Administration regimen of an AXL inhibitor

Abstract

The present disclosure relates to compositions and methods for treating AXL-related diseases such as cancer in a subject. In particular, the present disclosure relates to a novel dosing regimen for treating AXL-related diseases such as cancer using an inhibitor of AXL activity or expression (AXLi).

Description

Technical Field

[0001] The present disclosure relates to compositions and methods for treating AXL-related diseases such as cancer in a subject. In particular, the present disclosure relates to the administration of inhibitors of AXL activity or expression (AXLi).

Background Art

[0002] AXL All protein kinases identified to date in the human genome share a highly conserved catalytic domain of approximately 300 amino acids. This domain folds into a two-lobed structure in which the ATP-binding site and the catalytic site are present. The complexity of protein kinase regulation results in many potential inhibitory mechanisms, including competition with activating ligands, regulation of positive and negative regulators, interference with protein dimerization, and allosteric or competitive inhibition at the substrate or ATP-binding site. AXL (also known as UFO, ARK, and Tyro7; nucleotide accession numbers NM_021913, NM_001699, NM_001278599; protein accession numbers NP_068713, NP_001690, NP_001265528) is a receptor protein tyrosine kinase (RTK) that includes an N-terminal cytoplasmic region containing a C-terminal extracellular ligand-binding domain and a catalytic domain. The extracellular domain of AXL has a unique structure in which immunoglobulin and fibronectin type III repeats are juxtaposed, reminiscent of the structure of neural cell adhesion molecules. AXL and its two close relatives, Mer / Nyk and Sky (Tyro3 / Rse / Dtk), are collectively known as the Tyro3 family of RTKs, all of which bind to the same ligand, GAS6 (growth arrest specific-6), a secreted protein of approximately 76 kDa that has significant homology to the coagulation cascade regulator protein S, and are thereby stimulated to varying degrees. In addition to binding to the ligand, the AXL extracellular domain has been shown to undergo homophilic interaction-mediated cell aggregation, suggesting that one important function of AXL may be to mediate cell-cell adhesion.

[0003] AXL is mainly expressed in the vascular systems of endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), as well as in cells of the myeloid lineage, and has also been detected in mammary epithelial cells, chondrocytes, Sertoli cells, and neurons. Certain functions, including protection from apoptosis induced by serum starvation, TNF-α, or the viral protein E1A, as well as migration and cell differentiation, are thought to result from AXL signaling in cell culture. AXL has been found to function as an important checkpoint in interferon (IFN) signaling (Non-Patent Documents 1 and 2), and in the context of the viral response, picornavirus has been found to antagonize IFN action by interacting with AXL (Non-Patent Document 3). However, Axl− / − mice do not exhibit an obvious developmental phenotype, and the physiological function of AXL in vivo has not been clearly established in the literature.

[0004] AXL Pathology Overexpression of AXL and / or its ligand has also been reported in a wide variety of solid tumor types (including, but not limited to, breast cancer, kidney cancer, endometrial cancer, ovarian cancer, thyroid cancer, non-small cell lung cancer, and uveal melanoma) as well as in myeloid leukemia. Furthermore, it has transforming activity in NIH3T3 and 32D cells. Loss of Axl expression in tumor cells has been demonstrated to block the growth of solid human neoplasms in the in vivo MDA-MB-231 breast cancer xenograft model. That is, the data suggest that AXL signaling can independently regulate EC angiogenesis and tumor growth, and thus represents a novel class of targets for tumor therapy development. The expression of AXL and GAS6 proteins is upregulated in a variety of other disease states, including endometriosis, vascular injury, and kidney disease, and AXL signaling is functionally involved in the latter two indications. AXL-GAS6 signaling amplifies platelet responses and is involved in thrombosis. Thus, AXL may potentially represent a therapeutic target for a number of diverse pathological conditions, including, but not limited to, solid tumors such as breast cancer, kidney cancer, endometrial cancer, ovarian cancer, thyroid cancer, non-small cell lung cancer, and uveal melanoma; hematological tumors including leukemia (especially myeloid leukemia) and lymphoma; endometriosis, vascular diseases / injuries (including, but not limited to, restenosis, atherosclerosis, and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney diseases (including, but not limited to, glomerulonephritis, diabetic nephropathy, kidney diseases due to hypertension, and kidney transplant rejection), rheumatoid arthritis; osteoporosis, osteoarthritis, and cataracts.

[0005] AXL Inhibitor Given the role that AXL plays in many pathological conditions, the development of safe and effective AXL inhibitors has been the focus of recent interest. Different groups of AXL inhibitors have been discussed, inter alia, in Patent Documents 1 to 18.

[0006] Combination Therapy Using AXL Inhibitor The combination of one or more of the above AXL inhibitors with one or more other agents has been discussed, for example, in Patent Documents 19 and 20, and Patent Document 21 relates to the combination of AXL inhibitors with agents having immunomodulatory activity or regulatory activity. For example, inhibition of AXL by the small molecule bemcentinib (BGB324 / R428) has been found to enhance the efficacy of immune checkpoint inhibitor therapy with anti-PD1 and / or anti-CTLA4. The combination of AXL inhibitors with immune checkpoint inhibitor therapy and chemotherapy and / or radiotherapy has been described, for example, in Patent Document 22.

Prior Art Documents

Patent Documents

[0007] [Patent Document 1] U.S. Patent Application Publication No. 2007 / 0213375 [Patent Document 2] U.S. Patent Application Publication No. 2008 / 0153815 [Patent Document 3] U.S. Patent Application Publication No. 2008 / 0188454 [Patent Document 4] U.S. Patent Application Publication No. 2008 / 0176847 [Patent Document 5] U.S. Patent Application Publication No. 2008 / 0188455 [Patent Document 6] U.S. Patent Application Publication No. 2008 / 0182862 [Patent Document 7] U.S. Patent Application Publication No. 2008 / 0188474 [Patent Document 8] U.S. Patent Application Publication No. 2008 / 0117789 [Patent Document 9] U.S. Patent Application Publication No. 2009 / 0111816 [Patent Document 10] International Publication No. 2007 / 0030680 [Patent Document 11] International Publication No. 2008 / 045978 [Patent Document 12] International Publication No. 2008 / 083353 [Patent Document 13] International Publication No. 2008 / 083357 [Patent Document 14] International Publication No. 2008 / 083354 [Patent Document 15] International Publication No. 2008 / 083356 [Patent Document 16] International Publication No. 2008 / 080134 [Patent Document 17] International Publication No. 2009 / 054864 [Patent Document 18] International Publication No. 2008 / 083367 [Patent Document 19] International Publication No. 2010 / 083465 [Patent Document 20] International Publication No. 2016 / 193680 [Patent Document 21] International Publication No. 2016 / 193680 [Patent Document 22] International Publication No. 2021 / 191197 [Non-Patent Document]

[0008] [Non-Patent Document 1] Rothlin et al, 2007 [Non-Patent Document 2] Huang et al, 2015 [Non-Patent Document 3] Chen et al, 2018 [Summary of the Invention] [Problems to be Solved by the Invention]

[0009] Research has continued to further improve the efficacy, tolerability, and clinical utility of AXL inhibitor therapy. For this reason, the present inventors have identified a clinically advantageous dosing regimen for administering an inhibitor of AXL activity or expression (AXLi) to patients with AXL-related diseases such as cancer. [Means for Solving the Problems]

[0010] Through the treatment of subjects with the AXL inhibitor bemcentinib and the modeling of pharmacokinetic data obtained from two phase I trials and one phase II trial, the present inventors have developed a dosing regimen that can improve the efficacy, efficiency, and / or tolerability of AXLi therapy when used in the treatment of AXL-related diseases. Interestingly, it has been found that the parameters required for optimal therapeutic efficacy, efficiency, and / or tolerance vary depending on the indication and are affected by factors including the effect of food and the combination with other therapeutic agents.

[0011] Accordingly, the present disclosure provides a method for treating a disease associated with AXL in a subject, the method comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising a loading dose and a maintenance dose. In certain embodiments, the loading dose is administered on the first, second, and / or third day of the dosing regimen. Preferably, the loading dose is administered on the first and second days of the dosing regimen. The loading dose may be (i) about 100 - 300 mg, such as about 150 - 250 mg, about 175 - 225 mg, or about 190 - 210 mg. In certain preferred embodiments, the loading dose is about 200 mg. The loading dose may be (ii) about 50 - 250 mg, such as about 100 - 200 mg, about 125 - 175 mg, or about 140 - 160 mg. In certain preferred embodiments, the loading dose is about 150 mg. The loading dose may be about 50 - 150 mg, such as about 75 - 125 mg, or about 90 - 110 mg. In certain preferred embodiments, the loading dose is about 100 mg. In certain embodiments, the loading dose may be about 200 mg, about 150 mg, or about 100 mg administered once daily to the subject. In certain preferred embodiments, the loading dose is about 200 mg, about 150 mg, or about 100 mg administered once daily to the subject on the first and second days of the dosing regimen.

[0012] In certain embodiments, the maintenance dose is initiated and administered on the second, third, or fourth day of the dosing regimen. Preferably, the maintenance dose is initiated and administered on the third day of the dosing regimen. The maintenance dose may be administered on the second, third, or fourth day of the dosing regimen and each subsequent day. Preferably, the maintenance dose may be administered on the third day of the dosing regimen and each subsequent day. The maintenance dose may be administered once daily to the subject, such as once daily on the third day of the dosing regimen and each subsequent day.

[0013] The maintenance dose may be about 50% of the loading dose. The maintenance dose may be about 50 - 150 mg, about 75 - 125 mg, or about 90 - 110 mg, or may be about 60 - 90 mg, about 65 - 85 mg, or about 70 - 80 mg. Preferably, the maintenance dose may be about 100 mg or about 75 mg. The maintenance dose may be about 100 mg or about 75 mg administered once daily to the subject, for example, once daily on the 3rd day and each subsequent day of the dosing regimen.

[0014] The maintenance dose may be the same amount as the loading dose. In certain embodiments, the loading and maintenance doses may be about 100 mg, about 125 mg, or about 150 mg. In certain embodiments, the loading dose and the maintenance dose may be about 100 mg, about 125 mg, or about 150 mg administered once daily to the subject, for example, once daily on the 3rd day and each subsequent day of the dosing regimen.

[0015] The present disclosure also provides a method for treating a disease associated with AXL in a subject, comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein the AXLi is administered in a dosing regimen that comprises administering a fixed dose of AXLi to the subject each day after the first day of the dosing regimen. The fixed dose may be about 125 mg or about 150 mg. The fixed dose may be about 125 mg or about 150 mg administered once daily to the subject, for example, once daily each day after the first day of the dosing regimen. The fixed dose may be about 75 mg, about 100 mg, or about 150 mg. The fixed dose may be about 75 mg, about 100 mg, or about 150 mg and may be administered once daily to the subject, for example, once daily each day after the first day of the dosing regimen. Preferably, the fixed dose may be about 100 mg administered once daily to the subject, for example, once daily each day after the first day of the dosing regimen.

[0016] A maintenance dosage or a fixed dosage may be administered daily to a subject until treatment with AXLi is discontinued. The maintenance dosage or fixed dosage may be administered once daily to the subject until treatment with AXLi is discontinued. Treatment with AXLi may be discontinued when a treatment endpoint is reached for the subject. The treatment endpoint may be one or more of a partial disease remission achieving a partial remission [PR] state or a complete disease remission achieving a complete remission [CR] state, and the occurrence of toxicity and / or adverse events requiring discontinuation of treatment.

[0017] In certain embodiments, AXLi is administered to the subject under feeding conditions. That is, AXLi may be administered before, simultaneously with, or after food intake, for example, within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed / ingested food. The food is preferably a high-fat and / or high-protein meal or the like.

[0018] In certain embodiments, the disease associated with AXL is cancer, a fibrotic disorder, or neurofibromatosis. Preferably, the disease associated with AXL is cancer. The cancer may be selected from the group consisting of lung cancer, non-small cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), pancreatic cancer, kidney cancer, urothelial cancer, ovarian cancer, neurofibroma, cranial cancer or spinal meningioma, schwannoma, epithelioma, and glioblastoma. In certain preferred embodiments, the cancer is acute myeloid leukemia (AML) and / or lung cancer, preferably non-small cell lung cancer (NSCLC).

[0019] In certain embodiments, AXLi is administered in combination with one or more immune checkpoint modulators (ICMs); and / or one or more chemotherapeutic agents and / or radiation therapy. In certain embodiments, AXLi is administered in combination with an anti-PD1 antibody. Preferably, the anti-PD1 antibody is pembrolizumab. In certain embodiments, AXLi is administered in combination with anthracycline. Preferably, the anthracycline is doxorubicin. In certain embodiments, AXLi is administered in combination with ICM and anthracycline. Preferably, the anthracycline is doxorubicin. In certain embodiments, AXLi is administered in combination with a platinum-based chemotherapeutic agent. Preferably, the platinum-based chemotherapeutic agent is carboplatin or cisplatin. In certain embodiments, AXLi is administered in combination with an antifolate chemotherapeutic agent. Preferably, the antifolate chemotherapeutic agent is pemetrexed. In certain embodiments, AXLi is administered in combination with a platinum-based chemotherapeutic agent, an antifolate chemotherapeutic agent, and anti-PD1. In certain most preferred embodiments, AXLi may be administered in combination with carboplatin, an anticancer agent, and pembrolizumab.

[0020] AXLi may be a compound represented by the following formula (I), as described in more detail elsewhere in this specification:

[0021]

Chemical formula

Brief Description of the Drawings

[0022]

Figure 1

Mode for Carrying Out the Invention

[0023] Aspects and embodiments of the present disclosure are now discussed with reference to the accompanying drawings. Further aspects and embodiments will be apparent to those skilled in the art. As described in more detail below, the inventors have developed dosing regimens with improved efficacy and / or reduced toxicity compared to other AXL inhibitor (AXLi) dosing regimens through the treatment of subjects with the AXL inhibitor bemcentinib and the modeling of pharmacokinetic data obtained from two Phase I trials and one Phase II trial. Accordingly, the present disclosure provides a method for treating a disease associated with AXL in a subject, comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising a loading dose and a maintenance dose; in a dosing regimen in which a fixed dose level is administered to the subject; and / or in the fed state.

[0024] AXL Inhibitor Different groups of AXL inhibitors have been discussed, inter alia, in Patent Documents 1 to 18. Small Molecule AXL Inhibitor General Formula In one embodiment, the AXL inhibitor has the following formula (I):

[0025] [Chemical formula] (wherein, R 1 , R 4 and R 5 are each independently hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R 8 , -C(O)N(R 6 )R 7 and -C(=NR 6 )N(R 6 )R 7 selected from the group consisting of, R 2 and R 3 are each independently a polycyclic heteroaryl having more than 14 ring atoms, and optionally, the polycyclic heteroaryl having more than 14 ring atoms is oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R 9 -OR 8 , -R 9 -O-R 10 -OR 8 , -R 9 -O-R 10 -O-R 10 -OR 8 , -R 9 -O-R 10 -CN, -R 9 -O-R 10 -C(O)OR 8 , -R 9 -O-R 10 -C(O)N(R 6 )R 7 , -R 9 -O-R 10 -S(O) p R 8 (p is 0, 1 or 2), -R 9 -O-R 10 -N(R6 )R 7 、 -R 9 -O-R 10 -C(NR 11 )N(R 11 )H, -R 9 -OC(O)-R 8 、 -R 9 -N(R 6 )R 7 、 -R 9 -C(O)R 8 、 -R 9 -C(O)OR 8 、 -R 9 -C(O)N(R 6 )R 7 、 -R 9 -N(R 6 )C(O)OR 8 、 -R 9 -N(R 6 )C(O)R 8 、 -R 9 -N(R 6 )S(O) t R 8 (t is 1 or 2), -R 9 -S(O) t OR 8 (t is 1 or 2), -R 9 -S(O) p R 8 (p is 0, 1 or 2) and -R 9 -S(O) t N(R 6 )R 7 optionally substituted by one or more substituents selected from the group consisting of; Alternatively, R 2 is a polycyclic heteroaryl having more than 14 ring atoms as described above, and R 3is selected from the group consisting of aryl and heteroaryl, wherein said aryl and heteroaryl are each independently alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 13 -OR 12 、-R 13 -OC(O)-R 12 、-R 13 -O-R 14 -N(R 12 )2、-R 13 -N(R 12 )-R 14 -N(R 12 )2、-R 13 -N(R 12 )-R 14 -N(R 12 )2、-R 13 -N(R 12 )2、-R 13 -C(O)R 12 、-R 13 -C(O)OR 12 、-R 13 -C(O)N(R 12 )2、-R 13 -C(O)N(R 12 )-R 14 -N(R 12 )R 13 、-R 13 -C(O)N(R 12 )-R 14 -OR 12 、-R 13 -N(R 12 )C(O)OR 12 、-R13 -N(R 12 )C(O)R 12 、-R 13 -N(R 12 )S(O) t R 12 (t is 1 or 2), -R 13 -S(O) t OR 12 (t is 1 or 2), -R 13 -S(O) p R 12 (p is 0, 1 or 2) and -R 13 -S(O) t N(R 12 )2 (t is 1 or 2) and may be substituted by one or more substituents selected from the group consisting of; Alternatively, R 3 is a polycyclic heteroaryl having more than 14 ring atoms as described above, and R 2 is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each independently alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 13 -OR 12 、-R 13 -OC(O)-R 12 、-R 13 -O-R 14 -N(R 12 )2、-R 13 -N(R 12 )-R 14 -N(R 12)2, -R 13 -N(R 12 )-R 14 -N(R 12 )2, -R 13 -N(R 12 )2, -R 13 -C(O)R 12 , -R 13 -C(O)OR 12 , -R 13 -C(O)N(R 12 )2, -R 13 -C(O)N(R 12 )-R 14 -N(R 12 )R 13 , -R 13 -C(O)N(R 12 )-R 14 -OR 12 , -R 13 -N(R 12 )C(O)OR 12 , -R 13 -N(R 12 )C(O)R 12 , -R 13 -N(R 12 )S(O) t R 12 (t is 1 or 2), -R 13 -S(O) t OR 12 (t is 1 or 2), -R 13 -S(O) p R 12 (p is 0, 1 or 2) and -R 13 -S(O) t N(R 12 )2 (t is 1 or 2) and may be substituted by one or more substituents selected from the group consisting of; R 6 and R 7is, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 10 -OR 8 , -R 10 -CN, -R 10 -NO2, -R 10 -N(R 8 )2, -R 10 -C(O)OR 8 and -R 10 -C(O)N(R 8 )2 selected from the group consisting of, or any R 6 and R 7 both together with the common nitrogen to which they are attached form an optionally substituted N - heteroaryl or optionally substituted N - heterocyclyl; R 8 is, independently of each other, selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl and optionally substituted heteroarylalkynyl; R 9 is each independently selected from the group consisting of a direct bond, a linear or branched alkylene chain which may be substituted, a linear or branched alkenylene chain which may be substituted, and a linear or branched alkynylene chain which may be substituted; R 10 is each independently selected from the group consisting of a linear or branched alkylene chain which may be substituted, a linear or branched alkenylene chain which may be substituted, and a linear or branched alkynylene chain which may be substituted; R 11 is each independently selected from the group consisting of hydrogen, alkyl, cyano, nitro, and -OR 8 ; R 12 is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl which may be substituted, cycloalkylalkyl which may be substituted, aryl which may be substituted, aralkyl which may be substituted, heterocyclyl which may be substituted, heterocyclylalkyl which may be substituted, heteroaryl which may be substituted, heteroarylalkyl which may be substituted, -R 10 -OR 8 , -R 10 -CN, -R 10 -NO2, -R 10 -N(R 8 )2, -R 10 -C(O)OR 8 and -R 10 -C(O)N(R 8 )2, or two R 12 together with the common nitrogen to which both are attached form a N - heterocyclyl which may be substituted or a N - heteroaryl which may be substituted; R 13 is each independently selected from the group consisting of a direct bond, a linear or branched alkylene chain which may be substituted, and a linear or branched alkenylene chain which may be substituted; R 14 is each independently selected from the group consisting of a linear or branched alkylene chain which may be substituted and a linear or branched alkenylene chain which may be substituted) It is a compound represented by, an isolated stereoisomer or a mixture thereof, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof.

[0026] Certain Embodiment In certain embodiments, AXLi is a compound represented by formula (I) as defined on page 12, line 11 to page 49, line 14 of WO 2021 / 204713. In certain embodiments, the compound represented by formula (I) is the following: 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(3-Fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5-(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5 -(7-(S)-Pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(t-Butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(Acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((2R)-2-(Methoxycarbonyl)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4,4-Difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-(7-((Methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((2R)-2-(Carboxy)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((Carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-(7-(4-(Carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-yl)-1H-1,2,4-triazole-3,5-diamine;; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-Amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7s)-7-(Di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2-Methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((1-Cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(2-Propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-((3,3-Dimethylbutan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine;; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((5-Chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2-Carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine;; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((3-Bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(3-Pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2,2-Dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Di( bicyclo[2.2.1]hepta-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine;; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Bicyclo[2.2.1]hepta-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(3-Methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(2-Ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(But-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5 -((7S)-7-(tert-butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazoline-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; and 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(2-butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0027] Preferred Embodiment In a preferred embodiment, AXL inhibitor is one of the following: 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; and 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; is selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0028] Preferably, the AXL inhibitor is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7-(S)-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine. The most preferred AXL inhibitor is bemcentinib (CAS No. 1037624-75-1; UNII 0ICW2LX8AS).

[0029] Other Embodiment In certain other embodiments, the AXLi is one of the following: duvelmab (CAS No. 1341200-45-0; UNII 14D65TV20J); gilteritinib (CAS No. 1254053-43-4; UNII 66D92MGC8M); cabozantinib (CAS No. 849217-68-1; UNII 1C39JW444G); SGI7079 (CAS No. 1239875-86-5); maresinib (CAS No. 1206799-15-6; UNII 5OGS5K699E); ambatiniib (CAS No. 850879-09-3; UNII SO9S6QZB4R); bosutinib (CAS No. 380843-75-4; UNII 5018V4AEZ0); XL092 from Exelixis (CAS No. 2367004-54-2); citravatiniib (CAS No. 1123837-84-2; UNII CWG62Q1VTB); gresatiniib (CAS No. 936694-12-1; UNII 7Q29OXD98N); and foretinib (CAS No. 849217-64-7; UNII 81FH7VK1C4) and is selected from the group consisting of.

[0030] Definition As used herein, the following terms have the meanings set forth below unless otherwise specified. "Amino" refers to the -NH2 group. "Carboxy" refers to a -C(O)OH group. "Cyano" refers to a -CN group. "Nitro" refers to a -NO2 group. "Oxo" refers to an O group. "Oxo" refers to a =O group. "Thioxo" refers to a =S group. "Alkyl" consists of only carbon atoms and hydrogen atoms, contains no unsaturation, has 1 to 12 carbon atoms, preferably 1 to 8 or 1 to 6 carbon atoms, and is bonded to the rest of the molecule by a single bond, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, etc. It refers to a straight-chain or branched hydrocarbon chain group. For the purposes of the present disclosure, the term "lower alkyl" refers to an alkyl group having 1 to 6 carbon atoms.

[0031] "Optionally substituted alkyl" is halo, cyano, nitro, oxo, thioxo, trimethylsilyl, -OR 20 , -OC(O)-R 20 , -N(R 20 )2, -C(O)R 20 , -C(O)OR 20 , -C(O)N(R 20 )2, -N(R 20 )C(O)OR 20 , -N(R 20 )C(O)R 20 , -N(R 20 )S(O)2R 20 , -S(O) t OR 20 (t is 1 or 2), -S(O) p R 20 (p is 0, 1 or 2) and -S(O)2N(R 20 )2 (wherein R 20is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached, form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl), and refers to an alkyl group as defined above, optionally substituted by one or more substituents selected from the group consisting of

[0032] "Alkenyl" consists only of carbon atoms and hydrogen atoms, contains at least one double bond, has 2 to 12 carbon atoms, preferably 1 to 8 carbon atoms, and the remaining part of the molecule is bonded by single bonds, for example, ethenyl, prop - 1 - enyl - 1 - enyl, pent - 1 - enyl and penta - 1,4 - dienyl, and refers to a straight - chain or branched hydrocarbon chain group. "Optionally substituted alkenyl" is halo, cyano, nitro, oxo, thioxo, trimethylsilyl, - OR 20 , - OC(O) - R 20 , - N(R 20 )2, - C(O)R 20 , - C(O)OR 20 , - C(O)N(R 20 )2, - N(R 20 )C(O)OR 20 , - N(R 20 )C(O)R 20 , - N(R 20 )S(O)2R 20 , - S(O) t OR 20 (t is 1 or 2), - S(O) p R 20 (p is 0, 1 or 2) and - S(O)2N(R 20 )2 (wherein R 20is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached, form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl).

[0033] "Alkynyl" consists of only carbon and hydrogen atoms, contains at least one triple bond, and optionally contains at least one double bond, and has 2 - 12 carbon atoms, preferably 1 - 8 carbon atoms, and is a straight - chain or branched hydrocarbon chain group attached by single bonds to the rest of the molecule, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. "Optionally substituted alkynyl" is halo, cyano, nitro, oxo, thioxo, trimethylsilyl, - OR 20 , - OC(O) - R 20 , - N(R 20 )2, - C(O)R 20 , - C(O)OR 20 , - C(O)N(R 20 )2, - N(R 20 )C(O)OR 20 , - N(R 20 )C(O)R 20 , - N(R 20 )S(O)2R 20 , - S(O) t OR 20 (t is 1 or 2), - S(O) p R 20 (p is 0, 1 or 2) and - S(O)2N(R 20 )2 (wherein R 20is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached, form an optionally substituted N - heterocyclyl or an optionally substituted N - heteroaryl).

[0034] "Straight - chain or branched - chain alkylene chain" refers to a straight - chain or branched - chain divalent hydrocarbon chain consisting only of carbon atoms and hydrogen atoms, containing no unsaturation, having 1 to 12 carbon atoms, and with the remaining part of the molecule linked to a radical group. For example, it is methylene, ethylene, propylene, n - butylene. The alkylene chain is linked to the rest of the molecule via a single bond and to the radical group via a single bond. The attachment points to the rest of the molecule and the radical group of the alkylene chain may be through one carbon or any two carbon atoms in the alkylene chain. "Optionally substituted straight - chain or branched - chain alkylene chain" is halo, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilyl, - OR 20 , - OC(O) - R 20 , - N(R 20 )2, - C(O)R 20 , - C(O)OR 20 , - C(O)N(R 20 )2, - N(R 20 )C(O)OR 20 , - N(R 20 )C(O)R 20 , - N(R 20 )S(O)2R 20 , - S(O) t OR 20 (where t is 1 or 2), - S(O) p R 20 (where p is 0, 1 or 2) and - S(O)2N(R 20 )2 (wherein R 20is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached, form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl), and refers to an alkylene chain as defined above, optionally substituted by one or more substituents selected from the group consisting of

[0035] "Straight - chain or branched - chain alkenylene chain" consists of only carbon atoms and hydrogen atoms, contains at least one double bond, has 2 - 12 carbon atoms, and is a straight - chain or branched - chain divalent hydrocarbon chain in which the remaining part of the molecule is linked to a radical group, such as ethenylene, propenylene, and n - butenylene. The alkenylene chain is linked to the remaining part of the molecule via a double bond or a single bond and is linked to the radical group via a double bond or a single bond. The points of attachment of the remaining part of the molecule of the alkenylene chain and the radical group may be via one carbon or any two carbon atoms in the alkenylene chain. "Optionally substituted straight - chain or branched - chain alkenylene chain" is alkyl, alkenyl, halo, haloalkenyl, cyano, nitro, aryl, cycloalkyl, heterocyclyl, heteroaryl, oxo, thioxo, trimethylsilyl, - OR 20 , - OC(O) - R 20 , - N(R 20 )2, - C(O)R 20 , - C(O)OR 20 , - C(O)N(R 20 )2, - N(R 20 )C(O)OR 20 , - N(R 20 )C(O)R 20 , - N(R 20 )S(O)2R 20 , - S(O) t OR 20(where t is 1 or 2), -S(O) p R 20 (where p is 0, 1, or 2) and -S(O)2N(R 20 )2 (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl), and refers to an alkenylene chain as defined above, optionally substituted by one or more substituents selected from the group consisting of

[0036] "Aryl" refers to a hydrocarbon ring system group containing 6 - 14 carbon atoms and at least one aromatic ring. For the purposes of the present disclosure, an aryl group may be monocyclic, bicyclic, or tricyclic, and may include a spiro ring system. An aryl group is generally, but not necessarily, attached to the parent molecule through the aromatic ring of the aryl group. For the purposes of the present disclosure, the "aryl" group as defined herein cannot contain a ring having more than 7 members and cannot contain a ring in which two non - adjacent ring atoms are connected through an atom or group of atoms (i.e., a bridged ring system). Examples of aryl groups include acenaphthylene, anthracene, azulene, benzene, 6,7,8,9 - tetrahydro - 5H - benzo[7]annulene, fluorene, as - indacene, s - indacene, indane, indene, naphthalene, phenalene, and phenanthrene. "Optionally substituted aryl" is alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )2, -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -O-R 22 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 20 , -R 21 -N(R 20 )C(O)R 20 , -R 21 -N(R 20 )S(O)2R 20 , -R 21 -C(=NR 20 )N(R 20 )2, -R 21 -S(O) t OR 20(where t is 1 or 2), -R 21 -S(O) p R 20 (where p is 0, 1 or 2) and -R 21 -S(O)2N(R 20 )2 (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl, and R 21 are each independently a direct bond or a straight or branched alkylene chain or alkenylene chain, and, R 22 is a straight or branched alkylene or alkenylene chain) and refers to an aryl group as defined above which is optionally substituted by one or more substituents selected from the group consisting of

[0037] "Aralkyl" refers to a group represented by the formula -R b -R c (wherein R b is an alkylene chain as defined above, and R c is one or more aryl groups as defined above, for example, benzyl and diphenylmethyl). "Optionally substituted aralkyl" refers to an aralkyl group as defined above wherein the alkylene chain of the aralkyl group is an alkylene chain as defined above which is optionally substituted, and each aryl group of the aralkyl group is an aryl group as defined above which is optionally substituted.

[0038] "Aralkenyl" refers to a group represented by the formula -R d -R c (wherein R d is alkenylene as defined above, and R crefers to a group represented by (wherein one or more aryl groups are as defined above). "Optionally substituted aralkenyl" refers to an aralkenyl group wherein the alkenylene chain of the aralkenyl group is an alkenylene chain as defined above which may be optionally substituted, and each aryl group of the aralkenyl group is an aryl group as defined above which may be optionally substituted, i.e., an aralkenyl group as defined above.

[0039] "Aralkynyl" has the formula -R e R c (wherein R e is an alkynylene chain as defined above, and R c is one or more aryl groups as defined above). "Optionally substituted aralkynyl" refers to an aralkynyl group wherein the alkynylene chain of the aralkynyl group is an alkynylene chain as defined above which may be optionally substituted, and each aryl group of the aralkynyl group is an aryl group as defined above which may be optionally substituted, i.e., an aralkynyl group as defined above.

[0040] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon atoms and hydrogen atoms, having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 5 to 7 carbon atoms, including a fused, spiro or bridged ring system, and being saturated or unsaturated, and bonded to the rest of the molecule by a single bond. For the purposes of the present disclosure, a bridged ring system is a system in which two non-adjacent ring atoms are connected via an atom or a group of atoms, where the atom or group of atoms is a bridging element. An example of a bridged cycloalkyl (monovalent) group is norbornyl (also called bicyclo[2.2.1]heptanyl). For the purposes of the present disclosure, a non-bridged ring system is a system that does not contain a bridging element as described above. For the purposes of the present disclosure, a fused ring system is a system in which two adjacent ring atoms are connected via an atom or a group of atoms. An example of a fused cycloalkyl (monovalent) group is decahydronaphthalenyl (also called decalinyl). For the purposes of the present disclosure, a spiro ring system is a system in which two rings are bonded via a single carbon (quaternary) atom. An example of a spirocycloalkyl (monovalent) group is spiro[5.5]undecanyl. A monocyclic cycloalkyl group does not include a spiro, fused or bridged cycloalkyl group, and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Examples of polycyclic groups include fused, spiro or bridged cycloalkyl groups, such as C 10 groups, as well as C7 groups such as bicyclo[3.2.0]heptanyl (fused), norbornyl and norbornenyl (bridged), and substituted polycyclic groups, such as substituted C7 groups like 7,7-dimethylbicyclo[2.2.1]heptanyl (bridged). "Optionally substituted cycloalkyl" is alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 21 -OR 20 , -R 21 -OC(O)-R 20 , -R 21 -N(R 20 )2, -R 21 -C(O)R 20 , -R 21 -C(O)OR 20 , -R 21 -C(O)N(R 20 )2, -R 21 -N(R 20 )C(O)OR 20 , -R 21 -N(R 20 )C(O)R 20 , -R 21 -N(R 20 )S(O)2R 20 , -R 21 -C(=NR 20 )N(R 20 )2, -R 21 -S(O) t OR 20 (t is 1 or 2), -R 21 -S(O) p R20 (p is 0, 1 or 2) and -R 21 -S(O)2N(R 20 )2 (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl, and R 21 are each independently a direct bond or a linear or branched alkylene chain or alkenylene chain), and refers to a cycloalkyl group as defined above which is optionally substituted by one or more substituents selected from the group consisting of

[0041] "Cycloalkylalkyl" refers to a group of the formula -R b R g (wherein R b is an alkylene chain as defined above, and R g is a cycloalkyl group as defined above). "Optionally substituted cycloalkylalkyl" refers to a cycloalkyl group as defined above, wherein the alkylene chain of the cycloalkylalkyl group is an alkylene chain as defined above which is optionally substituted, and the cycloalkyl group of the cycloalkylalkyl group is a cycloalkyl group as defined above which is optionally substituted.

[0042] "Cycloalkylalkenyl" refers to a group of the formula -R d R g (wherein R d is an alkenylene as defined above, and R g is a cycloalkyl group as defined above). "Optionally substituted cycloalkylalkenyl" refers to a cycloalkylalkenyl group in which the alkenylene chain of the cycloalkylalkenyl group is an alkenylene chain as defined above, which may be optionally substituted, and the cycloalkyl group of the cycloalkylalkenyl group is a cycloalkyl group as defined above, which may be optionally substituted, that is, a cycloalkylalkenyl group as defined above.

[0043] "Cycloalkylalkynyl" refers to the group represented by the formula -R e R g (wherein R e is an alkynylene chain as defined above, and R g is a cycloalkyl group as defined above). "Optionally substituted cycloalkylalkynyl" refers to a cycloalkylalkynyl group in which the alkynylene chain of the cycloalkylalkynyl group is an alkynylene chain as defined above, which may be optionally substituted, and the cycloalkyl group of the cycloalkylalkynyl group is a cycloalkyl group as defined above, which may be optionally substituted, that is, a cycloalkylalkynyl group as defined above.

[0044] "Halo" refers to bromo, chloro, fluoro or iodo. "Haloalkyl" refers to an alkyl group as defined above, which is substituted by one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl and 1-bromomethyl-2-bromoethyl. "Haloalkenyl" refers to an alkenyl group as defined above, which is substituted by one or more halo groups as defined above. "Haloalkynyl" refers to an alkynyl group as defined above, which is substituted by one or more halo groups as defined above. "Heterocyclyl" refers to a stable non-aromatic ring system containing 1 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Unless specifically stated otherwise herein, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may include a spiro or bridged ring system; the nitrogen, carbon, or sulfur atoms in the heterocyclyl group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclyl group may be partially or fully saturated. Examples of bridged heterocyclyls include, but are not limited to, azabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[2.2.2]octanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.3.1]nonanyl, diazabicyclo[3.2.2]nonanyl, and oxaazabicyclo[2.2.1]heptanyl.

[0045] "Crosslinked N - heterocyclyl" is a crosslinked heterocyclyl that contains at least one nitrogen and optionally contains up to 4 additional heteroatoms selected from O, N, and S. For the purposes of the present disclosure, a non - crosslinked ring system is a system in which no two non - adjacent ring atoms are connected via an atom or group of atoms. Examples of heterocyclyl groups include dioxolanyl, 1,4 - diazepanyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, octahydro - 1H - pyrrolo[3,2 - c]pyridinyl, octahydro - 1H - pyrrolo[2,3 - c]pyridinyl, octahydro - 1H - pyrrolo[2,3 - b]pyridinyl, octahydro - 1H - pyrrolo[3,4 - b]pyridinyl, octahydropyrrolo[3,4 - c]pyrrolyl, octahydro - 1H - pyrido[1,2 - a]pyrazinyl, 2 - oxopiperazinyl, 2 - oxopiperidinyl, 2 - oxopyrrolidinyl, oxazolidinyl, 3,7 - diazabicyclo[3.3.1]nonan - 3 - yl, piperidinyl, piperazinyl, 4 - piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, thienyl[1,3]dithianyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 - oxo - thiomorpholinyl, 1,1 - dioxo - thiomorpholinyl, azetidinyl, octahydropyrrolo[3,4 - c]pyrrolyl, octahydropyrrolo[3,4 - b]pyrrolyl, decahydropyridino[1,2 - a]azepinyl, azepanyl, azabicyclo[3.2.1]octyl, and 2,7 - diazaspiro[4.4]nonanyl. "Optionally substituted heterocyclyl" is alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, heteroarylalkynyl, -R 21 -OR 20 、-R 21 -OC(O)-R 20 、-R 21 -N(R 20 )2、-R 21 -C(O)R 20 、-R 21 -C(O)OR 20 、-R 21 -C(O)N(R 20 )2、-R 21 -N(R 20 )C(O)OR 20 、-R 21 -N(R 20 )C(O)R 20 、-R 21 -N(R 20 )S(O)2R 20 、-R 21 -C(=NR 20 )N(R 20 )2、-R 21 -S(O) t OR 20 (t is 1 or 2), -R 21 -S(O)p R 20 (where p is 0, 1 or 2) and -R 21 -S(O)2N(R 20 )2 (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl, and R 21 each independently is a direct bond or a straight or branched alkylene chain or alkenylene chain) and refers to a heterocyclyl group as defined above which is optionally substituted by one or more substituents selected from the group consisting of.

[0046] "N-heterocyclyl" refers to a heterocyclyl group as defined above containing at least one nitrogen, and the point of attachment of the N-heterocyclyl group to the remainder of the molecule may be via a nitrogen atom in the N-heterocyclyl group or via a carbon atom in the N-heterocyclyl group. "Optionally substituted N-heterocyclyl" refers to an N-heterocyclyl as defined above which is optionally substituted by one or more substituents as defined above for optionally substituted heterocyclyl.

[0047] "Heterocyclylalkyl" refers to a group represented by the formula -R b R h (wherein R b is an alkylene chain as defined above and R h is a heterocyclyl group as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be attached to the alkylene chain by a nitrogen atom). "Optionally substituted heterocyclylalkyl" refers to a heterocyclylalkyl group as defined above, wherein the alkylene chain of the heterocyclylalkyl group is an alkylene chain as defined above which is optionally substituted, and the heterocyclyl group of the heterocyclylalkyl group is a heterocyclyl group as defined above which is optionally substituted.

[0048] "Heterocyclylalkenyl" refers to the group of formula -R d R h (wherein R d is alkenylene as defined above, and R h is a heterocyclyl group as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be bonded to the alkylene chain through a nitrogen atom). "Optionally substituted heterocyclylalkenyl" refers to a heterocyclylalkenyl group as defined above, wherein the alkenylene chain of the heterocyclylalkenyl group is an alkenylene chain as defined above which is optionally substituted, and the heterocyclyl group of the heterocyclylalkenyl group is a heterocyclyl group as defined above which is optionally substituted.

[0049] "Heterocyclylalkynyl" refers to the group of formula -R e R h (wherein R e is alkynylene as defined above, and R h is a heterocyclyl group as defined above, and when the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl may be bonded to the alkylene chain through a nitrogen atom). "Optionally substituted heterocyclylalkynyl" refers to a heterocyclylalkynyl group as defined above, wherein the alkynylene chain of the heterocyclylalkynyl group is an alkynylene chain as defined above which is optionally substituted, and the heterocyclyl group of the heterocyclylalkynyl group is a heterocyclyl group as defined above which is optionally substituted.

[0050] "Heteroaryl" refers to a 5- to 14-membered ring system group containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and at least one aromatic ring. A heteroaryl group generally, but not necessarily, binds to a parent molecule through the aromatic ring of the heteroaryl group. For the purposes of the present disclosure, the heteroaryl group may be a monocyclic, bicyclic, or tricyclic ring system that may include a spiro or bridged ring system; a nitrogen, carbon, or sulfur atom in the heteroaryl group may optionally be oxidized; and a nitrogen atom may optionally be quaternized. For the purposes of the present disclosure, the aromatic ring of the heteroaryl group need not contain a heteroatom as long as one ring of the heteroaryl group contains a heteroatom. For example, a benzocondensed heterocyclyl such as 1,2,3,4-tetrahydroisoquinolin-7-yl is considered "heteroaryl" for the purposes of the present disclosure. Except for polycyclic heteroaryls containing more than 14 ring atoms as defined below, the "heteroaryl" groups defined herein cannot contain a ring having more than 7 members and cannot contain a ring in which two non-adjacent members are bonded through an atom or atomic group (i.e., a bridged ring system). Examples of heteroaryl groups include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3 - benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, benzo[b]azepinyl, 1,4 - benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2 - d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2 - a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 3,4 - dihydro - 2H - benzo[b][1,4]dioxepinyl, cyclopenta[4,5]thieno[2,3 - d], for example 6,7 - dihydro - 5H - cyclopenta[4,5]thieno[2,3 - d]pyrimidinyl, 5,6 - dihydrobenzo[h]quinazolinyl, 3,4 - dihydro - 2H - benzo[b][1,4]thiazinyl, 5,6 - dihydrobenzo[h]cinnolinyl, 7’,8’ - dihydro - 5’H - spiro[[1,3]dioxolane - 2,6’ - quinoline] - 3’ - yl, 6,7 - dihydro - 5H - benzo[6,7]cyclohepta[1,2 - c]pyridazinyl, 2,3 - dihydro - 1H - pyrido[2,3 - b][1,4]oxazinyl, 3’,4’ - dihydrospiro[cyclobutane - 1,2’ - pyrido[3,2 - b][1,4]oxazinyl, 3,4 - dihydro - 2H - pyrido[3,2 - b][1,4]oxazinyl and other dihydropyridooxazinyl, 3,4 - dihydro - 2H - pyrido[3,2 - b][1,4]thiazinyl and other dihydropyridothiazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2 - c]pyridinyl, furopyrimidinyl, furopyridazinyl, furopyrazinyl, isothiazolyl, imidazolyl, imidazopyrimidinyl, imidazopyridazinyl, imidazopyrazinyl, imidazo[1,2-a] Pyridinyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolinyl (isoquinolyl), indolizinyl, isoxazolyl, naphthyridinyl, 1,6-naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 3'-oxo-3',4'-dihydrospiro[cyclobutane-1,2'-pyrido[3,2-b][1,4]oxazine]yl, 7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, phenanthridinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl (pyridyl), pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl (pyridazyl), pyrrolyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, 2H-pyrido[3,2-b][1,4]oxazinonyl, 1H-pyrido[2,3-b][1,4]oxazinonyl, pyrrolopyridinyl, for example 1H-pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 2,3,4,5-tetrahydrobenzo[b]oxepinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridinyl, 6,7,8,9-tetrahydro-5H-pyrido[3,2-c]azepinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, 1,2,3,4-tetrahydroisoquinolin-7-yl, triazinyl, thieno[2,3-d]pyrimidinyl, thienopyrimidinyl (for example, thieno[3,2-d]pyrimidinyl), thieno[2,3-c]pyridinyl, thienopyridazinyl, thienopyrazinyl and thiophenyl (thienyl) and the like can be mentioned.,

[0051] "Optionally substituted heteroaryl" is heteroaryl alkynyl optionally substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 21 -OR 20 ,-R 21 -OC(O)-R 20 ,-R 21 -N(R 20 )2,-R 21 -C(O)R 20 ,-R 21 -C(O)OR 20 ,-R 21 -C(O)N(R 20 )2,-R 21 -N(R 20 )C(O)OR 20 ,-R 21 -N(R 20 )C(O)R 20 ,-R 21 -N(R 20 )S(O)2R 20 ,-R 21 -C(=NR 20 )N(R 20 )2,-R 21-S(O) t OR 20 (t is 1 or 2), -R 21 -S(O) p R 20 (p is 0, 1 or 2) and -R 21 -S(O)2N(R 20 )2 (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 together with the common nitrogen to which both are attached form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl, and R 21 are each independently a direct bond or a straight or branched alkylene chain or alkenylene chain), and refers to a heteroaryl group as defined above which is optionally substituted by one or more substituents selected from the group consisting of).

[0052] "N-heteroaryl" refers to a heteroaryl group as defined above containing at least one nitrogen, and the point of attachment of the N-heteroaryl group to the remainder of the molecule may be via a nitrogen atom in the N-heteroaryl group or via a carbon atom in the N-heteroaryl group. "Optionally substituted N-heteroaryl" refers to an N-heteroaryl as defined above which is optionally substituted by one or more substituents as defined above which are optionally substituted.

[0053] "Polycyclic heteroaryl containing more than 14 ring atoms" refers to a 15- to 20-membered ring system group containing a hydrogen atom, 1 to 14 carbon atoms, 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. The "polycyclic heteroaryl containing more than 14 ring atoms" group is generally attached to the parent molecule via the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" group, but this is not necessarily the case. For the purposes of the present disclosure, the "polycyclic heteroaryl containing more than 14 ring atoms" group may be a bicyclic, tricyclic or tetracyclic ring system which may include fused or spiro ring systems; the nitrogen, carbon or sulfur atoms in the "polycyclic heteroaryl containing more than 14 ring atoms" group may optionally be oxidized; and the nitrogen atoms may also optionally be quaternized. For the purposes of the present disclosure, the aromatic ring of the "polycyclic heteroaryl containing more than 14 ring atoms" group need not contain heteroatoms as long as one of the rings of the "polycyclic heteroaryl containing more than 14 ring atoms" group contains heteroatoms.Examples of the group of "polycyclic heteroaryl containing more than 14 ring atoms" include 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl, 6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-yl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl, 6,7-dihydro-5H-benzo[2,3]azepino[4,5-c]pyridazin-3-yl, (Z)-dibenzo[b,f][1,4]thiazepin-11-yl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[4,5-c]pyridazin-2-yl, 6,7-dihydro-5H-benzo[2,3]oxepino[4,5-c]pyridazin-3-yl, spiro[chromeno[4,3-c]pyridazine-5,1’-cyclopentane]-3-yl, 6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2’-[1,3]dioxolane]-3-yl, 5,6,8,9-tetrahydrospiro[benzo[7]annulene-7,2’-[1,3]dioxolane]-3-yl, 5,7,8,9-tetrahydrospiro[cyclohepta[b]pyridine-6,2’-[1,3]dioxolane]-3-yl, 6,7-dihydro-5H-benzo[2,3]thieno[4,5-c]pyridazin-3-yl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl, 5,6,8,9-tetrahydrospiro[cyclohepta[b]pyridine-7,2’-[1,3]dioxolane]-3-yl, 6,8,9,10-tetrahydro-5H-spiro[cycloocta[b]pyridine-7,2’-[1,3]dioxane]-3-yl and 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-b]pyridin-2-yl.

[0054] "Polycyclic heteroaryl containing more than 14 ring atoms, optionally substituted" means a group of "polycyclic heteroaryl containing more than 14 ring atoms" as defined above, where alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R 21 -OR 20 、-R 21 -OC(O)-R 20 、-R 21 -N(R 20 )2、-R 21 -C(O)R 20 、-R 21 -C(O)OR 20 、-R 21 -C(O)N(R 20 )2、-R 21 -N(R 20 )C(O)OR 20 、-R 21 -N(R 20 )C(O)R 20 、-R 21 -N(R 20 )S(O) t R 20 (t is 1 or 2), -R 21 -C(=NR 20 )N(R 20 )2、-R21 -S(O) t OR 20 (t is 1 or 2), -R 21 -S(O) p R 20 (p is 0, 1 or 2), -R 21 -S(O) t OR 20 (t is 1 or 2) and -R 21 -S(O) t N(R 20 )2 (t is 1 or 2) (wherein R 20 is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl and optionally substituted heteroarylalkyl, or two R 20 may together with the common nitrogen to which both are attached form an optionally substituted N - heterocyclyl or optionally substituted N - heteroaryl, and R 21 are each independently a direct bond or a straight or branched alkylene chain or alkenylene chain) and is optionally substituted by one or more substituents selected from the group consisting of).

[0055] "Heteroarylalkyl" refers to a group of the formula -R b R i (wherein R b is an alkylene chain as defined above, and R i is a heteroaryl group as defined above, and when the heteroaryl is a nitrogen - containing heteroaryl, the heteroaryl may be attached to the alkylene chain by a nitrogen atom). "Optionally substituted heteroarylalkyl" refers to a heteroarylalkyl group in which the alkylene chain of the heteroarylalkyl group is an alkylene chain as defined above, which may be optionally substituted, and the heteroaryl group of the heteroarylalkyl group is a heteroaryl group as defined above, which may be optionally substituted.

[0056] "Heteroarylalkenyl" has the formula -R d R i (wherein R d is an alkenylene as defined above, and R i is a heteroaryl group as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be bonded to the alkylene chain through a nitrogen atom). "Optionally substituted heteroarylalkenyl" refers to a heteroarylalkenyl group in which the alkenylene chain of the heteroarylalkenyl group is an alkenylene chain as defined above, which may be optionally substituted, and the heteroaryl group of the heteroarylalkenyl group is a heteroaryl group as defined above, which may be optionally substituted.

[0057] "Heteroarylalkynyl" has the formula -R e R i (wherein R e is an alkynylene chain as defined above, and R i is a heteroaryl group as defined above, and when the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl may be bonded to the alkylene chain through a nitrogen atom). "Optionally substituted heteroarylalkynyl" refers to a heteroarylalkynyl group in which the alkynylene chain of the heteroarylalkynyl group is an alkynylene chain as defined above, which may be optionally substituted, and the heteroaryl group of the heteroarylalkynyl group is a heteroaryl group as defined above, which may be optionally substituted. "Hydroxyalkyl" refers to an alkyl group as defined above, which is substituted by one or more hydroxy groups (-OH).

[0058] The specific chemical groups named in this specification may be preceded by an abbreviated notation indicating the total number of carbon atoms found in the chemical group shown. For example, C7~C 12 Alkyl represents an alkyl group as defined below, having a total of 7 to 12 carbon atoms, and C4~C 12 Cycloalkylalkyl represents a cycloalkylalkyl group as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the abbreviated notation does not include carbons that may be present in substituents of the described group.

[0059] The compounds represented by formula (I) or their pharmaceutically acceptable salts may contain one or more asymmetric centers, and thus, enantiomers, diastereomers, and (R)- and (S)-stereoisomers from the perspective of absolute stereochemistry, or other stereoisomeric forms that can be defined as (D) and (L)-amino acids may occur. This disclosure means that it includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)-(S) or (D)-(L)-isomers can be prepared using a chiral synthon or chiral reagent, or can be resolved using conventional techniques such as HPLC using a chiral column. When the compounds described herein contain an olefin double bond or other geometrically asymmetric center, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers. Similarly, all tautomers are also intended to be included. "Stereoisomer" refers to a compound composed of the same atoms bonded by the same bonds, but having different three-dimensional structures that are not interchangeable. This disclosure contemplates various stereoisomers and their mixtures, including "enantiomers", which refer to two stereoisomers whose molecules are mirror images that cannot be superimposed on each other. "Tautomer" refers to the proton transfer from one atom of a molecule to another atom of the same molecule. This disclosure includes any tautomers of the said compounds. "Atropisomers" are stereoisomers that result from the restricted rotation around a single bond, and the barrier to rotation is high enough to allow for the isolation of the conformational isomers (Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; Wiley & Sons: New York, 1994; Chapter 14). Atropisomerism is important because it introduces an element of chirality in the absence of chiral atoms. This disclosure is meant to encompass atropisomers, and for example, when the rotation around a single bond resulting from the core triazole structure is restricted, atropisomers are also possible and are specifically included in the compounds of this disclosure.

[0060] The chemical nomenclature protocol and structural diagrams used herein are modified forms of the IUPAC nomenclature, and the compounds represented by formula (I) are named herein as derivatives of the central core structure, i.e., the triazole structure. For complex chemical names used herein, substituents are named before the group to which they are attached. For example, cyclopropyl ethyl contains an ethyl backbone with a cyclopropyl substituent. In chemical structural diagrams, all bonds are identified except for certain carbon atoms that are assumed to be bonded to hydrogen atoms sufficient to complete their valency.

[0061] For the purposes of this disclosure, the depiction of the bond attaching the R 3 substituent to the parent triazole moiety in formula (I) is shown below.

[0062]

Chemical formula

[0063]

Chemical formula

[0064] The numbering system for the ring atoms in compounds of formula (Ia) is shown below.

[0065] [ka] For example, a compound represented by formula (Ia) (wherein R 1 , R 4 and R 5 are each hydrogen, and R 2 is 4-(2-(pyrrolidin-1-yl)ethoxy)phenyl, R 3 is 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl), i.e., the compound of the formula:

[0066] [ka] In the present specification, the compound represented by 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 It is named -(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)-1H-1,2,4-triazole-3,5-diamine.

[0067] Formula (Ib):

[0068] [ka] The numbering system for ring atoms in compounds represented by the formula: Compounds of formula (Ib) are named similarly herein.

[0069] In the methods of the present disclosure, AXLi is preferably administered orally, for example as an oral capsule. AXLi may be administered via introduction through a feeding tube. AXLi may be administered by other suitable routes of administration, as described elsewhere herein.

[0070] Diseases Associated with AXL As referred to herein, diseases associated with AXL are those in which dysfunction of Axl expression or activity is a contributing factor. For example, a disease associated with AXL may be one in which overexpression of AXL is a contributing factor. Overexpression of AXL and / or its ligands has been reported in a wide variety of solid tumor types, as well as in other disease states including vascular injury and kidney disease. Alternatively, or additionally, a disease associated with AXL may be one in which tissue infiltration by AXL+ve cells such as AXL+ve immunosuppressive dendritic cells, NK cells, or macrophages is a contributing factor. Thus, for example, a disease associated with AXL may be a cancer or fibrotic disorder characterized by expression or overexpression of AXL. For example, a disease associated with AXL may be a cancer or fibrotic disorder characterized by tissue infiltration by AXL+ve cells such as AXL+ve immunosuppressive dendritic cells, NK cells, or macrophages. Diseases associated with AXL may be selected from the following: immune disorders, cardiovascular disorders, thrombosis, diabetes, immune checkpoint disorders, neurofibromatosis, fibrotic disorders (fibrosis), or cancer, particularly proliferative diseases such as metastatic cancer, etc. Furthermore, Axl is known to act in many cancers of epithelial origin.

[0071] In certain embodiments of the present disclosure, a disease associated with AXL is a proliferative disease. Proliferative diseases in the excessive proliferation of cells contribute to the etiology of the disease. Exemplary proliferative diseases include cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, and cirrhosis.

[0072] In certain embodiments of the present disclosure, a disease associated with AXL is a neoplastic disease. Neoplastic diseases are those in which abnormal and excessive growth (neoplasia) of cells / tissues occurs. Neoplasia is the abnormal growth and proliferation of abnormal cells or an abnormal amount of cells, and can result from benign or malignant processes. Exemplary neoplastic diseases include myeloproliferative diseases, myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML).

[0073] Cancer In certain preferred embodiments of the present disclosure, the disease associated with AXL is a solid tumor. In other preferred embodiments, the disease associated with AXL is a liquid tumor (which may also be referred to as a blood cancer or a hematological malignancy). In certain preferred embodiments of the present disclosure, the disease associated with AXL is cancer.

[0074] In certain embodiments, the cancer is one of the following cancers: leukemia (e.g., but not limited to, acute myeloid leukemia (AML) such as myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, leukemia, and myelodysplastic syndrome), acute leukemia, acute lymphoblastic leukemia, chronic leukemia (e.g., but not limited to, chronic myeloid leukemia (granulocytic), chronic lymphocytic leukemia, hairy cell leukemia); polycythemia vera; lymphoma (e.g., but not limited to, Hodgkin's disease, non-Hodgkin lymphoma); multiple myeloma (e.g., but not limited to, smoldering multiple myeloma, non-secretory multiple myeloma, osteosclerotic myeloma, plasmacytic leukemia, solitary plasmacytoma, and extramedullary plasmacytoma); Waldenström macroglobulinemia; monoclonal gammopathy; heavy chain disease; osteosarcoma and connective tissue sarcoma (e.g., but not limited to, glioma, astrocytoma, chondrosarcoma, Ewing sarcoma, malignant giant cell tumor, fibrosarcoma of bone, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (hemangiosarcoma), fibrosarcoma, Kaposi sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, schwannoma, rhabdomyosarcoma, synovial sarcoma); breast cancer (e.g., but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast carcinoma, mucinous breast carcinoma, tubular breast carcinoma, papillary breast carcinoma, primary carcinoma, Paget's disease, and inflammatory breast carcinoma); thyroid cancer (e.g., but not limited to, adenoma, papillary (small cell) carcinoma, follicular carcinoma, goiter, non-epithelial thyroid cancer, medullary thyroid cancer, pineoblastoma, primary cerebral lymphoma); breast cancer (e.g., but not limited to, adenoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary thyroid cancer, goiter, follicular epithelial carcinoma, ovarian epithelial carcinoma, ovarian squamous carcinoma, melanoma, melanoma, basal cell carcinoma, sarcoma, and Paget's disease); uterine cancer (e.g., but not limited to, adenoma, squamous carcinoma, ovarian epithelial carcinoma, ovarian squamous carcinoma, melanoma, melanoma, basal cell carcinoma, sarcoma, and adenocarcinoma); esophageal cancer (e.g., but not limited to, squamous carcinoma, adenocarcinoma, adenoid cell carcinoma, mucoepidermoid carcinoma, squamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma); gastric cancer (e.g., but not limited to, e.g., adenocarcinoma, adenocarcinoma tumor, anaplasia, classical (typical), spermatocytic, non-seminoma, embryonal carcinoma tumor, teratocarcinoma tumor, yolk sac tumor (villous carcinoma tumor), prostate cancer, e.g., adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; genital cancer, e.g., penile cancer;Oral cancers, such as squamous cell carcinoma; basal cell carcinoma; salivary gland cancers, such as, but not limited to, adenocarcinoma, squamous cell carcinoma tumor, nodular melanoma, malignant lentigo melanoma, acral lentiginous melanoma; skin cancers, such as, but not limited to, basal cell carcinoma tumor, squamous cell carcinoma tumor and melanoma, superficial spreading melanoma, nodular melanoma, malignant lentigo melanoma, transitional cell carcinoma (renal pelvis and / or ureter); kidney cancers, such as, but not limited to, renal cell carcinoma, adenocarcinoma tumor, adrenal tumor, fibrosarcoma, fibrosarcoma (renal pelvis and / or ureter), pinealocytoma gastrinoma mucoepidermoid carcinoma Wilms tumor; bladder cancers, such as, but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, one or more of carcinosarcoma are exemplified. Further, cancers include myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial cancer, cystadenocarcinoma, bronchial cancer, sweat gland cancer, sebaceous gland cancer, papillary cancer and papillary adenocarcinoma.;

[0075] The cancer may be selected from the group consisting of lung cancer, small cell lung cancer, non-small cell lung cancer, histiocytosis, glioma (glioma), astrocytoma, osteoma, gastrointestinal cancer, intestinal cancer, colon cancer, breast cancer, ovarian cancer, prostate cancer, testicular cancer, liver cancer, kidney cancer, urothelial cancer, bladder cancer, pancreatic cancer, brain cancer, glioblastoma (glioblastoma multiforme), sarcoma, osteosarcoma, Kaposi's sarcoma, melanoma, mesothelioma, lymphoma and leukemia. The cancer may be selected from lung cancer, non-small cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), pancreatic cancer, prostate cancer, ovarian cancer, colorectal cancer, glioma (glioma), kidney cancer, urothelial cancer, ovarian cancer, neurofibroma, cranial cancer or spinal meningioma, schwannoma, epithelioma and glioblastoma. The cancer may be metastatic.; The cancer may be one or more solid cancer tumors including, but not limited to, lung cancer, non-small cell lung cancer, breast cancer, kidney cancer, endometrial cancer, ovarian cancer, thyroid cancer and melanoma, prostate cancer, sarcoma, stomach cancer and uveal melanoma.;

[0076] Cancer may be one or more hematological tumors including, but not limited to, leukemia (especially myeloid leukemia) and lymphoma. Cancer may be acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia (e.g., myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, leukemia, and myelodysplastic syndrome), chronic leukemia (e.g., chronic myeloblastic (granulocytic) leukemia, chronic lymphocytic leukemia, hairy cell leukemia) (not limited to these); one or more leukemias such as polycythemia vera. Cancer may be one or more lymphomas such as Hodgkin's disease, non-Hodgkin's disease, etc., but not limited to these. In a particularly preferred embodiment, the disease associated with AXL may be leukemia such as acute myeloid leukemia (AML). In another particularly preferred embodiment, the disease associated with AXL may be lung cancer such as non-small cell lung cancer.

[0077] Fibrotic Disorder In certain embodiments of the present disclosure, the disease associated with AXL may be fibrosis (including, but not limited to, pulmonary fibrosis and hepatic fibrosis) or fibrotic disorders. Fibrotic disorders that may be subjects include strabismus, scleroderma, keloid, nephrogenic systemic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cystic fibrosis (CF), systemic sclerosis, cardiac fibrosis, non-alcoholic steatohepatitis (NASH) and other types of hepatic fibrosis, primary biliary cirrhosis, renal fibrosis, cancer, and atherosclerosis. In these diseases, the chronic development of fibrosis in tissues results in significant changes in the structure of the affected organs, and then defects occur in organ function.

[0078] Neurofibromatosis In certain embodiments of the present disclosure, the AXL-related disease may be neurofibromatosis. Neurofibromatosis is a group of genetic disorders that form tumors on nerve tissue. The tumors in this disorder are usually non-cancerous (benign), but may become cancerous (malignant). There are three types of neurofibromatosis: neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. Thus, in certain embodiments of the present disclosure, the AXL-related disease may be neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and / or schwannomatosis. The AXL-related disease may be a neurofibroma and / or a schwannoma.

[0079] Other Diseases Associated with AXL In certain embodiments of the present disclosure, the AXL-related disease may be one of the following: endometriosis, vascular diseases / injuries (including, but not limited to, restenosis, atherosclerosis, and thrombosis), psoriasis; visual impairment due to macular degeneration; diabetic retinopathy and retinopathy of prematurity; kidney diseases (including, but not limited to, glomerulonephritis, diabetic nephropathy, and kidney transplant rejection), rheumatoid arthritis; osteoarthritis, osteoporosis, and cataracts. In certain embodiments of the present disclosure, the AXL-related disease may be an immune checkpoint disorder. Examples of the immune checkpoint disorders of interest include the following: chronic viral infections, melanoma, colorectal cancer, breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), prostate cancer, renal cell cancer, pancreatic cancer, esophageal cancer, bladder cancer, multiple myeloma, kidney cancer, bladder cancer, brain tumors, and lymphoma.

[0080] Dosing Regimen In certain embodiments of the method for treating an AXL-related disease according to the present disclosure, AXLi is administered to a subject in a dosing regimen that includes a loading dose and a maintenance dose. In other embodiments of the method of the present disclosure, AXLi is administered to a subject in a dosing regimen in which a constant dose level is administered to the subject. The inventors have discovered that when these dosing regimens are used in the treatment of AXL-related diseases, they improve efficacy and / or reduce toxicity compared to other AXLi dosing regimens.

[0081] As described more fully below, a "loading dose" is an initial, higher dose of AXLi given during a "loading period" at the start of the course of treatment, after which this dose is reduced to a maintenance level (the "maintenance dose"). The loading dose acts such that AXLi can reach a desired steady-state concentration in the body where it has the desired therapeutic effect, while the maintenance dose acts to maintain the desired steady-state concentration of AXLi in the body. A regimen that includes a "constant dose level" is a regimen in which the same dose is administered to the subject throughout the dosing regimen (i.e., in effect, the "loading dose" and the "maintenance dose" are the same). In the methods of the present disclosure, AXLi may be administered to the subject QD (daily). That is, AXLi may be administered to the subject daily (each day of the dosing regimen). In certain preferred embodiments, AXLi may be administered to the subject once a day.

[0082] Loading Dose As used herein, the term "loading dose" refers to an initial, higher dose of AXLi given at the start of the course of treatment. That is, the "loading dose" is the dose initially administered to the subject during the course of treatment and may be, for example, an "initial dose", a "starting dose", a "first dose", or a "first dose level". The loading dose is administered over a loading period and AXLi can reach a desired steady-state concentration in the body where it has the desired therapeutic effect.

[0083] In certain embodiments, the loading dose of AXLi may be about 50-150 mg, about 60-140 mg, about 70-130 mg, about 75-125 mg, about 80-120 mg, about 85-115 mg, about 90-110 mg, about 95-105 mg, about 96-104 mg, about 97-103 mg, about 98-102 mg, or about 99-101 mg. In certain embodiments, the loading dose of AXLi may be about 95-105 mg, about 96-104 mg, about 97-103 mg, about 98-102 mg, or about 99-101 mg. In certain preferred embodiments, the loading dose of AXLi may be about 100 mg.

[0084] In certain embodiments, the loading dose of AXLi may be about 50-250 mg, about 100-200 mg, about 110-190 mg, about 120-180 mg, about 125-175 mg, about 130-170 mg, about 135-165 mg, about 140-160 mg, about 145-155 mg, about 146-154 mg, about 147-153 mg, about 148-152 mg, or about 149-151 mg. In certain preferred embodiments, the loading dose of AXLi may be about 145-155 mg, about 146-154 mg, about 147-153 mg, about 148-152 mg, or about 149-151 mg. In certain particularly preferred embodiments, the loading dose of AXLi may be about 150 mg.

[0085] In certain embodiments, the loading dose of AXLi may be about 100-300 mg, about 150-250 mg, about 160-240 mg, about 170-230 mg, about 175-225 mg, about 180-220 mg, about 185-215 mg, about 190-210 mg, about 195-205 mg, about 196-204 mg, about 197-203 mg, about 198-202 mg, or about 199-201 mg. In certain preferred embodiments, the loading dose of AXLi may be about 195-205 mg, about 196-204 mg, about 197-203 mg, about 198-202 mg, or about 199-201 mg. In certain particularly preferred embodiments, the loading dose of AXLi may be about 200 mg.

[0086] The loading period is the period during which the loading dose is administered to the subject, for example, a period of 1, 2, 3, 4, 5, 6, or 7 days at the start of the treatment process. In the methods of the present disclosure, the loading period may preferably be 1, 2, or 3 days, such as on days 1, 2, and 3 of the dosing regimen. In certain most preferred embodiments, the loading period may be 2 days, such as on days 1 and 2 of the dosing regimen. That is, in the method of the present disclosure, the loading dose may be administered on the first, second, third, and / or fourth day of the dosing regimen, for example, on the first, second, third, and fourth day of the dosing regimen. In some preferred embodiments, the loading dose may be administered on the first, second, and / or third day of the dosing regimen, for example, on the first, second, and third day of the dosing regimen, or on the first day of the dosing regimen. In a particularly preferred embodiment, the loading dose may be administered on the first and second day of the dosing regimen. In some embodiments, the loading dose may be about 100 mg administered on the first, second, and / or third day of the dosing regimen, for example, on the first, second, and third day of the dosing regimen, or on the first day of the dosing regimen. In some embodiments, the loading dose may be about 100 mg administered on the first and second day of the dosing regimen. In some preferred embodiments, the loading dose is about 150 mg administered on the first, second, and / or third day of the dosing regimen, for example, on the first, second, and third day of the dosing regimen, or on the first day of the dosing regimen. In some preferred embodiments, the loading dose is about 150 mg administered on the first and second day of the dosing regimen. In some most preferred embodiments, the loading dose is about 200 mg administered on the first, second, and / or third day of the dosing regimen, for example, on the first, second, and third day of the dosing regimen, or on the first day of the dosing regimen. In some most preferred embodiments, the loading dose is about 200 mg administered on the first and second day of the dosing regimen.

[0087] Maintenance Dose As used herein, the term "maintenance dose" refers to the dose of AXLi administered to a subject after the loading period. The maintenance dose is typically a reduced dose compared to the loading dose and may be referred to, for example, as a "subsequent dose", "reduced dose", "second dose", or "second dose level". The maintenance dose is administered over a maintenance period to maintain the desired steady-state concentration of AXLi in the body.

[0088] In certain embodiments, the maintenance dosage of AXL i may be about 30 - 120 mg, about 35 - 115 mg, about 45 - 105 mg, about 50 - 100 mg, about 55 - 95 mg, about 60 - 90 mg, about 65 - 85 mg, about 70 - 80 mg, about 71 - 79 mg, about 72 - 78 mg, about 73 - 77 mg, or about 74 - 76 mg. In certain preferred embodiments, the maintenance dosage of AXL i may be about 70 - 80 mg, about 71 - 79 mg, about 72 - 78 mg, about 73 - 77 mg, or about 74 - 76 mg. In certain particularly preferred embodiments, the maintenance dosage of AXL i may be about 75 mg. In certain such preferred embodiments, the loading dose of AXL i may be about 150 mg, and the maintenance dosage of AXL i may be about 75 mg. In certain embodiments, the maintenance dosage of AXL i may be about 50 - 150 mg, about 60 - 140 mg, about 70 - 130 mg, about 75 - 125 mg, about 80 - 120 mg, about 85 - 115 mg, about 90 - 110 mg, about 95 - 105 mg, about 96 - 104 mg, about 97 - 103 mg, about 98 - 102 mg, or about 99 - 101 mg. In certain preferred embodiments, the maintenance dosage of AXL i may be about 95 - 105 mg, about 96 - 104 mg, about 97 - 103 mg, about 98 - 102 mg, or about 99 - 101 mg. In certain particularly preferred embodiments, the maintenance dosage of AXL i may be about 100 mg. In certain such preferred embodiments, the loading dose of AXL i may be about 200 mg, and the maintenance dosage of AXL i may be about 75 mg. In embodiments where the disease associated with AXL is cancer, most preferably, the loading dose of AXL i may be about 200 mg administered on the first and second days of the dosing regimen, and the maintenance dosage of AXL i may be about 100 mg administered on the third day and each subsequent day of the dosing regimen.

[0089] In certain embodiments, the maintenance dosage may be about 45 - 55% of the loading dose, for example, about 46 - 54%, about 47 - 53%, about 48 - 52%, or about 49 - 51%. In certain such embodiments, the maintenance dosage may be about 50% of the loading dose. In a preferred embodiment, the maintenance dose may be about 50% of the loading dose. That is, a maintenance dose that is about 50% less than the loading dose can be determined. By way of example, the loading dose may be about 200 mg, the maintenance dose may be about 50% of the loading dose (100 mg), or the loading dose may be about 150 mg, and the maintenance dose may be about 50% of the loading dose (75 mg). In some embodiments, the maintenance dose may be about 95 - 100% of the loading dose, such as about 96 - 100%, about 97 - 100%, about 98 - 100%, or about 99 - 100%. In some such embodiments, the maintenance dose may be about 100% of the loading dose. In a preferred embodiment, the maintenance dose may be about 100% of the loading dose. That is, in some embodiments, the maintenance dose may be the same as the loading dose. By way of example, the loading dose may be about 200 mg, the maintenance dose may be about 100% of the loading dose (200 mg), or the loading dose may be about 150 mg, and the maintenance dose may be about 100% of the loading dose (150 mg). Similarly, the loading dose may be about 100 mg, and the maintenance dose may be about 100% of the loading dose (100 mg).

[0090] A regimen where the maintenance dose is the same as the loading dose is also a regimen in which a constant dose level is administered to a subject, as more fully described elsewhere herein. Such a regimen may be preferred in the methods of the present disclosure where AXLi is administered in combination with one or more additional therapies and / or therapeutic agents, as more fully described elsewhere herein.

[0091] The maintenance period is the period during which a maintenance dose is administered to the subject after the above loading period, for example, a period of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 days after the loading period. That is, for a given dosing regimen, the maintenance period is the period of the dosing regimen described elsewhere in this specification minus the loading period described elsewhere in this specification. The maintenance period can be the day after the last day of the loading period (e.g., the 3rd day if the loading dose is administered on the 1st and 2nd days) and each subsequent day of the dosing regimen, which can be until the treatment by AXLi is stopped, for example, until a treatment endpoint is achieved for the subject as more fully described elsewhere in this specification.

[0092] As a non-limiting example, the maintenance period can be 11, 12, or 13 days, such as the 2nd to 14th day, 3rd to 14th day, or 4th to 14th day of a 14-day dosing regimen. In a 14-day dosing regimen with a 2-day loading period, the maintenance period can be 12 days, such as the 3rd to 14th day of the dosing regimen. As a non-limiting example, the maintenance period can be 18, 19, or 20 days, such as the 2nd to 21st day, 3rd to 21st day, or 4th to 21st day of a 21-day dosing regimen. In a 21-day dosing regimen with a 2-day loading period, the maintenance period can be 19 days, such as the 3rd to 21st day of the dosing regimen. That is, in the method of the present disclosure, the maintenance dose may be administered on the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th and / or 31st day of the dosing regimen. The maintenance dose may be administered on the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th day of the dosing regimen and / or each subsequent day. This is illustrated in the following non-limiting examples. For example, in certain embodiments where the duration of the dosing regimen is 7 days, the maintenance dose may be administered on the 2nd, 3rd, 4th, 5th, 6th and / or 7th day of the dosing regimen. In a 7-day dosing regimen with a loading period of 2 days, the maintenance dose may be administered on the 3rd, 4th, 5th, 6th and / or 7th day of the dosing regimen, for example, on the 3rd, 4th, 5th, 6th and 7th day of the dosing regimen. For example, in certain embodiments where the duration of the dosing regimen is 14 days, the maintenance dose may be administered on the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th and / or 14th day of the dosing regimen. In a 14-day dosing regimen with a loading period of 2 days, the maintenance dose may be administered on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th and / or 14th day of the dosing regimen, for example, on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th and 14th day of the dosing regimen. For example, in certain embodiments where the duration of the dosing regimen is 21 days, the maintenance dose may be administered on the 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th and / or 21st day of the dosing regimen. In a 21-day dosing regimen with a loading period of 2 days, the maintenance dose may be administered on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th and / or 21st day of the dosing regimen, for example, on the 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th and 21st day of the dosing regimen.

[0093] In other words, in the method of the present disclosure, the maintenance dose may be administered starting on the second, third, or fourth day of the dosing regimen. In certain preferred embodiments, the maintenance dose may be administered starting on the third day of the dosing regimen. The maintenance dose may be administered on the second, third, or fourth day of the dosing regimen and on each subsequent day. Preferably, the maintenance dose may be administered on the third day of the dosing regimen and on each subsequent day, for example, on the third day of the dosing regimen and on each subsequent day until treatment with AXLi is discontinued. As a non-limiting example, in embodiments where the duration of the dosing regimen is 7 days, the maintenance dose may be administered on the third, fourth, fifth, sixth, and seventh days of the dosing regimen. For example, in embodiments where the duration of the dosing regimen is 14 days, the maintenance dose may be administered on the third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, and fourteenth days of the dosing regimen. For example, in embodiments where the duration of the dosing regimen is 21 days, the maintenance dose may be administered on the third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and twenty-first days of the dosing regimen.

[0094] In certain preferred embodiments, the maintenance dose is about 75 mg administered on the third day of the dosing regimen and on each subsequent day until treatment with AXLi is discontinued. In certain embodiments, the loading dose is preferably about 150 mg administered on the first and second days of the dosing regimen. In certain other preferred embodiments, the maintenance dose is about 100 mg administered on the third day of the dosing regimen and on each subsequent day until treatment with AXLi is discontinued. In certain embodiments, the loading dose is preferably about 200 mg administered on the first and second days of the dosing regimen. In certain preferred embodiments, the method includes administering a loading dose of AXLi on the first and second days of the dosing regimen and then administering a maintenance dose of AXLi. In certain preferred embodiments, the method includes administering a loading dose of AXLi on the first and second days of the dosing regimen and administering a maintenance dose on the third day of the dosing regimen and on each subsequent day.

[0095] Fixed Dose Embodiments of the method of the present disclosure include those in which a fixed AXLi dosage level is administered to a subject in a dosing regimen in which AXLi is administered to the subject. A regimen that includes a "fixed dosage level" is one in which the same dosage is administered to the subject throughout the dosing regimen (i.e., in practice, the "loading dose" and the "maintenance dose" are the same). Such a regimen may be preferred in the methods of the present disclosure in which AXLi is co-administered with one or more additional therapies and / or therapeutic agents, as described more fully elsewhere herein. In certain embodiments, a fixed dosage level of AXLi may be about 30-120 mg, about 35-115 mg, about 45-105 mg, about 50-100 mg, about 55-95 mg, about 60-90 mg, about 65-85 mg, about 70-80 mg, about 71-79 mg, about 72-78 mg, about 73-77 mg, or about 74-76 mg. In certain preferred embodiments, a fixed dosage level of AXLi may be about 70-80 mg, about 71-79 mg, about 72-78 mg, about 73-77 mg, or about 74-76 mg. In certain particularly preferred embodiments, a fixed dosage level of AXLi may be about 75 mg. In certain embodiments, a fixed dosage level of AXLi may be about 50-150 mg, about 60-140 mg, about 70-130 mg, about 75-125 mg, about 80-120 mg, about 85-115 mg, about 90-110 mg, about 95-105 mg, about 96-104 mg, about 97-103 mg, about 98-102 mg, or about 99-101 mg. In certain preferred embodiments, a fixed dosage level of AXLi may be about 95-105 mg, about 96-104 mg, about 97-103 mg, about 98-102 mg, or about 99-101 mg. In certain particularly preferred embodiments, a fixed dosage level of AXLi may be about 100 mg. In the most preferred regimen that includes a "fixed dosage level", the fixed dosage level of AXLi is about 100 mg. In certain embodiments, a fixed dosage level of AXLi may be about 75-175 mg, about 90-155 mg, about 95-155 mg, about 100-150 mg, about 105-145 mg, about 110-140 mg, about 115-135 mg, 120-130 mg, about 121-129 mg, about 122-128 mg, about 123-127 mg, or about 124-126 mg. In certain preferred embodiments, a fixed dosage level of AXLi may be about 120-130 mg, about 121-129 mg, about 122-128 mg, about 123-127 mg, or about 124-126 mg. In certain particularly preferred embodiments, a fixed dosage level of AXLi may be about 125 mg. In certain embodiments, a fixed dosage level of AXLi may be about 50-250 mg, about 100-200 mg, about 110-190 mg, about 120-180 mg, about 125-175 mg, about 130-170 mg, about 135-165 mg, about 140-160 mg, about 145-155 mg, about 146-154 mg, about 147-153 mg, about 148-152 mg, or about 149-151 mg. In certain preferred embodiments, a fixed dosage level of AXLi may be about 145-155 mg, about 146-154 mg, about 147-153 mg, about 148-152 mg, or about 149-151 mg. In certain particularly preferred embodiments, a fixed dosage level of AXLi may be about 150 mg.

[0096] A fixed dose of AXLi may be administered daily to a subject during the course of a dosing regimen, e.g., on each day after the first day of the dosing regimen, until the treatment with AXLi is discontinued, e.g., until a treatment endpoint, which is more fully described elsewhere herein for the subject, is reached. As a non-limiting example, in the method of the present disclosure, a fixed dose may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th, 21st, 22nd, 23rd, 24th, 25th, 26th, 27th, 28th, 29th, 30th and / or 31st day of the dosing regimen. For example, in certain embodiments where the dosing regimen is 7 days in duration, a fixed dose may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th and / or 7th day of the dosing regimen, preferably on the 1st, 2nd, 3rd, 4th, 5th, 6th and 7th day of the dosing regimen. For example, in certain embodiments where the dosing regimen is 14 days in duration, a fixed dose may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th and / or 14th day of the dosing regimen, preferably on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th and 14th day of the dosing regimen. For example, in certain embodiments where the dosing regimen is 21 days in duration, a fixed dose may be administered on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th and / or 21st day of the dosing regimen, preferably on the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th, 11th, 12th, 13th, 14th, 15th, 16th, 17th, 18th, 19th, 20th and 21st day of the dosing regimen. In certain preferred embodiments, the fixed dose is about 150 mg administered on the first day of the dosing regimen and on each subsequent day until treatment with AXLi is discontinued.

[0097] Regimen Duration In certain embodiments, the duration of the dosing regimen may be about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 days, or more. In certain embodiments, the duration of the dosing regimen may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, or more. In certain embodiments, the duration of the dosing regimen may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 months, or more. In certain embodiments, the duration of the dosing regimen may be about 24, 48, 72 or 96 weeks. Treatment with AXLi is expected to continue until a clinically relevant endpoint of treatment completion or discontinuation is reached. Thus, the duration of the dosing regimen stops the treatment with AXLi. "Discontinuation" (which may also be referred to as "withdrawal" or "cessation") can be done, for example, when the treatment endpoint is reached for the subject. The treatment endpoint for completion / discontinuation of AXLi treatment can be based on futility in terms of efficacy, or non - acceptability / harmfulness in terms of safety. The treatment endpoint for completion / discontinuation of AXLi treatment may be based on usefulness regarding efficacy such as partial or complete disease remission. That is, the methods of the present disclosure can include, for example, starting on the third day of the dosing regimen, administering a maintenance dose of AXLi and continuing to administer the maintenance dose to the subject daily until the treatment with AXLi is stopped, for example, when the treatment endpoint for the subject is reached. Similarly, the methods of the present disclosure can include starting on the first day of the dosing regimen, administering a fixed dose of AXLi and continuing to administer the fixed dose to the subject daily until the treatment with AXLi is stopped, for example, until the treatment endpoint is reached for the subject.

[0098] Treatment endpoints that can be stopped (termed "discontinued" or "being discontinued") by AXLi include, for example, the following: Partial disease remission to achieve a partial remission [PR] state or complete disease remission to achieve a complete remission [CR] state can be evaluated, for example, by changes in blast cells, normal maturation of cell lines, reduction of tumor burden, and / or absence of detectable tumors. Delay or absence of disease progression (achievement of stable disease [SD] state); can be evaluated, for example, by changes in blast cells, delay or absence of tumor expansion, and / or delay or absence of increase in tumor burden. Any positive patient outcome selected from: extension of survival period, progression-free survival period, hematological improvement, bone marrow response, hematological recovery, tumor shrinkage, reduction of tumor burden, delay or absence of tumor expansion, delay or absence of increase in tumor burden, negative response to gene markers, improvement in quality of life, and any other positive patient outcome; extension of survival period, progression-free survival period, hematological improvement (which can be evaluated, for example, by an increase in hemoglobin, platelet count, and / or neutrophil count in blood), bone marrow response (for example, (a) bone marrow with blast cells ≤ 5%; a 30%, 40%, 50% or more reduction in blast cells; absence of circulating blast cells and blast cells with Auer rods; absence of extramedullary disease), hematological recovery (which can be evaluated, for example, by ≥ 11 g / dL hemoglobin, ≥ 100 × 109 / L platelets, and / or ≥ 1 × 109 / L neutrophils in peripheral blood), tumor shrinkage (for example, a 5, 10, 20, 30, 40% or more reduction in tumor volume), reduction of tumor burden (for example, a 5, 10, 20, 30, 40% or more reduction in tumor burden), delay or absence of tumor expansion, delay or absence of increase in tumor burden, negative response to gene markers, improvement in quality of life (which can be evaluated, for example, using a health-related quality of life questionnaire such as the Functional Assessment of Cancer Therapy (FACT) questionnaire), or other quality of life questionnaires and any other positive patient outcome. Disease progression in a progressive disease [PD] state that prompts treatment discontinuation Occurrence of adverse events that require treatment discontinuation, including toxicity and / or death is.

[0099] Suitable methods for determining the above clinical endpoints are well known to those skilled in the art. Similarly, methods for determining tumor volume / tumor burden are, for example, computerized tomography (CT) or magnetic resonance imaging (MRI) imaging techniques; X-ray images, such as mammography; ultrasound images; nuclear images, such as positron emission tomography (PET), PET / CT scans, bone scans, gallium scans, or metaiodobenzylguanidine (MIBG) scans; bioluminescence imaging (BLI); fluorescence imaging (FLI); BD ToF (infrared-based 3D time-of-flight camera) images, and are well known to those skilled in the art.

[0100] Preferred treatment endpoints that can cause treatment with AXLi to be stopped (“discontinued” or “is discontinued”) include the following: · Complete disease remission (achieving a complete remission / complete response [CR] state). In certain embodiments, the AXLi treatment may be continued over a period after the initial determination if it is believed to be due to the AXLi effect and there are no concerns about tolerance. Thus, treatment endpoints that may result in stopping treatment with AXLi are a CR state at 1, 2, 3, 4, 5, 6 months or more. · Disease progression in a progressive disease [PD] state that prompts treatment discontinuation · Incidence of toxicity and / or adverse events that require treatment discontinuation (e.g., as determined by the NCI-CTCAE version 5.0 (v5.0, published November 27, 2017)) can be mentioned.

[0101] As used herein, the term “discontinued” treatment means that treatment with a therapeutic agent such as AXLi is stopped. Alternative terms such as “discontinued,” “discontinued,” etc. can be used interchangeably with “stopped.” Similarly, “treatment discontinuation” means that treatment of a subject with a therapeutic agent such as AXLi is stopped. Alternative terms such as “treatment discontinuation,” “stop treatment,” etc. can be used interchangeably. AXLi may be administered to the subject QD (daily).

[0102] In certain embodiments, AXLi may be administered to a subject daily. That is, AXLi may be administered to the subject on each day of a dosing regimen that may include day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and each day thereafter until treatment with AXLi is discontinued, e.g., until a treatment endpoint is reached for the subject. As a non-limiting example, if the duration of the dosing regimen is about 7 days, AXLi may be administered to the subject on days 1, 2, 3, 4, 5, 6 and 7 of the dosing regimen. Similarly, if the duration of the dosing regimen is about 14 days, AXLi may be administered to the subject on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 of the dosing regimen.

[0103] AXLi may be administered to a subject once a day. That is, AXLi may be administered to the subject once each day of a dosing regimen, which may be once each day 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 and each day thereafter until treatment with AXLi is discontinued, e.g., until a treatment endpoint is reached for the subject. As a non-limiting example, if the duration of the dosing regimen is about 7 days, AXLi may be administered to the subject once each day on days 1, 2, 3, 4, 5, 6 and 7 of the dosing regimen. Similarly, if the duration of the dosing regimen is about 14 days, AXLi may be administered to the subject once each day on days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14 of the dosing regimen.

[0104] In certain embodiments, the dosing regimen may include multiple treatment cycles of AXLi. As used herein, the term "treatment cycle" refers to a treatment period that is repeated on a regular schedule. For example, the course of treatment administered over one week, two weeks, or three weeks may be referred to as one treatment cycle. This cycle may be repeated to form the course of treatment, i.e., the course of treatment that includes multiple treatment cycles. Thus, in certain embodiments, the dosing regimen may represent the course of treatment that includes multiple treatment cycles. In these embodiments where the dosing regimen includes cycles of treatment with AXLi, the duration of each treatment cycle may be about one week, two weeks, three weeks, four weeks, five weeks, six weeks, seven weeks, eight weeks, or nine weeks. For example, the length of each treatment cycle may be about three weeks. In embodiments where the dosing regimen represents the course of treatment that includes multiple treatment cycles, the first treatment cycle may include administering a loading dose and a maintenance dose of AXLi, as more fully described elsewhere herein: for example, the first treatment cycle may include administering a loading dose of about 200 mg on days 1 and 2 of the cycle, and a maintenance dose of about 100 mg on days 3 and each subsequent day of the cycle (e.g., days 3 - 21 of a three-week treatment cycle). In such embodiments, the second and subsequent treatment cycles may include administering a maintenance dose of AXLi, as more fully described elsewhere herein: for example, the second and subsequent treatment cycles may include administering a maintenance dose of about 100 mg on day 1 and each subsequent day of the second and subsequent treatment cycles (e.g., days 1 - 21 of subsequent three-week treatment cycles). In other embodiments where the dosing regimen represents the course of treatment that includes multiple treatment cycles, the first treatment cycle and subsequent treatment cycles may include administering a fixed dose of AXLi, as more fully described elsewhere herein - for example, the first treatment cycle and subsequent treatment cycles may include administering a fixed dose of about 150 mg on each day of each cycle (e.g., days 1 - 21 of a three-week treatment cycle).

[0105] Certain Embodiment In certain embodiments, the disease associated with AXL is cancer. In certain other embodiments, the disease associated with AXL is a fibrotic disorder. Specific embodiments contemplated by the methods of the present disclosure include the following: A method of treating cancer in a subject, comprising administering to the subject an AXLi, such as bemcentinib, once daily in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 200 mg administered on the first and second days of the dosing regimen, and the maintenance dose is about 100 mg administered on the third day and each subsequent day of the dosing regimen. A method of treating cancer in a subject, comprising administering to the subject an AXLi, such as bemcentinib, once daily in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 200 mg administered on the first day of the dosing regimen, and the maintenance dose is about 100 mg administered on the second day and each subsequent day of the dosing regimen. A method of treating cancer in a subject, comprising administering to the subject an AXLi, such as bemcentinib, once daily in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 200 mg administered on the first, second, and third days of the dosing regimen, and the maintenance dose is about 100 mg administered on the fourth day and each subsequent day of the dosing regimen. A method of treating cancer in a subject, comprising administering to the subject an AXLi, such as bemcentinib, once daily in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 150 mg administered on the first and second days of the dosing regimen, and the maintenance dose is about 75 mg administered on the third day and each subsequent day of the dosing regimen.

[0106] A method of treating cancer in a subject, comprising administering to the subject an AXLi, such as bemcentinib, once daily in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 150 mg administered on the first day of the dosing regimen, and the maintenance dose is about 75 mg administered on the second day and each subsequent day of the dosing regimen. A method for treating cancer in a subject, comprising administering an AXLi such as bemcentinib to the subject once a day in a dosing regimen comprising a loading dose and a maintenance dose, wherein the loading dose is about 150 mg administered on the first, second, and third days of the dosing regimen, and the maintenance dose is about 75 mg administered on the fourth day and each subsequent day of the dosing regimen. A method for treating cancer in a subject, comprising a dosing regimen that includes administering a constant dose of about 75 mg of an AXLi such as bemcentinib to the subject once a day on each day after the first day of the dosing regimen.

[0107] A method for treating cancer in a subject, comprising administering an AXLi such as bemcentinib to the subject once a day in a dosing regimen that includes administering a constant dose of about 100 mg of the AXLi to the subject on each day after the first day of the dosing regimen. A method for treating cancer in a subject, comprising administering an AXLi such as bemcentinib to the subject once a day in a dosing regimen that includes administering a constant dose of about 125 mg of the AXLi to the subject on each day after the first day of the dosing regimen. A method for treating cancer in a subject, comprising administering an AXLi such as bemcentinib to the subject once a day in a dosing regimen that includes administering a constant dose of about 150 mg of the AXLi to the subject on each day after the first day of the dosing regimen.

[0108] In these embodiments, the AXLi, which can be bemcentinib, is preferably administered to the subject under fed conditions, as more fully described elsewhere herein.

[0109] Therapeutic Agent that Increases Gastric pH or Reduces Gastric Acid Production The inventors have discovered that co - administration of AXLi with a therapeutic agent that changes gastric pH or changes gastric acid production (described in more detail below) can affect absorption and subsequent exposure of the subject to AXLi. Without being bound by theory, the use of a therapeutic agent that changes gastric pH, such as a proton pump inhibitor, is thought to result in an increase in gastric pH and thus a decrease in the solubility and subsequent absorption of bemcentinib. Thus, in the methods of the present disclosure, the level of the loading and / or maintenance dose of AXLi may vary depending on whether the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production. Similarly, in the methods of the present disclosure, the level of a fixed dose of AXLi may vary depending on whether the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production. In such embodiments, the loading, maintenance dose and / or fixed dose of AXLi may be increased by about 100% when the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production, for example, a therapeutic agent that increases gastric pH or decreases gastric acid production. One of ordinary skill in the art can readily determine the increased dose levels based on the loading, maintenance and fixed doses described elsewhere in this specification. The following are given.

[0110] In certain embodiments, the loading and / or maintenance dose of AXLi may be increased by about 100% of the loading or maintenance dose detailed elsewhere in this specification when the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production, for example, a therapeutic agent that increases gastric pH or decreases gastric acid production. For example, a loading dose of about 200 mg may be increased to about 400 mg when the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production. For example, a maintenance dose of about 100 mg may be increased to about 200 mg when the subject has been administered or is being administered a therapeutic agent that changes gastric pH or changes gastric acid production.

[0111] In certain embodiments, when a subject has been administered, or is being administered, a therapeutic agent that changes gastric pH or changes gastric acid production, e.g., a therapeutic agent that raises gastric pH or reduces gastric acid production, the fixed dose of AXLi may be increased by about 100% of the fixed dose detailed elsewhere herein. For example, a fixed dose of about 150 mg may be increased to about 300 mg when a subject has been administered, or is being administered, a therapeutic agent that changes gastric pH or changes gastric acid production. For example, a fixed dose of about 100 mg may be increased to about 200 mg when a subject has been administered, or is being administered, a therapeutic agent that changes gastric pH or changes gastric acid production.

[0112] In certain embodiments, when a subject is administered a therapeutic agent that changes gastric pH or changes gastric acid production, e.g., a therapeutic agent that raises gastric pH or reduces gastric acid production, during the course of a dosing regimen, the loading and / or maintenance dose, or fixed dose, can be increased to levels according to the above embodiments (e.g., increased by about 100%). In these embodiments, the increased dose may be administered to the subject at the higher level for the remainder of the dosing regimen. By way of example, on day 4 of a dosing regimen where the loading dose of AXLi is 200 mg and the maintenance dose of AXLi is 100 mg, if a therapeutic agent that changes gastric pH or changes gastric acid production is administered to the subject, the maintenance dose can be increased to about 200 mg on day 4 of the dosing regimen and each subsequent day. By way of example, if a therapeutic agent that changes gastric pH or changes gastric acid production is administered to a subject on day 4 of a dosing regimen where a fixed dose of AXLi is 150 mg, that fixed dose may be increased to about 300 mg for day 4 of the dosing regimen and each subsequent day.

[0113] A therapeutic agent that changes the pH of the stomach or changes gastric acid production can be any therapeutic intervention administered to regulate the pH of the stomach or gastric acid production. For example, a therapeutic agent that changes the pH of the stomach or changes gastric acid production can be a drug for the treatment of acid-related disorders. Such drugs for acid-related disorders are classified under ATC code A02 in the World Health Organization (WHO)'s Anatomical Therapeutic Chemical Classification System and are classified under code A02 in the Medical Dictionary for Regulatory Activities (MedDRA). These subcategories are drugs for peptic ulcer and gastroesophageal reflux disease (GORD; ATC A02B). Thus, those skilled in the art are well aware of which agents can be considered agents that change the pH of the stomach or change gastric acid production and which agents can be considered drugs for acid-related disorders.

[0114] A therapeutic agent that changes the pH of the stomach or changes gastric acid production can be a therapeutic agent that raises the pH of the stomach or reduces gastric acid production. A therapeutic agent that changes the pH of the stomach or changes gastric acid production can be a gastric protectant, a gastric acid secretion inhibitor, or an agent that neutralizes gastric acid. Such agents include proton pump inhibitors (PPI; ATC A02BC), which inhibit the gastric H+ / K+ ATPase proton pump, thereby reducing gastric acid production. In certain embodiments, the PPI is omeprazole, lansoprazole, dexlansoprazole, dexlaprazole, bonoprazan, tegoprazan, esomeprazole, pantoprazole, rabeprazole, and / or ilaprazole.

[0115] H2 receptor antagonists (H2RAs; ATC A02BA) block the action of histamine at the H2 receptors of gastric parietal cells, thereby reducing gastric acid production. In certain embodiments, the H2 antagonist may be cimetidine, ranitidine, famotidine, nizatidine, roxatidine, ranitidine bismuth citrate, raf tidine, labotidine, and / or niperotidine.

[0116] Antacids (ATC A02A) contain alkaline ions that chemically neutralize gastric acid. In certain embodiments, the antacid may be an aluminum salt, a calcium salt, a magnesium salt, and / or a sodium salt. In certain embodiments, the antacid may be aluminum hydroxide, algeldrate, aluminum phosphate, dihydroxialumini sodium carbonate, aluminum acetoacetate, alloglutamol, aluminum glycinate, calcium carbonate, calcium silicate, magnesium carbonate, magnesium oxide, magnesium peroxide, magnesium silicate, magnesium trisilicate, magnesium hydroxide, sodium bicarbonate, magaldrate, almagate, hydrotalcite, aluminum silicate, and / or bismuth subsalicylate. Prostaglandins (ATC A02BB), such as misoprostol and / or enprostil. Other drugs for peptic ulcer and gastroesophageal reflux disease (GORD; ATC A02BX), such as carbenoxolone, sucralfate, pirenzepine, methiosulfonium chloride, bismuth subcitrate potassium, progulmid, gefarnate, sulglycotide, acetoxolone, zolimidine, troxipide, bismuth subnitrate, alginic acid, and / or levamiside.

[0117] A therapeutic agent that changes the gastric pH or changes gastric acid production may be a therapeutic agent that raises the gastric pH above pH 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In certain embodiments, the therapeutic agent can raise the gastric pH above pH 3.5, such as above pH 3.6, 3.7, 3.8, 3.9, or 4.0. A therapeutic agent that changes the gastric pH or changes gastric acid production may be a therapeutic agent that raises the gastric pH from within the range of pH 1.5 - 4.0, for example, from within the range of pH 1.5 - pH 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In certain embodiments, the therapeutic agent can raise the gastric pH from within the range of pH 2.0 - 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. In certain embodiments, the therapeutic agent can raise the gastric pH from within the range of pH 3.0 - 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0. As outlined elsewhere herein, these effects on gastric pH can be mediated through a decrease in gastric acid secretion and / or neutralization of gastric acid.

[0118] Administration in Fed State Food consumption can result in certain physiological changes that affect the pharmacokinetics of a drug compound, including, for example, changes in the pH of the stomach and intestines, delayed gastric emptying, increased bile secretion, and increased blood flow to the viscera and liver. The inventors unexpectedly discovered that administration of AXLi to a subject under fed conditions is associated with both an increase in exposure to AXLi and a decrease in variability of exposure among subjects. Without being bound by theory, it is speculated that the decrease in PK variability and the increase in exposure to food may result from inhibition of efflux transporters in the GI tract or an increase in transport via the lymphatic system due to an increase in lipid content in the GI tract by the addition of food. The surprising decrease in variability observed at fed state doses allows for a decrease in the dose of AXLi, which, in turn, decreases the incidence of adverse effects associated with AXLi administration. Accordingly, the methods of the present disclosure can include administering AXLi to a subject under fed conditions. That is, AXLi may be administered to subject pc (after cibum; postprandially). In a preferred embodiment of the methods of the present disclosure, AXLi is administered to a subject under fed conditions.

[0119] As used herein, drug administration "under feeding conditions" means drug administration and / or absorption that occurs during the period when the subject is in a food absorption phase, i.e., after ingestion of food during which the body is digesting food and absorbing nutrients (and catabolism exceeds anabolism). Drug administration "under feeding conditions" also encompasses scenarios where the subject receives liquid-form nutrition (e.g., enteral nutrition supplies, compositions containing blended foods, or other processed food substitutes) via enteral or parenteral administration routes. In such cases, drug administration (e.g., AXL i administration) may still be administered orally or via introduction through a feeding tube. Thus, drug administration "under feeding conditions" means drug administration simultaneous with food consumption / intake, which may be before, simultaneous with, and / or after drug administration. In certain embodiments, drug administration may be performed before or during a bolus or infusion feeding period (e.g., to allow for gastrointestinal and digestive and metabolic "rest" from feeding). Administration "under feeding conditions" may also be referred to as, for example, administration "in a fed state", administration "with food", etc. By comparison, drug administration "under fasting conditions" or "in a fasting state" means administration during a period when no food is consumed by the subject, as described more fully below. In certain embodiments, administering AXL i under feeding conditions may include administering AXL i to the subject before, simultaneous with, and / or after food consumption / intake.

[0120] In certain embodiments, administering AXL i under feeding conditions may include administering AXL i to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed / intaken food. Preferably, AXL i is administered to the subject within about 240 minutes after the subject has consumed / intaken food. In this context, within about 240 minutes after consuming / intaking food means within the 240-minute time frame before or after consuming / intaking food. In certain embodiments, administering AXLi under feeding conditions may include administering AXLi to a subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed / ingested food. Preferably, AXLi is administered to the subject within about 240 minutes after the subject has consumed / ingested food. In certain embodiments, administering AXLi under feeding conditions may include administering AXLi to a subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before or after the subject has consumed / ingested food. Preferably, AXLi is administered to the subject within about 240 minutes before or after the subject has consumed / ingested food. In certain embodiments, administering AXLi under feeding conditions may include administering AXLi to a subject. It may include administering AXLi to the subject within at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has consumed / ingested food. In certain embodiments, administering AXLi under feeding conditions includes administering AXLi to a subject within about 1 hour. It can be within 0 - 240 minutes, for example, about 30 - 240 minutes, 60 - 240 minutes, 90 - 240 minutes, 120 - 240 minutes, 150 - 240 minutes, 180 - 240 minutes, or 210 - 240 minutes, or for example, about 0 - 210 minutes, 0 - 180 minutes, 0 - 150 minutes, 0 - 120 minutes, 0 - 90 minutes, 0 - 60 minutes, or 0 - 30 minutes. In certain embodiments, the step of administering AXLi under feeding conditions includes administering AXLi to the subject within about 5 - 60 minutes, for example within about 10 - 50 minutes, or within about 20 - 40 minutes after the subject has consumed / ingested food. In this context, within about 0 - 240 minutes after consuming / ingesting food means within the time frame of 0 - 240 minutes before or after consuming / ingesting food.

[0121] Preferably, administering AXLi under feeding conditions can include administering AXLi to the subject within 240 minutes after the subject has consumed / ingested food. That is, administering AXLi to the subject is within about 240 minutes before or after the subject has consumed / ingested food, and less than about 240 minutes after the subject has consumed / ingested food.

[0122] In certain embodiments, the food may include, or be, a meal such as a high-fat and / or high-protein meal. In certain embodiments, the food may include, or be, an oral nutritional supplement (ONS). In certain embodiments, the food may include, or be, an enteral nutritional feed such as a high-fat and / or high-protein diet formulated for enteral administration. In certain embodiments, the food may include, or be, a parenteral nutritional feed such as a high-fat and / or high-protein diet formulated for parenteral administration. Food may be consumed / ingested via the oral route. In certain embodiments, food may be consumed / ingested via the enteral route, such as via the nasogastric (NG), percutaneous endoscopic gastrostomy (PEG), or nasojejunal (NJ) route. In certain embodiments, food may be consumed / ingested via the parenteral route.

[0123] Those skilled in the art recognize, as part of their common general knowledge, suitable high-fat and / or high-protein diets that can be used in the methods of the present disclosure, such as a standardized high-fat diet defined for use in the investigation of drug interactions by the European Medicines Agency (see, e.g., EMA "Guideline on the investigation of drug interactions" at https: / / www.ema.europa.eu / en / documents / scientific-guideline / guideline-investigation-drug-interactions-revision-1_en.pdf), or a diet having a comparable total calorie content, with a similar amount of calories derived from protein, carbohydrates, and fat. Similarly, those skilled in the art recognize, as part of their common general knowledge, suitable oral nutritional supplements (ONS), as well as enteral and parenteral nutritional supplies, that can be used in the methods of the present disclosure. In certain embodiments, the high-fat diet contains about 800 - 1000 kcal, about 500 - 600 kcal of which are derived from fat and 250 kcal are derived from carbohydrates. An example of a high-fat diet is two eggs fried in butter, two strips of bacon, two slices of toast with butter, 120 ml of hash brown potatoes, and 240 ml of whole milk. Substitutions for this example diet can be made provided that the diet provides a similar amount of calories from protein, carbohydrates, and fat and has an equivalent meal volume and viscosity. That is, in certain embodiments, the high-fat diet contains about 700 - 1100 kcal, about 750 - 1050 kcal, or about 800 - 1000 kcal, and about 45, 50, 55, 60, 65, or 70% of the calorie content is derived from fat. In certain embodiments, about 10, 15, 20, 25, 30, or 35% of the calorie amount may be derived from carbohydrates. Thus, in certain embodiments, a high-fat diet is greater than about 25% of the total calorie content of the diet, such as about 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or greater than 70% from saturated or unsaturated fat. In certain embodiments, a high-fat diet is greater than about 35% of the total calorie content of the diet from either saturated or unsaturated fat. In certain embodiments, a high-fat diet is greater than about 45% of the total calorie content of the diet from either saturated or unsaturated fat. In certain preferred embodiments, a high-fat diet is greater than about 50% of the total calorie content of the diet from saturated or unsaturated fat. In certain embodiments, a high-fat diet is about 25 - 65% of the total calorie content of the diet, such as about 35 - 65%, 45 - 65%, 50 - 65%, or 55 - 65% from saturated or unsaturated fat. In certain embodiments, a high-protein diet is greater than about 15% of the total calorie content of the diet, such as about 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or greater than 35% from protein. In certain embodiments, a high-protein diet is greater than about 20% of the total calorie content of the diet from protein.

[0124] Administration in Fasting State In contrast to the above “feeding state” / “feeding condition”, “fasting condition”, “under fasting condition”, “fasting state”, or drug administration under “fasting condition” means administration during a period when food is not consumed by the subject, for example, during a period of at least 1, 2, 3, or 4 hours after drug administration after an overnight fast when food is not consumed. Administration under “fasting condition” may also be referred to as, for example, “fasting condition”, “fasting state”, administration under “fasting condition”, administration “without food”, etc. The methods of the present disclosure may include administering AXLi to a subject under fasting conditions.

[0125] In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject after an overnight fast. In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject after an overnight fast and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject consumes / ingests any food. For example, AXLi can be administered to the subject at least about 1 hour before the subject consumes / ingests any food. An "overnight" fast can be a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours overnight during which the subject does not consume / ingest any food. Preferably, the "overnight" fast can be a period of at least about 4 hours overnight during which the subject does not consume / ingest any food. "Not consuming food" can mean that the subject does not ingest / consume anything other than water.

[0126] In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject on an empty stomach. In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject on an empty stomach and at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180 minutes before, or more preferably 240 minutes or 300 minutes before the subject consumes / ingests any food. For example, AXLi can be administered to the subject at least about 1 hour before the subject consumes / ingests any food. "On an empty stomach" can mean that the subject has not consumed / ingested food for a period of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours prior to administration of AXLi. Preferably, "on an empty stomach" can mean that the subject has not consumed / ingested food for a period of at least about 4 hours prior to administration of AXLi. "Not consuming food" can mean that the subject does not ingest / consume anything other than water.

[0127] In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed / ingested food or will consume / ingest food. AXLi can be administered to the subject at least about 120 minutes before the subject has consumed / ingested food or will consume / ingest food. For example, AXLi can be administered to the subject at least about 60 minutes before the subject has consumed / ingested food or will consume / ingest food.

[0128] In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed / ingested food. Preferably, administering AXLi under fasting conditions can include administering AXLi to a subject at least about 4 hours or more after the subject last consumed / ingested food. For example, AXLi can be administered to the subject at least about 8 hours after the subject last consumed / ingested food.

[0129] In certain embodiments, administering AXLi under fasting conditions can include administering AXLi to a subject at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or more preferably 240, or 300 minutes before the subject has consumed / ingested food or will consume / ingest food and at least about 1, 2, 3, or more preferably 4, 5, 6, 7, 8, 9, or 10 hours after the subject last consumed / ingested food. For example, AXLi can be administered to the subject at least about 60 minutes before the subject has consumed / ingested food or will consume / ingest food and at least about 8 hours after the subject last consumed / ingested food. For example, AXLi can be administered to the subject at least about 240 minutes before the subject has consumed / ingested food or will consume / ingest food and at least about 4 hours after the subject last consumed / ingested food. In certain embodiments, administering AXLi under fasting conditions may preferably include administering AXLi to a subject on an empty stomach after an overnight fast and at least about 1 hour before the subject consumes / ingests any food. AXLi may be administered with water.

[0130] Combination Agent In certain embodiments, the AXLi described herein may be administered in combination with one or more additional therapies and / or therapeutic agents, either simultaneously or sequentially in any order. Examples of therapies and therapeutic agents include, but are not limited to, chemotherapy (e.g., administration of an active agent comprising a drug such as a chemotherapeutic agent), immunotherapy (e.g., administration of an active agent comprising a cell-based therapy or a drug such as an immune checkpoint modulator (ICM)), and / or radiation therapy.

[0131] Chemotherapeutic Agent A "chemotherapeutic agent" is a compound useful in the treatment of cancer, regardless of its mechanism of action. Classes of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolites, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Chemotherapeutic agents include compounds used in "targeted therapies," immuno-oncology drugs such as checkpoint inhibitors, and conventional chemotherapy. In the methods disclosed herein, AXLi may be administered in combination with one or more chemotherapeutic agents.

[0132] Examples of chemotherapeutic agents that can be used in the disclosed method include the following: Lenalidomide (REVLIMID®, Celgene), Vorinostat (ZOLINZA®, Merck), Panobinostat (FARYDAK®, Novartis), Mocetinostat (MGCD0103), Everolimus (ZORTRESS®, CERTICAN®, Novartis), Bendamustine (TREAKISYM®, RIBOMUSTIN®, LEVACT®, TREANDA®, MSD International), Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Docetaxel (TAXOTERE®, Sanofi Aventis), 5-FU (Fluorouracil, 5-Fluorouracil, CAS No. 51-21-8), Gemcitabine (GEMZAR®, Lilly), PD-0325901 (CAS No. 391210-10-9, Pfizer), Paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton NJ), Trastuzumab (HERCEPTIN®, Genentech), Temozolomide (4-Methyl-5-oxo-2,3,4,6,8-pentaazabicyclo[4.3.0]nona-2,7,9-triene-9-carboxamide, CAS No. 85622-93-1, TEMODAR®, TEMODAL®, Schering Plough), Tamoxifen ((Z)-2-[4-(1,2-Diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, NOLVADEX®, ISTUBAL®, VALODEX®), Doxorubicin (ADRIAMYCIN®), Akti-1 / 2, HPPD, Rapamycin, and the like.

[0133] Examples of additional chemotherapeutic agents include the following: oxaliplatin (Eloxatin (registered trademark), Sanofi), bortezomib (VELCADE (registered trademark), Millennium Pharm.), Sutent (SUNITINIB (registered trademark), SU11248, Pfizer), letrozole (FEMARA (registered trademark), Novartis), imatinib mesylate (Gleevec (registered trademark), Novartis), XL-518 (MEK inhibitor, Exelixis, International Publication No. 2007 / 044515), ARRY-886 (MEK inhibitor, AZD6244, Array BioPharma, AstraZeneca), SF-1126 (PI3K inhibitor, Semaphore Pharma), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis), PTK787 / ZK 222584, fulvestrant (FASLODEX (registered trademark), AstraZeneca), leucovorin (folic acid), rapamycin (sirolimus, Rapamune (registered trademark), Wyeth), lapatinib (TYKERB (registered trademark), GSK572016, GlaxoSmithKline), lonafarnib (SARASARTM SCH 66336, Schering-Plough), sorafenib (NEXAVAR (registered trademark), BAY43-9006, Bayer Research), gefitinib (IRESSA (registered trademark), AstraZeneca), irinotecan (CAMPTOSAR (registered trademark), CPT-11, Pfizer), tipifarnib (ZARNESTRATM, Johnson & Johnson), ABRAXANE (trademark), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Il), vandetanib (rINN, ZD6474, ZACTIMA (registered trademark), AstraZeneca), chlorambucil, AG1478, AG1571 (SU5271; Chongyuan Institute), temsirolimus (VELCADE (registered trademark), Millennium Pharm.), pazopanib (GlaxoSmithKline), ifosfamide (SUNITINIB (registered trademark), SU11248, Pfizer), thiotepa and cyclophosphamide (FEMARA (registered trademark), Novartis); busulfan, improsulfan, piposulfan and other alkyl sulfonates; benzodopa, carbocone, metredopa, uredopa and other aziridines;Ethylenimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analogue topotecan); bryostatin; calistatin; CC-1065 (including adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (synthetic analogues, KW-2189, and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, nobenbine, phenesterine, prednisolone, trophosphamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as enediyne antibiotics (for example, calicheamicin, calicheamicin gamma 1I, calicheamicin omega I1 (Angew Chem.Intl.Ed.Engl. (1994) 33:183-186); dynemicin, dynemicin A; bisphosphonate agents such as clodronate; esperamicin; neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, calminomycin, cardinophilin, chromomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, nemorubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quaromycin, rhodomycin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin;Antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, and trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, and thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, didoxyruridine, doxifluridine, enocitabine, and floxuridine; androgens such as calusterone, drostanolone propionate, epithiostanol, mepithiostane, and testolactone; antiadrenal drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; deferoxamine; dexamethasone; diacodone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene or OR); razoxane; rizoxin; sizofiran; spirogermanium; tenuazonic acid; triacodone; 2,2’,2’-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gasitocin; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (navelbine (registered trademark)); novantrone; teniposide; edatraxate; daunomycin; aminopterin; capecitabine (Xeloda (registered trademark), Roche); ibandronic acid; CPT-11;Topoisomerase inhibitors RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids, and derivatives of any of these may be mentioned.

[0134] Examples of chemotherapeutic agents used for the treatment of anal cancer include the following: Gardasil, Gardasil9, recombinant human papillomavirus (HPV) 9-valent vaccine, recombinant human papillomavirus (HPV) 4-valent vaccine.

[0135] Examples of chemotherapeutic agents used for the treatment of bladder cancer include the following: atezolizumab, avelumab, Erdafitinib, Bavencio (avelumab), cisplatin, doxorubicin hydrochloride, durvalumab, Erdafitinib, Imfinzi (durvalumab), Keytruda (pembrolizumab), nivolumab, Opdivo (nivolumab), pembrolizumab, Tecentriq (atezolizumab), thiotepa, valrubicin, and Valtrex (valrubicin).

[0136] Examples of chemotherapeutic agents used for the treatment of bone cancer include the following: Cosmegen (dactinomycin), dactinomycin, denosumab, doxorubicin hydrochloride, methotrexate, Trexall (methotrexate), and Xgeva (denosumab).

[0137] Examples of chemotherapeutic agents used for the treatment of brain tumors include the following: Afinitor (everolimus), Afinitor Dispersible (everolimus), Avastin (bevacizumab), bevacizumab, BiCNU (carmustine), carmustine, carmustine implant, everolimus, Gliadel Wafer (carmustine implant), Lomustine, Mvasi (bevacizumab), Temodal (temozolomide), and temozolomide.

[0138] Examples of chemotherapeutic agents used in the treatment of breast cancer include the following: abemaciclib, Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), ado-trastuzumab emtansine, Afinitor (everolimus), Afinitor Dispersible (everolimus), alpelisib, anastrozole, Aredia (disodium pamidronate), Arimidex (anastrozole), Aromasin (exemestane), atezolizumab, capecitabine, cyclophosphamide, docetaxel, doxorubicin hydrochloride, Ellence (epirubicin hydrochloride), Enhertu (Fam-trastuzumab deruxtecan-nxki), epirubicin hydrochloride, eribulin mesylate, everolimus, exemestane, 5-FU (fluorouracil injection), (Fam-trastuzumab deruxtecan-nxki, Fareston (toremifene), Faslodex (fulvestrant), Femara (letrozole), tamoxifen citrate, Taxol (paclitaxel), Lynparza (olaparib), megestrol acetate, methotrexate, neratinib maleate, hyaluronidase-ditosylate, thiotepa, toremifene, trastuzumab, trastuzumab and hyaluronidase-oysk, Trexall (methotrexate), Tykerb (lapatinib ditosylate), Verzenio (abemaciclib), vinblastine sulfate, Xeloda (capecitabine) and Zoladex (goserelin acetate).

[0139] Examples of chemotherapeutic agents used in the treatment of cervical cancer include the following: Avastin (bevacizumab), bevacizumab, bleomycin sulfate, Hycamtin (topotecan hydrochloride), Keytruda (pembrolizumab), Mvasi (bevacizumab), pembrolizumab, topotecan hydrochloride.

[0140] Examples of chemotherapeutic agents used in the treatment of colorectal and rectal cancer include the following: Avastin (bevacizumab), bevacizumab, Camptosar (irinotecan hydrochloride), capecitabine, cetuximab, Cyramza (ramucirumab), Eloxatin (oxaliplatin), Erbitux (cetuximab), 5-FU (fluorouracil injection), fluorouracil injection, ipilimumab, irinotecan hydrochloride, Keytruda (pembrolizumab), leucovorin calcium, Lonsurf (trifluridine and tipiracil hydrochloride), Mvasi (bevacizumab), nivolumab, Opdivo (nivolumab), oxaliplatin, panitumumab, pembrolizumab, ramucirumab, regorafenib, Stivarga (regorafenib), trifluridine and tipiracil hydrochloride, Vectibix (panitumumab), Xeloda (capecitabine), Yervoy (ipilimumab), Zaltrap (Ziv-aflibercept), Ziv-aflibercept.

[0141] Examples of chemotherapeutic agents used in the treatment of ovarian, fallopian tube, or primary peritoneal cancer include the following: Alkeran (melphalan), Avastin (bevacizumab), bevacizumab, carboplatin, cisplatin, cyclophosphamide, doxorubicin hydrochloride, Doxil (doxorubicin hydrochloride liposome), doxorubicin hydrochloride liposome, gemcitabine hydrochloride, Gemzar (gemcitabine hydrochloride), Hycamtin (topotecan hydrochloride), Lynparza (olaparib), melphalan, niraparib tosylate monohydrate, olaparib, paclitaxel, Rubraca (rucaparib camsylate), rucaparib camsylate, Taxol (paclitaxel), thiotepa, topotecan hydrochloride, Zejula (niraparib tosylate monohydrate).

[0142] Examples of chemotherapeutic agents used in the treatment of non-small cell lung cancer include the following: Abraxane (paclitaxel albumin-stabilized nanoparticle formulation), afatinib dimaleate, Afinitor (everolimus), Afinitor Dispersible (everolimus), Alecensa (alectinib), alectinib, Alimta (anticancer agent), Alunbrig (brigatinib), amivantamab vmjw, atezolizumab, Avastin (bevacizumab), bevacizumab, brigatinib, cabozantinib, carboplatin, capmatinib, Cemiplimab-rwk, ceritinib, crizotinib, Cyramza (ramucirumab), dabrafenib mesylate, dacomitinib, docetaxel, doxorubicin hydrochloride, Gemzar (gemcitabine hydrochloride), ceritinib, Iressa (gefitinib), Keytruda (pembrolizumab), Lorlatinib, lorlatinib, mechlorethamine hydrochloride, Mekinist (trametinib), methotrexate, Taxol (paclitaxel), Taxotere (docetaxel), Tencentriq (atezolizumab), trametinib, Trexall (methotrexate), vemurafenib, Vitsiprol (dacomitinib), vinorelbine tartrate, Xalkori (crizotinib), Zykadia (ceritinib).

[0143] Examples of preferred chemotherapeutic agents for use in the treatment of non-small cell lung cancer are pemetrexed in combination with carboplatin. Other examples of preferred chemotherapeutic agents for use in the treatment of non-small cell lung cancer are carboplatin in combination with pemetrexed and pembrolizumab. Other examples of preferred chemotherapeutic agents for use in the treatment of non-small cell lung cancer are cisplatin in combination with pemetrexed. Other examples of preferred chemotherapeutic agents for use in the treatment of non-small cell lung cancer are cisplatin in combination with pemetrexed and pembrolizumab. In the methods of the present disclosure in which AXLi is co-administered (e.g., in combination with pembrolizumab, or in combination with carboplatin, an anticancer agent, and pembrolizumab) with a chemotherapeutic agent for the treatment of non-small cell lung cancer, a dosing regimen in which a certain dose level of AXLi is administered to a subject may be preferred.

[0144] Examples of chemotherapeutic agents used in the treatment of small cell lung cancer include the following: Afinitol (everolimus), atezolizumab, bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin hydrochloride, durvalumab, etopophos (etoposide phosphate), etoposide, etoposide phosphate, everolimus, gemcitabine (Gemzar), hycamtin (topotecan hydrochloride), irinotecan, Keytruda (pembrolizumab), lurbinectedin, mechlorethamine hydrochloride, methotrexate, mustargen (mechlorethamine hydrochloride), nivolumab, Opdivo (nivolumab), paclitaxel, pembrolizumab, Tencentriq (atezolizumab), topotecan hydrochloride, Trexall (methotrexate), vinorelbine, vincristine, Zepzelca (lurbinectedin).

[0145] Examples of chemotherapeutic agents used in the treatment of melanoma include the following: aldesleukin, binimetinib, Braftovi (encorafenib), cobimetinib, Cotellic (cobimetinib), dabrafenib mesylate, dacarbazine, encorafenib, IL-2 (aldesleukin), Imlygic (talimogene laherparepvec), interleukin-2 (aldesleukin), Intron A (recombinant interferon α-2b), ipilimumab, Keytruda (pembrolizumab), Mekinist (trametinib), Mektovi (binimetinib), nivolumab, Opdivo (nivolumab), peginterferon α-2b, Sylatron (peginterferon α-2b), Tafinlar (dabrafenib mesylate), talimogene laherparepvec, trametinib, vemurafenib, Yervoy (ipilimumab), Zelboraf (vemurafenib). Examples of chemotherapeutic agents used in the treatment of mesothelioma include Alimta (pemetrexed disodium), carboplatin, cisplatin, bevacizumab, nivolumab, ipilimumab, and pemetrexed disodium.

[0146] Examples of chemotherapeutic agents used in the treatment of AML include ATRA, arsenic trioxide, azacitidine, cerubidine (daunorubicin hydrochloride), cladribine, clofarabine, cyclophosphamide, cytarabine, daunorubicin hydrochloride, daunorubicin hydrochloride and cytarabine liposomes, daurismo (glasdegib maleate), decitabine, dexamethasone, doxorubicin hydrochloride, enasidenib mesylate, etoposide, fludarabine, gemtuzumab ozogamicin, gilteritinib fumarate, glasdegib maleate, idamycin PFS (idarubicin hydrochloride), idarubicin hydrochloride, idhifa (enasidenib mesylate), ivosidenib, midostaurin, mitoxantrone hydrochloride, mylotarg (gemtuzumab ozogamicin), rubidomycin (daunorubicin hydrochloride), ridapt (midostaurin), sorafenib, tabloid (thioguanine), thioguanine, tibsovo (ivosidenib), trisenox (arsenic trioxide), venetoclax, venetoclax, vincristine sulfate, viscios (daunorubicin hydrochloride and cytarabine liposomes) and zospata (gilteritinib fumarate).

[0147] Examples of chemotherapeutic agents used in the treatment of pancreatic cancer include the following: abraxane (paclitaxel albumin-stabilized nanoparticle formulation), afinitor (everolimus), capecitabine, cisplatin, entrectinib, erlotinib hydrochloride, everolimus, 5-FU (fluorouracil injection), fluorouracil injection, gemcitabine hydrochloride, gemzar (gemcitabine hydrochloride), irinotecan hydrochloride liposomes, larotrectinib, lympharza (olaparib), mitomycin C, olaparib, onivyde (irinotecan hydrochloride liposomes), paclitaxel albumin-stabilized nanoparticle formulation, pembrolizumab, rucaparib, sunitinib malate, sutent (sunitinib malate) and tarceva (erlotinib hydrochloride).

[0148] Examples of chemotherapeutic agents used in the treatment of kidney cancer include the following: Afinitor (everolimus), Afinitor Dispersible (everolimus), Aldesleukin, Axitinib, Avastin (bevacizumab), Avelumab, Axitinib, Bavencio (avelumab), Bevacizumab, Cabometyx (cabozantinib S-malate), Cabozantinib S-malate, Everolimus, IL-2 (aldesleukin), Inlyta (axitinib), Interleukin-2 (aldesleukin), Ipilimumab, Keytruda (pembrolizumab), Lenvatinib mesylate, Lenvima (lenvatinib mesylate), Mvasi (bevacizumab), Nexavar (sorafenib tosylate), Nivolumab, Opdivo (nivolumab), Pazopanib hydrochloride, Pembrolizumab, Proleukin (aldesleukin), Sorafenib tosylate, Sunitinib malate, Sutent (sunitinib malate), Temsirolimus, Tivozanib, Tresiba (temsirolimus), Botrient (pazopanib hydrochloride) and Yervoy (ipilimumab).

[0149] Examples of chemotherapeutic agents used in the treatment of solid tumors in any part of the body include the following: Entrectinib, Keytruda (pembrolizumab), Lartruvo (olaratumab), Rozlytrek (entrectinib) and Vitrakvi (larotrectinib sulfate).

[0150] Combination therapy is also included in the definition of the term "chemotherapeutic agent" as used herein. Examples of combination therapy of chemotherapeutic agents include gemcitabine-cisplatin, MVAC (methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin), PCV (procarbazine hydrochloride, lomustine, vincristine sulfate), AC (doxorubicin hydrochloride, cyclophosphamide), AC-T (doxorubicin hydrochloride, cyclophosphamide, paclitaxel), CAF (cyclophosphamide, doxorubicin hydrochloride, fluorouracil), CMF (cyclophosphamide, methotrexate, fluorouracil), FEC (fluorouracil, epirubicin hydrochloride), TAC (docetaxel, doxorubicin hydrochloride, cyclophosphamide), CAPOX (capecitabine, oxaliplatin), FOLFIRI (calcium leucovorin, doxorubicin hydrochloride, irinotecan hydrochloride), FOLFIRI-bevacizumab, FOLFIRI-cetuximab, FOLFOX (calcium leucovorin, fluorouracil hydrochloride, oxaliplatin), FU-LV (fluorouracil, doxorubicin hydrochloride, bleomycin, vincristine sulfate, etoposide phosphate), BEACOPP (bleomycin, etoposide hydrochloride, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone), ICE (ifosfamide, carboplatin, etoposide phosphate), MOPP (doxorubicin hydrochloride, vincristine sulfate, procarbazine hydrochloride, prednisone), COPP-ABV (doxorubicin hydrochloride, doxorubicin hydrochloride, cyclophosphamide, vincristine sulfate, procarbazine hydrochloride, prednisone), BEACOPP (bleomycin hydrochloride, doxorubicin hydrochloride, vincristine hydrochloride, procarbazine hydrochloride, prednisone), ADE (cytarabine hydrochloride, daunorubicin hydrochloride, etoposide phosphate), VAMP (vincristine sulfate, doxorubicin phosphate, prednisone), hyper-CVAD (mechlorethamine hydrochloride, doxorubicin hydrochloride, cyclophosphamide, busulfan hydrochloride, CEM (carboplatin, etoposide phosphate, mechlorethamine hydrochloride), EPOCH (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide hydrochloride), CHOP (doxorubicin, prednisone, cyclophosphamide,Vincristine), EPOCH (etoposide phosphate, prednisone, vincristine sulfate, doxorubicin hydrochloride), etc. BuMel procarbazine hydrochloride COPDAC docetaxel mOEPAICE (ifosfamide, carboplatin, etoposide phosphate) R-CHOP (rituximab, doxorubicin, prednisone, cyclophosphamide, vincristine), R-CVP (rituximab, cyclophosphamide, vincristine sulfate, prednisone) R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride), R-ICE (rituximab, ifosfamide, carboplatin, etoposide phosphate), BEP (bleomycin, etoposide phosphate, cisplatin), JEB (carboplatin, etoposide phosphate, bleomycin), PEB (cisplatin, etoposide phosphate, bleomycin) VAC (vincristine sulfate, dactinomycin, cyclophosphamide), VeIP (vinblastine sulfate, ifosfamide, cisplatin), carboplatin / doxil, carboplatin / gemcitabine, carboplatin / topotecan, taxol / avastin, FOLFIRINOX (calcium leucovorin, fluorouracil, irinotecan hydrochloride, oxaliplatin), gemcitabine-cisplatin, gemcitabine oxaliplatin, OFF (oxaliplatin, fluorouracil, calcium leucovorin), CEV (carboplatin, etoposide phosphate, vincristine sulfate) and VIP (etoposide, ifosfamide, cisplatin) can be mentioned.,

[0151] In addition, the definition of "chemotherapeutic agent" includes (i) antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), for example, tamoxifen (including NOLVADEX (registered trademark); tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and Fareston (registered trademark) (toremifene citrate): (ii) aromatase inhibitors that inhibit aromatase, an enzyme that regulates estrogen production in the adrenal glands, for example, 4(5)-imidazole, aminoglutethimide, MEGASE (registered trademark) (megestrol acetate), AROMASIN (registered trademark) (exemestane; Pfizer), formestane, fadrozole, RIVISOR (registered trademark) (vorozole), FEMARA (registered trademark) (letrozole; Novartis), and ARIMIDEX (registered trademark) (anastrozole; AstraZeneca): (iii) antiandrogen agents such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin; and troxacitabine (a nucleoside cytosine analog of a-1,3-dioxolane); (iv) protein kinase inhibitors such as MEK inhibitors (International Publication No. 2007 / 044515); (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, for example, PKC-α, Raf, H-Ras, for example, oblimersen (GENASENSE (registered trademark) by Genta); (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME (registered trademark)), HER2 expression inhibitors; (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN (registered trademark), LEUVECTIN (registered trademark), VAXID (registered trademark); Proleukin (registered trademark) rIL-2; topoisomerase 1 inhibitors (registered trademarks) such as irinotecan; abarelix (registered trademark) rmRH; angiogenesis inhibitors such as bevacizumab (AVASTIN (registered trademark) by Genentech); and pharmaceutically acceptable salts, acids, and derivatives of any of these may be mentioned.

[0152] In addition, examples of the definition of "chemotherapeutic agent" include therapeutic antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN (registered trademark), Genentech); cetuximab (ERBITUX (registered trademark), ImClone); panitumumab (VECTIBIX (registered trademark), Amgen), rituximab (RITUXAN (registered trademark), Genentech / Biogen Idec), ofatumumab (ARZERRA (registered trademark), GSK), pertuzumab (PERJETA TM, OMNITARG (trademark), 2C4, Genentech), trastuzumab (HERCEPTIN (registered trademark), Genentech), tositumomab (Bexxar, Corixia), MDX-060 (Medarex), etc.

[0153] Antibody-drug conjugates, particularly AXL antibody-drug conjugates, are also included in the definition of "chemotherapeutic agent". For example, gemtuzumab ozogamicin (MYLOTARG (registered trademark), Wyeth), enapotamab vedotin (HuMax (registered trademark)-AXL-ADC, Genmab), CAB-AXL-ADC (BioAtla) can be mentioned.

[0154] Humanized monoclonal antibodies that may be therapeutically useful as chemotherapeutic agents when used in combination with the complex described in this specification include alemtuzumab, apolizumab, aselizumab, atorizumab, bapineuzumab, bevacizumab, bivatuzumab mertansine, canertuzumab mertansine, cediranib, certolizumab pegol, cidfostuxizumab, cidotuzumab, daclizumab, eclizumab, efalizumab, epratuzumab, elotuzumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, norovizumab, numavizumab, ofatumumab, omalizumab, palivizumab, pascolizumab, pecificimab, pecilizumab, pertuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, reslizumab, recevimab, rovelizumab, rupatuzumab, sibrotuzumab, siprilizumab, sonrozumab, takatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab, tralivizumab, trastuzumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, ultuxizumab, and visilizumab.

[0155] In addition, the definition of "chemotherapeutic agent" also includes therapeutic immunocomplexes such as antibody-drug conjugates (ADCs). An ADC is a class of biopharmaceutical agents designed as a targeted therapy and includes an antibody (or a functional fragment thereof) conjugated to a payload or drug. The payload may be a cytotoxic drug, for example, one or more of the above anti-cancer chemotherapeutic agents. The antibody portion of the ADC specifically targets an antigen present on the target cell, for example, a tumor antigen on a tumor cell, and delivers the payload to the target cell. The specific targeting of the ADC can limit side effects and can result in a broader therapeutic concentration range than other chemotherapeutic agents.

[0156] Thus, in certain embodiments, the chemotherapeutic agent may be an antibody-drug conjugate. The antibody-drug conjugate may include, as its antibody portion, one of the antibodies disclosed herein. The antibody-drug conjugate may include, as its payload, one or more anti-cancer chemotherapeutic agents disclosed herein. The antibody-drug conjugate may include, as its payload, an anthracycline, such as doxorubicin, or a taxane, such as docetaxel. The drug conjugate may be gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, polatuzumab vedotin, enfortumab vedotin, trastuzumab deruxtecan, sacituzumab govitecan, belantamab mafodotin, or moxetumomab pasudotox.

[0157] Certain chemotherapeutic agents are known to affect pathways involved in the immune response. For example, the class of cytotoxic chemotherapeutic agents known as anthracyclines are known to induce a type I interferon response that mimics the immune response to viruses, and the clinical response to anthracycline therapy correlates with a type I IFN gene signature (Sistigue et al 2014; Zitvogel et al, 2015). Since AXL functions as an important checkpoint for interferon (IFN) signaling, stimulating IFN signaling in the context of AXL inhibition can result in an enhanced anti-cancer T cell response during immune checkpoint inhibition. Thus, in certain embodiments, the chemotherapeutic agent may be a chemotherapeutic agent that induces an immune response in a subject. In certain embodiments, the chemotherapeutic agent may be a chemotherapeutic agent that induces a type I interferon response in a subject.

[0158] In certain preferred embodiments, the chemotherapeutic agent may be an anthracycline. In certain embodiments, the chemotherapeutic agent may be selected from the group consisting of daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, and valrubicin. In certain particularly preferred embodiments, the chemotherapeutic agent may be doxorubicin. In another preferred embodiment, the chemotherapeutic agent may be a platinum-based chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent may be selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin. In a particularly preferred embodiment, the chemotherapeutic agent may be carboplatin. In another preferred embodiment, the chemotherapeutic agent may be an antimetabolite chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent may be selected from the group consisting of pemetrexed, methotrexate, pralatrexate, and trimetrexate. In a particularly preferred embodiment, the chemotherapeutic agent may be pemetrexed.

[0159] In another preferred embodiment, the combination chemotherapeutic agent may include a platinum-based chemotherapeutic agent and an antimetabolite chemotherapeutic agent. A particularly preferred combination is carboplatin and pemetrexed, which may be used in combination with an anti-PD1 antibody such as pembrolizumab, for example. The combination of carboplatin, pemetrexed, and pembrolizumab is particularly preferred when the disease associated with AXL being treated is non-small cell lung cancer. In such an embodiment, a dosing regimen in which a certain dose level of AXLi is administered to the subject may be preferred. In another preferred embodiment, the combination chemotherapeutic agent may include cytarabine. The combination with cytarabine may be particularly preferred when the disease associated with AXL being treated is AML.

[0160] In certain other preferred embodiments, the combination chemotherapeutic agent may include EGFR targeted therapy such as an EGFR inhibitor and / or HER2 targeted therapy such as an HER2 inhibitor. The EGFR targeted therapy may be selected from the group consisting of gefitinib, erlotinib, osimertinib, lapatinib, brigatinib, rociletinib, ormutinib, nazartinib, natanib, maviretinib, neratinib, dacomitinib, mobocertinib, and vandetanib. The EGFR targeted therapy may be selected from the group consisting of cetuximab, panitumumab, and necitumumab. The HER2 targeted therapy may be selected from the group consisting of lapatinib, afatinib, canertinib, peritinib, neratinib, dacomitinib, and tucatinib. The HER2 targeted therapy may be selected from the group consisting of trastuzumab, pertuzumab, margetuximab, trastuzumab emtansine, and trastuzumab deruxtecan.

[0161] Immune Checkpoint Modulator The immune checkpoint modulator functions to modulate the immune response against a disease, such as a disease associated with AXL of the present disclosure. This can be achieved, for example, by enhancing the activity of the stimulatory pathway and reducing the activity of the inhibitory pathway. It is known that the immune response against diseases associated with AXL, such as cancer, can control tumor growth and, in some cases, lead to tumor elimination. Through the therapeutic targeting of tumor immune regulators, successful immunotherapy approaches for cancer treatment have been developed, such as drugs that block the activity of negative regulators of T cell immunity, such as cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death receptor-1 (PD1). In the disclosed methods, AXLi may be co-administered with one or more ICMs.

[0162] In certain embodiments, the immune checkpoint modulator (ICM) may be an immune checkpoint inhibitor (ICI). Examples include agents that act on T cell co-inhibitory receptors such as CTLA4, PD1, PDL1, BTLA, TIM3, VISTA, LAG3, and TIGIT.

[0163] In certain embodiments, the immune checkpoint modulator (ICM) may be a T cell co - stimulatory agonist. For example, agonists of T cell co - stimulatory receptors such as CD28, ICOS, 41BB, OX40, GITR, CD27, TWEAKR, HVEM, and TIM - 1 can be mentioned. In certain embodiments, the immune checkpoint modulator (ICM) can act on dendritic cell co - stimulatory receptors such as CD40 and 41BB.

[0164] In certain embodiments, the immune checkpoint modulator may be an immune checkpoint regulatory antibody. In certain embodiments, the immune checkpoint modulator may be selected from the group consisting of anti - CTLA4 antibody, anti - PD1 antibody, anti - PD - L1 antibody, anti - 1BB antibody, anti - OX40 antibody, anti - GITR antibody, anti - CD27 antibody, anti - CD28 antibody, anti - CD40 antibody, anti - LAG3 antibody, anti - ICOS antibody, anti - TWEAKR antibody, anti - HVEM antibody, anti - TIM1 antibody, anti - TIM3 antibody, anti - VISTA antibody, and anti - TIGIT antibody.

[0165] In certain preferred embodiments, the immune checkpoint modulator may be selected from the group consisting of anti - PD1 antibody, anti - PDL1 antibody, anti - CTLA4 antibody, anti - 41BB antibody, anti - OX40 antibody, anti - GITR antibody, anti - CD27 antibody, anti - CD40 antibody, and anti - LAG3 antibody. In certain particularly preferred embodiments, the immune checkpoint modulator may be selected from the group consisting of anti - PD1 antibody, anti - PDL1 antibody, and anti - CTLA - 4 antibody. In certain most preferred embodiments, the immune checkpoint modulator may be an anti - PD1 antibody.

[0166] Examples of ICMs suitable for use in the methods described herein include atezolizumab, abelumab, camrelizumab, semaprimab, dostarlimab, durvalumab, ipilimumab, sintilimab, tislelizumab, tripalimumab, tremelimumab, pembrolizumab, nivolumab and urelumab, and drug candidate identifiers AMP-514 / MEDI0680 (MedImmune / AstraZeneca), MPDL3280A (Genentech / Roche), MEDI4736 (MedImmune / AstraZeneca), MSB0010718C (EMD Serono), BMS-936559 (Bristol Myers Squibb), PF-05082566 (Pfizer), MEDI6469 (MedImmune / AstraZeneca), MEDI6383 (rOX40L; MedImmune / AstraZeneca), MOXR0916 (Genentech / Roche), TRX518 (Trelux), CDX-1127 (Celdex), CP-870,893 (Genentech / Roche) and BMS-986016 (Bristol Myers Squibb) (preferably ipilimumab, tremelimumab, pembrolizumab and nivolumab).

[0167] In certain embodiments, the anti-PD1 is selected from pembrolizumab, nivolumab, MEDI0680, PDR001 (spartalizumab), camrelizumab, AUNP12, pidilizumab, sintilimab (REGN-2810), AMP224, BGB-A317 (tislelizumab), and BGB-108. In certain embodiments, the anti-PDL1 antibody is selected from atezolizumab (Tecentriq), BMS-936559 / MDX1105, durvalumab / MEDI4736, and MSB0010718C (avelumab). In certain embodiments, the anti-CTLA4 antibody is selected from ipilimumab and tremelimumab. In certain embodiments, the anti-GITR antibody or GITR agonist is selected from MEDI1873, TRX518, GWN323, MK-1248, MK4166, BMS-986156, and INCAGN1876. In certain embodiments, the anti-OX40 antibody or OX40 agonist is selected from MEDI0562, MEDI6383, MOXR0916, RG7888, OX40mAb24, INCAGN1949, GSK3174998, and PF-04518600.

[0168] In certain preferred embodiments of the methods disclosed herein, two or more immune checkpoint modulators may be administered. As a result of using at least two different immune checkpoint (activating) modulators, in particular, a synergistic effect has been shown to be improved, especially when such immune checkpoint (activating) modulators act on different cell receptor subtypes. For example, it is a combination of at least one immune checkpoint inhibitor and at least one T cell costimulatory receptor agonist or dendritic cell costimulatory receptor agonist. Preferably, at least one of the two or more immune checkpoint (activating) modulators is an anti-CTLA4 antibody, an anti-PD1 antibody, or an anti-PDL1 antibody. In particular, the combination of an anti-CTLA4 antibody and an anti-PD1 antibody has been proven to be particularly effective. For example, in the methods disclosed herein, the TKI can be combined with two ICMs such as nivolumab and ipilimumab. In some cases, the TKI is combined with three ICMs. In certain preferred embodiments, the two or more immune checkpoint (activating) modulators may comprise (i) an immune checkpoint inhibitor and (ii) a T cell co-stimulatory receptor agonist or a dendritic cell co-stimulatory receptor agonist. In certain embodiments, the two or more immune checkpoint (activating) modulators may comprise (i) an anti-CTLA4 antibody and / or (ii) either an anti-PD1 antibody or an anti-PDL1 antibody.

[0169] In certain preferred embodiments, the anti-CTLA4 antibody is ipilimumab or tremelimumab. In certain preferred embodiments, the anti-PD1 is pembrolizumab, nivolumab, spartalizumab, camrelizumab, pidilizumab, or cemiplimab. Preferably, the anti-PD1 antibody is pembrolizumab or nivolumab. In certain embodiments, the anti-PDL1 antibody is atezolizumab (CAS number 1380723-44-3), avelumab (CAS number 1537032-82-8) or durvalumab (CAS number 1428935-60-7).

[0170] In certain embodiments, the two or more immune checkpoint (activating) modulators may be administered simultaneously. In other embodiments, the two or more immune checkpoint (activating) modulators may be administered separately and / or sequentially in any order. In certain embodiments, the immune checkpoint modulator is pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelimumab and durvalumab, or is one of them. In certain preferred embodiments, the two or more immune checkpoint (activating) modulators may be ipilimumab and pembrolizumab, or ipilimumab and nivolumab.

[0171] In a preferred embodiment, the ICM may be an anti-PD1 antibody such as pembrolizumab. A particularly preferred ICM is, for example, pembrolizumab which can be used in combination with platinum-based chemotherapeutic agents such as carboplatin and pemetrexed and folic acid antagonist chemotherapeutic agents. The combination of carboplatin, pemetrexed and pembrolizumab is particularly preferred when the disease associated with AXL to be treated is non-small cell lung cancer. In a preferred embodiment, the ICM may include an anti-PD1 antibody, an anti-PDL1 antibody, or an anti-PD1 antibody and an anti-CTLA4 antibody. In a preferred embodiment, the ICM may include pembrolizumab, atezolizumab, semiprimab (semiprimab-rELk), or nivolumab and ipilimumab. In an embodiment where the ICM includes pembrolizumab, the ICM can be administered in combination with platinum-based chemotherapeutic agents such as carboplatin and pemetrexed and folic acid antagonist chemotherapeutic agents. In an embodiment where the ICM includes atezolizumab, the ICM may be administered in combination with an anti-VEGF-A antibody such as bevacizumab. In another embodiment where the ICM includes atezolizumab, the ICM may be administered in combination with a taxane chemotherapeutic agent such as paclitaxel. In another embodiment where the ICM includes atezolizumab, the ICM may be administered in combination with a platinum-based chemotherapeutic agent such as carboplatin. In a preferred embodiment where the ICM includes atezolizumab, the ICM may be administered in combination with taxane chemotherapeutic agents and platinum-based chemotherapeutic agents such as paclitaxel and carboplatin. In another preferred embodiment where the ICM includes atezolizumab, the ICM may be administered in combination with an anti-VEGFA antibody, a taxane chemotherapeutic agent and a platinum-based chemotherapeutic agent, for example, bevacizumab, paclitaxel and carboplatin. In an embodiment where the ICM includes nivolumab and ipilimumab, the ICM may be administered in combination with a platinum-based chemotherapeutic agent such as carboplatin or cisplatin. Such ICMs and combinations are particularly preferred when the disease associated with AXL to be treated is non-small cell lung cancer.

[0172] Radiation Therapy The term "radiation therapy (radiation therapy or radiotherapy)" can be used medically for ionizing radiation as one of the cancer treatments to control or eradicate malignant cells. Radiation therapy can be used for curative, adjuvant or palliative treatment. Suitable radiation therapies include conventional external beam radiation therapy, stereotactic radiation therapy (e.g., Axesse, CyberKnife, Gamma Knife, Novalis, Primatom, Synergy, X Knife, Tomotherapy or Trilogy), intensity modulated radiation therapy, particle beam therapy (e.g., proton beam therapy), brachytherapy, delivery of radioisotopes, intraoperative radiation therapy, Auger therapy, volumetric modulated arc therapy (VMAT), virtual simulation, three-dimensional conformal radiation therapy and intensity modulated radiation therapy. In certain embodiments, radiation therapy uses high energy radiation to shrink tumors and kill cancer cells. The radiation may be, for example, X-rays, gamma rays, or charged particles. Examples of the mode of cell death by radiation include DNA damage by directly damaging DNA or by generating free radicals in the cell and then damaging DNA. The radiation may be delivered by an external machine (external beam radiation therapy) or may result from radioactive substances placed in the body near the cancer cells (also called internal radiation therapy or brachytherapy). In one example of total body radiation therapy, a radioactive substance that travels in the blood to kill cancer cells, such as radioactive iodine, is used. Preferably, radiation therapy may be administered in a regimen designed to minimize any immunosuppressive effects of radiation. For example, preclinical evidence indicates that high radiation doses exceeding 12 - 18 Gy result in attenuation of tumor immunogenicity (Vanpouille-Box C., et al., Nat Commun 2017; 8: 15618). Additionally, circulating lymphocytes are known to be particularly radiosensitive (see Yovino S., et al., Cancer Invest 2013; 31: 140 - 144), indicating that radiation therapy regimens aimed at stimulating the anti-tumor immune response should aim to minimize both (1) the amount of vasculature exposed in each treatment and (2) the number of exposures in the treatment regimen. The radiation dose may be fractionated and administered continuously, for example, administered daily continuously until the desired total radiation dose is delivered.

[0173] Certain Embodiment Particularly contemplated embodiments of the present disclosure are as follows: A method of co-administering AXLi with cytarabine. A method of co-administering AXLi with an EGFR targeted therapy such as an EGFR inhibitor and / or a HER2 targeted therapy such as a HER2 inhibitor. A method of co-administering AXLi with an anti-PD1 antibody and an anthracycline. Preferably, the anti-PD1 antibody is pembrolizumab. Preferably, the anthracycline is doxorubicin. A method of administering AXLi in combination with an anti-PD1 antibody. Preferably, the anti-PD1 antibody is pembrolizumab. The anti-PD1 antibody may be administered to a subject before, simultaneously with, or after AXLi. In certain embodiments, the dosage of the anti-PD1 antibody may be about 200 mg. The anti-PD1 antibody may be administered to the subject by intravenous infusion. The anti-PD1 antibody may be administered to the subject by intravenous infusion over about 30 minutes. In certain embodiments, the anti-PD1 antibody may be administered on a Q3W (once every three weeks) dosing regimen. Administration of the anti-PD1 antibody may be initiated on any of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the AXLi dosing regimen fully described herein. Preferably, administration of the anti-PD1 antibody is initiated on day 1 of the AXLi dosing regimen fully described herein.

[0174] AXLi is a platinum-based chemotherapeutic agent, preferably, the platinum-based chemotherapeutic agent is carboplatin. The platinum-based chemotherapeutic agent may be administered to a subject before, simultaneously with, or after AXLi. In certain embodiments, the dosage of the platinum-based chemotherapeutic agent may be about 5 area under the curve (AUC5) based on the Calvert formula for calculating the dosage of carboplatin (Calvert et al. J Clin Oncol. 1989;7:1748-1756). The platinum-based chemotherapeutic agent may be administered to the subject by intravenous infusion. The platinum-based chemotherapeutic agent may be administered to the subject by intravenous infusion over about 15 minutes or about 30 minutes. In certain embodiments, the platinum-based chemotherapeutic agent may be administered on a Q3W (once every three weeks) dosing regimen. Administration of the platinum-based chemotherapeutic agent may be initiated on any of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the AXLi dosing regimen fully described herein. Preferably, administration of the platinum-based chemotherapeutic agent is initiated on day 1 of the AXLi dosing regimen fully described herein.

[0175] AXLi is a folic acid antagonist chemotherapeutic agent, preferably, the folic acid antagonist chemotherapeutic agent is pemetrexed. The folic acid antagonist chemotherapeutic agent may be administered to a subject before, at the same time as, or after AXLi. In certain embodiments, the dosage of the folic acid antagonist chemotherapeutic agent may be about 500 mg / m 2 2. The folic acid antagonist chemotherapeutic agent may be administered to the subject by intravenous infusion. The folic acid antagonist chemotherapeutic agent may be administered to the subject by intravenous infusion over about 10 minutes. In certain embodiments, the folic acid antagonist chemotherapeutic agent may be administered on a Q3W (once every three weeks) dosing regimen. Administration of the folic acid antagonist chemotherapeutic agent may be initiated on any of days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 of the AXLi dosing regimen fully described herein. Preferably, administration of the folic acid antagonist chemotherapeutic agent is initiated on day 1 of the AXLi dosing regimen fully described herein.

[0176] AXLi is a method of co - administration with an anti - PD1 antibody, a platinum - based chemotherapeutic agent, and a folic acid antagonist chemotherapeutic agent. Preferably, the anti - PD1 antibody is pembrolizumab, the platinum - based chemotherapeutic agent is carboplatin, and the folic acid antagonist chemotherapeutic agent is pemetrexed. These agents can be administered as outlined above.

[0177] Reduced Toxicity and Improved Efficacy In the methods of the present disclosure, the dosing regimens disclosed herein reduce the toxicity and / or side effects associated with the treatment of a subject with AXLi. Alternatively, or additionally, the dosing regimens disclosed herein enhance the therapeutic efficacy associated with the administration of AXLi to a subject. Accordingly, the present disclosure provides a method of reducing the toxicity and / or side effects associated with the administration of AXLi to a subject; and / or a method of enhancing the therapeutic efficacy associated with the administration of AXLi to a subject, the method comprising administering AXLi according to the dosing regimens according to the present disclosure. Reduction of toxicity and / or side effects, or increase of efficacy, can be measured compared to alternative comparative dosing regimens, for example, regimens where the fixed AXLi dose level, loading and / or maintenance dose levels are different, the loading and / or maintenance periods are different, and / or the treatment period is longer or shorter.

[0178] As used herein in the context of treating a condition, the term "treatment" or "treating" generally relates to a treatment and therapy of humans and animals (e.g., veterinary uses) in which any desired therapeutic effect, e.g., inhibition of the progression of a condition, is achieved, including reduction of the rate of progression, cessation of the rate of progression, regression of the condition, improvement of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prevention, prophylaxis) is also included.

[0179] In some cases, the toxicity level is measured as the incidence of treatment-emergent adverse events (TEAE) that occur after a treatment period, e.g., 21 days of treatment, with a given total dose of AXLi. An AE that emerges during treatment (TEAE) is defined as any event that was not present prior to exposure to AXLi, or any event that was already present and whose intensity or frequency has worsened after exposure to AXLi. The incidence of AEs according to the dosing regimens of the present disclosure may be 95% or less, e.g., 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less of the incidence of AEs in an alternative comparative dosing regimen. Adverse events may be classified according to the NCI-CTCAE version 5.0 (v5.0, published November 27, 2017). For example, if treatment with an alternative, comparative dosing regimen in 100 subjects results in 10 AEs and treatment with the dosing regimen of the present disclosure results in 5 AEs, the incidence of AEs with the dosing regimen of the present disclosure is 50% of the incidence of AEs in the corresponding comparative dosing regimen.

[0180] In some cases, the toxicity level is measured as the incidence of serious adverse events (SAEs) that occur after a treatment period such as 21 days of treatment with a given total dose of AXLi. A serious adverse event (SAE) is defined as any event that is fatal, immediately life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant physical impairment / disability, or is a congenital anomaly / birth defect. Hospitalization for elective procedures or for protocol compliance is not considered an SAE. An important medical event that does not result in death, is life-threatening, or would not require hospitalization may be considered an SAE if, based on appropriate medical judgment, the patient is at risk or a medical or surgical intervention may be required to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, a blood disorder or spasm for which the patient is not hospitalized, or the occurrence of drug dependence or drug abuse. The incidence of SAEs according to the dosing regimen of the present disclosure may be 95% or less, such as 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less of the incidence of SAEs in an alternative comparative dosing regimen. Adverse events may be classified according to the NCI-CTCAE version 5.0 (v5.0, published November 27, 2017). In some cases, the toxicity level is measured as the incidence of dose-limiting toxicity (DLT) that occurs after a treatment period such as 21 days of treatment with a given total dose of AXLi. The incidence of DLT according to the dosing regimen of the present disclosure may be 95% or less, such as 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less of the incidence of DLT in an alternative comparative dosing regimen. For example, if treatment with an alternative, comparative dosing regimen in 100 subjects results in 10 DLTs and treatment with the dosing regimen of the present disclosure results in 5 DLTs, the incidence of DLT according to the dosing regimen of the present disclosure is 50% of the incidence of DLT in the corresponding comparative dosing regimen.

[0181] As used herein, the term DLT is defined as any of the following events, except those clearly due to underlying disease or external causes. - Grade 4 non-hematological toxicity (not in the laboratory) - Grade 4 hematological toxicity lasting for more than 7 days, excluding thrombocytopenia: · Any period of Grade 4 thrombocytopenia · Grade 3 thrombocytopenia with clinically significant bleeding - All non-hematological AEs of Grade 3 or higher should be considered DLTs, except for the following exceptions · Grade 3 fatigue lasting for 3 days or less; · Grade 3 diarrhea, nausea, or vomiting lasting for a shorter period than 7 days, even with optimal prophylactic dosing with standard therapy - Any Grade 3 or Grade 4 non-hematological laboratory values in the following cases · Clinically important medical intervention is required to treat the participant · The abnormality leads to hospitalization The abnormality persists for > 7 days The abnormality results in drug-induced liver injury (DILI) Grade 3 QTcF by CTCAE version 5.0 in 3 ECGs (mean QTc >= 501 ms; change > 60 ms from baseline) Exception: Clinically insignificant, treatable, or reversible laboratory abnormalities, including liver function tests, uric acid, etc. - Grade 3 or Grade 4 febrile neutropenia: Grade 3 is defined as ANC < 1000 / mm with a single temperature > 38.3°C (101°F) or a sustained temperature >= 38°C (100.4°F) for more than 1 hour 3 as defined Grade 4 is defined as ANC < 1000 / mm3 with a single temperature > 38.3°C (101°F) or a sustained temperature >= 38°C (100.4°F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated - Long-term delay in the start of cycle 2 due to treatment-related toxicity (> 2 weeks) - Any treatment-related toxicity that causes the treatment to be interrupted during cycle 1 for the participant - More than 25% deficit in partner drug dosage as a result of drug-related AEs during the first cycle - Grade 5 toxicity. The above adverse events are classified according to the National Cancer Institute - Common Terminology Criteria for Adverse Events, 5.0th Edition (v5.0, released on November 27, 2017).

[0182] In some cases, the level of toxicity is measured as the incidence of QT / QTc prolongation. QT / QTc prolongation is a measure of delayed ventricular repolarization. Excessive QT / QTc prolongation makes the myocardium prone to early afterdepolarization, which can induce reentrant tachycardia. Prolongation of the QT / QTc interval has been observed with tyrosine kinase inhibitors, including AXL inhibitors such as bemcentinib. In the dosing regimens of the present disclosure, the incidence of QT / QTc adverse events (AEs) may be 95% or less, such as 90% or less, 80% or less, 70% or less, 60% or less, 50% or less, 40% or less, 30% or less, 20% or less, 10% or less, or 5% or less of the incidence of QT / QTc AEs in the corresponding comparative dosing regimens. Methods for measuring the QT interval and QT / QTc prolongation are known to those skilled in the art and include, for example, using an electrocardiogram. In some cases, the dosing regimens of the present disclosure may provide an optimal balance of therapeutic efficacy (which can be evaluated by the outcomes outlined below), toxicity, and / or the incidence of adverse events (which can be evaluated as outlined above). For example, the dosing regimens of the present disclosure may provide an optimal balance between the efficacy of AXLi treatment and the incidence of QT / QTc prolongation and / or an optimal balance between the efficacy of AXLi treatment and the incidence of QT / QTc prolongation caused by the disease.

[0183] In some cases, the dosing regimen of the present disclosure induces a change in QTc of less than about 30 ms, for example, less than about 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, or 19 ms. In some preferred cases, the dosing regimen of the present disclosure induces a change in QTc of less than about 20 ms. In other words, in some cases, the dosing regimen of the present disclosure results in an extension of the QTc interval that is not longer than about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 ms. In some preferred cases, the dosing regimen of the present disclosure results in an extension of the QTc interval that is not longer than about 20 ms.

[0184] In some cases, the level of efficacy is measured as the proportion of subjects who achieve at least stable disease [SD] after the treatment period with AXLi (i.e., the proportion of subjects who achieve any of stable disease [SD], partial response [PR], or complete response [CR]). The proportion of subjects who achieve at least SD is at least 110% of the proportion of subjects who achieve at least stable disease [SD] in an alternative comparative dosing regimen, for example, at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200%. For example, if treatment with an alternative, comparative dosing regimen in 100 subjects results in at least SD in 50 subjects and treatment with the dosing regimen of the present disclosure results in at least SD in 80 subjects, the proportion of subjects who achieve at least SD with the dosing regimen of the present disclosure is 160% of the proportion of subjects who achieve at least partial response [SD] with the corresponding comparative dosing regimen. One of ordinary skill in the art will recognize the appropriate criteria used to evaluate the response to treatment with AXLi as part of their common general knowledge. Thus, the evaluation of the response to treatment with AXLi can be based on any criteria commonly used to evaluate response rates, for example, for solid tumors, the RECIST (or mRECIST, or iRECIST; Response Evaluation Criteria in Solid Tumors) criteria, or for lymphoma, the Lugano classification criteria (using the new "Cheson" criteria).

[0185] In some cases, the level of efficacy is measured as the proportion of subjects achieving one or more of the following outcomes: - A partial remission [PR] state, a complete remission [CR] state of achieving a complete disease remission, or a partial disease remission can be evaluated, for example, by the percentage of blast cells, normal maturation of cell lines, reduction of tumor burden, and / or absence of detectable tumors. - Delay or absence of disease progression (achievement of stable disease [SD] state); can be evaluated, for example, by changes in blast cell percentage, delay or absence of tumor growth, and / or delay or absence of increase in tumor burden. - Any positive patient outcome selected from: extension of survival period, progression-free survival period, hematological improvement, bone marrow response, hematological recovery, tumor shrinkage, reduction of tumor burden, delay or absence of tumor growth, delay or absence of increase in tumor burden, negative response to gene markers, improvement in quality of life, and any other positive patient outcome; - Extension of survival period, progression-free survival period, hematological improvement (which can be evaluated, for example, by an increase in blood hemoglobin, platelet count, and / or neutrophil count), bone marrow response (e.g., less than 5% blast cells in the bone marrow; a decrease of 30%, 40%, 50% or more of bone marrow blast cells; absence of circulating blast cells and blast cells with Auer rods; absence of extramedullary disease), hematological recovery (which can be evaluated, for example, by ≧11 g / dL hemoglobin, ≧100×109 / L platelets, and / or ≧1×109 / L neutrophils in peripheral blood), tumor shrinkage (e.g., a decrease in tumor burden of 5, 10, 20, 30, 40% or more), reduction of tumor burden (e.g., a decrease in tumor burden of 5, 10, 20, 30, 40% or more), delay or absence of tumor growth, delay or absence of increase in tumor burden, negative response to gene markers, improvement in quality of life (which can be evaluated, for example, using a health-related quality of life questionnaire such as the Functional Assessment of Cancer Therapy [FACT] questionnaire), and any other positive patient outcome. The ratio of subjects achieving one or more of these is at least 110%, such as at least 120%, at least 130%, at least 140%, at least 150%, at least 160%, at least 170%, at least 180%, at least 190%, or at least 200% of the ratio of subjects achieving the same outcome with an alternative comparative dosing regimen.

[0186] The dosing regimens disclosed herein can also increase AXLi exposure in a subject; and / or can reduce the variability of AXLi exposure in a subject. Accordingly, the present disclosure also provides a method of increasing AXLi exposure in a subject; and / or reducing the variability of AXLi exposure in a subject, the method comprising administering AXLi according to a dosing regimen according to the present disclosure.

[0187] As used herein, the term "exposure" refers to the level of drug achieved in the body. In pharmacokinetics, drug exposure is most often estimated by the area under the curve (AUC) method, but may be reported as a parameter such as Cmax (maximum concentration) or Tmax (time at maximum concentration) as understood by and readily derivable by one of ordinary skill in the art. In some cases, the enhancement of exposure and / or the reduction of variability of exposure are measured relative to an alternative comparative dosing regimen, such as a regimen in which AXLi is administered to a fasting subject, or a regimen in which dosing in the fed or fasting state is not controlled. In the dosing regimens of the present disclosure, the variability of exposure may be less than 95%, such as less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, or less than 5% of the variability of exposure in the comparative dosing regimen.

[0188] Subject Selection In certain embodiments, the subject is selected as being suitable for treatment by the treatment according to the present disclosure prior to treatment being administered. As used herein, a subject considered suitable for treatment is a subject who would benefit from treatment or is expected to respond to treatment. "Benefit from" or "respond to" can refer to any beneficial therapeutic effect observed in a subject to whom the treatment has been administered. This can be any overall clinical benefit obtained from treatment, such as an extension of survival, partial or complete disease remission, delay or absence of disease progression, tumor shrinkage (e.g., a decrease in tumor volume of 5, 10, 20, 30, 40% or more), a decrease in tumor burden (e.g., a decrease in tumor burden of 5, 10, 20, 30, 40% or more), delay or absence of tumor growth, delay or absence of an increase in tumor burden, or an improvement in quality of life. "Does not benefit from" or "does not respond to" means the absence of these measures of overall clinical benefit obtained from treatment. "Additional benefit" can be an additional overall clinical benefit (which can be cumulative or synergistic) obtained from an additional therapeutic agent when administered in combination (e.g., as evaluated by any of the above outcomes).

[0189] In some cases, the subject may be selected based on the amount or pattern of expression or activity of a target marker protein, such as STK11 or STK11IP. In certain cases, the subject may be selected based on the response / benefit (or lack thereof) obtained from a previous treatment, such as an immune checkpoint modulator, or a combination treatment comprising one or more chemotherapeutic agents and an immune checkpoint modulator. In some cases, the subject may be selected based on both the amount or pattern of expression or activity of a target marker protein; and the response / benefit (or lack thereof) resulting from a previous treatment administered.

[0190] In certain embodiments, the subject may be selected based on identifying a subject having a disease associated with AXL that is characterized by the presence of cells in which STK11 activity or expression is modified. In certain embodiments, STK11 activity or expression being modified means that STK11 activity or expression is decreased. In certain embodiments, the subject may be selected based on identifying a subject who has been previously treated with an immune checkpoint modulator (ICM) and / or a chemotherapeutic agent (such as ICMs and chemotherapeutic agents described in more detail elsewhere herein) but did not respond to treatment with the ICM and / or chemotherapeutic agent. In other words, the diseases associated with AXL treated by the methods of the present disclosure may be characterized by the presence of cells in which STK11 activity or expression is modified, such as decreased STK11 activity or expression.

[0191] A subject who “did not respond to” treatment with an ICM and / or chemotherapeutic agent is a subject who did not obtain any clinical benefit from the treatment. In certain embodiments, this may be a subject in whom no delay or absence of disease progression was observed after the treatment, or in whom the delay or absence of disease progression was not due to the treatment. In certain embodiments, this may be a subject in whom no decrease in tumor volume was observed after the treatment, or in whom the decrease in tumor volume was not due to the treatment. In certain embodiments, this may be a subject in whom the decrease in tumor volume observed after the treatment was less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or in whom the decrease in tumor volume due to the treatment was less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. In certain embodiments, this may be a subject in whom no decrease in tumor burden was observed after the treatment with the ICM, or in whom the decrease in tumor burden was not due to the treatment. In certain embodiments, this may be a subject in whom the decrease in tumor burden observed after the treatment was less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%, or in whom the decrease in tumor burden due to the treatment was less than 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10%. In certain embodiments, the subject may be selected based on the methods described in WO 2021 / 214492 Pamphlet.

[0192] Evaluation of Upregulation / Downregulation of Expression As used herein, the term “expression” refers to the transcription of the DNA template of a gene to produce the corresponding mRNA and the translation of this mRNA to produce the corresponding gene product (i.e., peptide, polypeptide, or protein), as well as the “expression” of one or more forms of the protein that may be modified post-translationally. Suitable means for determining or detecting the level and pattern of expression, including gene expression, are known to those of skill in the art and include, for example, PCR techniques such as microarray analysis, Western blotting, or QPCR. Changes in expression can also be detected by analyzing the protein content of a sample using methods such as ELISA, PET, or SELDI-TOF MS, or by analytical techniques such as two-dimensional gel electrophoresis. Such techniques may be particularly useful for detecting altered expression in the form of alternative post-translational modification forms of the protein. In certain embodiments, the modification of STK11 activity or expression can be evaluated using the experimental methods (whole exome sequence analysis of tumor biopsy materials) described in the examples of WO 2021 / 214492 Pamphlet.

[0193] In certain embodiments, a decrease in STK11 activity or expression can be evaluated by determining the level of activity or expression of STK11IP. In certain embodiments, a high level of activity or expression of STK11IP compared to a control indicates a decrease in the activity or expression of STK11. In certain embodiments, a decrease in the activity or expression of STK11IP compared to a control may indicate a decrease in the activity or expression of STK11. In certain embodiments of the present disclosure, the enhancement of STK11 activity or expression can be evaluated by determining the activity or expression level of STK11IP. In certain embodiments, an enhancement of STK11 activity or expression is indicated when the activity or expression of STK11IP is high compared to a control. In certain embodiments, an enhancement of STK11 activity or expression may be indicated when the activity or expression of STK11IP is decreased compared to a control.

[0194] In certain embodiments of the present disclosure, that the expression has been modified (enhanced or decreased) can be evaluated by determining the copy number of the gene encoding the protein of interest (e.g., STK11 or STK11IP) compared to a control sample, wherein an increase in the copy number indicates an enhancement of the expression level and a decrease in the copy number indicates a decrease in the expression level. In certain embodiments, that the expression has been modified (enhanced or decreased) is evaluated by determining the level of the protein of interest or mRNA, e.g., STK11 or STK11IP, compared to a control sample. In certain embodiments, that the activity or expression has been modified (enhanced or decreased) can be evaluated by determining the presence or absence of mutations in the nucleotide, mRNA, or amino acid protein sequence of the protein of interest. Suitable means for determining or detecting the presence or absence of such mutations are well known to those skilled in the art, such as nucleotide sequencing, DNA hybridization, restriction enzyme digestion, and the like.

[0195] In certain embodiments of the methods of the present disclosure, that the STK11 activity or expression is modified can be evaluated by determining the presence or absence of STK11 mutations and / or STK11IP mutations. In certain embodiments, the STK11 mutations and / or STK11IP mutations may be mutations selected from mutations in the nucleotide sequence encoding STK11 or STK11IP; mutations in regulatory sequences that control the expression of the nucleotide sequence encoding STK11 or STK11IP; or mutations in nucleotides encoding proteins that interact with the transcript of the STK11 or STK11IP gene. In certain embodiments, the STK11 mutation and / or STK11IP mutation are mutations in the translation products of the STK11 or STK11IP gene. In certain embodiments, the STK11 mutation and / or STK11IP mutation are mutations in the transcription products of the STK11 or STK11IP gene. In certain embodiments, the STK11 mutation and / or STK11IP mutation are mutations in miRNAs that regulate the expression of STK11 and / or STK11IP. In certain embodiments, the STK11 mutation may be an inactivating mutation. In certain embodiments, the STK11 mutation may be an activating mutation. In certain embodiments, the STK11IP mutation may be an activating mutation. In certain embodiments, the STK11IP mutation may be an inactivating mutation. In certain embodiments, the STK11 mutation may be L160P, LD140PY, or D115V. In certain embodiments, the STK11P mutation may be E30V, LG334FW, W162C, or R1065Q.

[0196] In certain embodiments, the STK11 mutation can reduce the level of activity or expression of the STK11 protein. In certain embodiments, the STK11 mutation can enhance the level of activity or expression of the STK11 protein. In certain embodiments, the STK11IP mutation can enhance the level of activity or expression of the STK11IP protein. In certain embodiments, the STK11IP mutation can reduce the level of activity or expression of the STK11IP protein. In certain embodiments, the STK11IP mutation can change the pattern of activity or expression of the STK11 protein and / or change the intracellular localization of the STK11 protein. For example, it can enhance the cytoplasmic sequestration of the STK11 protein and / or reduce the localization of the STK11 protein to the nucleus.

[0197] As used herein, the term "activating" mutation is a mutation that results in a transcriptional and / or translational product of a gene whose function is enhanced (which can be either enhanced activity or enhanced expression). As used herein, the term "inactivating" mutation is a mutation that results in a transcriptional and / or translational product of a gene whose function is reduced or non-functional (either activity or expression can be reduced). The mutation can be a mutation in a nucleotide, mRNA, or protein sequence.

[0198] Sample In certain embodiments of the methods of the present disclosure, whether activity or expression is enhanced or reduced is determined in a sample derived from a subject. That is, the methods of the present disclosure can be performed in vitro (in vitro or ex vivo) on a sample isolated from a subject. The sample can include an amount of blood; an amount of serum derived from the subject's blood that can include the fluid portion of the blood obtained after removal of fibrin clots and blood cells; an amount of pancreatic juice; a tissue sample or biopsy; a urine sample; or can include or be derived from cells isolated from the subject. The sample can be taken from any tissue or body fluid. In certain embodiments, the sample can include or be derived from a tissue sample, biopsy, resection, or isolated cells from the subject. In certain preferred embodiments, the sample can be a tissue sample. The sample can be a sample of tumor tissue, such as a neoplastic tumor tissue. The sample can be obtained by a tumor biopsy.

[0199] In certain embodiments, the sample can be taken from a body fluid, more preferably one that circulates in the body. Thus, the sample can be a blood sample or a lymph sample. In certain embodiments, the sample is a urine sample or a saliva sample. In certain other embodiments, the sample is a blood sample or a blood-derived sample. A blood-derived sample can be a selected fraction of the subject's blood, such as a selected cell-containing fraction or a plasma or serum fraction.

[0200] The selected cell-containing fraction may contain the cell types to be subjects, which may include white blood cells (WBCs), particularly peripheral blood mononuclear cells (PBMCs) and / or granulocytes and / or red blood cells (RBCs). Thus, the methods according to the present disclosure may include the detection of marker polypeptides or nucleic acids in blood, white blood cells, peripheral blood mononuclear cells, granulocytes, and / or red blood cells. The sample may be fresh or preserved. For example, archived tissue may be from the subject's initial diagnosis or a biopsy at recurrence. In certain preferred embodiments, the sample may be a fresh biopsy.

[0201] Control Enhancement or reduction of the activity or expression of the marker protein of interest may be determined by comparison to a control. Controls are useful for supporting the validity of staining and identifying experimental artifacts. In certain embodiments, the target expression or activity in a subject is compared to the target expression or activity in a control. In some cases, the control may be a reference sample or reference dataset. The reference may be a sample previously obtained from an individual known to be compatible, e.g., an individual known to be responsive to a treatment disclosed herein. The reference may be a dataset obtained from analyzing a reference sample. The control may be a positive control known to have the target molecule present or expressed at a high level, or a negative control known to not have the target molecule present or expressed at a low level. The control may be a tissue sample from an individual known to benefit from treatment. The tissue may be of the same type as the sample being tested. For example, a sample of tumor tissue from an individual can be compared to a control sample of tumor tissue from an individual known to be suitable for treatment, such as an individual who has previously responded to treatment. In some cases, the control may be a sample obtained from tissue known to be healthy but from the same individual as the test sample. Thus, a sample of cancerous tissue from an individual can be compared to a non-cancerous tissue sample. In some cases, the control is a cell culture sample. In some cases, the control may be a sample from an equivalent AXL-related disease that is not characterized by a modified activity or expression of STK11 and / or STK11IP. In some other cases, the control may be a sample of healthy tissue. In a preferred embodiment, the control is of the same sample type as the test sample, e.g., a sample of the same tissue type as the AXL-related disease. In some other preferred embodiments, the control is a reference sample or dataset obtained from an individual(s) known to respond to the AXLi or combination therapy disclosed herein.

[0202] Subject and Its Condition The subject may be a mammal, a placental mammal, a marsupial (e.g., kangaroo, opossum), a monotreme (e.g., platypus), a rodent (e.g., guinea pig, hamster, rat, mouse), a murine (e.g., mouse), a lagomorph (e.g., rabbit), a bird (e.g., chicken), a canine (e.g., dog), a feline (e.g., cat), a equine (e.g., horse), a porcine (e.g., pig), a ovine (e.g., sheep), a bovine (e.g., cow), a primate, an ape (e.g., monkey or ape), a monkey (e.g., marmoset, baboon), an ape (e.g., gorilla, chimpanzee, orangutan, langur), or a human. In a preferred embodiment, the subject is a human. Furthermore, the subject may be in any of its developmental forms, e.g., a fetus. The terms "subject", "patient" and "individual" are used interchangeably herein. In some cases, the subject has, is suspected of having, or has been diagnosed with an AXL-related disease such as cancer or fibrosis.

[0203] Treatment Method As used herein in the context of treating a condition, the term "treatment" generally relates to procedures and therapies in humans and animals (e.g., in veterinary applications) in which some desired therapeutic effect, such as inhibition of the progression of a condition, is achieved, including a reduction in the rate of progression, a halt in the rate of progression, regression of the condition, improvement of the condition, and cure of the condition. Treatment as a prophylactic measure (i.e., prevention, prophylaxis) is also included. Typically, in the treatment methods described herein, an agent (e.g., AXLi) is administered in a therapeutically or prophylactically effective amount. As used herein, the term "therapeutically effective amount" or "effective amount" relates to the amount of an active compound, or a material, composition or dosage form containing an active compound, that is effective to produce some desired therapeutic effect when administered according to a desired therapeutic regimen, commensurate with a reasonable benefit / risk ratio. Similarly, the term "prophylactically effective amount" as used herein relates to the amount of an active compound, or a material, composition or dosage form containing an active compound, that is effective to produce some desired prophylactic effect when administered according to a desired therapeutic regimen, commensurate with a reasonable benefit / risk ratio. Typically, the subject being treated is in need of the above treatment.

[0204] Treatment methods are disclosed herein. Also provided are treatment methods that include administering to a subject in need of treatment a therapeutically effective amount of AXLi. The term "therapeutically effective amount" is an amount sufficient to demonstrate benefit to the subject. The benefit may be at least an improvement in at least one symptom. The actual amount administered, as well as the rate and time course of administration, depends on the nature and severity of what is being treated. Prescription of treatment, e.g., determination of dosage, is within the responsibility of the general practitioner and other physicians. A subject may be tested to determine its eligibility to receive treatment by the methods disclosed herein. A treatment method may include determining whether a subject is eligible for treatment using the methods disclosed herein. Treatment may include administering AXLi, simultaneously or sequentially, alone or in further combination with other treatments, depending on the condition being treated.

[0205] The compositions according to the present disclosure are preferably pharmaceutical compositions. Pharmaceutical compositions according to and for use in accordance with the present disclosure may include, in addition to the active ingredient, i.e., the complex compound, pharmaceutically acceptable excipients, carriers, buffers, stabilizers or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The exact nature of the carrier or other material depends on the route of administration, which may be oral or by injection, for example, dermal, subcutaneous or intravenous.

[0206] Pharmaceutical compositions for oral administration may be in the form of tablets, capsules, powders or liquids. Tablets may contain solid carriers or adjuvants. Liquid pharmaceutical compositions generally contain liquid carriers such as water, petroleum, animal or vegetable oils, mineral oils or synthetic oils. Physiological saline, dextrose or other sugar solutions, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. Capsules may contain solid carriers such as gelatin. For intravenous, dermal or subcutaneous injection, or injection into the affected area, the active ingredient is in the form of a parenterally acceptable aqueous solution that is pyrogen-free and has appropriate pH, isotonicity and stability. Those skilled in the art can prepare appropriate solutions using, for example, isotonic vehicles such as sodium chloride injection, Ringer's injection, lactated Ringer's injection, etc. Preservatives, stabilizers, buffers, antioxidants and / or other additives may be included as necessary. In certain embodiments of the treatment methods disclosed herein, AXLi is included in a pharmaceutical composition that may optionally further contain pharmaceutically acceptable excipients. In addition to the above methods and compositions, there are provided agents and reagents for use in the methods disclosed herein, and compositions and kits containing such agents and reagents, and the use of such agents and reagents, and compositions and kits containing such agents and reagents, in the manufacture of medicaments for use in the methods of the present disclosure.

[0207] Dose Those skilled in the art will appreciate that the appropriate dosage of a composition containing AXLi and an active ingredient may vary from subject to subject. Determining the optimal dosage generally involves balancing the level of therapeutic benefit against any risk or adverse side effects. The dosage level selected will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of treatment, other drugs, compounds and / or materials used in combination, the severity of the condition, and the species, sex, age, weight, condition, general health and previous medical history of the subject. The amount and route of administration of the compound are ultimately at the discretion of the physician, veterinarian, or clinician, but generally the dosage is selected to achieve a local concentration at the site of action that will achieve the desired effect without causing substantially harmful or toxic side effects.

[0208] Administration can be carried out in a single dose, continuously or intermittently (e.g., in divided doses at appropriate intervals) throughout the course of treatment. The most effective means of administration and dosage regimen will vary according to the formulation used in the treatment, the purpose of the treatment, the target cells being treated and the subject being treated, and are well known to those skilled in the art. Single or multiple administrations can be carried out at dosage levels and patterns selected by the treating physician, veterinarian, or clinician. Generally, the appropriate dosage of each active compound is in the range of about 100 ng to about 25 mg per kilogram of body weight of the subject per day (more typically, about 1 μg to about 10 mg). Where the active compound is a salt, ester, amide, prodrug, etc., the amount administered is calculated on the basis of the parent compound, and thus the actual weight used will increase proportionally.

[0209] Definition As used herein, the term "about" refers to any minimal change in the recited absolute value (e.g., the dosage, concentration, or amount of a therapeutic agent) that does not change the recited efficacy, activity, action, result, etc. In some cases, the term "about" may include ±10% of a particular numerical value. The term "about" includes the recited value (e.g., "about 1%" includes 1% and its minimal change), and a preferred embodiment of a numerical value expressed as "about" is that the value is an absolute value (e.g., a preferred embodiment of "about 1%" is "1%"). As used herein, the terms "consume" or "ingest" food include administering food / nutrition to a subject when the subject is unable to orally ingest the food, e.g., administering food / nutrition via an enteral or parenteral route.

[0210] Certain Embodiment Particularly contemplated embodiments of the present disclosure are as follows. In certain preferred embodiments, the disease associated with AXL is cancer. The most preferred diseases associated with AXL include lung cancer such as non-small cell lung cancer and AML. In certain preferred embodiments, the AXL-related disease is cancer and AXLi is bemcentinib.

[0211] In certain such preferred embodiments, the loading dose is administered on days 1 and 2 of the dosing regimen, and the maintenance dose is administered on day 3 and each subsequent day until treatment with AXLi is discontinued. Preferably, the loading dose is about 200 mg and the maintenance dose is about 100 mg. In other preferred embodiments, the loading dose is about 150 mg and the maintenance dose is about 75 mg. In certain other such preferred embodiments, a fixed dose of AXLi is administered each day after day 1 of the dosing regimen. Preferably, the fixed dose is about 150 mg. In other preferred embodiments, the fixed dose is about 125 mg.

[0212] In certain other such preferred embodiments, a fixed dose of AXLi is administered on each day after the first day of the dosing regimen. The most preferred fixed amount of AXLi is about 100 mg. In these embodiments, AXLi is preferably co-administered with one or more additional treatments and / or therapeutic agents (such as pembrolizumab, or carboplatin, pemetrexed and pembrolizumab) as fully described herein. In certain embodiments, the cancer is preferably non-small cell lung cancer. In the most preferred embodiments of these regimens, AXLi is administered to the subject under fed conditions. Specifically contemplated embodiments of the present disclosure are also as follows: AXLi for use in the methods of the present disclosure. Cultured bemcentinib for use in the methods of the present disclosure. Use of AXLi in the manufacture of a medicament for use in the methods of the present disclosure. Use of cultured bemcentinib in the manufacture of a medicament for use in the methods of the present disclosure. A chemotherapeutic agent for use in the methods of the present disclosure. ICM for use in the methods of the present disclosure. Use of a chemotherapeutic agent in the manufacture of a medicament for use in the methods of the present disclosure. Use of ICM in the manufacture of a medicament for use in the methods of the present disclosure.

[0213] Disclosure Description The following numbered descriptions, which summarize aspects of the present disclosure, are also part of the description. Treatment Method 101. A method for treating a disease associated with AXL in a subject, comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising a loading dose and a maintenance dose. Dosing interval 102. The method of 101, wherein the loading dose is administered on the first and second days of the dosing regimen. 103. The method according to 101 or 102, wherein the maintenance dose is administered on the third day of the dosing regimen. 104. The method according to 101 or 102, wherein the maintenance dose is administered on each day after the third day of the dosing regimen. 105. The method according to any one of 101 to 104, wherein the loading dose of the AXLi is administered on the first and second days of the dosing regimen, and thereafter, the maintenance dose of the AXLi is administered. 106. The method according to any one of 101 to 105, wherein the AXLi is administered to the subject daily. 107. The method according to any one of 101 to 106, wherein the AXLi is administered to the subject once a day.

[0214] 108. The method according to 107, comprising administering the loading dose of the AXLi to the subject once a day on the first and second days of the dosing regimen, and thereafter, administering the maintenance dose of the AXLi to the subject once a day. 109. The method according to any one of 101 to 108, wherein the administration of the maintenance dose is started on the third day of the dosing regimen and is administered to the subject daily until treatment with the AXLi is stopped, for example, until the treatment endpoint of the subject is reached. 110. The treatment endpoint is as follows: (i) Partial remission [PR] state to achieve partial disease remission or complete remission [CR] state to achieve complete disease remission; (ii) Delay or absence of disease progression (achievement of stable disease [SD] state); (iii) Any positive patient outcome selected from: extension of survival period, progression-free survival period, hematological improvement, bone marrow response, hematological recovery, tumor shrinkage, reduction of tumor burden, delay or absence of tumor enlargement, delay or absence of increase in tumor burden, negative response to gene markers, improvement in quality of life and any other positive patient outcome; (iv) Disease progression in a progressive disease [PD] state that prompts treatment discontinuation; and / or (v) Occurrence of toxicity and / or adverse events requiring treatment discontinuation; The method according to claim 108, wherein there is one or more.

[0215] Loading Dose 111. The loading dose is (i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg or (ii) about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg; The method according to any one of claims 101 to 110. 112. The loading dose is (i) about 200 mg; or (ii) about 150 mg The method according to any one of claims 101 to 111. 113. The loading dose is (i) administered to the subject at about 200 mg once a day; or (ii) administered to the subject at about 150 mg once a day, The method according to any one of claims 101 to 112. 114. The loading dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg. The method according to any one of claims 101 to 113. 115. The loading dose is about 100 mg. The method according to any one of claims 101 to 114. 116. The loading dose is administered to the subject at about 100 mg once a day. The method according to any one of claims 101 to 115.

[0216] Maintenance Dose 117. The maintenance dose is about 45 to 55% of the loading dose, for example, about 46 to 54%, about 47 to 53%, about 48 to 52%, or about 49 to 51%. The method according to any one of claims 101 to 116. 118. The maintenance dose is about 50% of the loading dose. The method according to any one of claims 101 to 117. 119. The method according to any one of 101 to 118, wherein the maintenance dose is about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg. 120. The method according to any one of 101 to 119, wherein the maintenance dose is about 100 mg. 121. The method according to any one of 101 to 121, wherein the maintenance dose is administered to the subject at about 100 mg once a day. 122. The method according to any one of 101 to 118, wherein the maintenance dose is about 50 to 100 mg, about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg. 123. The method according to 122, wherein the maintenance dose is about 75 mg. 124. The method according to 123, wherein the maintenance dose is administered to the subject at about 75 mg once a day. 125. The method according to any one of 101 to 117, wherein the maintenance dose is the same amount as the loading dose. 126. The maintenance dose is as follows: (i) about 100 to 300 mg, such as about 150 to 250 mg, about 175 to 225 mg, or about 190 to 210 mg (ii) about 200 mg; and / or (iii) about 200 mg administered to the subject once a day; The method according to 125, wherein it is as above. 127. The maintenance dose is as follows: (i) about 50 to 250 mg, such as about 100 to 200 mg, about 125 to 175 mg, or about 140 to 160 mg; (ii) about 150 mg; and / or (iii) about 150 mg administered to the subject once a day The method according to 125, wherein it is as above. 128. The loading dose and the maintenance dose are as follows: (i) about 50 to 150 mg, about 75 to 125 mg, or about 90 to 110 mg; (ii) about 100 mg; or (iii) about 100 mg administered to the subject once a day; Or, (iv) about 50 to 100 mg, about 60 to 90 mg, about 65 to 85 mg, or about 70 to 80 mg; (v) about 75 mg; or (vi) about 75 mg administered to the subject once a day; or, (vii) about 125 mg; or (viii) about 125 mg administered to the subject once a day; which is the method according to item 125.

[0217] Administration in Fed State 129. The method according to any one of items 101 to 128, including administering the AXLi to the subject under feeding conditions. 130. The method according to item 129, including administering the AXLi to the subject under feeding conditions before a meal, simultaneously with a meal, or after a meal. 131. The method according to item 129, including administering the AXLi to the subject under feeding conditions within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has ingested food. 132. The method according to item 129, including administering the AXLi to the subject under feeding conditions within less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes after the subject has ingested food. 133. The method according to item 129, including administering the AXLi to the subject under feeding conditions within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, 240, or 300 minutes before or after the subject has ingested food. 134. The method according to item 129, including administering the AXLi to the subject under feeding conditions within about 0 to 240 minutes after the subject has ingested food, for example, within about 30 to 240 minutes, 60 to 240 minutes, 90 to 240 minutes, 120 to 240 minutes, 150 to 240 minutes, 180 to 240 minutes, or 210 to 240 minutes, or within about 0 to 210 minutes, 0 to 180 minutes, 0 to 150 minutes, 0 to 120 minutes, 0 to 90 minutes, 0 to 60 minutes, or 0 to 30 minutes. 135. The method according to any one of 130 to 134, wherein the food is a diet such as a high-fat and / or high-protein diet.

[0218] Diseases Associated with AXL 136. The method according to any one of 101 to 135, wherein the disease associated with AXL is a proliferative disease. 137. The method according to any one of 101 to 135, wherein the disease associated with AXL is a neoplastic disease. 138. The method according to any one of 101 to 137, wherein the disease associated with AXL is a solid tumor. 139. The method according to any one of 101 to 138, wherein the disease associated with AXL is a liquid tumor (blood cancer). 140. The method according to any one of 101 to 139, wherein the disease associated with AXL is cancer, a fibrotic disorder or neurofibromatosis. 141. The method according to 140, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), pancreatic cancer, kidney cancer, urothelial cancer, ovarian cancer, neurofibroma, cranial cancer or spinal meningioma, schwannoma, epithelioma and glioblastoma. 142. The method according to 141, wherein the cancer is acute myeloid leukemia (AML). 143. The method according to 141, wherein the cancer is lung cancer. 144. The method according to 141, wherein the cancer is non-small cell lung cancer (NSCLC).

[0219] AXLi 145. The method according to any one of 101 to 144, wherein the AXLi is orally administered, for example, as an oral capsule. 146. The AXLi is represented by the following formula (I):

[0220]

Chemical formula

[0221] 147. Said AXLi is as follows: 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(R)-Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(3-Fluoro-4-(4-(pyrrolidin-1-yl)piperidin-1-yl)phenyl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5 -(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5-(7-(S)-Pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(t-Butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(Acetamido)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((2R)-2-(Methoxycarbonyl)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4,4-Difluoropiperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((Methoxycarbonylmethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-(7-((2R)-2-(Carboxy)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Ethoxycarbonyl)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Carboxy)piperidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-((Carboxymethyl)(methyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Ethoxycarbonylmethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -(7-(4-(Carboxymethyl)piperazin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-(7-(Pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-1-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-Amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2-Methylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Propyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((1-Cyclopentylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(2-Propylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((3,3-Dimethylbutan-2-yl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-((Cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclohexylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((5-Chlorothien-2-yl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2-Carboxyphenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((3-Bromophenyl)methyl)amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-(Cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(3-Pentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((2,2-Dimethylpropyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Cyclopentylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-((Bicyclo[2.2.1]hept-2-en-5-ylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(3-methylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(di(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(2-ethylbutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(but-2-enylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(butyl(but-2-enyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 5-((7S)-7-(tert-Butoxycarbonylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-Amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Dimethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Diethylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Dipropylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Di(cyclopropylmethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3-((7S)-7-Bis(3-methylbutyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclobutylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclohexylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-((Methylethyl)amino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(Cyclopentylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; and 1-(6,7-Dihydro-5H-pyrido[2’,3’:6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7S)-7-(2-Butylamino)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine; A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof, the method according to any one of claims 101 to 146.

[0222] 148. The method according to any one of items 101 to 147, wherein AXLi is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N 3 -((7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine or a pharmaceutically acceptable salt thereof. 149. The method according to any one of items 101 to 148, wherein AXLi is bemcentinib.

[0223] 150. AXLi is one of the following: Dulveratinib (CAS number 1341200-45-0; UNII 14D65TV20J); Gilteritinib (CAS number 1254053-43-4; UNII 66D92MGC8M); Cabozantinib (CAS number 849217-68-1; UNII 1C39JW444G); SGI7079 (CAS number 1239875-86-5); Meresatinib (CAS number 1206799-15-6; UNII 5OGS5K699E); Amuvatinib (CAS number 850879-09-3; UNII SO9S6QZB4R); Bosutinib (CAS number 380843-75-4; UNII 5018V4AEZ0); Citravatinib (CAS number 1123837-84-2; UNII CWG62Q1VTB); XL092 from Exelixis (CAS number 2367004-54-2); Glesatinib (CAS number 936694-12-1; UNII 7Q29OXD98N); and Foretinib (CAS number 849217-64-7; UNII 81FH7VK1C4) The method according to any one of items 1 to 186, which is selected from the group consisting of.

[0224] Subject The method according to any one of 101 to 150, wherein the subject is a human. The method according to any one of 101 to 151, wherein the subject has, is suspected of having, or is diagnosed as having a disease associated with AXL.

[0225] Further Treatment The method according to any one of 101 to 152, wherein AXLi is administered in combination with another therapeutic agent. The method according to any one of 101 to 153, wherein AXLi is administered in combination with one or more immune checkpoint modulators (ICM); and / or one or more chemotherapeutic agents and / or radiotherapy. 155. One or more immune checkpoint modulators are the following: (i) one or more immune checkpoint inhibitors (ICI); and / or (ii) one or more immune checkpoint regulatory antibodies The method according to 154, comprising. 156. One or more immune checkpoint regulatory antibodies are (i) selected from the group consisting of anti-CTLA4 antibody, anti-PD1 antibody, anti-PDL1 antibody, anti-41BB antibody, anti-OX40 antibody, anti-GITR antibody, anti-CD27 antibody, anti-CD28 antibody, anti-CD40 antibody, anti-LAG3 antibody, anti-ICOS antibody, anti-TWEAKR antibody, anti-HVEM antibody, anti-TIM1 antibody, anti-TIM3 antibody, anti-VISTA antibody and anti-TIGIT antibody; (ii) selected from the group consisting of anti-CTLA4 antibody, anti-PD1 antibody, anti-PDL1 antibody, anti-41BB antibody, anti-OX40 antibody, anti-GITR antibody, anti-CD27 antibody, anti-CD40 antibody and anti-LAG3 antibody; or (iii) selected from the group consisting of anti-CTLA4 antibody, anti-PD1 antibody and anti-PDL1 antibody, The method according to 154. 157. One or more immune checkpoint modulators are the following: (i) one or more T cell co-stimulatory agonists; and / or one or more dendritic cell co-stimulatory receptor agonists; (ii) At least two immune checkpoint modulators; (iii) An immune checkpoint inhibitor; and a T cell costimulatory receptor agonist or a dendritic cell costimulatory receptor agonist; and / or (iv) An anti-CTLA-4 antibody; and an anti-PD1 antibody and / or an anti-PDL1 antibody; The method according to any one of 154 to 156, comprising the above. 158. (i) The anti-CTLA-4 antibody is ipilimumab or tremelimumab; (ii) The anti-PD1 antibody is pembrolizumab or nivolumab; and / or (iii) The anti-PDL1 antibody is atezolizumab (CAS No. 1380723-44-3), avelumab (CAS No. 1537032-82-8) or durvalumab (CAS No. 1428935-60-7), The method according to 157. 159. The method according to any one of 154 to 158, wherein the immune checkpoint modulator comprises or consists of pembrolizumab; ipilimumab; ipilimumab and nivolumab; ipilimumab and pembrolizumab; tremelilumab and durvalumab.

[0226] 160. The chemotherapeutic agent is as follows: (i) Inducing immunogenic cell death of cancer cells; (ii) Inducing an immune response in a subject; and / or (iii) Inducing a type I interferon response in a subject The method according to 154, which is a chemotherapeutic agent. 161. The method according to 160, wherein the chemotherapeutic agent is anthracycline. 162. The anthracycline is as follows: (i) Doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin; or (ii) Doxorubicin The method according to 161, which is as above. 163. The method according to any one of 101 to 162, wherein AXL i is administered in combination with an anti-PD1 antibody, preferably pembrolizumab. 164. AXL i is (i) a platinum-based chemotherapeutic agent, preferably carboplatin; (ii) a folic acid antagonist, preferably pemetrexed; (iii) a platinum-based chemotherapeutic agent and a folic acid antagonist chemotherapeutic agent, preferably carboplatin and pemetrexed; or (iv) a platinum-based chemotherapeutic agent, a folic acid antagonist chemotherapeutic agent and an anti-PD1 antibody, preferably carboplatin, pemetrexed and pembrolizumab, and is administered in combination with the method according to any one of 101 to 163. 165. The anti-PD1 antibody is (i) its dosage is about 200 mg; (ii) administered in a Q3W (once every three weeks) dosing regimen; and / or (iii) administered simultaneously with AXL i, in the method according to 163 or 164. 166. (i) The disease associated with AXL is characterized by the presence of cells with modified STK11 activity or expression; and / or (ii) Based on the presence of cells with decreased STK11 activity or expression in the disease associated with AXL, the subject to be treated is selected, in the method according to any one of 154 to 165. 167. (i) By determining the copy number of the gene encoding STK11 to evaluate the decrease in expression compared to a control sample, and the decrease in copy number indicates the decrease in expression level; (ii) The decrease in the expression is evaluated by determining the level of STK11 protein or mRNA compared to the control sample; (iii) The modification of STK11 activity or expression is evaluated by determining the presence or absence of STK11 mutations and / or STK11IP mutations; in the method according to 166. 168. The STK11 mutation and / or STK11IP mutation is the following: (i) Mutations in the nucleotide sequence encoding STK11 or STK11IP; (ii) Mutations in regulatory sequences that control the expression of the nucleotide sequence encoding STK11 or STK11IP; (iii) Mutations in nucleotides encoding proteins that interact with the transcript of the STK11 or STK11IP gene; (iv) Mutations in the translation product of the STK11 or STK11IP gene; (v) Mutations in the transcript of the STK11 or STK11IP gene; (vi) STK11 inactivating mutations; and / or (vii) STK11IP activating mutations The method according to 167, which is a mutation selected from the above. 169. The method according to any one of 101 - 168, wherein AXLi is administered in combination with cytarabine.

[0227] Effect of Treatment / Regimen 170. The method according to any one of 101 - 169, which improves the survival of a subject or provides a clinical benefit to the subject, Optionally, the clinical benefit may be one or more of survival extension, partial or complete disease remission, delay or disappearance of disease progression, improvement in quality of life, tumor shrinkage, reduction of tumor burden, delay or disappearance of tumor enlargement, delay or disappearance of increase in tumor burden, hematological improvement, bone marrow response, hematological recovery, negative response to gene markers or any other positive patient outcome. 171. The method according to any one of 101 - 170, wherein the dosing regimen reduces the toxicity and / or side effects associated with the administration of AXLi to the subject and / or enhances the efficacy of the treatment associated with the administration of AXLi to the subject. 172. The method according to any one of 101 - 171, wherein the dosing regimen increases AXLi exposure in the subject and / or reduces the variability of AXLi exposure in the subject. 173. The method according to any one of 101 to 172, wherein the dosing regimen improves the survival of the subject or the clinical benefit to the subject, Optionally, the clinical benefit may be one or more of: prolongation of survival, partial or complete disease remission, delay or disappearance of disease progression, improvement in quality of life, tumor shrinkage, reduction of tumor burden, delay or disappearance of tumor expansion, delay or disappearance of increase in tumor burden, hematological improvement, bone marrow response, hematological recovery, negative response to gene markers or any other positive patient outcome. 174. The method according to any one of 171 to 173, wherein a reduction in toxicity, an increase in efficacy, an improvement in survival rate, and / or an improvement in clinical benefit are determined as compared to a comparative dosing regimen.

[0228] Second Medical Use 201. An inhibitor of AXL activity or expression (AXLi) for use in a method for treating an AXL-related disease according to any one of 101 to 174. 202. The AXLi according to 201, as specified in any one of 146 to 150. 203. Use of an inhibitor of AXL activity or expression (AXLi) in the manufacture of a medicament for treating an AXL-related disease in a subject, wherein the treatment comprises the method according to any one of 101 to 174. 204. The use according to 203, wherein the AXLi is specified in any one of 146 to 150.

[0229] Kit 301. A packaged pharmaceutical product comprising an AXLi specified in any one of 146 to 150, in combination with a label or package insert advising that the AXLi should be administered by the method according to any one of 1 to 174. A kit comprising: a first medicament comprising AXLi as specified in any one of 302.146 to 150; optionally, one or more immune checkpoint modulators (ICMs) and / or one or more chemotherapeutic agents; and package inserts or labels containing instructions for administering said AXLi by the method according to any one of 1 to 174. 303. The kit according to 302, wherein one or more immune checkpoint modulators (ICMs) and / or one or more chemotherapeutic agents are specified in any one of 155 to 169.

[0230] Further Method 401. A method for reducing side effects associated with the administration of AXLi to a subject and / or enhancing the efficacy of treatment associated with the administration of AXLi to a subject, the method comprising performing the method according to any one of 101 to 174. 404. A method for enhancing AXLi exposure in a subject and / or reducing the variability of AXLi exposure in a subject, the method comprising performing the method according to any one of 101 to 174.

[0231] Further Embodiment 501. A method for treating a disease associated with AXL in a subject, comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein said AXLi is administered to the subject in a dosing regimen comprising a loading dose and a maintenance dose, the loading dose is administered on the first and second days of the dosing regimen, and the maintenance dose is administered on each day after the third day of the dosing regimen, said AXLi is of the following formula (I):

[0232]

Chemical formula

Example

[0233] Example 1: Development of an Optimal Administration Regimen of the AXL Inhibitor Bemcentinib Based on PKPD Modeling An investigation was conducted to achieve a free concentration at the target site (e.g., the lung) that provides maximum efficacy (based on achieving 80 - 90% receptor occupancy and saturation of the pAXL target) with an acceptable risk (TKIs are known to prolong the QT / QTc interval), and the optimal administration regimen of bemcentinib in various indications including cancer was identified. During a Phase 2 clinical trial of SARS-CoV-2 infection (BGBC020, described in Example 10 of International Publication No. 2021 / 204713; NCT04890509), PK samples were collected together with ECG measurements to understand the relationship between bemcentinib exposure and response (clinical efficacy and safety). The population PK model was first developed using data from the first-phase BGBC001 healthy volunteer trial, to which data from the second-phase BGBC020 trial was added. During this part of the modeling, it was observed that approximately 70% of the patients during the trial had a 2- to 3-fold difference in the exposure of bemcentinib within the second-phase trial. After examination of the data, the patient was determined to have received a protein pump inhibitor (PPI) as a result of GI disorders induced by the extensive use of corticosteroids as part of the SOC for the treatment of SARS-CoV-2 infection. As a result of the increased gastric pH due to the extensive use of PPI, it was thought that the solubility and subsequent absorption of bemcentinib decreased. To further understand the effects of food and PPI use, separate food and gastric pH studies were conducted (BGBC018), where the PK parameters of bemcentinib were determined in the fasting and fed states with or without the use of PPI. In this part of the study, extensive ECG measurements were also performed to understand the relationship between exposure and QT / QTc prolongation. The data generated from this study were added to the above PopPK model and used to simulate different dosing regimens to predict Cmax and AUC levels. Data from the PopPK model showed that Cmax and AUC increased by 60% and 70% when given with food, and the variability in PK exposure between individuals decreased by 60%, resulting in a coefficient of variation (CoV) of 30%, which is within the normal range of variability. Previously, when dosed in the fasting state, the CoV for bemcentinib was 90 - 100%. The possible reasons for the decrease in PK variability and the increase in exposure to food may be the result of inhibition of efflux transporters in the GI tract or an increase in the amount transported through the lymphatic system due to an increase in the lipid content in the GI tract by the addition of food. This surprising decrease in variability provides a unique opportunity to reduce the dose and lower the incidence of QT / QTc prolongation seen in previous oncology studies with an incidence of grade 3 AEs (>500 ms or >60 ms D-QT / QTc) related to QT / QTc changes.

[0234] To understand the relationship between bemcentinib exposure (Cmax and AUC) and QT / QTc, a separate PKPD model was developed to investigate this opportunity. As outlined above, the development of this PKPD model included the collection of electrocardiogram data, which was done in both actively treated and standard-of-care control patients during the initial acute phase of hospitalization. Surprisingly, this data showed an increase in QTcF (Fridericia-corrected QT interval) in patients treated in the control group (due to either the disease etiology or the therapy administered), which had not been previously reported in controlled clinical trials. From this PKPD modeling, it was determined that by reducing the dose of bemcentinib and administering it with food, exposure was approximately 50% of the dose but with high variability and a very low likelihood of QT / QTc prolongation. As a result of this information, different dosing regimens were developed to provide the maximum clinical benefit with acceptable risks based on different indications. Based on this modeling, the optimal dose of cultured bemcentinib for chronic / long-term dosing was determined. In the acute setting, the planned doses were as follows: A 200 mg loading dose for 2 days, followed by a maintenance dose of 100 mg in the fed state; A 150 mg loading dose for 2 days, followed by a maintenance dose of 75 mg in the fed state; A single daily dose of 150 mg in the fed state; and A single daily dose of 100 mg in the fed state, as follows. The dosage has been modeled to provide exposure that engages and inhibits the biological target and reduces the potential for QT / QTc prolongation as a result of the accumulation of bemcentinib with chronic dosing. The dosage is predicted to result in a change in QTc within the acceptable non-oncology and oncology regulatory limits for QTc, and a dosage of 200 / 100 mg is predicted to result in a 19 ms change in QTc (based on 90% CI), while 150 mg once daily is predicted to result in a 29 ms change (based on 90% CI). The 19 ms and 29 ms intervals are below the 20 ms and 30 ms levels, which are the acceptable non-oncology and oncology regulatory limits for QTc. When bemcentinib is co-administered with other drugs (e.g., in combination with other cancer treatments), a regimen without a loading dose (e.g., a 100 mg once-daily dose in the fed state) may be preferred. Use the dosing regimen in future clinical trials investigating the safety and efficacy of bemcentinib, such as the planned Phase 1b / 2a clinical trial (BGBC016) of the safety and efficacy of bemcentinib + standard of care (SoC) for the treatment of untreated progressive / metastatic non-squamous NSCLC. The interpretation of PKPD model outputs required clinical consideration of the additional risk of ECG changes due to bemcentinib as a relative risk increase compared to the dynamic risks observed in the standard of care group. Thus, the specified dosages and their timing required careful judgment of the risk added early during the loading dose period (and a 33% shortening of that period) versus the need to maintain the manifestation of efficacy apparent from clinical data within the first 2 days of the trial. The maintenance dose after selection ...

Claims

1. A method for treating a disease associated with AXL in a subject, comprising administering to the subject an effective amount of an inhibitor of AXL activity or AXL expression (AXLi), wherein the AXLi is administered to the subject in a dosing regimen comprising a loading dose and a maintenance dose, the loading dose is administered on the first and second days of the dosing regimen, and the maintenance dose is administered on each day after the third day of the dosing regimen, the AXLi is a compound of the following formula (I): 【Chemical 1】 (wherein, R １ 、 R ４ and R ５ are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, aryl, aralkyl, -C(O)R ８ , -C(O)N(R ６ ), R ７ and -C(=NR ６ ), N(R ６ ), R ７ and are selected from the group consisting of: R ２ and R ３ are each independently a polycyclic heteroaryl having more than 14 ring atoms, and optionally, the polycyclic heteroaryl having more than 14 ring atoms is oxo, thioxo, cyano, nitro, halo, haloalkyl, alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heterocyclyl, -R ９ -OR ８ 、-R ９ -O-R １０ -OR ８ ,-R ９ -O-R １０ -O-R １０ -OR ８ 、-R ９ -O-R １０ -CN、-R ９ -O-R １０ -C(O)OR ８ 、-R ９ -O-R １０ -C(O)N(R ６ )R ７ 、-R ９ -O-R １０ -S(O) ｐ R ８ (p is 0, 1 or 2), -R ９ -O-R １０ -N(R ６ )R ７ 、-R ９ -O-R １０ -C(NR １１ )N(R １１ )H、-R ９ -OC(O)-R ８ 、-R ９ -N(R ６ )R ７ 、-R ９ -C(O)R ８ 、-R ９ -C(O)OR ８ 、-R ９ -C(O)N(R ６ )R ７ 、-R ９ -N(R ６ )C(O)OR ８ 、-R ９ -N(R ６ ),C(O)R ８ ,-R ９ -N(R ６ ),S(O) ｔ R ８ (t is 1 or 2),-R ９ -S(O) ｔ OR ８ (t is 1 or 2),-R ９ -S(O) ｐ R ８ (p is 0, 1 or 2) and -R ９ -S(O) ｔ N(R ６ ),R ７ )(t is 1 or 2) and may be substituted by one or more substituents selected from the group consisting of; Or R ２ is a polycyclic heteroaryl having more than 14 ring atoms as described above, and R ３ is selected from the group consisting of aryl and heteroaryl, wherein the aryl and heteroaryl are each independently alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R １３ -OR １２ , -R １３ -OC(O)-R １２ , -R １３ -O-R １４ -N(R １２ ) ２ , -R １３ -N(R １２ )-R １４ -N(R １２ ) ２ , -R １３ -N(R １２ )-R １４ -N(R １２ ) ２ , -R １３ -N(R １２ ) ２ , -R １３ -C(O)R １２ , -R １３ -C(O)OR １２ , -R １３ -C(O)N(R １２ ) ２ , -R １３ -C(O)N(R １２ )-R １４ -N(R １２ )R １３ , -R １３ , -C(O)N(R １２ ), -R １４ , -OR １２ , -R １３ , -N(R １２ ), -C(O)OR １２ , -R １３ , -N(R １２ ), -C(O)R １２ , -R １３ , -N(R １２ ), -S(O ｔ ), -R １２ (t is 1 or 2), -R １３ , -S(O ｔ ), -OR １２ (t is 1 or 2), -R １３ , -S(O ｐ ), -R １２ (p is 0, 1 or 2) and -R １３ , -S(O ｔ ), -N(R １２ ), - ２ (t is 1 or 2), and may be substituted by one or more substituents selected from the group consisting of; Alternatively, R ３ is a polycyclic heteroaryl having more than 14 ring atoms as described above, and R ２ is selected from the group consisting of aryl and heteroaryl, where the aryl and heteroaryl are each independently alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R １３ -OR １２ , -R １３ -OC(O)-R １２ , -R １３ -O-R １４ -N(R １２ ), -R ２ -N(R １３ )-R １２ -N(R １４ ), -R １２ -N(R ２ ), -R １３ -N(R １２ )-R １４ -N(R １２ ), -R ２ , -R １３ -N(R １２ ), -R ２ , -R １３ -C(O)R １２ , -R １３ -C(O)OR １２ , -R １３ -C(O)N(R １２ ), -R ２ , -R １３ -C(O)N(R １２ )-R １４ -N(R １２ )R １３ , -R １３ -C(O)N(R １２ )-R １４ -OR １２ , -R １３ -N(R １２ )C(O)OR １２ , -R １３ -N(R １２ )C(O)R １２ , -R １３ -N(R １２ )S(O) ｔ R １２ (where t is 1 or 2), -R １３ -S(O) ｔ OR １２ (where t is 1 or 2), -R １３ -S(O) ｐ R １２ (where p is 0, 1 or 2) and -R １３ -S(O) ｔ N(R １２ ) ２ may be substituted by one or more substituents selected from the group consisting of; R ６ and R ７ are each independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted cycloalkylalkenyl, optionally substituted cycloalkylalkynyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heterocyclylalkenyl, optionally substituted heterocyclylalkynyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylalkenyl, optionally substituted heteroarylalkynyl, -R １０ -OR ８ , -R １０ -CN, -R １０ -NO ２ , -R １０ -N(R ８ ) ２ , -R １０ -C(O)OR ８ and -R １０ -C(O)N(R ８ ) ２ selected from the group consisting of, or any R ６ and R ７ also together with the common nitrogen to which both are attached form an optionally substituted N - heteroaryl or optionally substituted N - heterocyclyl; R ８ each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, aryl which may be substituted, aralkyl which may be substituted, aralkenyl which may be substituted, aralkynyl which may be substituted, cycloalkyl which may be substituted, cycloalkylalkyl which may be substituted, cycloalkylalkenyl which may be substituted, cycloalkylalkynyl which may be substituted, heterocyclyl which may be substituted, heterocyclylalkyl which may be substituted, heterocyclylalkenyl which may be substituted, heterocyclylalkynyl which may be substituted, heteroaryl which may be substituted, heteroarylalkyl which may be substituted, heteroarylalkenyl which may be substituted and heteroarylalkynyl which may be substituted; R ９ each independently selected from the group consisting of a direct bond, a linear or branched alkylene chain which may be substituted, a linear or branched alkenylene chain which may be substituted, and a linear or branched alkynylene chain which may be substituted; R １０ each independently selected from the group consisting of a linear or branched alkylene chain which may be substituted, a linear or branched alkenylene chain which may be substituted, and a linear or branched alkynylene chain which may be substituted; R １１ each independently represents hydrogen, alkyl, cyano, nitro or -OR ８ and is selected from the group consisting of; R １２ is, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R １０ -OR ８ , -R １０ -CN, -R １０ -NO ２ , -R １０ -N(R ８ ) ２ , -R １０ -C(O)OR ８ and -R １０ -C(O)N(R ８ ) ２ is selected from the group consisting of, or two Rs １２ together with the common nitrogen to which both are attached, form an optionally substituted N-heterocyclyl or optionally substituted N-heteroaryl; R １３ each independently selected from the group consisting of a direct bond, a straight or branched alkylene chain which may be substituted, and a straight or branched alkenylene chain which may be substituted; R １４ each independently selected from the group consisting of a straight-chain or branched alkylene chain which may be substituted and a straight-chain or branched alkenylene chain which may be substituted) a compound represented by, an isolated stereoisomer or a mixture thereof, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt or N-oxide thereof).

2. wherein AXL i is 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N ３ -( (7-(S)-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazole-3,5-diamine, or a pharmaceutically acceptable salt thereof, the method according to claim 1.

3. The method according to claim 1 or 2, wherein the AXLi is bemcentinib.

4. The method according to any one of claims 1 to 3, wherein the disease associated with AXL is cancer, a fibrotic disorder or neurofibromatosis.

5. The method according to claim 4, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, breast cancer, melanoma, mesothelioma, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), pancreatic cancer, kidney cancer, urothelial cancer, ovarian cancer, neurofibroma, cranial cancer or spinal meningioma, schwannoma, epithelioma and glioblastoma.

6. The method according to claim 4, wherein the cancer is (i) acute myeloid leukemia (AML); and / or (ii) lung cancer or non-small cell lung cancer (NSCLC).

7. The loading dose is (i) about 100 - 300 mg, about 150 - 250 mg, about 175 - 225 mg or about 190 - 210 mg; or (ii) about 50 - 150 mg, about 75 - 125 mg or about 90 - 110 mg The method according to any one of claims 1 to 6.

8. The loading dose is (i) about 200 mg; or (ii) about 100 mg The method according to any one of claims 1 to 7.

9. The method according to any one of claims 1 to 8, wherein the maintenance dose is about 50% of the loading dose.

10. The method according to claim 9, wherein the maintenance dose is about 50 - 150 mg, about 75 - 125 mg or about 90 - 110 mg.

11. The method according to claim 9, wherein the maintenance dose is about 100 mg.

12. The method according to any one of claims 1 to 8, wherein the maintenance dose is the same amount as the loading dose.

13. The method according to claim 12, wherein the loading dose and the maintenance dose are about 100 mg.

14. The method according to claim 1, wherein the maintenance dose is administered to the subject daily until the treatment with AXL i is stopped.

15. The method according to claim 14, wherein the treatment with AXL i is stopped when a treatment endpoint is reached for the subject.

16. The treatment endpoint is (i) a partial or complete disease remission that achieves a partial remission [PR] state or a complete remission [CR] state; (ii) disease progression in a progressive disease [PD] state that prompts treatment discontinuation; and / or (iii) the occurrence of toxicity and / or adverse events that require treatment discontinuation, The method according to claim 15.

17. The method according to any one of claims 1 to 16, comprising administering the AXL i to the subject under feeding conditions.

18. Administering the AXL i under feeding conditions is as follows: (i) administering the AXL i to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180 or 240 minutes after the subject has ingested food; (ii) administering the AXL i to the subject within less than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180 or 240 minutes after the subject has ingested food; and / or (iii) administering the AXL i to the subject within about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 120, 180, or 240 minutes after or before the subject has ingested food, The method according to claim 17.

19. The method according to any one of claims 1 to 10, wherein the AXL i is co-administered with one or more immune checkpoint modulators (ICMs); and / or one or more chemotherapeutic agents and / or radiation therapy.

20. The method according to any one of claims 1 to 19, wherein the subject is a human.

21. (i) enhancing AXL i exposure in the subject; and / or (ii) reducing the variability of AXL i exposure in the subject; The method according to any one of claims 1 to 20 for.

22. The method according to any one of claims 1 to 21, wherein the administration regimen reduces toxicity and / or side effects associated with the administration of the AXL inhibitor (AXLi) to the subject and / or enhances the efficacy of the treatment associated with the administration of the AXL inhibitor (AXLi) to the subject.

23. An inhibitor of AXL activity or expression (AXLi) for use in the method according to any one of claims 1 to 22.

24. Use of an inhibitor of AXL activity or expression (AXLi) in the manufacture of a medicament for treating an AXL-related disease in a subject, wherein the treatment comprises the method according to any one of claims 1 to 22.

25. A packaged pharmaceutical product comprising an AXL inhibitor (AXLi) and a label or insert advising that the AXL inhibitor (AXLi) should be administered by the method according to any one of claims 1 to 22.

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