,000 rpm and 4°C for 6 minutes and stored at -20°C until analysis.

[0077] Plasma sample (50 μL) was extracted with 200 μL of acetonitrile containing internal standard on a linear shaker for 10 min, followed by centrifugation at 3700 g for 10 min at 4 °C (Allegra X-15R centrifuge, Beckman Coulter, Inc., Fullerton, CA). 100 μL of the resulting supernatant was transferred to a new plate and mixed with 100 μL of 0.1% formic acid aqueous solution for LC-MS / MS analysis.

[0078] Calibration standards were prepared from blank Sprague-Dawley rat plasma at concentrations of 5000, 2500, 1000, 500, 100, 50, 20, 10, 4, 2, and 1 ng / mL. Three levels of standard stock solutions (1000, 100, and 10 ng / mL) were infused into male Sprague-Dawley rat plasma and used as QC samples. The plasma standards and QC samples were treated in the same manner and prepared in parallel with the plasma samples. The extracted samples were analyzed by LC-MS / MS.

[0079] Mass spectrometry data acquisition and integration were performed using Applied Biosystems-Sciex Analyst software (version 1.4.2). Calibration curves were obtained through quadratic regression, with a calibration range of 2–5000 ng / mL.

[0080] instrument: • API 3000 mass spectrometer (Applied Biosystems, Foster City, CA) • Agilent 1100 HPLC binary pump (Santa Clara, CA) • LEAP Technologies HTS Pal Automated Sampler (Carrboro, NC) • Thermo Scientific Cohesive Aria LX-2 Dual System (Waltham, MA) Column: Zorbax Eclipse XDB Phenyl 2.1 × 50 mm (Agilent, Santa Clara, CA) Injection volume: 10 µL Flow rate: 0.60 mL / min.

[0081] Table 1. HPLC gradient .

[0082] Ionization mode: Electrospray ionization (ESI). Detection mode: Positive ion MRM. For each route of administration, descriptive pharmacokinetic parameters were determined from plasma concentration-time curves using standard non-compartmental analysis (Wagner, 1993). Pharmacokinetic analysis was performed using XLFit® v.4.3.1 (ID Business Solutions Inc., Alameda, CA) in conjunction with Microsoft Excel 2003.

[0083] Table 2. Pharmacokinetic parameters of compounds Ib and PF-04136309 in Sprague-Dawley rats .

[0084] Compared to PF-4136309, compound Ib has a much lower clearance rate and a much higher exposure (AUC).

[0085] Example 3 - Pharmacokinetic parameters of compound Ib in beagle dogs The pharmacokinetic profile of compound Ib was evaluated in male beagle dogs following intravenous (iv) and oral (po) administration. A single dose of compound Ib was administered intravenously at 0.5 mg / kg and orally at 2 mg / kg. Blood samples were collected at predetermined time points after each administration, and the corresponding plasma samples were analyzed using LC-MS / MS. Plasma concentration-time curves were constructed using plasma concentrations, and the corresponding pharmacokinetic parameters were obtained through non-compartmental analysis.

[0086] Six animals weighing 11.5, 9.9, 9.9, 14.6, 11.1 and 9.8 kg were given compound Ib intravenously at 0.5 mg / kg (the first three animals) and compound Ib orally at 2 mg / kg (the last three animals).

[0087] For intravenous administration, a solution of compound Ib was prepared at 0.5 mg / mL in 35.8% water / 31.6% propylene glycol / 31.6% N,N-dimethylacetamide, and each animal received 1 mL / kg. For oral administration of 2 mg / kg, a solution was prepared at 0.5 mg / mL in 1% hydroxypropyl methylcellulose, and each animal received 4 mL / kg.

[0088] For administration, blood (~1 mL) was drawn before administration and at 5, 15, and 30 minutes, and at 1, 2, 4, 8, 12, and 24 hours after administration. Blood was collected from a forelimb vein via a butterfly catheter and placed in a frozen polypropylene tube containing K2EDTA as an anticoagulant, and kept on ice until centrifugation. Plasma was collected by centrifugation and transported on dry ice for sample analysis.

[0089] Plasma sample (50 μL) was extracted for 10 min on a linear shaker using 200 µL of 0.1% formic acid / acetonitrile containing an internal standard, followed by centrifugation at 3700 g for 10 min at 4 °C (Allegra X-15R centrifuge, Beckman Coulter, Inc., Fullerton, CA). 100 μL of the resulting supernatant was transferred to a new plate and mixed with 100 μL of 0.1% formic acid aqueous solution for LC-MS / MS analysis.

[0090] Calibration standards were prepared using blank canine plasma at concentrations of 5000, 2500, 1000, 500, 100, 50, 20, 10, 4, 2, and 1 ng / mL of compound Ib. Three levels of standard stock solutions (1000, 100, and 10 ng / mL) were incorporated into male beagle plasma and used as QC samples. The plasma standards and QC samples underwent the same treatment and were prepared in parallel with the plasma samples.

[0091] Sample analysis was performed by LC-MS / MS (details below). Acquisition and peak integration were performed using Applied Biosystems-Sciex Analyst software (version 1.4.2). Calibration curves were obtained through quadratic regression with a weight of 1 / x. The calibration range was 1–5000 ng / mL.

[0092] instrument: • Applied Biosystems API 3000 mass spectrometer (Foster City, CA) • Agilent 1100 HPLC binary pump (Santa Clara, CA) • LEAP Technologies HTS Pal Automated Sampler (Carrboro, NC) • Thermo Scientific Cohesive Aria LX-2 Dual System (Waltham, MA) Column: Zorbax Eclipse XDB Phenyl 2.1x50 mm (Agilent, Santa Clara, CA) Injection volume: 10 µL Flow rate: 0.60 mL / min.

[0093] Table 3: HPLC gradient Ionization mode: Turbo Ionspray ESI Detection mode: Positive ion MRM For each route of administration, descriptive pharmacokinetic parameters were determined from plasma concentration-time curves using standard non-compartmental analysis (Wagner, 1993).

[0094] •CL: Total clearance rate •AUC: Area under the curve •F: Bioavailability.

[0095] Pharmacokinetic analysis was performed using XLFit® v.4.3.1 (ID Business Solutions Inc., Alameda, CA) in conjunction with Microsoft Excel 2003.

[0096] Table 4: Mean pharmacokinetic parameters of compounds Ib and PF-04136309 after intravenous and oral administration (N=3) .

[0097] The pharmacokinetic parameters of PF-4136309 are disclosed in ACS Med. Chem. Lett. 2011, 2, 913-918.

[0098] Compared to PF-4136309, compound Ib exhibits significantly lower clearance and significantly higher exposure (AUC) at comparable doses.

[0099] Figure 1 This indicates the average plasma concentration of compound Ib after intravenous administration in dogs.

[0100] Figure 2 This indicates the mean plasma concentration of compound Ib after oral administration in dogs.

[0101] The specific pharmacological response observed may vary depending on the specific active compound selected or the presence of a drug carrier, as well as the type of formulation and route of administration, and such expected variations or differences in the results should be considered in accordance with the practice of this disclosure.

[0102] Although this document provides detailed descriptions of specific embodiments of the present disclosure, the disclosure is not limited thereto. The above detailed description is provided as examples of the present disclosure and should not be construed as constituting any limitation thereof. Modifications will be apparent to those skilled in the art, and all modifications without departing from the spirit of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. Use of compounds of formula Ib or pharmaceutically acceptable salts thereof in the preparation of medicaments for treating patients with pancreatic cancer: ， The pancreatic cancer mentioned therein is stage I, II, III or IV pancreatic cancer.

2. The use of claim 1, wherein the patient suffers from: pancreatic adenocarcinoma, unresectable pancreatic cancer, locally advanced pancreatic cancer, marginally resectable pancreatic cancer, locally advanced pancreatic ductal adenocarcinoma, marginally resectable pancreatic ductal adenocarcinoma, metastatic pancreatic cancer, chemotherapy-resistant pancreatic cancer, pancreatic ductal adenocarcinoma, squamous pancreatic cancer, pancreatic progenitor cells, immunogenic pancreatic cancer, abnormally differentiated endocrine-exocrine (ADEX) tumor, exocrine pancreatic cancer, pancreatic intraepithelial neoplasia, intraductal papillary myxoma, mucinous cystic tumor, mucinous pancreatic cancer, adenosquamous carcinoma, signet ring cell carcinoma, hepatoid carcinoma, colloid carcinoma, undifferentiated carcinoma, undifferentiated carcinoma with osteoclast-like giant cells, pancreatic cystic tumor, islet cell tumor, pancreatic endocrine tumor, or pancreatic neuroendocrine tumor.

3. The use of claim 1, further comprising administering one or more additional therapeutic compounds to the patient.

4. The use of claim 3, wherein the one or more additional therapeutic compounds are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, mTOR inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, and poly(kJ / ... ADP-ribose polymerase inhibitors, poly-ADP-ribose polymerase 1 inhibitors, poly-ADP-ribose polymerase 2 inhibitors, poly-ADP-ribose polymerase 3 inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL-17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 Inhibitors, PD-L1 inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, Notch-2 receptor antagonists, Notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM-CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors. Hedgehog protein inhibitors; Smoothened receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β2 receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, Ras GTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators.

5. The use of claim 3, wherein the one or more additional therapeutic compounds are selected from one or more of the following: bavitimab, IMM-101, CAP1-6D, Rexin-G, genistein, CVac, MM-D37K, PCI-27483, TG-01, mocetinostat, LOAd-703, CPI-613, upamostat, CRS-207, NovaCaps, trametinib, Atu-027, sonidira, GRASPA, trabedersen, nastorazepide, Vaccell, ogovanumab, istiramumab, refumetinib, regorafenib, lapatinib, selmetinib, rucapranib, pelareorep, taretoximate, pegylated hyaluronidase, velitinib, aglatimagene besadenovec, GBS-01, GI-4000, WF-10, galunisertib, afatinib, RX-011, FG-3019, pertuzumab, DCVax-Direct, selinexor, glucosamine, virulencerin, yttrium (90Y) clivatuzumab tetraxetan, brivudine, nimotuzumab, algenpantucel-L, tegafur + germstroemia + otetracil potassium + leucovorin, olaparib, ibrutinib, pirarubicin, Rh-Apo2L, tertomotide, tegafur + germstroemia + otetracil potassium, tegafur + germstroemia + Oteiracil potassium, masatitinib, Rexin-G, mitomycin, erlotinib, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, paclitaxel, interferons, platinum derivatives, taxane, paclitaxel, vinca alkaloids, vinca alkaloids, anthracyclines, doxorubicin, epipodophyllotoxin, etoposide, cisplatin, rapamycin, methotrexate, actinomycin D, serotonin 10, colchicine, vomiting Radix et al., Trimethyltroxazone, Chlorpheniramine, Cyclosporine, Donomycin, Teniposide, Amphotericin B, Alkylating Agents, Chlorobutazone, 5-Fluorouracil, Camptothecin, Cisplatin, Metronidazole, Gleevec, Avastin, Vectib, Abaric, Aldehyde Leukin, Alemumab, Aliretinoin, Allopurinol, Hexamethylmelamine, Amifostine, Anastrozole, Arsenic Trioxide, Asparaginase, Azacitidine, AZD9291, BCGLiver, Bevacizumab, Fluorouracil, Besalodin, Bleomycin, Bortezomib, Busulfan, Capprotestone, Capecitabine, Camptothecin, Carboplatin, Carmustine, Celecoxib, Cetuximab, Chlorbutacil, Cladribine, Clofarabine, Cyclophosphamide, Cytarabine, Dermazomycin, Alfadabepoetin, Docetaxel, Dermazoline, Dexrazosen, Docetaxel, Doxorubicin (neutral), Doxorubicin Hydrochloride, Dermazoline Propionate, Epirubicin, Ephosteroids, Etoposide Phosphate, Etoposide, Exemestane, Filgrastim, Fluorouracil, Fluoride Darabine, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab, Goserelin Acetate, Histamine Relin Acetate, Hydroxyurea, Tiimomab, Idarubicin, Ifosfamide, Imatinib Mesylate, Interferon Alpha-2a, Interferon Alpha-2b, Irinotecan, Lenalidomide, Letrozole, Levofloxacin, Leuprolide Acetate, Levamisole, Lomustine, Medroxyprogesterone Acetate, Melphalan, Mercaptopurine, 6-MP, Mesna, Methotrexate, Methoxam, Mitomycin C, Mitotan, Mitoxantrone, Nandrolone, Nerapine, Nofetumab, Oxaliplatin, Interleukin Paclitaxel, Palivmin, Pamidronate, Pegasys, Pegaspargase, Pemetrexed Disodium, Pentostatin, Piperbromophenazine, Procarbazine, Porphyrom sodium, Procarbazine, Quinacrine, Raburicase, Rituximab, Nostinib, Saxaglastine, Sorafenib, Streptozotocin, Sunitinib Maleate, Talc, Tamoxifen, Temozolomide, Teniposide, VM-26, Testrolide, Thioguanine, 6-TG, Thiotepa, Topotecan, Toremifene, Tosimomab, Trastuzumab, Retinoic Acid, ATRA, Uramustine, Pentorubicin, Vincristine, Long Vinpocetine, vinorelbine, zoledronic acid, pembrolizumab, nivolumab, IBI-308, mDX-400, BGB-108, MEDI-0680, SHR-1210, PF-06801591, PDR-001, GB-226, STI-1110, duvastatinab, atezolizumab, avelumab, BMS-936559, ALN-PDL, TSR-042, KD-033, CA-170, STI-1014, FOLFIRINOX, and KY-1003.

6. A pharmaceutical combination product comprising a compound of formula Ib: Or a pharmaceutically acceptable salt thereof, and one or more other therapeutic compounds; The one or more additional therapeutic compounds mentioned herein are selected from one or more of the following: Btk tyrosine kinase inhibitors, Erbb2 tyrosine kinase receptor inhibitors; Erbb4 tyrosine kinase receptor inhibitors, thymidine synthase inhibitors, EGFR tyrosine kinase receptor inhibitors, epidermal growth factor antagonists, Fyn tyrosine kinase inhibitors, kit tyrosine kinase inhibitors, Lyn tyrosine kinase inhibitors, NK cell receptor modulators, PDGF receptor antagonists, PARP inhibitors, poly-ADP-ribose polymerase inhibitors, poly-ADP-ribose polymerase 1 inhibitors, poly-ADP-ribose polymerase 2 inhibitors, poly-ADP-ribose polymerase 3 inhibitors, galactosyltransferase modulators, dihydropyrimidine dehydrogenase inhibitors, orotate phosphoribosyltransferase inhibitors, telomerase modulators, mucin 1 inhibitors, mucin inhibitors, secretin agonists, TNF-related apoptosis-inducing ligand modulators, IL17 gene stimulators, interleukin-17E ligands, neurokinin receptor agonists, cyclin G1 inhibitors, checkpoint inhibitors, PD-1 inhibitors, PD-L1 inhibitors. Inhibitors, CTLA4 inhibitors, topoisomerase I inhibitors, Alk-5 protein kinase inhibitors, connective tissue growth factor ligand inhibitors, Notch-2 receptor antagonists, Notch-3 receptor antagonists, hyaluronidase stimulators, MEK-1 protein kinase inhibitors; MEK-2 protein kinase inhibitors, GM-CSF receptor modulators; TNFα ligand modulators, mesothelin modulators, asparaginase stimulators, caspase-3 stimulators; caspase-9 stimulators, PKN3 gene inhibitors, he... Dgehog protein inhibitors; Smoothened receptor antagonists, AKT1 gene inhibitors, DHFR inhibitors, thymidine kinase stimulators, CD29 modulators, fibronectin modulators, interleukin-2 ligands, serine protease inhibitors, D40LG gene stimulators; TNFSF9 gene stimulators, 2-oxoglutarate dehydrogenase inhibitors, TGF-β type II receptor antagonists, Erbb3 tyrosine kinase receptor inhibitors, cholecystokinin CCK2 receptor antagonists, Wilms tumor protein modulators, Ras GTPase modulators, histone deacetylase inhibitors, cyclin-dependent kinase 4 inhibitor A modulators, estrogen receptor β modulators, 4-1BB inhibitors, 4-1BBL inhibitors, PD-L2 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, BTLA inhibitors, HVEM inhibitors, TIM3 inhibitors, GAL9 inhibitors, LAG3 inhibitors, VISTA inhibitors, KIR inhibitors, 2B4 inhibitors, CD160 inhibitors, and CD66e modulators.

7. Use of the pharmaceutical combination product of claim 6 in the preparation of a medicament for treating pancreatic cancer.

8. Use of compounds of formula Ib or pharmaceutically acceptable salts thereof in the preparation of medicaments for limiting the overexpression of oncogenes, activating tumor suppressor genes, or regulating signal transduction proteins in patients in need of them: The overexpression of oncogenes, inactivation of tumor suppressor genes, or dysregulation of various signaling proteins led to the diagnosis of pancreatic cancer.

9. Use of compounds of formula Ib or pharmaceutically acceptable salts thereof in the preparation of medicaments for controlling adenocarcinoma in patients: The adenocarcinoma mentioned above is pancreatic adenocarcinoma.

10. The use of claim 9, further comprising administering one or more additional therapeutic compounds to the patient.

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