Pharmaceutical composition comprising emtricitinib

Abstract

Disclosed herein is a pharmaceutical composition comprising emtricitinib. The pharmaceutical composition is suitable for treating cancer subjects. The present disclosure also provides methods for preparing these pharmaceutical compositions and methods of treating cancer subjects using the pharmaceutical compositions provided herein.

Description

[0001] This application is a divisional application of 201880047029.1. The original application was filed on July 18, 2018, with application number 201880047029.1 and the invention title: Pharmaceutical Composition Including Entrectinib.

[0002] Cross-reference of related applications

[0003] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 534,585, filed July 19, 2017, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0004] This disclosure relates to pharmaceutical compositions and dosage forms suitable for treating subjects with cancer. This disclosure also provides methods for preparing these pharmaceutical compositions and dosage forms, and methods for treating subjects with cancer using the pharmaceutical compositions and dosage forms provided herein. Background Technology

[0005] The compound N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide and its preparation method are disclosed in U.S. Patent No. 8,299,057, the contents of which are incorporated herein by reference in their entirety. N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide is a potent inhibitor of tyrosine kinases, NTRK1 / 2 / 3-converting tyrosine kinase proteins (TrkA, TrkB, TrkC), proto-oncogene tyrosine protein kinase 1 (ROS1), and anaplastic lymphoma kinase (ALK). In various in vitro studies, N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide inhibited the proliferation of the CRC cell line KM12, whose proliferation depends on the activity of TrkA kinase, which affects proliferation and survival. It also effectively inhibited the proliferation of ALK-dependent pleomorphic large cell lymphoma cell lines.

[0006] In a single-dose feeding effect study of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide in dogs, in formulations excluding the acidifier, the exposure levels of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide in dogs were approximately twice as high under feeding conditions compared to those observed under fasting conditions. Such feeding effects may pose challenges during human drug testing, as patient feeding or fasting conditions can lead to significant variations in drug exposure or bioavailability.

[0007] In early human clinical studies, N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide has been shown to have antitumor effects in patients with various forms of cancer having at least one molecular alteration of one or more of ALK, ROS1, TrkA, TrkB, and TrkC. In studies using formulations of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide that do not contain at least one acidifying agent, systemic exposure to N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide increased when co-administered with food. Specifically, when taken with food, 200 mg / m² was significantly increased. 2 / day and 400 mg / m 2At a daily dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, the AUC values ​​of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide are approximately 200% and 50% higher, respectively. With food, the Cmax values ​​of both doses are approximately 150% higher. Additionally, in these studies, some patients received N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide in combination with a proton pump inhibitor (PPI), such as lansoprazole, and showed altered N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide exposure. Furthermore, at concentrations above 800 mg / m²... 2 At a dose of / day, there is a loss of dose ratio. Therefore, the objective of this disclosure is to provide pharmaceutical compositions and dosage forms comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, which are unaffected by changes in absorption in subjects (e.g., humans) with or without food and with or without a PPI. Summary of the Invention

[0008] In some embodiments, a pharmaceutical composition is provided comprising a weakly basic organic compound and at least one acidifier. In some embodiments, the at least one acidifier is an organic acidifier. In some embodiments, the at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, the at least one acidifier is fumaric acid. In some embodiments, the at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0009] In any of the embodiments described herein, at least one acidifier is an organic acidifier. In some embodiments, the at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, the at least one acidifier is fumaric acid. In some embodiments, the at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0010] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier. In some embodiments, the at least one acidifier is an organic acidifier. In some embodiments, the at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, the at least one acidifier is fumaric acid. In some embodiments, the at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0011] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 0.5 to about 2.

[0012] In some embodiments, a pharmaceutical composition is provided in the form of a tablet or a capsule. In some embodiments, a pharmaceutical composition is provided in the form of a tablet. In some embodiments, a pharmaceutical composition is provided in the form of a capsule.

[0013] In some embodiments, a pharmaceutical composition is provided, wherein the pharmaceutical composition comprises about 10 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent.

[0014] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein less than about 2% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the pharmaceutical composition is degraded after the pharmaceutical composition has been stored in an open container at 40°C and 75% relative humidity for 3 months.

[0015] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least an acidifying agent, wherein more than about 98% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is present in the pharmaceutical composition after the pharmaceutical composition has been stored in an open container at 40°C and 75% relative humidity for 3 months.

[0016] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein less than about 2% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the pharmaceutical composition is degraded after the pharmaceutical composition has been stored in an open container at 60°C and 75% relative humidity for 3 months.

[0017] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the composition is non-hygroscopic.

[0018] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile in which, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer at pH 4.5 and about 37°C, at least about 30% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule at about 60 minutes. In some embodiments, such pharmaceutical formulations are provided wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer and at pH 4.5 and about 37°C, at about 60 minutes, at least about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90%, or about 90%, or about 95% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule.

[0019] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the tablet or capsule has a solubility profile wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer and at pH 4.5 and about 37°C, at least about 20% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule at about 45 minutes.

[0020] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the tablet or capsule has a solubility profile wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer at pH 4.5 and about 37°C, at least about 15% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule at about 30 minutes.

[0021] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a fasting state when administered to the subject, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject is [data missing]. max Between approximately 2 and 6 hours.

[0022] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the C60 of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing] after administration of the pharmaceutical composition to the subject. max Between approximately 2080 nM and approximately 2110 nM.

[0023] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the C60 of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing] after administration of the pharmaceutical composition to the subject. max Between 80% and 125% of 2560 nM, based on a 90% confidence interval.

[0024] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 28,900 nM×hr and about 30,800 nM×hr.

[0025] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a C-terminus for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state at a concentration between about 2080 nM and about 2100 nM. maxThe device, wherein the composition comprises a total dose of about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0026] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state at an AUC (0 to 24) between about 28,900 nM×hr and about 30,800 nM×hr. The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0027] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a T-phase of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state between about 2 hours and about 6 hours. max The device.

[0028] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) an apparatus for administering the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide to a subject who has not shown an effect of oral intake.

[0029] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) an apparatus for administering the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide to a subject who does not show a significant effect from food intake.

[0030] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the pharmaceutical composition does not show an ingestion effect when administered to a subject.

[0031] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the pharmaceutical composition does not exhibit an eating effect when administered to a subject and also to the subject with one or more proton pump inhibitor compounds.

[0032] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the Tg of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing] after administration of the pharmaceutical composition to the subject. maxBetween approximately 2 hours and approximately 5 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0033] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition. max Between approximately 2 hours and approximately 8 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0034] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject in an eating state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the Tg of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing] after administration of the pharmaceutical composition to the subject. max Between approximately 4 hours and approximately 8 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0035] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition. maxBetween approximately 4 hours and approximately 8 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0036] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the C60 of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing] after administration of the pharmaceutical composition to the subject. max Between approximately 1200 nM and approximately 3500 nM. In some embodiments, at least one acidifying agent is an organic acidifying agent. In some embodiments, at least one acidifying agent is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0037] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C60 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition. max Between approximately 1200 nM and approximately 3500 nM. In some embodiments, at least one acidifying agent is an organic acidifying agent. In some embodiments, at least one acidifying agent is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0038] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject in an eating state, the pharmaceutical composition provides pharmacokinetic profiles in the subject, wherein, after administration of the pharmaceutical composition to the subject, the C60 of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is [value missing]. maxBetween approximately 1500 nM and approximately 3500 nM. In some embodiments, at least one acidifying agent is an organic acidifying agent. In some embodiments, at least one acidifying agent is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0039] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C60 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition. max Between approximately 1500 nM and approximately 3500 nM. In some embodiments, at least one acidifying agent is an organic acidifying agent. In some embodiments, at least one acidifying agent is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0040] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 120) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 30,000 nM×hr and about 85,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0041] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject in a state where the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 120) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 30,000 nM×hr and about 85,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0042] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in an eating state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 120) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 35,000 nM×hr and about 90,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0043] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 120) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 35,000 nM×hr and about 90,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0044] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a fasting subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (infinity) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 30,000 nM×hr and about 85,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0045] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (infinity) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 30,000 nM×hr and about 85,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0046] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in an eating state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (infinity) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 35,000 nM×hr and about 90,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0047] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 600 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (infinity) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 35,000 nM×hr and about 90,000 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is tartaric acid. In some embodiments, the at least one acidifying agent is maleic acid. In some embodiments, the at least one acidifying agent is citric acid. In some embodiments, the at least one acidifying agent is betaine hydrochloride.

[0048] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a C-terminus for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state at a concentration between about 1200 nM and about 3500 nM. max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0049] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a C-terminus for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject at a concentration between about 1200 nM and about 3500 nM after administration of the pharmaceutical composition to the subject. max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0050] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a C-terminus of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in an oral state, at a concentration between about 1500 nM and about 3500 nM. max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0051] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a C-terminus for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject at a concentration between about 1500 nM and about 3500 nM after administration of the pharmaceutical composition to the subject. maxThe device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0052] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state at an AUC (0 to 120) between about 30,000 nM×hr and about 85,000 nM×hr, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0053] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at an AUC (0 to 120) between about 30,000 nM×hr and about 85,000 nM×hr after administration of the pharmaceutical composition to the subject, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0054] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a feeding state at an AUC (0 to 120) between about 35,000 nM×hr and about 90,000 nM×hr, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0055] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at an AUC (0 to 120) between about 35,000 nM×hr and about 90,000 nM×hr after administration of the pharmaceutical composition to the subject, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0056] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject in a fasting state, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide with an AUC (infinity) between about 30,000 nM×hr and about 85,000 nM×hr, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0057] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in an AUC (infinity) between about 30,000 nM×hr and about 85,000 nM×hr after administration of the pharmaceutical composition to the subject, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0058] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject in a feeding state, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in an AUC (infinity) between about 35,000 nM×hr and about 90,000 nM×hr, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0059] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in an AUC (infinity) between about 35,000 nM×hr and about 90,000 nM×hr after administration of the pharmaceutical composition to the subject, and wherein the composition comprises about 600 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0060] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a T-phase of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state between about 2 hours and about 5 hours. maxThe device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0061] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a T-phase of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject between about 2 hours and about 5 hours after administration of the pharmaceutical composition to the subject. max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0062] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a T-type of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide for providing a T-type of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a feeding state for a period of about 4 hours and about 8 hours. max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0063] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a T-type of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide for providing the drug composition to a subject's plasma between about 4 hours and about 8 hours after administration of the pharmaceutical composition to the subject.max The device, wherein the composition comprises a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. Attached Figure Description

[0064] Figure 1 The diagram illustrates the bioavailability (area under the curve, AUC) of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, measured in nM×hr / mL, after administration of the F2A formulation under fasting conditions with and without PPI.

[0065] Figure 2 This is a graphical illustration of the effect of oral administration on the bioavailability (area under the curve, AUC) of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, measured in nM×hr / mL. The F2A formulation was administered under fed or fasting conditions in the absence of a PPI.

[0066] Figure 3 This is a graphical illustration of the effect of oral administration on the bioavailability (area under the curve, AUC) of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, measured in nM×hr / mL. The F2A formulation was administered with or without a PPI.

[0067] Figure 4 A graphical illustration of the mean plasma levels (in nanomoles) of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide over time following F2A treatment. Diamond (♦) indicates F2A administration under fasting conditions without a PPI. Square (■) indicates F2A administration under fasting conditions with a PPI. Triangle (▲) indicates F2A administration under eating conditions without a PPI. Circle (○) indicates F2A administration under eating conditions with a PPI. Detailed Implementation

[0068] Unless the context clearly specifies otherwise, the singular forms “a / an” and “the” include plural references. For example, the term “cell” includes one or more cells, including mixtures thereof. The use of “A and / or B” herein includes all the following alternative forms: “A”, “B”, “A or B”, and “A and B”.

[0069] As used herein, the term "N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide" refers to a compound having Chemical Abstracts Service Registry No. 1108743-60-7 and having the following chemical structure:

[0070] .

[0071] All references to N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide herein include references to its solvates, complexes, polycrystalline forms, stereoisomers, and isotopically labeled forms. The scope provided herein also includes pharmaceutical compositions comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, including its solvates, complexes, polycrystalline forms, stereoisomers, and isotopically labeled forms.

[0072] As used herein, the term “about” means within 10% of the provided value, or rounded to the nearest significant figure, in all cases including the provided value. Where a range is provided, it includes boundary values.

[0073] As used herein, the term "acidifier" refers to a chemical compound that is inherently acidic. As used herein, the term "organic acidifier" refers to an acidifier whose chemical composition contains carbon. As used herein, the term "inorganic acidifier" refers to an acidifier whose composition does not contain carbon.

[0074] As used herein, the term "administration / administering" means delivery of a bioactive composition or formulation via (but not limited to) the following routes of administration: oral, intravenous, intra-arterial, intramuscular, intraperitoneal, subcutaneous, intramuscular, topical, or a combination thereof. In some embodiments, administration to a subject is oral.

[0075] As used herein, the term "admixture" means a mixture of one or more chemical compounds in a composition. Those skilled in the art will understand that the pharmaceutical compositions disclosed herein comprise an admixture of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent.

[0076] As used in this article, the term "ALK" refers to the anaplastic lymphoma kinase receptor or CD246 (a cluster of differentiation 246), which is an enzyme encoded by the ALK gene in the human body and also has the UniProt identifier ALK_HUMAN.

[0077] As used herein, the term "antibody" refers to an immunoglobulin that specifically binds to a particular spatial and polar structure of another molecule and is therefore defined as complementary to the particular spatial and polar structure of said other molecule. Antibodies can be monoclonal or polyclonal and can be prepared by techniques well known in the art, such as host immunization and serum collection (polyclonal), or by preparing sequential hybrid cell lines and collecting secreted proteins (monoclonal), or by cloning and expressing a nucleotide sequence or a mutagenic form thereof that encodes at least the amino acid sequence required for specific binding of a natural antibody. Antibodies may comprise complete immunoglobulins or fragments thereof, including various classes and isotypes such as IgA, IgD, IgE, IgG1, IgG2a, IgG2b, and IgG3, IgM, etc. Fragments may comprise Fab, Fv, and F(ab′)2, Fab′, etc. Additionally, polymers, aggregates, and conjugates of immunoglobulins or fragments thereof may be used, if appropriate, provided that binding affinity to a specific target is maintained.

[0078] As used in this article, the term “AUC” refers to the area under the curve of a graph showing the concentration of a compound in a subject’s plasma relative to time.

[0079] As used herein, the term "betaine hydrochloride" refers to compounds having Chemical Abstracts Service Registry No. 590-46-5 and the common names 1-carboxy-n,n,n-trimethylammonium chloride and (carboxymethyl)trimethylammonium hydrochloride.

[0080] As used herein, the term "biological sample" means a sample obtained from a living organism that may be used in diagnostic or surveillance testing. The sample may be healthy tissue, diseased tissue, or tissue suspected of being diseased. The sample may be, for example, a biopsy obtained during surgical procedures. Samples may be collected by aspiration, scraping, or washing of a cavity with a fine needle to collect cells or tissue from it. The sample may be a tumor, such as a solid or hematopoietic tumor, and adjacent healthy tissue. The sample may be a smear of a single cell or tissue section. The term encompasses biologically derived blood and other fluid samples, solid tissue samples such as biopsy samples or tissue cultures or cells derived therefrom and their progeny. The term encompasses samples that are manipulated in any way after acquisition, such as by treatment with reagents, dissolution, or enrichment of certain components. The term encompasses clinical samples and also includes cells in cell cultures, cell supernatants, cell lysates, cell extracts, cell homogenates, and subcellular components (including synthetic proteins, serum, plasma, body fluids, and other biological fluids), as well as tissue samples. Biological samples may contain compounds that are not naturally mixed with cells or tissues, such as preservatives, anticoagulants, buffers, fixatives, nutrients, antibiotics, or the like. In some embodiments, samples are preserved as frozen samples or as tissue preparations in paraffin-embedded (FFPE) fixed in formaldehyde or paraformaldehyde. For example, samples may be embedded in a matrix, such as FFPE blocks or frozen samples.

[0081] As used herein, the term "biomarker" means one or more compounds whose nucleic acid or protein product levels have a quantitative concentration or level difference relative to an aspect of a subject's biological state. The term "biomarker" is used interchangeably with the term "marker" herein. The level of a biomarker can be measured at both the nucleic acid and peptide levels. At the nucleic acid level, a nucleic acid gene or transcript transcribed from any part of a subject's chromosome and extrachromosomal genome (including, for example, the mitochondrial genome) can be measured. Preferably, it is an RNA transcript, more preferably comprising primary transcripts, spliced ​​transcripts, alternating spliced ​​transcripts, or the mRNA from which the biomarker is measured. At the peptide level, the biomarker can be measured as a propeptide, propeptide, mature peptide, or secreted peptide. Biomarkers can be used alone or in combination with one or more other identified biomarkers to allow for association with the biological state of interest as defined herein. Specific examples of biomarkers covered by this disclosure include those associated with ALK, ROS1, TrkA, TrkB, and TrkC.

[0082] As used in this article, the term "C" max"This refers to the peak concentration of the compound reached in the plasma of the subject after administration of the compound or a pharmaceutical composition comprising the compound to the subject. In some embodiments, the compound or a pharmaceutical composition comprising the compound is administered orally to the subject to achieve a specific C." max .

[0083] As used herein, the terms “cancer” and “tumor” are used interchangeably. These terms refer to the presence of cells that possess the hallmarks of cancerous cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rates, and certain characteristic morphological features. Cancer cells typically take the form of tumors, but these cells can exist alone in animals or can be non-tumorigenic cancer cells, such as leukemia cells. These terms encompass solid tumors, soft tissue tumors, or metastatic lesions. As used herein, the term “cancer” includes pre-malignant cancer as well as malignant cancer. In some embodiments, cancer is a solid tumor, a soft tissue tumor, or a metastatic lesion. The term also refers to solid tumors named for the cell types that form solid tumors, blood, bone marrow, or lymphatic system cancers. Examples of solid tumors include (but are not limited to) sarcomas and carcinomas. Examples of blood cancers include (but are not limited to) leukemia, lymphoma, and myeloma. These terms include (but are not limited to) primary cancer originating in a specific part of the body, metastatic cancer that has spread from its origin to other parts of the body, recurrence of the original primary cancer after remission, and a second primary cancer, which is a new primary cancer in a person with a history of cancer of a different type than the latter. As used herein, “cancer” means any malignant and / or invasive growth or tumor caused by abnormal cell growth.

[0084] As used in this article, the term "chemotherapeutic agent" refers to chemical substances used to treat conditions, particularly cancer, such as cytotoxic agents or cell inhibitors.

[0085] As used herein, the terms “combination” and “in combination with” mean the administration of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide together with at least one other drug or pharmaceutical agent (e.g., an anticancer agent), sequentially or simultaneously. This includes administration of the pharmaceutical composition provided herein simultaneously, or within minutes or hours of each other, or on the same day, or on every other day, or on a daily or weekly basis, for example, administration of another compound, such as a chemotherapeutic agent, during at least a portion of the time during which the pharmaceutical composition disclosed herein is administered, either simultaneously or concurrently with it, on the same day, every other day, every other week, or on a cyclical basis, or during at least a portion of the time during which the pharmaceutical composition disclosed herein is administered. For example, a pharmaceutical composition containing N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, as provided herein, may be administered daily or several days per week, while a chemotherapeutic agent is administered every other day or every other week or at other time intervals, such as every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or more days.

[0086] As used in this article, the term “contact” when referring to specificity or specific binding means that two molecules are close enough that short-range non-covalent chemical interactions, such as van der Waals forces, hydrogen bonding, hydrophobic interactions, and other dominant molecular interactions, are present.

[0087] As used herein, the term “cell line” refers to one or more generations of cells derived from cloned cells. The term “clone” or “cloned cell” refers to a single cell that has been expanded to produce a segregating population (i.e., a “cloned cell population”) of phenotypically similar cells.

[0088] As used herein, parameters DV10, Dv50, Dv90, and Dv99 represent the particle size at the 10%, 50%, 90%, and 99% points of the cumulative volumetric sieve particle size distribution. Therefore, "Dv10" of a material represents the particle size where 10% of the material volume consists of particles with a diameter equal to or less than the Dv10 value. "Dv50" of a material represents the particle size where 50% of the material volume consists of particles with a diameter equal to or less than the Dv50 value. "Dv90" of a material represents the particle size where 90% of the material volume consists of particles with a diameter equal to or less than the Dv90 value. "Dv99" of a material represents the particle size where 99% of the material volume consists of particles with a diameter equal to or less than the Dv99 value.

[0089] As used herein, the term "feeding effect" means the change in the rate and / or extent of compound absorption in a subject when the compound is administered shortly after a meal (feeding condition) compared to the rate and / or extent of absorption when the compound is administered to the subject under fasting conditions. As used herein, the term "no-feeding effect" means that there is no significant difference in the rate and / or extent of compound absorption in a subject when the compound is administered to the subject under feeding conditions compared to fasting conditions.

[0090] As used herein, the term "immunohistochemistry" refers to the process of locating antigens (e.g., proteins) in the cells of biological samples, cells, and / or tissue sections using the principle of specific binding of antibodies to antigens. Immunohistochemical staining is widely used to diagnose abnormal cells, such as those found in cancerous tumors. Specific molecular markers are characterized by specific cellular events such as cell proliferation or cell death. Antibody-antigen interactions can be visualized in a variety of ways. In the most common case, antibodies are coupled to enzymes (such as peroxidases) that catalyze color-producing reactions. Alternatively, antibodies can be labeled as fluorophores, employing the principle of immunofluorescence. Immunohistochemistry can also be used to assess the tumor content in a sample (for which qPCR is performed) to explain why qPCR results will be affected by the amount of tumor tissue present.

[0091] As used in this article, the term “micronization” refers to the process of reducing the average particle size of a solid material, typically in order to obtain particles with a diameter of a few micrometers.

[0092] As used in this article, the term “micronized” refers to materials that have been micronized.

[0093] As used herein, the terms “monoclonal antibody,” “mAb,” and “MAB” refer to an antibody that is an immunoglobulin produced by a single clone of a lymphocyte that recognizes only a single epitope on an antigen. For example, monoclonal antibodies that can be used in the methods provided herein exhibit single binding specificity and affinity for a specific epitope of one or more tyrosine kinases.

[0094] As used herein, the term “multiplex assay” means an assay in which multiple assay reactions (e.g., simultaneous assay of multiple target biomarkers) are performed in a single reaction chamber and / or analyzed in a single isolation and detection mode.

[0095] As used herein, the term "multiplex identification" refers to the simultaneous identification of one or more target biomarkers in a single mixture. For example, dual testing means the simultaneous identification of two different target biomarkers in a single reaction mixture.

[0096] As used herein, the term “one or more molecular alterations” refers to any change in the sequence of a gene or protein in one or more cells of a subject compared to the corresponding wild-type gene or protein. One or more molecular alterations include, but are not limited to, gene mutations, gene amplifications, splicing variants, deletions, insertions / deletions, gene rearrangements, single nucleotide variants (SNVs), insertions, and aberrant RNA / protein expression.

[0097] As used herein, the term "particle size distribution" refers to the relative proportion of compound particles having a given particle size. While the particle size of a spherical object can be defined precisely and quantitatively by its diameter, particles comprising active pharmaceutical ingredients or excipients can be non-spherical and irregularly shaped. Those skilled in the art can measure and express the size of non-spherical and irregular particles in several ways, such as by measuring the size of such particles using laser diffraction and by expressing the size of such particles based on replacing a given particle with an imaginary sphere possessing one of many properties of said particles. Such properties can be selected from, for example (but not limited to), the diameter of an imaginary sphere having the same volume as the particle being measured (volume-based particle size), the diameter of an imaginary sphere having the same weight as the particle being measured (weight-based particle size), and the diameter of an imaginary sphere having the same surface area as the particle being measured (area-based particle size). Those skilled in the art are familiar with such methods and the ways in which the results of such methods are expressed, and such methods can be applied to the embodiments disclosed herein without excessive experimentation. Particle size distribution can be represented, for example, in the form of a graph. A common type of graph is the cumulative undersize graph, which represents the fraction of particles smaller than a specified size (e.g., by number, volume, or mass).

[0098] As used herein, the term "polyclonal antibody" refers to a composition of different antibody molecules capable of binding or reacting with several different specific antigenic determinants on the same or different antigens. The variability in the antigen specificity of a polyclonal antibody resides in the variable regions of the individual antibodies constituting the polyclonal antibody, particularly in the complementarity-determining regions (CDRs). Preferably, polyclonal antibodies are prepared by immunization of an animal having a target tyrosine kinase or a portion thereof. Alternatively, polyclonal antibodies can be prepared by mixing multiple monoclonal antibodies having desired specificity for the target tyrosine kinase.

[0099] As used herein, the term "proton pump inhibitor" or "PPI" refers to a drug that reduces the production of stomach acid. PPIs that may be used in some embodiments include, but are not limited to, dexlansoprazole, esomeprazole, ilaprazole, lansoprazole, omeprazole, pantoprazol, picoprazole, rabeprazole, yenatoprazole, and timoprazole.

[0100] As used in this article, “ROS1” refers to a ROS1 receptor tyrosine protein kinase with UniProt-specified ROS1_HUMAN.

[0101] As used herein, the term “selective binding” means a situation in which one member of a specific intraspecific or interspecific binding pair will not exhibit any significant binding (e.g., about 100 times less affinity) to molecules other than its specific intraspecific or interspecific binding partner, which means that only minimal cross-reactivity occurs.

[0102] As used herein in reference to the binding of two molecules or a complex of one or more compounds with a molecule, the term "specificity" means the distinctness of the molecule with itself compared to the significantly less distinguishable molecule from others and the lack thereof in forming a stable complex with such other molecules. Preferably, the reference to "specificity" in binding means that, with respect to the formation of a complex with other molecules or complexes, one or more compounds form a complex with at least fifty percent of the molecules or complexes that are specific to said molecules or complexes. Typically, the molecules or complexes have regions on their surface or in cavities that create a specific distinguishing effect between the two binding sites. Examples of specific binding are antibody-antigen interactions, enzyme-substrate interactions, polynucleotide hybridization and / or double helix formation, cell receptor-ligand interactions, etc.

[0103] As used herein, the term "subject" refers to a mammal, including (but not limited to) humans, dogs, or cats. In some embodiments, the subject is a human. In some embodiments, the subject is a dog. In some embodiments, the subject is a cat.

[0104] As used in this article, the term "T" max "This refers to the time when the peak concentration of the compound in the plasma of the subject is reached after administration of the compound or a pharmaceutical composition comprising the compound.

[0105] As used herein, the term “therapeutic effective amount” means an amount of one or more compounds or a pharmaceutically acceptable salt thereof that, when administered to a subject, will alleviate, to some extent, the symptoms of the treated condition. Referring to the treatment of cancer, the therapeutic effective amount means an amount that has the following effects: (1) reducing the size of the cancerous tumor; (2) inhibiting (i.e., slowing, preferably stopping) the metastasis of the cancerous tumor; (3) inhibiting (i.e., slowing, preferably stopping) the growth of the cancerous tumor; and / or (4) alleviating (or preferably eliminating) one or more symptoms associated with cancer to some extent.

[0106] As used herein, the terms "tropomyosin receptor kinase," "Trks," and "Trk" refer to the tropomyosin receptor kinase (Trks) family, which is activated by peptide hormones of the neurotrophic factor family and includes (but is not limited to) TrkA, TrkB, and TrkC. As used herein, the term "TrkA" refers to wild-type tropomyosin receptor kinase A having the UniProt identifier NTRK1_HUMAN. As used herein, the term "TrkB" refers to wild-type tropomyosin receptor kinase B having the UniProt identifier NTRK2_HUMAN. As used herein, the term "TrkC" refers to wild-type tropomyosin receptor kinase C having the UniProt identifier NTRK3_HUMAN. Those skilled in the art will also refer to TrkA, TrkB, and TrkC as Trk1, Trk2, and Trk3, respectively. Reference to TrkA refers to Trk1. Reference to TrkB refers to Trk2. Reference to TrkC refers to Trk3.

[0107] As used herein, the term "Type I USP device" refers to device 1 (basket device or basket method) and uses the United States Pharmacopeia (USP) General Rules. <711> The program for the device described in the document.

[0108] As used herein, the term "Type II USP device" refers to Device 2 (paddle device or paddle method) and uses the United States Pharmacopeia (USP) General Rules. <711> The program for the device described in the document.

[0109] A pharmaceutical composition is provided in one state comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and at least one pharmaceutically acceptable excipient.

[0110] A pharmaceutical composition is provided in one state comprising an N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and at least one pharmaceutically acceptable excipient.

[0111] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and at least one pharmaceutically acceptable excipient. Acidifiers that can be used in the pharmaceutical compositions disclosed herein are organic and inorganic acidifiers. In some embodiments, the at least one acidifier is an organic acidifier. In some embodiments, the at least one acidifier is an inorganic acidifier. In some embodiments, the at least one organic acidifier is selected from organic carboxylic acids, ammonium salts, and ammonium salts.

[0112] In some embodiments, the acidifier is selected from acetic acid, ascorbic acid, benzoic acid, benzosulfonic acid, betaine hydrochloride, carbonic acid, cinnamic acid, citric acid, ethanesulfonic acid, ethylenediaminetetraacetic acid, dodecyl sulfonic acid, fumaric acid, glucuronic acid, glutamic acid, glycolic acid, lactic acid, lactobionic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, methanesulfonic acid, mucilage, naphthalenesulfonic acid, propionic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid, trifluoroacetic acid, (D) or (L) tartaric acid or mixtures thereof, valeric acid, etc.

[0113] In some embodiments, at least one acidifying agent is selected from acetic acid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid, glucuronic acid, lactic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid and (D) or (L) tartaric acid or mixtures thereof.

[0114] In some embodiments, at least one acidifying agent is selected from benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L) maleic acid or mixtures thereof and (D) or (L) tartaric acid or mixtures thereof.

[0115] In some embodiments, at least one acidifying agent is selected from betaine hydrochloride, citric acid, fumaric acid, maleic acid and (D) or (L) tartaric acid or mixtures thereof.

[0116] In some embodiments, at least one acidifying agent is betaine hydrochloride. In some embodiments, at least one acidifying agent is citric acid. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is maleic acid. In some embodiments, at least one acidifying agent is (D) or (L) tartaric acid or a mixture thereof.

[0117] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the at least one acidifying agent is (D) tartaric acid. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the at least one acidifying agent is (L) tartaric acid.

[0118] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition is prepared using wet granulation.

[0119] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition is prepared using dry granulation. In some embodiments, at least one acidifying agent is included in the dry granulation step of pharmaceutical manufacturing to create a low pH microenvironment that enhances the solubility of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0120] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier, wherein the pharmaceutical composition is prepared using wet granulation and the at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, the at least one acidifier is fumaric acid. In some embodiments, the at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride. In some embodiments, the at least one acidifier is (D) or (L) tartaric acid or a mixture thereof. In some embodiments, the at least one acidifier is (D) tartaric acid. In some embodiments, the at least one acidifier is (L) tartaric acid. In some embodiments, at least one acidifying agent is a mixture of (D) and (L) tartaric acid.

[0121] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier, wherein the pharmaceutical composition is prepared using dry granulation and the at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, the at least one acidifier is fumaric acid. In some embodiments, the at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride. In some embodiments, the at least one acidifier is (D) or (L) tartaric acid or a mixture thereof. In some embodiments, the at least one acidifier is (D) tartaric acid. In some embodiments, the at least one acidifier is (L) tartaric acid. In some embodiments, at least one acidifying agent is a mixture of (D) and (L) tartaric acid.

[0122] In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 15°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 20°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 25°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 30°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 40°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 50°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 75°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 100°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 150°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 200°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 250°C. In some embodiments, at least one acidifying agent has a melting point greater than or equal to about 300°C.

[0123] In some embodiments, at least one acidifier has a pKa of less than about 9, or less than about 8, or less than about 7, or less than about 6, or less than about 5, or less than about 4, or less than about 3, or less than about 2.

[0124] In some embodiments, at least one acidifier has a pKa of about 1 to about 9, or about 1 to about 8, or about 1 to about 7, or about 1 to about 6, or about 1 to about 5, or about 1 to about 4, or about 1 to about 3.5, or about 1 to about 3.25, or about 1 to about 3, or about 1 to about 2.75, or about 1 to about 2.5, or about 1 to about 2.25, or about 1 to about 2, or about 1 to about 1.9, or about 1.5 to about 5, or about 1.5 to about 4.5, or about 1.5 to about 4, or about 1.5 to about 3.5, or about 1.5 to about 3.25, or about 1.8 to about 3.5.

[0125] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 0.5 to about 2, or about 0.75 to about 1.75, or about 1 to about 1.75, or about 1 to about 1.5, or about 1.25 to about 1.75, or about 1 to about 1.5.

[0126] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 2, or about 1.75, or about 1.5, or about 1.25, or about 1, or about 0.75, or about 0.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 1.5.

[0127] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier, wherein the at least one acidifier is (D) tartaric acid, (L) tartaric acid, or a mixture of (D) and (L) tartaric acid, and further wherein the molar ratio between the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifier is about 2, or about 1.75, or about 1.5, or about 1.25, or about 1, or about 0.75, or about 0.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier, wherein the at least one acidifier is (D) tartaric acid, (L) tartaric acid, or a mixture of (D) and (L) tartaric acid, and further wherein the molar ratio between the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifier is about 1.5.

[0128] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 0.5 to about 5, or about 0.5 to about 4.5, or about 0.5 to about 4, or about 0.5 to about 3.5, or about 0.5 to about 3, or about 0.5 to about 2.75, or about 0.5 to about 2.5, or about 0.5 to about 2.25.

[0129] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 0.5 to about 5, or about 0.5 to about 4.5, or about 0.5 to about 4, or about 0.5 to about 3.5, or about 0.5 to about 3, or about 0.5 to about 2.75, or about 0.5 to about 2.5, or about 0.5 to about 2.25.

[0130] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 0.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 1. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 1.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 2. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 2.25.In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 2.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 2.75. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 3. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 3.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 4.In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 4.5. In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride, wherein the molar ratio between N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and betaine hydrochloride is about 5.

[0131] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent. In some embodiments, the formulation comprises about 10 mg to about 1000 mg, or about 25 mg to about 1000 mg, or about 50 mg to about 1000 mg, or about 100 mg to about 1000 mg, or about 100 mg to about 800 mg, or about 100 mg to about 750 mg, or about 100 mg to about 500 mg, or about 100 mg to about 300 mg, or about 100 mg to about 250 mg, or about 100 mg to about 200 mg, or about 100 mg to about 150 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg. mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 150 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 350 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 400 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 450 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 500 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0132] The pharmaceutical compositions provided herein are presented in forms suitable for oral administration, such as tablets, capsules, powders, granules, sustained-release formulations, dissolved suspensions, suspensions, or emulsions. In some embodiments, the pharmaceutical composition is in tablet or capsule form. In some embodiments, the pharmaceutical composition is in tablet form. In some embodiments, the tablet is a multilayer tablet. In some embodiments, the tablet is a multilayer tablet comprising one or more layers of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide separated from one or more layers comprising at least one acidifying agent. In some embodiments, the tablet is a bilayer tablet comprising a layer of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide separated from a layer comprising at least one acidifying agent. In some embodiments, any multilayer tablet described herein further comprises at least one pharmaceutically acceptable excipient.

[0133] In some embodiments, the pharmaceutical composition is in tablet form, wherein the tablet comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier. In some embodiments, the pharmaceutical composition is in tablet form, wherein the tablet comprises a blend of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier. In some embodiments, any tablet described herein further comprises at least one pharmaceutically acceptable excipient.

[0134] In some embodiments, the pharmaceutical composition is in tablet form, wherein the tablet comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and at least one filler. In another embodiment, the tablet further comprises at least one disintegrant. In another embodiment, the tablet further comprises at least one flow aid. In another embodiment, the tablet further comprises at least one lubricant. In another embodiment, the tablet further comprises at least one pore-forming agent. In another embodiment, the tablet further comprises at least one binder. In another embodiment, the tablet further comprises at least one gel-forming agent.

[0135] In some embodiments, the pharmaceutical composition is in tablet form, wherein the tablet comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier. In some embodiments, the at least one acidifier is selected from acetic acid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid, glucuronic acid, lactic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, the at least one acidifier is selected from benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L) maleic acid or mixtures thereof, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, at least one acidifying agent is selected from betaine hydrochloride, citric acid, fumaric acid, maleic acid, and (D) or (L) tartaric acid, or mixtures thereof. In some embodiments, at least one acidifying agent is betaine hydrochloride. In some embodiments, at least one acidifying agent is citric acid. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is maleic acid. In some embodiments, at least one acidifying agent is (D) or (L) tartaric acid, or mixtures thereof.

[0136] In some embodiments, the pharmaceutical composition is in tablet form, wherein the tablet comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and magnesium stearate. In some embodiments, the at least one acidifier is selected from acetic acid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid, glucuronic acid, lactic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, the at least one acidifier is selected from benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L) maleic acid or mixtures thereof, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, at least one acidifying agent is selected from betaine hydrochloride, citric acid, fumaric acid, maleic acid, and (D) or (L) tartaric acid, or mixtures thereof. In some embodiments, at least one acidifying agent is betaine hydrochloride. In some embodiments, at least one acidifying agent is citric acid. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is maleic acid. In some embodiments, at least one acidifying agent is (D) or (L) tartaric acid, or mixtures thereof.

[0137] In some embodiments, the pharmaceutical composition is in capsule form. In some embodiments, the capsule is a multilayer capsule. In some embodiments, the capsule is a multilayer capsule comprising one or more layers of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide separated from one or more layers comprising at least one acidifying agent. In some embodiments, the capsule is a bilayer capsule comprising a layer of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide separated from a layer comprising at least one acidifying agent. In some embodiments, any multilayer capsule described herein further comprises at least one pharmaceutically acceptable excipient.

[0138] In some embodiments, the pharmaceutical composition is in the form of a capsule, wherein the capsule comprises an intraparticle component and an extraparticle component, and is composed of, or primarily composed of, the intraparticle component and the extraparticle component. In some embodiments, the intraparticle component comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier. In some embodiments, the intraparticle component further comprises a filler, binder, disintegrant, or lubricant, or any combination of two or more thereof. In some embodiments, the intraparticle component further comprises lactose, hydroxypropyl methylcellulose, crospovidone, or magnesium stearate, or any combination of two or more thereof. In some embodiments, the extraparticle component comprises a filler, disintegrant, flow aid, or lubricant, or any combination of two or more thereof. In some embodiments, the extraparticle component comprises microcrystalline cellulose, crospovidone, colloidal silica, or magnesium stearate, or any combination of two or more thereof.

[0139] In some embodiments, the pharmaceutical composition is in capsule form, wherein the capsule comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent. In some embodiments, the pharmaceutical composition is in capsule form, wherein the capsule comprises a blend of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent. In some embodiments, any capsule described herein further comprises at least one pharmaceutically acceptable excipient.

[0140] In some embodiments, the pharmaceutical composition is in the form of a capsule, wherein the capsule comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifier, and at least one filler. In another embodiment, the capsule further comprises at least one disintegrant. In another embodiment, the capsule further comprises at least one flow aid. In another embodiment, the capsule further comprises at least one lubricant.

[0141] In some embodiments, the pharmaceutical composition is in the form of a capsule, wherein the capsule comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent. In some embodiments, the at least one acidifying agent is selected from acetic acid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid, glucuronic acid, lactic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, the at least one acidifying agent is selected from benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L) maleic acid or mixtures thereof, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, at least one acidifying agent is selected from betaine hydrochloride, citric acid, fumaric acid, maleic acid, and (D) or (L) tartaric acid, or mixtures thereof. In some embodiments, at least one acidifying agent is betaine hydrochloride. In some embodiments, at least one acidifying agent is citric acid. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is maleic acid. In some embodiments, at least one acidifying agent is (D) or (L) tartaric acid, or mixtures thereof.

[0142] In some embodiments, the pharmaceutical composition is in the form of a capsule, wherein the capsule comprises N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifying agent, and magnesium stearate. In some embodiments, the at least one acidifying agent is selected from acetic acid, benzoic acid, betaine hydrochloride, citric acid, fumaric acid, glucuronic acid, lactic acid, (D) or (L) malic acid or mixtures thereof, maleic acid, mandelic acid, malonic acid, salicylic acid, stearic acid, succinic acid, p-toluenesulfonic acid, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, the at least one acidifying agent is selected from benzoic acid, betaine hydrochloride, citric acid, fumaric acid, (D) or (L) maleic acid or mixtures thereof, and (D) or (L) tartaric acid or mixtures thereof. In some embodiments, at least one acidifying agent is selected from betaine hydrochloride, citric acid, fumaric acid, maleic acid, and (D) or (L) tartaric acid, or mixtures thereof. In some embodiments, at least one acidifying agent is betaine hydrochloride. In some embodiments, at least one acidifying agent is citric acid. In some embodiments, at least one acidifying agent is fumaric acid. In some embodiments, at least one acidifying agent is maleic acid. In some embodiments, at least one acidifying agent is (D) or (L) tartaric acid, or mixtures thereof.

[0143] In some embodiments, a pharmaceutical composition is provided comprising an amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, or about 10 mg to about 2000 mg, or about 10 mg to about 1500 mg, or about 10 mg to about 10 ... Furthermore, the pharmaceutical compositions provided herein may contain an amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, or about 500 mg. In some embodiments, the pharmaceutical compositions provided herein contain an amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of about 100 mg to about 200 mg. In some embodiments, the pharmaceutical compositions provided herein contain an amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of about 25 mg to about 800 mg.

[0144] In some embodiments, a pharmaceutical composition is provided comprising about 0.5 w / w% to about 95 w / w%, or about 1 w / w% to about 95 w / w%, or about 1 w / w% to about 75 w / w%, or about 5 w / w% to about 75 w / w%, or about 10 w / w% to about 75 w / w%, or about 10 w / w% to about 50 w / w% of an amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0145] In some embodiments, the pharmaceutical composition further comprises lactose. In some embodiments, lactose is present in the composition in an amount of about 15% w / w to about 35% w / w. This includes about 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, and 35% w / v, including increments therein and ranges between two of these values ​​(including endpoints). In some embodiments, lactose is present in the composition in an amount of about 25% w / w to about 30% w / w. In some embodiments, the lactose is anhydrous lactose.

[0146] In some embodiments, the pharmaceutical composition further comprises hydroxypropyl methylcellulose (hydroxypropyl methylcellulose). In some embodiments, hydroxypropyl methylcellulose is present in the composition in an amount of about 1% w / w to about 10% w / w. This includes about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10% w / w, including increments therein, and a range (including endpoints) between two of these values. In some embodiments, hydroxypropyl methylcellulose is present in the composition in an amount of about 3% w / w to about 5% w / w.

[0147] In some embodiments, the pharmaceutical composition further comprises microcrystalline cellulose. In some embodiments, microcrystalline cellulose is present in the composition in an amount of about 1% w / w to about 5% w / w. This includes about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% w / w, including increments therein, and a range (including endpoints) between two of these values. In some embodiments, microcrystalline cellulose is present in the composition in an amount of about 2% w / w to about 4% w / w.

[0148] In some embodiments, the pharmaceutical composition further comprises crospovidone. In some embodiments, crospovidone is present in the composition in an amount of about 1% w / w to about 10% w / w. This includes about 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10% w / w, including increments therein, and a range (including endpoints) between two of these values. In some embodiments, crospovidone is present in the composition in an amount of about 4% w / w to about 7% w / w.

[0149] In some embodiments, the pharmaceutical composition further comprises colloidal silica. In some embodiments, colloidal silica is present in the composition in an amount of about 0.5% w / w to about 5% w / w. This includes about 0.05, 0.10, 0.15, 0.20, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% w / w, including increments therein, and ranges (including endpoints) between two of these values. In some embodiments, colloidal silica is present in the composition in an amount of about 0.1% w / w to about 1% w / w. In some embodiments, colloidal silica is present in the composition in an amount of about 0.1% w / w to about 0.5% w / w.

[0150] In some embodiments, the pharmaceutical composition further comprises magnesium stearate. In some embodiments, magnesium stearate is present in the composition in an amount from about 0.1% w / w to about 5% w / w. This includes about 0.10, 0.15, 0.20, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, or 5% w / w, including increments therein, and ranges (including endpoints) between two of these values. In some embodiments, magnesium stearate is present in the composition in an amount from about 0.5% w / w to about 2% w / w.

[0151] In some embodiments, the pharmaceutical composition further comprises lactose, hydroxypropyl methylcellulose, crospovidone, microcrystalline cellulose, colloidal silica, or magnesium stearate, or any combination of two or more thereof. In some embodiments, the lactose is anhydrous lactose.

[0152] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, tartaric acid, lactose, hydroxypropyl methylcellulose, crospovidone, and magnesium stearate. In some embodiments, the composition comprises about 10 mg to about 1000 mg of the aforementioned N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 50 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 750 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 500 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 100 mg to about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg. The N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is present in mg. In some embodiments, the composition comprises about 10 mg to about 100 mg of tartaric acid. This comprises about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, and about 30 mg to about 60 mg.In some embodiments, tartaric acid is in the form of 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, 5 The amounts of 3, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg are present in the composition, including increments or ranges between two of these values ​​(inclusive).

[0153] In some embodiments, a pharmaceutical composition is provided comprising, consisting of, or primarily consisting of: N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, tartaric acid, lactose, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate. In some embodiments, the composition comprises about 10 mg to about 1000 mg of the aforementioned N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 50 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 750 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 500 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 100 mg to about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg. The N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is present in mg. In some embodiments, the composition comprises about 10 mg to about 100 mg of tartaric acid. This comprises about 10 mg to about 90 mg, about 10 mg to about 80 mg, about 10 mg to about 70 mg, about 10 mg to about 60 mg, about 20 mg to about 100 mg, about 20 mg to about 90 mg, about 20 mg to about 80 mg, about 20 mg to about 70 mg, about 20 mg to about 60 mg, about 30 mg to about 100 mg, about 30 mg to about 90 mg, about 30 mg to about 80 mg, about 30 mg to about 70 mg, and about 30 mg to about 60 mg.In some embodiments, tartaric acid is in the form of 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, 5 The amounts of 3, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 mg are present in the composition, including increments or ranges between two of these values ​​(inclusive).

[0154] In some embodiments, a pharmaceutical composition is provided comprising, consisting primarily of, or consisting of the following: about 20% w / w to about 60% w / w N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, about 5% w / w to about 20% w / w tartaric acid, about 15% w / w to about 35% w / w lactose, about 1% w / w to about 10% w / w hydroxypropyl methylcellulose, about 1% w / w to about 5% w / w microcrystalline cellulose, about 1% w / w to about 10% w / w crospovidone, about 0.05% w / w to about 5% w / w colloidal silica, and about 0.1% w / w to about 5% w / w magnesium stearate. In some embodiments, a pharmaceutical composition is provided comprising, consisting primarily of, or consisting of the following: about 40% w / w to about 50% w / w N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, about 10% w / w to about 15% w / w tartaric acid, about 25% w / w to about 30% w / w lactose, about 3% w / w to about 5% w / w hydroxypropyl methylcellulose, about 2% w / w to about 4% w / w microcrystalline cellulose, about 4% w / w to about 7% w / w crospovidone, about 0.1% w / w to about 1% w / w colloidal silica, and about 0.5% w / w to about 2% w / w magnesium stearate.

[0155] In some embodiments, the pharmaceutical composition comprises, is primarily composed of, or is composed of the following: N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, tartaric acid, anhydrous lactose, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate, wherein the composition is prepared in a method comprising, is primarily composed of, or is composed of:

[0156] N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; anhydrous lactose; hydroxypropyl methylcellulose; the granular portion of cross-linked polyvinylpyrrolidone; and tartaric acid are added together and blended to form a first blend;

[0157] The first blend is sieved to form a sieved first blend;

[0158] The first blend, after being sieved, is mixed to form the second blend;

[0159] The second blend is sieved to form a sieved second blend;

[0160] The second blend, after being sieved, is mixed to form a third blend;

[0161] Magnesium stearate particles are added to the third blend and mixed to form a fourth blend;

[0162] The fourth blend is compacted and ground to form the fifth blend;

[0163] Microcrystalline cellulose, the extragranular portion of crospovidone, and colloidal silica are added to the fifth blend and mixed to form the sixth blend; and

[0164] Magnesium stearate is added to the extraparticle portion of the sixth blend and mixed to form a pharmaceutical composition.

[0165] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, fumaric acid, mannitol, pregelatinized starch, colloidal silica, and magnesium stearate. In some embodiments, the composition comprises about 10 mg to about 1000 mg of the aforementioned N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 50 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 750 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 500 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 100 mg to about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg. mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0166] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, betaine hydrochloride, isomaltitol, pregelatinized starch, colloidal silica, and magnesium stearate. In some embodiments, the composition comprises about 10 mg to about 1000 mg of the aforementioned N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 50 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 1000 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 750 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 500 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 300 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 100 mg to about 250 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.In some embodiments, the composition comprises about 100 mg to about 200 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide. In some embodiments, the composition comprises about 25 mg, or about 50 mg, or about 75 mg, or about 100 mg, or about 125 mg, or about 150 mg, or about 175 mg, or about 200 mg, or about 225 mg, or about 250 mg, or about 275 mg, or about 300 mg, or about 325 mg, or about 350 mg, or about 375 mg, or about 400 mg, or about 475 mg, or about 500 mg, or about 525 mg, or about 550 mg, or about 575 mg, or about 600 mg, or about 625 mg, or about 650 mg, or about 700 mg, or about 750 mg, or about 800 mg, or about 850 mg, or about 900 mg, or about 950 mg, or about 1000 mg. mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0167] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein less than about 2% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the pharmaceutical composition is degraded after the pharmaceutical composition has been stored in an open container at 40°C and 75% relative humidity for 3 months.

[0168] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition contains more than about 98% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide after being stored in an open container at 40°C and 75% relative humidity for 3 months.

[0169] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein less than about 2% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the pharmaceutical composition is degraded after the pharmaceutical composition has been stored in an open container at 60°C and 75% relative humidity for 3 months.

[0170] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition contains more than about 98% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide after being stored in an open container at 60°C and 75% relative humidity for 3 months.

[0171] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile, wherein when used in a Type I USP basket method at 50 rpm in 500 mL of sodium acetate buffer at pH [value missing]. When tested at 4.5°C and about 37°C, at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule after about 60 minutes. In some embodiments, the pharmaceutical composition further comprises at least one acidifier.

[0172] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile, wherein when used in a Type I USP basket method at 50 rpm in 500 mL of sodium acetate buffer at pH [value missing]. When tested at 4.5°C and about 37°C, at least about 20%, at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 75% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule after about 45 minutes. In some embodiments, the pharmaceutical composition further comprises at least one acidifier.

[0173] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer at pH 4.5 and about 37°C, at about 30 minutes, at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule. In some embodiments, the pharmaceutical composition further comprises at least one acidifier.

[0174] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer at pH 4.5 and about 37°C, at least about 10%, or at least about 15%, or at least about 20% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule at about 15 minutes. In some embodiments, the pharmaceutical composition further comprises at least one acidifier.

[0175] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifying agent, and mannitol or isomaltitol. In some embodiments, a pharmaceutical composition comprising mannitol is provided. In some embodiments, a pharmaceutical composition comprising isomaltitol is provided.

[0176] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifying agent, mannitol or isomaltitol, and starch. In some embodiments, the weight ratio of the mannitol or isomaltitol to the starch in the pharmaceutical composition is about 1:1 to about 10:1, or about 1:1 to about 7:1, or about 1:1 to about 6:1, or about 1:1 to about 5:1, or about 1.5:1 to about 3:1, or about 1.75:1 to about 3:1, or about 1:1 to about 2.5:1, or about 1:1 to about 2:1.

[0177] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifying agent, mannitol or isomaltitol, and starch. In some embodiments, the weight ratio of the mannitol or isomaltitol to the starch in the pharmaceutical composition is about 10:1, or about 7:1, or about 6:1, or about 5:1, or about 4:1, or about 3:1, or about 2:1, or about 1.8:1, or about 1.5:1, or about 1:1.

[0178] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, at least one acidifying agent, and at least one pharmaceutically acceptable excipient. In some embodiments, a pharmaceutical composition is provided wherein the at least one pharmaceutically acceptable excipient is selected from diluents, lubricants, binders, disintegrants, foaming mixtures, dyes, sweeteners, and humectants.

[0179] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a fasting state when administered to the subject, wherein the Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 2 hours and 6 hours after administration of the pharmaceutical composition to the subject. In some embodiments, after administration of the pharmaceutical composition to the subject, the Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is about 5 hours.

[0180] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifier, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a feeding state when administered to the subject, wherein the Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 5 hours and 12 hours after administration of the pharmaceutical composition to the subject. In some embodiments, the Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject is about 8 hours after administration of the pharmaceutical composition to the subject.

[0181] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a fasting state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the Cmax of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 2080 nM and about 2110 nM after administration of the pharmaceutical composition to the subject.

[0182] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a fasting state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the Cmax of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between about 2080 nM and about 2560 nM after administration of the pharmaceutical composition to the subject.

[0183] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a fasting state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein, after administration of the pharmaceutical composition to the subject, the Cmax of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between 80% and 125% of 2080 nM, based on a 90% confidence interval.

[0184] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in an eating state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein, after administration of the pharmaceutical composition to the subject, the Cmax of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma is between 80% and 125% of 2560 nM, based on a 90% confidence interval.

[0185] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a fasting state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 28,900 nM×hr and about 30,800 nM×hr.

[0186] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a feeding state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is about 40,400 nM×hr.

[0187] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject in a fasting state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is within about 80% to about 125% of 30,800 nM × hr at a 90% confidence interval.

[0188] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein when at about 800 When the total dose of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide of mg is administered to a subject in a feeding state, the pharmaceutical composition provides a pharmacokinetic profile in the subject, wherein the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition to the subject is within about 80% to about 125% of 40,400 nM × hr at a 90% confidence interval.

[0189] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of the subject, the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at a Cmax between about 2080 nM and 2100 nM after administration of the pharmaceutical composition to the subject in a fasting state, and wherein the composition comprises about 800 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0190] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing about 2560 nM of the Cmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a feeding state after administration of the pharmaceutical composition to the subject, and wherein the composition comprises a total dose of about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0191] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state at an AUC (0 to 24) between about 28,900 nM×hr and about 30,800 nM×hr. The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0192] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing about 40,400 nM×hr of the AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a feeding state after administration of the pharmaceutical composition to the subject, and wherein the composition comprises about 800 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0193] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing a Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a fasting state between about 2 hours and about 6 hours.

[0194] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing the Tmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of a subject in a feeding state between about 5 hours and about 12 hours after administration of the pharmaceutical composition to the subject in a feeding state.

[0195] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject in a fasting state, between 80% and 125% (based on a 90% confidence interval) of the Cmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at 2080 nM, and wherein the composition comprises about 800 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0196] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject in a feeding state, between 80% and 125% (based on a 90% confidence interval) of the Cmax of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at 2560 nM, in the subject's plasma, and wherein the composition comprises about 800 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0197] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, in the plasma of a subject in a fasting state, between 80% and 125% (based on a 90% confidence interval) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide at an AUC (0 to 24) of 30,800 nM × hr. The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0198] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) a device for providing, after administration of the pharmaceutical composition to a subject in a feeding state, an AUC (0 to 24) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject at a concentration of 40,400 nM × hr (based on a 90% confidence interval), wherein the composition comprises about 800 The total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is given in mg.

[0199] In some embodiments, a pharmaceutical composition is provided comprising (a) N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; and (b) an apparatus for providing the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide to a subject who does not show an effect from oral intake.

[0200] In some embodiments, a pharmaceutical composition is provided comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the pharmaceutical composition does not show an ingestion effect when administered to a subject.

[0201] Those skilled in the art will understand that references such as "the pharmaceutical compositions provided herein" refer to the pharmaceutical compositions described herein by way of examples. For example only, the term "method of treating a cancerous subject by administering a pharmaceutical composition as provided herein" means a method of treating a cancerous subject by administering any of the compositions described herein, comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide.

[0202] In some embodiments, the pharmaceutical compositions provided herein are provided for use as medicines. In some embodiments, the medicine is used to treat abnormal cell growth in mammals. In some embodiments, the abnormal cell growth is cancer. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by one or more of ALK, ROS1, TrkA, TrkB, and TrkC. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of one or more of ALK, ROS1, TrkA, TrkB, and TrkC. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of ALK. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of ROS1. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of TrkA. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of TrkB. In some embodiments, the medicine is used to treat abnormal cell growth in mammals mediated by at least one molecular alteration of TrkC. In some such embodiments, the molecular alteration is an EML4-ALK fusion protein. In some embodiments, the molecular alteration is an EML4-ALK fusion protein having at least one mutation. In some embodiments, the mutation is L1196M. In some embodiments, the mutation is C1156Y.

[0203] In some embodiments, a method for treating abnormal cell growth in mammals is provided, comprising administering to the mammal a therapeutically effective amount of one or more pharmaceutical compositions provided herein. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of one or more of ALK, ROS1, TrkA, TrkB, and TrkC. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of ALK in mammals. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of ROS1 in mammals. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of TrkA in mammals. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of TrkB in mammals. In some embodiments, the abnormal cell growth is mediated by at least one molecular alteration of TrkC in mammals. In some such embodiments, the molecular alteration is an EML4-ALK fusion protein. In some embodiments, the molecular alteration is an EML4-ALK fusion protein having at least one mutation. In some embodiments, the mutation is L1196M. In some embodiments, the mutation is C1156Y.

[0204] In some embodiments, a method for treating abnormal cell growth in mammals is provided, comprising administering to the mammal a combination of one or more pharmaceutical compositions provided herein with a quantity of an antitumor agent, said quantities together effectively treating said abnormal cell growth. In some embodiments, the antitumor agent is selected from the group consisting of: mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modulators, antibodies, cytotoxins, antihormones, and antiandrogens.

[0205] In some embodiments, one or more pharmaceutical compositions provided herein are provided for treating abnormal cell growth in mammals. In another aspect, the use of one or more pharmaceutical compositions described herein for treating abnormal cell growth in mammals is disclosed.

[0206] In another aspect, the use of one or more pharmaceutical compositions described herein for the preparation of a medicament for treating abnormal cell growth is disclosed.

[0207] In common embodiments of the methods and uses described herein, abnormal cell growth is cancer. In some embodiments, the cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, head or neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) sarcoma, primary CNS lymphoma, spinal cord axis tumors, brainstem glioma, pituitary adenoma, and combinations thereof.

[0208] In some embodiments, the cancer is selected from the group consisting of: non-small cell lung cancer (NSCLC), squamous cell carcinoma, hormone-resistant prostate cancer, papillary renal cell carcinoma, colorectal adenocarcinoma, neuroblastoma, pleomorphic large cell lymphoma (ALCL), and gastric cancer.

[0209] In some embodiments, the method described herein further includes administering to a mammal a dose of an anticancer therapeutic agent or palliative agent, the dose of which together effectively treats the abnormal cell growth. In some such embodiments, one or more anticancer therapeutic agents are selected from antitumor agents, anti-angiogenic agents, signal transduction inhibitors, and antiproliferative agents, the dose of which together effectively treats the abnormal cell growth.

[0210] In other embodiments, the uses described herein include the use of one or more pharmaceutical compositions provided herein in combination with one or more substances selected from antitumor agents, antiangiogenic agents, signal transduction inhibitors and antiproliferative agents.

[0211] In some embodiments, the pharmaceutical compositions described herein are suitable for use in combination with one or more substances selected from antitumor agents, antiangiogenic agents, signal transduction inhibitors, and antiproliferative agents.

[0212] Each of the examples of pharmaceutical compositions provided herein may be combined with one or more other examples of pharmaceutical compositions described herein, which may not be consistent with the examples in which they are combined.

[0213] Additionally, each of the pharmaceutical compositions contemplated within the scope of the examples provided herein may comprise a pharmaceutically acceptable salt of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide or N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0214] In some embodiments, a method is provided for treating diseases caused by and / or associated with dysregulated protein kinase activity, particularly the PLK family, protein kinases C, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R, ALK, PI3K, Weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk / cyclin kinase family, more particularly Aurora 2, IGF-1R, and ALK activity, and ROS1 activity, and even more particularly ALK activity and / or ROS1 activity, said method comprising administering an effective amount of one or more pharmaceutical compositions provided herein to a mammal in need of it.

[0215] In some embodiments, methods are provided for treating diseases caused by and / or associated with dysregulated protein kinase activity, said diseases being selected from the group consisting of cancer and cell proliferation disorders.

[0216] In some embodiments, methods are provided for treating cancers including specific types such as: carcinoma, squamous cell carcinoma, bone marrow or lymphoid hematopoietic tumors, mesenchymal tumors, tumors of the central and peripheral nervous systems, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma, glioblastoma, cholangiocarcinoma, inflammatory myofibroblastoma, epithelioid angioendothelioma, astrocytoma, meningioma, angiosarcoma, epithelioid angioepithelial tumor, keratoacanthoma, follicular thyroid carcinoma, Kaposi's sarcoma, and pancreatic cancer.

[0217] In some embodiments, methods are provided for treating cancers such as (but not limited to) the following specific types: breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, invasive ductal carcinoma (breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, pancreatic cancer, neuroblastoma, and neurotubular cell tumor.

[0218] In some embodiments, methods are provided for treating ALK+ anaplastic large cell lymphoma (ALCL) and possibly other conditions in which ALK activity may play a role, such as neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory myofibroblastic tumors, and some types of melanoma, breast cancer, Ewing's sarcoma, retinoblastoma, and non-small cell lung cancer (NSCLC).

[0219] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence in the regulation of ROS1 activity in the conditions may play a role.

[0220] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence in the regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0221] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence in the regulation of ROS1 activity in the conditions may play a role.

[0222] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence in the regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0223] In some embodiments, methods are provided to treat, alleviate, improve, delay onset, or otherwise pharmacologically resolve pancreatic cancer associated with ROS1 downregulation (e.g., null mutations, such as ROS1 deletion) by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous pancreatic cells in a subject and administering one or more pharmaceutical compositions provided herein to the subject.

[0224] In some embodiments, methods are provided to treat, alleviate, improve, delay onset, or otherwise pharmacologically resolve pancreatic cancer associated with downregulation of ALK, ROS1, TrkA, TrkB, or TrkC by identifying downregulation defects (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletions) in cancerous or precancerous pancreatic cells in a subject and administering one or more pharmaceutical compositions provided herein to the subject.

[0225] In some embodiments, identifying ROS1 regulatory deficiencies, such as upregulation or downregulation, in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases) includes examining ROS1 activity in cells extracted from a population of cancerous or precancerous pancreatic cells.

[0226] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions.

[0227] In some embodiments, a method is provided to treat pancreatic cancer in a subject and other possible conditions of such subjects, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering one or more pharmaceutical compositions provided herein to the subject, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role in the condition.

[0228] In some embodiments, a method is provided to treat, alleviate, improve, delay, or otherwise pharmacologically resolve pancreatic cancer in a subject by identifying downregulation defects (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletions) in cancerous or precancerous pancreatic cells in the subject and administering one or more pharmaceutical compositions provided herein to the subject. The cancer is associated with downregulation defects (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletions).

[0229] In some embodiments, a method is provided to treat a subject’s condition, alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it by administering to a subject one or more pharmaceutical compositions provided herein, said condition being selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer and possibly other conditions, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0230] In some embodiments, a method is provided to treat a subject’s condition, alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it by administering to a subject one or more pharmaceutical compositions provided herein, said condition being selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer and possibly other conditions, wherein a deficiency in the regulation of ROS1, TrkA, TrkB, or TrkC activity or combinations thereof, or their activity, upregulation, misregulation, or absence, may play a role.

[0231] In some embodiments, methods are provided to treat a subject’s condition, alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it by identifying a ROS1 downregulation defect (e.g., null mutation, such as ROS1 deletion) in cancerous or precancerous cells in the subject and administering one or more pharmaceutical compositions provided herein to the subject. The condition is selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer, and the condition is associated with a ROS1 downregulation defect (e.g., null mutation, such as ROS1 deletion).

[0232] In some embodiments, a method is provided to treat a subject’s condition, alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it by identifying downregulation defects (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletions) in cancerous or precancerous cells in the subject and administering one or more pharmaceutical compositions provided herein to the subject. The condition is selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer associated with downregulation defects (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletions).

[0233] In some embodiments, methods are provided for treating cell proliferation disorders such as (but not limited to) the following: benign prostatic hyperplasia, familial gonadal hyperplasia polyposis, neurofibromatosis, psoriasis, atherosclerosis and conditions involving vascular smooth muscle proliferation or neointimal formation (such as angioplasty or postoperative restenosis), pulmonary fibrosis, arthritis, glomerulonephritis, retinopathy (including diabetic retinopathy and neonatal retinopathy and age-related macular degeneration), transplant vascular disease (such as that that may occur after vascular or organ transplantation), acromegaly and conditions secondary to acromegaly, as well as other hypertrophic conditions involving IGF / IGF-1R signaling, such as fibrotic lung disease, lesions associated with chronic or acute oxidative stress or hyperoxia-induced tissue damage, and metabolic disorders involving elevated IGF levels or IGF-1R activity (such as obesity).

[0234] In some embodiments, methods for influencing tumor angiogenesis and metastasis inhibition are provided.

[0235] In some embodiments, the methods provided herein further include a combination of radiotherapy or chemotherapy regimens on the desired mammal with at least one cell inhibitor or cytotoxic agent. In some embodiments, the methods provided herein further include inhibiting active ALK protein, which includes contacting the protein with an effective amount of one or more pharmaceutical compositions provided herein.

[0236] In some embodiments, this document provides a method for inhibiting the activity of at least one or a combination of ALK, ROS1, TrkA, TrkB, or TrkC kinases in cells, comprising contacting the cells with an effective amount of one or more pharmaceutical compositions provided herein.

[0237] In some embodiments, a pharmaceutical composition is provided, which includes one or more pharmaceutical compositions provided herein and a pharmaceutically acceptable excipient, carrier, or diluent.

[0238] Some embodiments provide a method for inhibiting the activity of ALK, ROS1, TrkA, TrkB, or TrkC, or combinations thereof, in a subject, comprising administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0239] Some embodiments provide a method of treating cancer in a subject of need, the method comprising inhibiting the activity of ALK, ROS1, TrkA, TrkB, or TrkC, or a combination thereof, in the subject by administering an effective amount of one or more pharmaceutical compositions provided herein to the subject.

[0240] Some embodiments provide methods for treating a subject with non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, or colorectal cancer, comprising administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0241] Some embodiments provide a method for treating a tumor in a subject, the method comprising administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0242] Some embodiments provide methods in which the tumor is caused by the presence of non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, or colorectal cancer in the subject. Some embodiments provide methods in which one or more tumor-containing cells in the subject test positive for a gene expressing at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases, or for the presence of one or more tumor-containing cells in the subject, confirming at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase activity.

[0243] Some embodiments provide methods in which one or more tumor cells in a subject are positive for at least one gene rearrangement test, including a fragment thereof, of a gene expressing at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide such methods in which cells are positive for at least one of ROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide methods in which cells are positive for ROS1 kinase. Some embodiments provide methods in which cells are positive for at least one of TrkA, TrkB, and TrkC kinases. Some embodiments provide methods in which cells are positive for TrkA kinase. Some embodiments provide methods in which cells are positive for TrkB kinase. Some embodiments provide such methods in which cells are positive for TrkC kinase.

[0244] Some embodiments provide a method of treating a subject with cancer, the method comprising: (1) testing one or more tumor-containing cells in a subject for the presence of at least one of ALK, ROS1, TrkA, TrkB or TrkC kinases; and (2) administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0245] Some embodiments provide a method of treating a subject with cancer, the method comprising: (1) testing one or more tumor-containing cells in the subject for the presence of at least one molecular alteration of ALK, ROS1, TrkA, TrkB or TrkC kinases; and (2) administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0246] Some embodiments provide a method of treating a subject with cancer, wherein one or more cancer cells in the subject express at least one of ROS1, TrkA, TrkB, or TrkC kinases, the method comprising administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0247] Some embodiments provide methods for treating subjects with cancer, wherein the tumor from the subject is positive for ROS1, TrkA, TrkB, or TrkC, or a combination thereof, the methods comprising administering to the subject an effective amount of one or more pharmaceutical compositions provided herein.

[0248] Some embodiments provide a method of treating a cancer subject, comprising (a) acquiring knowledge of the presence of at least one gene alteration in at least one target gene in the cancer subject, wherein the at least one target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; (b) selecting one or more pharmaceutical compositions provided herein as a treatment for the cancer subject based on identification that the pharmaceutical composition is effective in treating a cancer subject having the at least one gene alteration in the at least one target gene; and (c) administering a therapeutically effective amount of one or more of the pharmaceutical compositions to the cancer subject.

[0249] Some embodiments provide a method of treating a cancer subject, comprising administering to the cancer subject a therapeutically effective amount of one or more pharmaceutical compositions provided herein, wherein the cancer subject is known to have at least one gene alteration in at least one target gene selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3 prior to the administration of the one or more pharmaceutical compositions.

[0250] Some embodiments provide a method for treating a cancer subject, wherein the subject is known prior to the treatment to have at least one gene alteration in at least one target gene, the method comprising administering to the cancer subject a therapeutically effective amount of one or more pharmaceutical compositions provided herein, wherein the at least one target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0251] Some embodiments provide any of the methods described herein, wherein the subject has cancer selected from at least one of non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer.

[0252] In one embodiment, this document provides a method for treating a cancer subject, comprising (a) acquiring knowledge of the presence of one or more molecular alterations in a biological sample from the cancer subject, wherein the one or more molecular alterations are detected by a test including one or more antibodies binding to one or more ALK, ROS1, TrkA, TrkB, and TrkC biomarkers; (b) selecting a chemotherapeutic agent as treatment for the cancer subject, wherein the test detects the presence of one or more molecular alterations, and wherein the selected chemotherapeutic agent is one or more pharmaceutical compositions provided herein or a pharmaceutically acceptable salt thereof; and (c) administering a therapeutically effective amount of one or more of the selected chemotherapeutic agents to the cancer subject.

[0253] In another embodiment, this document provides a method for selecting cancer subjects predicted to respond to the administration of a therapeutic regimen, the method comprising (a) acquiring knowledge of the presence of one or more molecular alterations in a biological sample from the cancer subject, wherein the one or more molecular alterations are detected by a test comprising one or more antibodies binding to one or more ALK, ROS1, TrkA, TrkB, and TrkC biomarkers; and (b) selecting the subject as predicted to respond to the administration of the therapeutic regimen if one or more molecular alterations are detected in one or more biomarkers, or selecting the subject as predicted not to respond to the administration of the therapeutic regimen if one or more molecular alterations are not detected in the biomarkers. In the method according to this aspect of the invention, the therapeutic regimen comprises administering a therapeutically effective amount of one or more pharmaceutical compositions provided herein to the selected subject.

[0254] It should be understood that the actual dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide will vary depending on the specific formulation, route of administration, specific site, subject, and disease being treated. Given the experimental data on N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, those skilled in the art can determine the optimal dose for a given condition group using standard dosimetry testing. For oral administration, exemplary daily doses generally used will be from about 0.001 to about 1000 mg / kg, or from about 0.1 mg to about 1000 mg / kg body weight, repeated at appropriate intervals.

[0255] This amount will vary depending on a number of factors, including (but not limited to) the characteristics of the pharmaceutical compositions and formulations provided herein (including their activity, pharmacokinetics, pharmacodynamics, and bioavailability), the physiological condition of the subject being treated (including age, sex, disease type and stage, general physical condition, responsiveness to a given dose, and type of drug) or cells, the pharmaceutically acceptable loading mg / kg or the nature of the loading in the formulation, and the route of administration. Furthermore, the effective or therapeutically effective amount may vary depending on whether one or more of the pharmaceutical compositions provided herein are administered alone or in combination with other drugs, other therapies, or other therapeutic methods or modalities / pharmacological features. Those skilled in the art of clinical and pharmacology will be able to determine the effective or therapeutically effective amount through routine experiments, i.e., by monitoring the cellular or subject response to administration of one or more of the pharmaceutical compositions and formulations provided herein and adjusting the dosage accordingly.

[0256] In some embodiments, the dosage range of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide may be from about 0.1 mg / kg to about 100 mg / kg or more, depending on the factors mentioned above. In other alternatives, the dosage range may be from about 0.1 mg / kg to about 100 mg / kg; or from about 1 mg / kg to about 100 mg / kg; or from about 5 mg / kg to about 100 mg / kg. For topical application, such as for the treatment of various hair conditions according to some of the alternatives provided herein, a suitable dosage range may be from about 1 mg / kg to about 10 g / kg; or from about 10 mg / kg to about 1 g / kg; or from about 50 mg / kg to about 10 g / kg. Further guidance on this subject can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Univ. of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005.

[0257] Some embodiments include any of the methods described herein, wherein a subject is administered, in an amount comprising any pharmaceutical composition provided herein including N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide such that the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg / m². 2 Approximately 1600 mg / m 2 or approximately 200 mg / m 2 Approximately 1200 mg / m 2 or approximately 200 mg / m 2 Approximately 1000 mg / m 2 or approximately 400 mg / m 2 Approximately 1200 mg / m 2 or approximately 400 mg / m 2 Approximately 1000 mg / m 2 or approximately 800 mg / m 2 Approximately 1000 mg / m 2 or approximately 800 mg / m 2 Approximately 1200 mg / m 2 or approximately 800 mg / m 2 Approximately 1200 mg / m 2 or approximately 800 mg / m 2 Approximately 1600 mg / m 2 Within the range.

[0258] Some embodiments include any of the methods described herein, wherein a subject is administered with an amount of any pharmaceutical composition provided herein comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide such that the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg / m². 2 Approximately 300 mg / m 2 Approximately 400 mg / m 2 Approximately 500 mg / m 2 Approximately 600 mg / m 2 Approximately 700 mg / m 2 Approximately 800 mg / m2 Approximately 900 mg / m 2 Approximately 1000 mg / m 2 Approximately 1100 mg / m 2 Approximately 1200 mg / m 2 Approximately 1300 mg / m 2 Approximately 1400 mg / m 2 Approximately 1500 mg / m 2 Approximately 1600 mg / m 2 Approximately 1700 mg / m 2 Approximately 1800 mg / m 2 Approximately 1900 mg / m 2 Or approximately 2000 mg / m 2 In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg / m³. 2 Approximately 300 mg / m 2 Approximately 400 mg / m 2 Approximately 500 mg / m 2 Approximately 600 mg / m 2 In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg / m³. 2 In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 300 mg / m³. 2 In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 400 mg / m³. 2 In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 500 mg / m². 2In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 600 mg / m². 2 .

[0259] Some embodiments include any of the methods described herein, wherein a subject is administered an amount of any pharmaceutical composition provided herein comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide such that the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, or about 1500 mg. mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 200 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 300 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 400 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 500 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 600 mg.In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 700 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 800 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 900 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject is about 1000 mg.

[0260] Some embodiments include any of the methods described herein, wherein a subject is administered once daily with an amount of any pharmaceutical composition provided herein comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide such that the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject daily is about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, or about 1500 mg. mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject once daily is about 200 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject once daily is about 300 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide administered once daily to the subject is about 400 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide administered once daily to the subject is about 500 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide administered once daily to the subject is about 600 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received by the subject once daily is about 700 mg.In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received once daily by the subject is about 800 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received once daily by the subject is about 900 mg. In some embodiments, the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide received once daily by the subject is about 1000 mg.

[0261] Those skilled in the art will understand that, relative to the pharmaceutical compositions provided herein, including N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, the specific pharmaceutical composition, dosage, and amount of dosage to be administered daily to mammals requiring such treatment are all options within the knowledge of those skilled in the art and can be determined without excessive experimentation.

[0262] Therefore, while certain dosages and administration regimens are illustrated herein, they are by no means limited to the dosages and administration regimens that may be provided to subjects when implementing the methods disclosed herein.

[0263] It should be noted that dosage values ​​may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. It should be further understood that, for any particular subject, a specific dosage regimen should be adjusted over time based on the subject's needs and the professional judgment of the person administering or supervising the administration of the composition, and the dosage ranges set forth herein are merely exemplary and not intended to limit the scope or implementation of the claimed compositions. For example, dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxicity and / or laboratory values. The embodiments provided herein are intended to cover intra-subject dose escalation as determined by one of skill in the art. Determining appropriate dosages and regimens for administering chemotherapeutic agents is well known in the relevant art and, once the teachings provided herein are provided, are to be understood as being encompassed by one of skill in the art.

[0264] Implementations of the methods disclosed herein may include one or more of the following features. In some embodiments, one or more pharmaceutical compositions of selected chemotherapeutic agents are provided herein. In some embodiments, the test comprises one or more antibodies that bind to at least two of the biomarkers ALK, ROS1, TrkA, TrkB, and TrkC. In some embodiments, one or more molecular alterations detected in a biological sample involve at least two, at least three, or at least four biomarkers. In some embodiments, knowledge of the presence of one or more molecular alterations in a biological sample is obtained from a test comprising contacting the biological sample with one or more antibodies or fragments thereof that are specific to the biomarkers. In some embodiments, the specific antibody is a monoclonal antibody. In some embodiments, the specific antibody comprises at least one of D5F3®, D4D5®, C17F1®, and combinations thereof. In some embodiments, the biological sample is simultaneously contacted with one or more specific antibodies. In some embodiments, the biological sample is sequentially contacted with specific antibodies. In some embodiments, one or more molecular alterations cause an increase in the expression of one or more of the biomarkers ALK, ROS1, TrkA, TrkB, and TrkC. In some embodiments, knowledge of one or more molecular alterations is obtained from a test, wherein determining whether the expression of one or more biomarkers is elevated comprises: (a) determining the expression level of one or more biomarkers in a biological sample; and (b) comparing the determined expression level with a reference expression level. In some embodiments, knowledge of one or more molecular alterations is obtained from an antibody-based test. In some embodiments, the antibody-based test is selected from the group consisting of ELISA, immunohistochemistry, Western blotting, mass spectrometry, flow cytometry, protein microarray, immunofluorescence, and multiplex detection tests. In some embodiments, the antibody-based test includes immunohistochemical analysis.

[0265] In some embodiments, implementations of the methods provided herein further include, prior to the application step, obtaining knowledge of genetic alterations in the subject's cancer from a second analytical test, wherein the second analytical test is selected from the group consisting of: capillary electrophoresis, nucleic acid sequencing, peptide sequencing, restriction digestion, nucleic acid amplification-based tests, nucleic acid hybridization tests, comparative genomic hybridization, real-time PCR, quantitative reverse transcription PCR (qRT-PCR), PCR-RFLP tests, HPLC, mass spectrometry genotyping, fluorescence in situ hybridization (FISH), next-generation sequencing (NGS), and kinase activity tests. In some embodiments, the cancer is selected from the group consisting of: anaplastic large cell lymphoma (ALCL), colorectal cancer (CRC), cholangiocarcinoma, gastric cancer, glioblastoma (GBM), leiomyosarcoma, melanoma, non-small cell lung cancer (NSCLC), squamous cell lung cancer, neuroblastoma (NB), ovarian cancer, pancreatic cancer, prostate cancer, medullary thyroid carcinoma, breast cancer, and papillary thyroid carcinoma. In some embodiments, knowledge of one or more molecular alterations is obtained from tests performed simultaneously on multiple biological samples. In some embodiments, the plurality of biological samples comprises at least 6, 12, 24, 48, 96, 200, 384, 400, 500, 1000, 1500, or 3000 samples. In some embodiments, the one or more molecular alterations are selected from gene mutations, gene amplifications, gene rearrangements, single nucleotide variants (SNVs), deletions, insertions, insertion-deletion mutations, single nucleotide point mutations (SNPs), epigenetic alterations, splicing variants, RNA / protein overexpression, aberrant RNA / protein expression, and any combination thereof. In some embodiments, the one or more molecular alterations comprise the insertion of a heterologous nucleic acid sequence into the coding sequence of a biomarker gene. In some embodiments, the insertion forms a chimeric nucleic acid sequence encoding a fusion peptide. In some embodiments, obtaining knowledge of one or more molecular alterations further comprises identifying the nucleic acid sequence and / or amino acid sequence comprising one or more molecular alterations.

[0266] Some embodiments provide pharmaceutical compositions comprising one or more pharmaceutical compositions provided herein combined with one or more chemotherapeutic agents or radiotherapy, such as radiotherapy commonly administered to treat, improve symptoms of cancer, or prevent or delay the onset of cancer. Such agents may include (but are not limited to) antihormonal agents (such as antiestrogens, antiandrogens, and aromatase inhibitors), topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-targeting agents, platinum-based agents, alkylating agents, DNA-damaging or inserting agents, anti-hypertrophic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, kinin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyltransferase inhibitors, and hypoxia response inhibitors.

[0267] Some embodiments provide products or kits comprising one or more pharmaceutical compositions and one or more chemotherapeutic agents provided herein, as combination preparations for simultaneous, separate or sequential use in anticancer therapy.

[0268] Some embodiments provide one or more pharmaceutical compositions as provided herein for use as a medicine.

[0269] Some embodiments provide the use of one or more pharmaceutical compositions as provided herein for the manufacture of a drug having antitumor activity.

[0270] Some embodiments include any of the methods described herein, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer. Some embodiments are any of the methods described herein, wherein the cancer is non-small cell lung cancer. Some embodiments include any of the methods described herein, wherein the cancer is papillary thyroid carcinoma. Some embodiments include any of the methods described herein, wherein the cancer is neuroblastoma. Some embodiments include any of the methods described herein, wherein the cancer is pancreatic cancer. Some embodiments include any of the methods described herein, wherein the cancer is colorectal cancer.

[0271] Pharmaceutically acceptable carriers may include conventional drug carriers or excipients. Suitable drug carriers include inert diluents or fillers, flow aids, lubricants, water, and various organic solvents (such as hydrates and solvates). If desired, the pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, etc. Thus, for oral administration, tablets containing various excipients such as citric acid may be used with various disintegrants (such as starch, alginate, and certain complex silicates) and binders (such as sucrose, gelatin, and gum arabic). In some embodiments, the excipient includes pregelatinized starch. In some embodiments, the pharmaceutical composition includes a flow aid. In some embodiments, the pharmaceutical composition includes colloidal silica. Additionally, lubricants such as magnesium stearate, sodium dodecyl sulfate, and talc are commonly used for tableting purposes. Similar types of solid compositions may also be used in soft and hard-filled gelatin capsules. Thus, non-limiting examples of materials include lactose or milk sugar and high molecular weight polyethylene glycol.

[0272] For the treatment or prevention of diseases or conditions mediated by ALK, ROS1, TrkA, TrkB, or TrkC, or combinations thereof, the pharmaceutical compositions provided herein are administered by combining a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide with at least one acidifier. Optionally, such pharmaceutical compositions may include one or more pharmaceutically suitable carriers selected, for example, diluents, excipients, and adjuvants that facilitate the processing of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide into a final pharmaceutical formulation.

[0273] The drug carrier used can be solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, etc. Exemplary liquid carriers are syrup, peanut oil, olive oil, water, etc. Similarly, the compositions of the present invention may contain time-release or delayed-release materials known in the art, such as glyceryl monostearate or glyceryl distearate alone or in combination with waxes, ethyl cellulose, hydroxypropyl methylcellulose, methyl methacrylate, etc. Additional additives or excipients may be added to achieve desired formulation properties. For example, bioavailability enhancers (such as Labrasol, Gelucire, etc.) or formulations such as CMC (carboxymethyl cellulose), PG (propylene glycol), or PEG (polyethylene glycol) may be added. For example, Gelucire®, a semi-solid mediator that protects the active ingredient from light, moisture, and oxidation, may be added when preparing capsule formulations.

[0274] If a solid carrier is used, the formulation can be compressed into tablets, placed in hard gelatin capsules in powder or granule form, or formed into sugar-coated tablets or lozenges. The amount of solid carrier can vary, but will typically be from about 25 mg to about 1 g. If a liquid carrier is used, the formulation can be in the form of a sterile injectable solution or suspension or non-aqueous liquid suspension in syrup, emulsion, soft gelatin capsules, ampoules, or vials. If a semi-solid carrier is used, the formulation can be in the form of both hard and soft gelatin capsule formulations. The compositions of the present invention are prepared in unit dosage forms suitable for administration methods (e.g., oral or non-enteral).

[0275] To obtain a stable, water-soluble dosage form, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide can be dissolved in an aqueous solution of an organic or inorganic acid, such as 0.3 M succinic acid or citric acid. If a soluble salt form cannot be obtained, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide can be dissolved in a suitable co-solvent or combination of co-solvents. Examples of suitable co-solvents include ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, etc., with concentrations ranging from 0% to 60% of the total volume. In one exemplary embodiment, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is dissolved in DMSO and diluted with water. The pharmaceutical composition may also be in the form of a salt of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in a solution in a suitable aqueous medium (such as water, isotonic saline, or dextran solution).

[0276] The appropriate formulation depends on the chosen route of administration. For injection, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is preferably prepared as an aqueous solution in a physiologically compatible buffer (such as Hanks' solution, Ringer's solution, or physiological saline buffer). For mucosal administration, a penetrant suitable for the target permeation barrier is used in the formulation. Such penetrants are generally known in the art.

[0277] For oral administration, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide can be formulated by combining it with pharmaceutically acceptable carriers known in the art. These carriers enable N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide to be formulated as tablets, pills, sugar-coated pills, capsules, powders, granules, liquids, gels, syrups, liquids, suspensions, etc., for oral ingestion in treated subjects. Orally administered pharmaceutical formulations can be obtained by blending a solid excipient with N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, optionally grinding the resulting mixture, and, if necessary, processing the granule mixture after adding suitable excipients to obtain tablets or sugar-coated pill cores. Suitable excipients include: fillers, such as sugars including isomaltitol, lactose, sucrose, mannitol, or sorbitol; and cellulose formulations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, or polyvinylpyrrolidone (PVP). In some embodiments, the filler is mannitol, isomaltitol, hydroxypropyl methylcellulose, or microcrystalline cellulose. In some embodiments, the filler is mannitol. In some embodiments, the filler is isomaltitol. In some embodiments, the filler is microcrystalline cellulose. In some embodiments, the filler is lactose. In some embodiments, the filler is anhydrous lactose. If desired, a disintegrant such as cross-linked polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, may be added.

[0278] Sugar-coated pill cores have a suitable coating. For this purpose, a concentrated sugar solution can be used, which may optionally contain gum arabic, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments may be added to the coating of the tablet or sugar-coated pill.

[0279] Orally administered pharmaceutical formulations include push-fit capsules made of gelatin and soft-sealable capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Push-fit capsules may contain a mixture of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide with fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally, stabilizers. In soft capsules, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydropyran-4-ylamino)-benzamide may be dissolved or suspended in a suitable liquid, such as fatty oil, liquid paraffin, or liquid polyethylene glycol. Additionally, stabilizers may be added. All formulations for oral administration should be in a dosage suitable for such administration. For buccal administration, the composition may be in the form of tablets or lozenges prepared in a conventional manner.

[0280] The pharmaceutical compositions described herein are indicated for the treatment of cancers including (but not limited to) the following: circulatory system cancers, such as cardiac (sarcomas [angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma], myxoma, rhabdomyosarcoma, fibroma, lipoma, and teratoma), mediastinum and pleura, and other intrathoracic organs, vascular tumors, and tumor-associated vascular tissue; respiratory system cancers, such as nasal cavity and middle ear, sinuses, larynx, trachea, bronchi, and lungs (e.g., small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC)), bronchial carcinomas (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinomas, bronchial carcinomas, etc. Tracheal adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal system, such as esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), stomach, pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid, vasoactive intestinal peptide tumor), small intestine (adenocarcinoma, lymphoma, carcinoid, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villonoma, hamartoma, leiomyoma); genitourinary tract, such as kidney (adenocarcinoma, Wilms' tumor). Tumors (nephroblastoma, lymphoma, leukemia), bladder and / or urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testes (seminoblastoma, teratoma, embryonal carcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver, such as hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma, pancreatic endocrine tumors (such as pheochromocytoma, insulinoma, vasoactive intestinal peptide tumor, islet cell tumor and glucagonoma); bone, such as osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticular lymphoma). Cellular sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondroma), benign chondroma, chondroblastoma, chondromycinoid fibroma, osteoid osteoma and giant cell tumor; nervous system, such as central nervous system (CNS) lesions, primary CNS lymphoma, skull cancer (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, neuroblastoma, glioma, ependymoma, germ cell tumor [pineal tumor], glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), spinal neurofibroma, meningioma, glioma, sarcoma);The reproductive system, such as gynecology, uterus (endometrial cancer), cervix (cervical cancer, pretumoral cervical dysplasia), ovary (ovarian cancer [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa cell carcinoma, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tubes (canceromas) and other sites associated with the female reproductive organs; placenta, penis, prostate, testes and other sites associated with the male reproductive organs; the hematopoietic system, such as blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myeloproliferative disorders). Abnormal syndromes), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; oral cavity, such as lips, tongue, gums, floor of mouth, palate and other parts of the oral cavity, parotid glands and other parts of the salivary glands, tonsils, oropharynx, nasopharynx, pyriform fossa, hypopharynx, and other parts of the lips, oral cavity and pharynx; skin, such as malignant melanoma, cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, developmental nevus, lipoma, hemangioma, dermatofibroma and keloid; adrenal glands: neuroblastoma; and other tissues, including connective tissue and soft tissue, retroperitoneal space and peritoneum, eye, intraocular melanoma and adnexa, breast, head and / or neck, anal region, thyroid gland, parathyroid glands, adrenal glands and other endocrine glands and related structures, secondary and unspecified malignant lymph node vesicles, secondary malignant vesicles of the respiratory and digestive systems and other sites.

[0281] More specifically, when used in conjunction with the pharmaceutical compositions provided herein, examples of cancer include cancers selected from the following: lung cancer (NSCLC and SCLC), head or neck cancer, ovarian cancer, colon cancer, rectal cancer, prostate cancer, anal cancer, stomach cancer, breast cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) lesions, primary CNS lymphoma, non-Hodgkin's lymphoma, spinal cord axis tumors, or a combination of one or more of the aforementioned cancers.

[0282] In some embodiments, the pharmaceutical compositions provided herein are suitable for treating cancers including Spitz melanoma, perineural invasive cancer, large cell neuroendocrine carcinoma of the lung, uterine cancer, juvenile breast cancer, nasopharyngeal carcinoma, adenoid cystic carcinoma, myeloid thyroid carcinoma, salivary carcinoma, congenital infantile fibrosarcoma, mesodermal nephroma, esophageal squamous cell carcinoma, diffuse large B-cell lymphoma, papillary thyroid carcinoma, and mammary gland analogue secretory carcinoma.

[0283] In some embodiments, a method is provided for treating diseases caused by and / or associated with dysregulated protein kinase activity, particularly the PLK family, protein kinases C, Met, PAK-4, PAK-5, ZC-1, STLK-2, DDR-2, Aurora 1, Aurora 2, Bub-1, Chk1, Chk2, HER2, raf1, MEK1, MAPK, EGF-R, PDGF-R, FGF-R, FLT3, JAK2, IGF-R, ALK, PI3K, Weel kinase, Src, Abl, Akt, MAPK, ILK, MK-2, IKK-2, Cdc7, Nek, Cdk / cyclin kinase family, more particularly Aurora 2, IGF-1R, and ALK activity, and ROS1 activity, and even more particularly ALK activity and / or ROS1 activity, said method comprising administering an effective amount of one or more pharmaceutical compositions provided herein to a mammal in need of it.

[0284] In some embodiments, this document discloses treatment of diseases caused by and / or associated with dysregulated protein kinase activity, selected from the group consisting of cancers and cell proliferation disorders.

[0285] In some embodiments, methods are provided for treating cancers including the following specific types: carcinoma, squamous cell carcinoma, bone marrow or lymphoid hematopoietic tumors, mesenchymal tumors, tumors of the central and peripheral nervous systems, melanoma, seminoma, teratoma, osteosarcoma, xeroderma pigmentosum, angiosarcoma, glioblastoma, cholangiocarcinoma, inflammatory myofibroblastoma, epithelioid angioendothelioma, astrocytoma, meningioma, angiosarcoma, epithelioid angioepithelial tumor, keratoacanthoma, follicular thyroid carcinoma, Kaposi's sarcoma, and pancreatic cancer.

[0286] In some embodiments, methods are provided for treating cancers such as (but not limited to) the following specific types of cancer: breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, endometrial cancer, gastric cancer, clear cell renal cell carcinoma, invasive ductal carcinoma (breast), uveal melanoma, multiple myeloma, rhabdomyosarcoma, Ewing's sarcoma, Kaposi's sarcoma, pancreatic cancer, and neuroblastoma.

[0287] In some embodiments, methods are provided for treating ALK+ anaplastic large cell lymphoma (ALCL) and possibly other conditions in which ALK activity may play a role, such as neuroblastoma, rhabdomyosarcoma, glioblastoma, inflammatory myofibroblastic tumors, and some types of melanoma, breast cancer, Ewing's sarcoma, retinoblastoma, and non-small cell lung cancer (NSCLC).

[0288] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence in the regulation of ROS1 activity in the conditions may play a role.

[0289] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1 activity in the condition may be effective.

[0290] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering the pharmaceutical compositions provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions.

[0291] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1 activity in the condition may be effective. In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1 activity in the condition may be effective. In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1 activity in the condition may be effective.

[0292] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions.

[0293] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions. In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions by administering a pharmaceutical composition as provided herein, to alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it, in which a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0294] In some embodiments, methods are provided to treat pancreatic cancer associated with ROS1 downregulation (e.g., null mutations, such as ROS1 deletion) by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject, thereby alleviating, improving, delaying, or otherwise pharmacologically resolving the cancer. In some embodiments, methods are provided to treat, alleviate, improve, delay onset, or otherwise pharmacologically resolve pancreatic cancer associated with ROS1 downregulation (e.g., null mutations, such as ROS1 deletion) by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0295] In some embodiments, methods are provided to treat pancreatic cancer associated with downregulation of ALK, ROS1, TrkA, TrkB, or TrkC (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deficiency) by identifying downregulation defects of ALK, ROS1, TrkA, TrkB, or TrkC in cancerous or precancerous pancreatic cells in a subject, alleviating its symptoms, improving its symptoms, delaying its onset, or otherwise pharmacologically resolving it by identifying downregulation defects of ALK, ROS1, TrkA, TrkB, or TrkC (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deficiency) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0296] In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous pancreatic cells in a subject includes examining ROS1 activity in cells extracted from a population of cancerous or precancerous pancreatic cells. In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous pancreatic cells in a subject includes examining ROS1 transcript accumulation in an RNA population derived from a population of cancerous or precancerous pancreatic cells. In some embodiments, identifying ROS1 regulatory defects, such as up-regulation or down-regulation defects (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases) in cancerous or precancerous pancreatic cells in a subject includes identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) from cells or cell populations comprising cancerous or precancerous pancreatic cells.

[0297] In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining ALK, ROS1, TrkA, TrkB, or TrkC activity in cells extracted from a pancreatic cancerous or precancerous cell population. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining the accumulation of ALK, ROS1, TrkA, TrkB, or TrkC transcripts in RNA populations from cancerous or precancerous pancreatic cell populations. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC kinases, or chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) from cells or cell populations comprising cancerous or precancerous pancreatic cells.

[0298] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions.

[0299] In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions, alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the treatment of these conditions. In some embodiments, methods are provided to treat pancreatic cancer and possibly other conditions by administering a pharmaceutical composition as provided herein, to alleviate its symptoms, improve its symptoms, delay its onset, or otherwise pharmacologically resolve it, in which a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0300] In some embodiments, methods are provided to treat pancreatic cancer associated with ROS1 downregulation (e.g., null mutations, such as ROS1 deletion) by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject, thereby alleviating, improving, delaying, or otherwise pharmacologically resolving the cancer. In some embodiments, methods are provided to treat, alleviate, improve, delay onset, or otherwise pharmacologically resolve pancreatic cancer associated with ROS1 downregulation (e.g., null mutations, such as ROS1 deletion) by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0301] In some embodiments, methods are provided to treat pancreatic cancer associated with downregulation of ALK, ROS1, TrkA, TrkB, or TrkC (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deficiency) by identifying downregulation defects of ALK, ROS1, TrkA, TrkB, or TrkC in cancerous or precancerous pancreatic cells in a subject, alleviating its symptoms, improving its symptoms, delaying its onset, or otherwise pharmacologically resolving it by identifying downregulation defects of ALK, ROS1, TrkA, TrkB, or TrkC (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deficiency) in cancerous or precancerous pancreatic cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0302] In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous pancreatic cells in a subject includes examining ROS1 activity in cells extracted from a population of cancerous or precancerous pancreatic cells. In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous pancreatic cells in a subject includes examining ROS1 transcript accumulation in an RNA population derived from a population of cancerous or precancerous pancreatic cells. In some embodiments, identifying ROS1 regulatory defects, such as up-regulation or down-regulation defects (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases) in cancerous or precancerous pancreatic cells in a subject includes identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) from cells or cell populations comprising cancerous or precancerous pancreatic cells.

[0303] In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining ALK, ROS1, TrkA, TrkB, or TrkC activity in cells extracted from a pancreatic cancerous or precancerous cell population. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining the accumulation of ALK, ROS1, TrkA, TrkB, or TrkC transcripts in RNA populations from cancerous or precancerous pancreatic cell populations. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC kinases, or chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) from cells or cell populations comprising cancerous or precancerous pancreatic cells.

[0304] In some embodiments, methods are provided to treat conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer, and possible other conditions, by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in these conditions. In some embodiments, methods are provided to treat pancreatic cancer and possible other conditions, by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, or their activity, upregulation, misregulation, or absence, may be effective in these conditions.

[0305] In some embodiments, methods are provided to treat conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer, and possible other conditions, by administering a pharmaceutical composition as provided herein, to alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them, wherein a deficiency, activity, or upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the condition. In some embodiments, methods are provided to treat conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer, and possible other conditions, by administering a pharmaceutical composition as provided herein, to alleviate their symptoms, improve their symptoms, delay their onset, or otherwise pharmacologically resolve them, wherein a deficiency, activity, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, may be effective in the condition. In some embodiments, methods are provided to treat, alleviate, improve, delay onset, or otherwise pharmacologically resolve conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer by administering a pharmaceutical composition as provided herein, wherein a deficiency, upregulation, misregulation, or absence of regulation of ROS1, TrkA, TrkB, or TrkC activity or combinations thereof may play a role.

[0306] In some embodiments, methods are provided to treat, alleviate, improve, delay, or otherwise pharmacologically resolve conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer by identifying ROS1 downregulation deficiencies (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous cells in a subject and administering a pharmaceutical composition as provided herein to the subject. In some embodiments, methods are provided to treat, alleviate, improve, delay, or otherwise pharmacologically resolve conditions selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer by identifying ROS1 downregulation defects (e.g., null mutations, such as ROS1 deletion) in cancerous or precancerous cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0307] In some embodiments, a method is provided to treat, alleviate, improve, delay, or otherwise pharmacologically resolve a condition selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer by identifying downregulation defects of ALK, ROS1, TrkA, TrkB, or TrkC (e.g., null mutations such as ALK, ROS1, TrkA, TrkB, or TrkC deletion) in cancerous or precancerous cells in a subject and administering a pharmaceutical composition as provided herein to the subject.

[0308] In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous cells in a subject includes examining ROS1 activity in cells extracted from a pancreatic cancerous or precancerous cell population. In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous cells in a subject includes examining ROS1 transcript accumulation in an RNA population derived from a cancerous or precancerous cell population. In some embodiments, identifying ROS1 regulatory deficiencies, such as up-regulation or down-regulation deficiencies (e.g., null mutations, such as ROS1 deletion or ROS1 chimeric loci encoding constitutively active ROS1 kinases), in cancerous or precancerous cells in a subject includes identifying nucleic acid sequences (e.g., genomic deoxyribonucleic acid sequences) in cells derived from a pancreatic cancerous or precancerous cell population or in a cell population comprising said cells.

[0309] In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancer or precancerous cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining ALK, ROS1, TrkA, TrkB, or TrkC activity in cells extracted from cancerous or precancerous cell populations. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes examining the accumulation of ALK, ROS1, TrkA, TrkB, or TrkC transcripts in RNA populations from cancerous or precancerous cell populations. In some embodiments, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC kinases, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) includes identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) in cells from a cancerous or precancerous cell population or in a cell population comprising said cells.

[0310] In some embodiments, a method is provided for inhibiting the activity of at least one or a combination of ALK, ROS1, TrkA, TrkB, or TrkC kinases in cells, the method comprising contacting the cells with an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide. Some embodiments provide a method for inhibiting the activity of at least one or a combination of ALK, ROS1, TrkA, TrkB, or TrkC kinases in cells by contacting cells with an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide. Some embodiments provide a method for inhibiting the activity of at least one or a combination of ALK, ROS1, TrkA, TrkB, or TrkC kinases in cells, said method comprising contacting said cells with an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide. In some embodiments, N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide is delivered to the cells in the form of a pharmaceutical composition as provided herein.

[0311] Some embodiments provide methods for inhibiting the activity of ALK, ROS1, TrkA, TrkB, or TrkC, or combinations thereof, in a subject, the methods comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0312] Some embodiments provide methods for treating cancer in a subject of need, the methods comprising inhibiting the subject's ALK, ROS1, TrkA, TrkB, or TrkC activity, or combinations thereof, by administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0313] Some embodiments provide methods for treating a subject with non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, or colorectal cancer, said methods comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0314] Some embodiments provide a method of treating a subject's tumor, the method comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0315] Some embodiments provide methods in which the tumor is caused by the presence of non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, or colorectal cancer in the subject. Some embodiments provide methods in which one or more tumor-containing cells in the subject test positive for a gene expressing at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases, or for the presence of one or more tumor-containing cells in the subject, confirming at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinase activity.

[0316] Some embodiments provide methods in which one or more tumor cells in a subject are positive for at least one gene rearrangement test, including a fragment thereof, of a gene expressing at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide such methods in which cells are positive for at least one of ROS1, TrkA, TrkB, or TrkC kinases. Some embodiments provide methods in which cells are positive for ROS1 kinase. Some embodiments provide methods in which cells are positive for at least one of TrkA, TrkB, and TrkC kinases. Some embodiments provide methods in which cells are positive for TrkA kinase. Some embodiments provide methods in which cells are positive for TrkB kinase. Some embodiments provide such methods in which cells are positive for TrkC kinase.

[0317] Some embodiments provide a method of treating a subject with cancer, the method comprising: (1) testing one or more tumor-containing cells in the subject for the presence of at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases; and (2) if the one or more cells are positive for at least one of ALK, ROS1, TrkA, TrkB, or TrkC kinases, administering to the subject a pharmaceutical composition as provided herein comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0318] Some embodiments provide a method of treating a subject with cancer, the method comprising: (1) testing one or more tumor-containing cells in a subject for the presence of at least one of ROS1, TrkA, TrkB, or TrkC kinases; and (2) if the one or more cells are positive for at least one of ROS1, TrkA, TrkB, or TrkC kinases, administering to the subject a pharmaceutical formulation as provided herein comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0319] Some embodiments provide a method of treating a subject's cancer, wherein one or more cancer cells of the subject express at least one of ROS1, TrkA, TrkB, or TrkC kinases, the method comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0320] Some embodiments provide a method of treating a subject's cancer, wherein one or more cancer cells of the subject express at least one of ROS1, TrkA, TrkB, or TrkC kinases, the method comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0321] Some embodiments provide methods for treating subjects with cancer, wherein the tumor from the subject is ALK, ROS1, TrkA, TrkB, or TrkC positive or a combination thereof, the methods comprising administering to the subject a pharmaceutical composition as provided herein comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0322] Some embodiments provide methods for treating subjects with ALK, ROS1, TrkA, TrkB, or TrkC positive cancers, the methods comprising administering to the subject a pharmaceutical composition, as provided herein, comprising an effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0323] Some embodiments provide a method for treating a cancer subject, the method comprising (a) acquiring knowledge of the presence of at least one gene alteration in at least one target gene of the cancer subject, wherein the at least one target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; and (b) administering to the cancer subject a pharmaceutical composition as provided herein, the pharmaceutical composition comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0324] Some embodiments provide a method for treating a cancer subject, the method comprising administering to the cancer subject a pharmaceutical composition, as provided herein, comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, wherein prior to the administration of the pharmaceutical composition, the cancer subject is known to have at least one genetic alteration selected from at least one target gene selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0325] Some embodiments provide a method of treating a subject with cancer, the method comprising administering to the cancer subject a pharmaceutical composition, as provided herein, comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, wherein the cancer subject is known to have at least one genetic alteration selected from at least one target gene of ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0326] Some embodiments provide a method for treating a cancer subject, wherein the subject is known to have at least one gene alteration in at least one target gene, the method comprising administering to the cancer subject a pharmaceutical composition comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, wherein the target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0327] Some embodiments provide a method for treating a cancer subject, wherein prior to the treatment, the subject is known to have at least one genetic alteration in at least one target gene, the method comprising administering to the cancer subject a pharmaceutical composition, as provided herein, comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, wherein the target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0328] Some embodiments provide a method for treating a cancer subject, the method comprising administering to the cancer subject a pharmaceutical composition, as provided herein, comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide, and wherein, prior to administering the pharmaceutical composition to the subject, the subject is known to have at least one genetic alteration selected from at least one target gene chosen from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3.

[0329] Some embodiments provide methods for treating cancer subjects, the methods comprising (a) acquiring knowledge of the presence of at least one gene alteration selected from at least one target gene of ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3; and (b) administering to the subject a pharmaceutical composition as provided herein comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide.

[0330] Some embodiments provide any of the methods described herein, wherein the subject has cancer selected from at least one of non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer. Some embodiments provide any of the methods described herein, wherein the subject has non-small cell lung cancer. Some embodiments provide any of the methods described herein, wherein the subject has papillary thyroid carcinoma. Some embodiments provide any of the methods described herein, wherein the subject has neuroblastoma. Some embodiments provide any of the methods described herein, wherein the subject has pancreatic cancer. Some embodiments provide any of the methods described herein, wherein the subject has colorectal cancer.

[0331] In some embodiments, the pharmaceutical compositions provided herein may be used in combination with one or more additional anticancer agents described below. When using combination therapy, one or more additional anticancer agents may be administered sequentially or concurrently with the pharmaceutical compositions provided herein. In some embodiments, the additional anticancer agent is administered to a mammal (e.g., a human) prior to administration of the pharmaceutical compositions provided herein. In some embodiments, the additional anticancer agent is administered to a mammal (e.g., a human) after administration of the pharmaceutical compositions provided herein. In some embodiments, the additional anticancer agent is administered to a mammal (e.g., a human) concurrently with administration of the pharmaceutical compositions provided herein.

[0332] Some embodiments also relate to pharmaceutical compositions for treating abnormal cell growth in mammals, including humans, comprising an amount of one or more pharmaceutical compositions provided herein, said one or more pharmaceutical compositions comprising a hydrate, solvate, and polymorph of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in combination with one or more (preferably one to three) anticancer agents (selected from the group consisting of anti-angiogenic agents and signal transduction inhibitors) and a pharmaceutically acceptable carrier, wherein the amount of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the combined anticancer agents is considered as a whole for therapeutic efficacy in treating said abnormal cell growth.

[0333] In some embodiments, the anticancer agent used in combination with the pharmaceutical compositions described herein is an antiangiogenic agent (e.g., an agent that prevents tumors from developing new blood vessels). Examples of antiangiogenic agents include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKC-β inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred antiangiogenic agents include sunitinib (Sutent®), bevacizumab (Avastin®), axitinib (AG 13736), SU 14813 (Pfizer) and AG 13958 (Pfizer).

[0334] Other anti-angiogenic agents include vtalanib (CGP 79787), sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE 941), tetrathiomolybdata (Coprexa®), AMG 706 (Amgen), VEGF Trap (AVE0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 57-9352), and CP-868,596 (Pfizer).

[0335] Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex®), and UCN 01 (Kyowa Hakko).

[0336] Other examples of antiangiogenic agents that can be used in combination with one or more pharmaceutical compositions described herein include celecoxib (Celebrex®), parecoxib (Dynastat®), deracoxib (SC 59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia®).

[0337] Other anti-angiogenic agents include exisulind (Aptosyn®), salsalate (Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen (Orudis®), nabumetone (Relafen®), piroxicam (Feldene®), naproxen (Aleve®, Naprosyn®), diclofenac (Voltaren®), indomethacin (Indocin®), sulindac (Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac (Toradol®), and oxaprozin (Daypro®).

[0338] Other anti-angiogenic agents include ABT 510 (Abbott), apratastat (TMI 005), AZD8955 (AstraZeneca), incyclinide (Metastat®), and PCK 3145 (Procyon).

[0339] Other anti-angiogenic agents include atratin (Neotigason®), plitidepsin (Aplidine®), cilengtide (EMD 121974), comprbetastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin®), Panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab®), lenalidomide (Revlimid®), squalene (EVIZON®), thalidomide (Thalomid®), Ukrain® (NSC 631570), and Vitaxin® (MEDI). 522) and zoledronic acid (Zometa®).

[0340] In some embodiments, the anticancer agent is a so-called signal transduction inhibitor (e.g., an inhibitory mechanism by which regulatory molecules govern fundamental processes of cell growth, differentiation, and intracellular survival). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, ALK inhibitors, ROS1 inhibitors, TrkA inhibitors, TrkB inhibitors, TrkC inhibitors, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multi-target kinase inhibitors.

[0341] Preferred signal transduction inhibitors include gefitinib (Iressa®), cetuximab (Erbitux®), erlotinib (Tarceva®), trastuzumab (Herceptin®), sunitinib (Sutent®), imatinib (Gleevec®), and PD325901 (Pfizer).

[0342] Other examples of signal transduction inhibitors that can be used in combination with one or more of the pharmaceutical compositions provided herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar®), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), vandetanib (Zactima®), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene® (TP 38).

[0343] Other examples of signal transduction inhibitors include PF-2341066 (Pfizer), PF-299804 (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg®), lapatinib (Tycerb®), pelitinib (EKB 569), miltefosine (Miltefosin®), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge®), NeuVax® (E75 cancer vaccine), and Osidem® (IDM). 1) mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix®), lapatinib (Tycerb®), PF-299804 (Pfizer), pelitinib (EKB 569), and pertuzumab (Omnitarg®).

[0344] Other examples of signal transduction inhibitors include ARRY 142886 (Array Biopharm), everolimus (Certican®), zotarolimus (Endeavor®), temsirolimus (Torisel®), AP 23573 (ARIAD), and VX 680 (Vertex).

[0345] Other signal transduction inhibitors include XL 647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (GlobeImmune).

[0346] Other signal transduction inhibitors include ABT 751 (Abbott), avocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (One Bio), BMS 387032 (Bristol-Myers Squibb), PD 0332991 (Pfizer), AG 024322 (Pfizer), LOXO-101 (Loxo Oncology), crizotinib, and ceritinib.

[0347] In some embodiments, the pharmaceutical compositions provided herein are used in conjunction with classic anti-hypertrophic agents. Classic anti-hypertrophic agents include (but are not limited to) hormone modulators such as hormones, anti-hormones, androgen agonists, androgen antagonists and anti-estrogen therapies, histone deacetylase (HDAC) inhibitors, gene silencing or gene activating agents, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors, tubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.

[0348] Examples of classic anti-hypertrophic agents used in combination therapy with one or more pharmaceutical compositions provided herein, or optionally with one or more other agents, include (but are not limited to) glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, and hydrocortisone; and progestins such as medroxyprogesterone and megestrol acetate. Acetate (Megace), mifepristone (RU-486); selective estrogen receptor modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afimoxifen, azoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi)); selective estrogen receptor downregulators (SERDs; such as fulvestrant and exemestane). Aromasin, anastrozole, arimidex, atamestane, fadrozole, letrozole, and Femara; gonadotropin-releasing hormone (GnRH);Commonly known as luteinizing hormone-releasing hormone (LHRH) agonists, such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), triptorelin (Trelstar), abalexix (Plenaxis), bicalutamide (Casodex), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), osaterone, dutasteride, epristeride, finasteride, saw palmetto extract (Serenoa repens), and PHL. 00801. Abarelix, Goserelin, Leuprorelin, Triptorelin, Bicalutamide, Tamoxifen, Exemestane, Anastrozole, Faldrozole, Formestane, Letrozole, and combinations thereof.

[0349] Other examples of classic anti-hypertrophic agents used in combination with the pharmaceutical compositions provided herein include (but are not limited to) succinyl aniline oxime acid (SAHA, Merck Inc. / Aton Pharmaceuticals), peptides (FR901228 or FK228), G2M-777, MS-275, tervastatin butyrate and PXD-101; onconase / ranpirnase, PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecone, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl. HCl (Camptosar), lurtotecan, rubitecan (Orathecin / rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edocaline, topotecan, aclarubicin, paclitaxel, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin icin), etoposide, idarubicin, galarubicin, hydroxyurea, nemorubicin, novantrone (mitoxantrone), pirarubicin, pixantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard (N-oxide)N-oxide), cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactalol, mitomycin C C), mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkyl compounds such as cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, oxaliplatin (Sanofi), streptozocin, satraplatin, and combinations thereof.

[0350] In some embodiments, the pharmaceutical compositions provided herein are used in conjunction with the following: dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetrexate)), purine antagonists (such as 6-mercaptopurine nucleoside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed)), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosine arabinoside, Gemzar® (gemcitabine, Eli Lilly), and tegafur (UFT)). Orzel or Uforal containing TS-1 combinations of nifedipine, gimestat, and otostat; deoxyfluorouridine; carmofur; cytarabine (containing oxaphosphonate, stearate phosphate, sustained-release and liposomal forms); enocitabine; 5-azacitidine (Vidaza); decitabine (and ethynylcytidine) and other antimetabolites such as efornithine, hydroxyurea, formyltetrahydrofolate, noratrilate (Thymitaq), 3-aminopyridine-2-carboxaldehyde thiocarbamate (triapine), trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazoline-6-ylmethyl)-N-methylamino]-2-thienocarbamoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm Inc.) and combinations thereof.

[0351] Other examples of classic anti-proliferative cytotoxic agents for combination therapy with one or more pharmaceutical compositions provided herein, or optionally with one or more other agents, include (but are not limited to) Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), and Actinomycin D. D), Bleomycin, Mitomycin C, Neocarzinostatin (Zinostatin), Vinblastine, Vincristine, Vindesine, Vinorelbine (Navelbine), Docetaxel (Taxotere), Ortataxel, Paclitaxel (including Taxoprexin and DHA / Paclitaxel conjugates), Cisplatin, Carboplatin, Nedaplatin, Eloxatin, Satraplatin, Captopril, Xeloda (Xeloda), Eloxatin, Taxotere alitretinoin, canfosfamide (Telcyta®), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar®), Efaproxiral (Efaproxyn® - for radiotherapy), bexarotene (Targretin®), temilifene (DPPE for cytotoxicity - for enhanced efficacy), Theratope® (Biomira), tretinoin (Vesanoid®), tirapazamine (Trizaone®), motexafingadolinium (Xcytrin®), Cotara® (mAb), and NBI-3001 (protoporphyrinogen oxidase therapy), polyglutamate-paclitaxel (Xyotax®), and combinations thereof.

[0352] Other examples of classic anti-proliferative cytotoxic agents for combination therapy with one or more pharmaceutical compositions provided herein, or optionally with one or more other agents, include (but are not limited to) Advexin (ING 201), TNFerade (GeneVec, one or more compounds expressing TNFα in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), and Pravastatin (Pravachol, Bristol-Myers Squibb). Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovastatin, Niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Torcetrapib, and combinations thereof.

[0353] Some embodiments relate to methods for treating breast cancer in humans who require such treatment. In some embodiments, the method comprises, for example, administering to the human a combination of one or more pharmaceutical compositions provided herein with one or more (preferably one to three) anticancer agents selected from the group consisting of trastuzumab, tamoxifen, docetaxel, paclitaxel, capecitabine, gemcitabine, vinorelbine, exemestane, letrozole, and anastrozole.

[0354] Some embodiments provide a method for treating colorectal cancer in mammals (such as humans) requiring such treatment by administering a combination of one or more pharmaceutical compositions provided herein with one or more (preferably one to three) anticancer agents. Examples of specific anticancer agents include those commonly used as adjuvant chemotherapy, such as FOLFOX, 5-fluorouracil (5-FU) or capecitabine (Xeloda), leucovorin, and oxaliplatin / Eloxatin. Further examples of specific anticancer agents include those commonly used as chemotherapy for metastatic disease, such as FOLFOX or a combination of FOLFOX and bevacizumab (Avastin); and a combination of FOLFIRI, 5-FU or capecitabine, leucovorin, and irinotecan (Captopril). Other examples include 17-DMAG, ABX-EFR, AMG-706, AMT-2003, ANX-510 (CoFactor), aplidine (plitidepsin, aplidin), aroplatin, axitinib (AG-13736), AZD-0530, AZD-2171, Bacillus Calmette-Guerin (BCG), bevacizumab (Avastin), BIO-117, BIO-145, BMS-184476, BMS-275183, BMS-528664, bortezomib (Velcade), C-1311 (Symadex), and cantuzumab (metazidine). Mertansine, capecitabine (Xeloda), cetuximab (Erbitux), clofarabine (Clofarex), CMD-193, cobretastatin, cotara, CT-2106, CV-247, decitabine (Dacogen), E-7070, E-7820, edocaline, EMD-273066, enzatolin (LY-317615), epothilone B)(EPO-906), erlotinib (Tarceva), flavopyridol, GCAN-101, gefitinib (Iressa), huA33, huC242-DM4, imatinib (Gleevec), indisolan, ING-1, irinotecan (CPT-11),Captopril ISIS 2503, Ixabepilone, Lapatinib (Tykerb), Mapatumumab (HGS-ETR1), MBT-0206, MEDI-522 (Abregrin), Mitomycin C, MK-0457 (VX-680), MLN-8054, NB-1011, NGR-TNF, NV-1020, Genasense (G3139), OncoVex, ONYX 015 (CI-1042), Oxaliplatin, Panitumumab (ABX-EGF, Vectibix), Peritolinib (EKB-569), Pemetrexed (Alimta), PD-325901, PF-0337210, PF-2341066, RAD-001 (everolimus), RAV-12, Resveratrol, Rexin-G, S-1 (TS-1), Celixib, SN-38 liposome, Sodium gluconate (SSG), Sorafenib (Nexavar), SU-14813, Sunitinib (Sutent), Tamsulosinib (CCI) 779), tetrathiomolybdate, thalomide, TLK-286 (Telcyta), topotecan (Hycamtin), trabectedin (Yondelis), vantalanib (PTK-787), vorinostat (SAHA, Zolinza), WX-UK1, and ZYC300, in which the active agents, together with the combined anticancer agents, are effective in treating colorectal cancer.

[0355] Some embodiments provide a method for treating renal cell carcinoma in humans requiring such treatment, the method comprising administering to the human a combination of a pharmaceutical composition provided herein with one or more (preferably one to three) anticancer agents selected from the group consisting of capecitabine (Xeloda), interferon-alpha, interleukin-2, bevacizumab (Avastin), gemcitabine (Gemzar), thalidomide, cetuximab (Erbitux), vantalanib (PTK-787), sucralfate, AG-13736, SU-11248, erlotinib, gefitinib, lapatinib, and imatinib, wherein the amount of active agent, together with the amount of combined anticancer agents, is effective in treating renal cell carcinoma.

[0356] Some embodiments provide a method for treating melanoma in humans requiring such treatment, the method comprising administering to the human a combination of a pharmaceutical composition provided herein with one or more (preferably one to three) anticancer agents selected from the group consisting of interferon-alpha, interleukin-2, temozolomide (Termodol), docetaxel (Crizotinib), paclitaxel, dacarbazine (DTIC), carmustine (also known as BCNU), cisplatin, vincristine, tamoxifen, PD-325,901, axitinib, bevacizumab (Avastin), thalidomide, sorafenib, vantalanib (PTK-787), sucralfate, CpG-7909, AG-13736, gefitinib, lapatinib, and imatinib, wherein the amount of the pharmaceutical composition provided herein, together with the amount of the combined anticancer agents, is effective in treating melanoma.

[0357] Some embodiments provide a method for treating lung cancer in humans requiring such treatment, the method comprising administering to the human an amount of one or more pharmaceutical compositions provided herein combined with one or more (preferably one to three) anticancer agents selected from the group consisting of capecitabine (Xeloda), bevacizumab (Avastin), gemcitabine (Gemzar), docetaxel (Carefree), paclitaxel, pemetrexed disodium (Alimta), erlotinib, gefitinib, irinotecan, etoposide, vinblastine, and carboplatin, wherein the amount of the active agent described herein, together with the amount of the combined anticancer agents, is effective in treating lung cancer.

[0358] The presence of at least one gene alteration in at least one target gene in a cancer subject can be detected using a test comprising one or more antibodies that bind to at least two, three, four, or all of the biomarkers ALK, ROS1, TrkA, TrkB, and TrkC, wherein the at least one target gene is selected from ALK1, BDNF, NGF, NGFR, NTF3, NTF4, ROS1, SORT1, NTRK1, NTRK2, and NTRK3. One or more molecular alterations detected in a biological sample may involve at least two, three, or four biomarkers. Knowledge of the presence of one or more molecular alterations in a biological sample is obtained from a test comprising contacting the biological sample with one or more antibodies or fragments thereof that are specific to the biomarker. In some cases, the specific antibody is a monoclonal antibody. In some cases, the specific antibody comprises at least one of D5F3®, D4D5®, C17F1®, and combinations thereof. In some cases, the biological sample is contacted simultaneously with one or more specific antibodies. In some cases, the biological sample is contacted sequentially with the specific antibodies. In some cases, alterations in one or more molecules can cause an increase in the expression of one or more of the biomarkers ALK, ROS1, TrkA, TrkB, and TrkC. In some cases, knowledge of one or more molecular alterations is obtained from a test in which determining whether the expression of one or more biomarkers is increased includes: (a) determining the expression level of one or more biomarkers in a biological sample; and (b) comparing the determined expression level with a reference expression level.

[0359] As used herein, the term "reference level" refers to the known expression level of a target biomarker in a control or subject. In some cases, the reference expression level is the expression level of the target biomarker in a healthy person or subject. In some cases, the reference expression level is the expression level of the target biomarker in a healthy control cell population. In some cases, the reference expression level is the expression level of the target biomarker in a control person or subject who has been previously identified to have one or more molecular alterations. In some cases, the reference expression level is the expression level of the target biomarker in a control cell population that has been previously identified to have one or more molecular alterations.

[0360] In some cases, antibody-based tests yield knowledge of one or more molecular alterations. Antibody-based tests can generally be any antibody-based test and can include, for example, ELISA, immunohistochemistry, Western blotting, mass spectrometry, flow cytometry, protein microarrays, immunofluorescence, and multiplex assays. In some cases, antibody-based tests include immunohistochemical analysis.

[0361] In some cases, identifying deficiencies in the regulation of ALK, ROS1, TrkA, TrkB, or TrkC in cancerous or precancerous pancreatic cells in subjects (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) involves examining ALK, ROS1, TrkA, TrkB, or TrkC activity in cells extracted from pancreatic cancerous or precancerous cell populations. In some cases, identifying deficiencies in the regulation of ALK, ROS1, TrkA, TrkB, or TrkC in cancerous or precancerous pancreatic cells in subjects (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) involves examining the accumulation of ALK, ROS1, TrkA, TrkB, or TrkC transcripts in RNA populations derived from cancerous or precancerous pancreatic cell populations. In some cases, identifying up- or down-regulated deficiencies in ALK, ROS1, TrkA, TrkB, or TrkC regulation in cancerous or precancerous pancreatic cells in a subject (e.g., null mutations such as deletions of ALK, ROS1, TrkA, TrkB, or TrkC, or ALK, ROS1, TrkA, TrkB, or TrkC kinases, or chimeric loci encoding constitutively active ALK, ROS1, TrkA, TrkB, or TrkC kinases) involves identifying nucleic acid sequences (such as genomic deoxyribonucleic acid sequences) from cells or cell populations comprising cancerous or precancerous pancreatic cells.

[0362] As used herein, the term "microarray" refers to an ordered arrangement of array elements (e.g., small samples of biological samples from a subject, such as tissue samples) mounted on a solid support capable of binding other molecular species or antibodies. The array elements are arranged such that at least one or more different array elements are preferably present.

[0363] As used herein, the term "solid support" refers to a solid material to which various readily understood components, such as proteins and nucleic acids, are physically attached, thereby securing said components. As used herein, the term "solid support" refers to a non-liquid substance. Solid supports can be (but are not limited to) membranes, sheets, gels, glass, plastics, or metals. For example, secured components can be associated with the solid support via covalent bonds and / or by means of non-covalent attractive forces, such as hydrogen bonding interactions, hydrophobic attractive forces, and ionic forces.

[0364] In some cases, microarrays suitable for the methods presented herein have at least 1, 2, 4, 6, 8, or 10 points / cm. 2 Preferably, at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, more preferably at least 210, 220, 230, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, or 9000 points / cm. 2 .

[0365] In some cases, the points on the array are expected to represent different types of biomarkers, or multiple points on the array may represent the same type of biomarker. In other cases, the points may each represent array elements with different properties or characteristics.

[0366] In some cases, embodiments of the methods according to this disclosure further include, prior to the application step, knowledge of genetic alterations in the subject's cancer obtained from a second analytical test. The second analytical test can generally be any analytical test known to a person skilled in the art, and can be, for example, an antibody-based test, a nucleotide-based test, or an enzyme-based activity test. Other examples of suitable second analytical tests for mass spectrometry genotyping include ELISA, immunohistochemistry, Western blotting, mass spectrometry, flow cytometry, protein microarrays, immunofluorescence, and multiplex assays.

[0367] In some cases, FISH analysis is used to identify chromosomal rearrangements that produce one or more molecular alterations, such as fusion genes or gene products as described herein. For example, to perform FISH, at least a first probe labeled with a first detectable marker can be designed to target a first gene (e.g., in one or more exons of the gene) that is a fusion gene, and a second probe labeled with a second detectable marker can be designed to target a second gene (e.g., in one or more exons of the gene, such as exons containing a protein portion comprising a tyrosine kinase domain). At least one first probe and at least one second probe in a subject carrying a fusion will be closer together than in a subject carrying a fusion gene or gene product. In some cases, a variation of the FISH test (e.g., “split FISH”) is used to assess selected subjects using the methods provided herein. This method utilizes at least one probe targeting fusion conjugation and at least one probe targeting the subject’s gene that is a fusion, for example, at one or more exons and / or introns of said gene. In normal cells, two probes will be observed (or a second color will be observed due to the close proximity of the two genes in a gene fusion), and when a translocation occurs, only a single gene probe will be observed, or probes of different colors will separate, allowing a person skilled in the art to determine the presence of the relevant gene fusion or deletion in the sample by observing the probes. Typically, FISH testing is performed using formalin-fixed paraffin-embedded tissue sections placed on slides. DNA from a portion of the tissue sample is denatured into single-stranded form and then hybridized with suitable DNA probes designed and prepared using methods and techniques known to a person skilled in the art. After hybridization, any unbound probes can be removed by a series of washes, and the cell nuclei are counterstained with DAPI (4',6 diamidino-2-phenylindole) (a DNA-specific dye that fluoresces blue). The hybridization of the probes is examined using a fluorescence microscope equipped with suitable excitation and emission filters, thus visualizing the fluorescence signal.

[0368] For example, the split FISH test can be used to detect various types of rearrangements involving the ALK locus. In this method, tumor cells from some subjects with non-small cell lung cancer (NSCLC) showed ALK-positive FISH patterns, detected using a single interference filter that included green (FITC), red (Texas Red), and blue (4',6-dimethylamidine-2-phenylindole) bandpass filters, as well as dual (red / green) and triple (blue, red, green) bandpass filters. ALK gene fusions were observed as split orange and green signals, a single orange signal, or a single orange and a single green signal.

[0369] The same method as described above is used, but the relevant molecular alterations of ROS1, TrkA, TrkB, and TrkC in biological samples derived from cancer subjects are examined in a manner suitable for the target molecular alterations by modifying reagents, probes, and other materials, and can be easily determined by a person skilled in the art.

[0370] Other variations of the FISH method known in the field are suitable for evaluating subjects selected according to the method presented herein.

[0371] In some cases of the methods presented herein, the cancers are selected from the group consisting of: anaplastic large cell lymphoma (ALCL), colorectal cancer (CRC), cholangiocarcinoma, gastric cancer, glioblastoma (GBM), leiomyosarcoma, melanoma, non-small cell lung cancer (NSCLC), squamous cell lung cancer, neuroblastoma (NB), ovarian cancer, pancreatic cancer, prostate cancer, medullary thyroid carcinoma, breast cancer, and papillary thyroid carcinoma. In some cases, such methods are provided in which knowledge of the presence of one or more molecular alterations is obtained from tests performed simultaneously on multiple biological samples. In some cases, multiple biological samples can be tested in a multiplex testing platform.

[0372] As used herein, the term "multiplex testing platform" is intended to encompass any suitable apparatus containing one or more reaction mixtures, suspensions, or detection reactions. Thus, the results of multiple screening events can be assembled onto a single surface, creating a "multiplex testing platform" having or consisting of multiple elements or portions to perform more than one experiment simultaneously. It is hoped that the term "multiplex testing platform" will encompass protein chips, microtiter plates, multiwell culture plates, microcards, test tubes, Petri plates, trays, slides, etc. In some cases, multiplexing can further encompass the simultaneous performance of multiple screening events in each of multiple individual biological samples. For example, the number of biological samples analyzed can be based on the number of spots on a slide and the number of tests performed at each spot (as described in more detail in Example 2). In another example, the number of biological samples analyzed can be based on the number of wells in a multiwell plate and the number of tests performed in each well. For example, although those skilled in the art will understand that 6-well, 12-well, 24-well, 48-well, 96-well, 384-well, 1536-well, or 3456-well microtiter plates can be used in the methods of this disclosure, not every microtiter well needs to contain an individual biological sample. Depending on the size of the microtiter plate and the number of individual biological samples in each well, a large number of tests can be performed simultaneously. Although multiplexing has been illustrated with reference to microcarriers in Example 2, it should be understood that other types can also be used for multiplexing.

[0373] In some cases, such methods are provided where multiple biological samples comprise at least 6, 12, 24, 48, 96, 200, 384, 400, 500, 1000, 1250, 1500, or 3000 samples.

[0374] In some cases, such methods are provided where one or more molecular alterations are selected from gene mutations, gene amplifications, gene rearrangements, single nucleotide variants (SNVs), deletions, insertions, insertion-deletion mutations, single nucleotide point mutations (SNPs), epigenetic alterations, splicing variants, RNA / protein overexpression, and aberrant RNA / protein expression. In some cases, such methods are provided where the gene alteration involves the insertion of a heterologous nucleic acid sequence into the coding sequence of a biomarker gene. In some cases, such methods are provided where the insertion forms a chimeric nucleic acid sequence encoding a fusion peptide.

[0375] In some cases, such methods are provided, wherein acquiring knowledge of one or more molecular alterations further includes determining the nucleic acid and / or amino acid sequences comprising said one or more molecular alterations. In some cases, nucleic acid sequences comprising one or more molecular alterations are sequenced from tumors of selected cancer subjects. In some cases, the sequences are determined using next-generation sequencing methods.

[0376] Some embodiments provide pharmaceutical compositions comprising a therapeutically effective amount of N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide in combination with one or more chemotherapeutic agents or radiotherapy (such as radiotherapy commonly administered to treat cancer, improve cancer symptoms, or prevent or delay the onset of cancer). Such agents may comprise (but are not limited to) antihormonal agents (such as antiestrogens, antiandrogens, and aromatase inhibitors), topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-targeting agents, platinum-based agents, alkylating agents, DNA-damaging or inserting agents, anti-hypertrophic antimetabolites, other kinase inhibitors, other anti-angiogenic agents, kinin inhibitors, therapeutic monoclonal antibodies, mTOR inhibitors, histone deacetylase inhibitors, farnesyltransferase inhibitors, and hypoxia response inhibitors.

[0377] Some embodiments provide products or kits comprising pharmaceutical compositions as provided herein as combination formulations for simultaneous, single, or sequential use in anticancer therapy, said pharmaceutical compositions comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)-benzamide and one or more chemotherapeutic agents.

[0378] Some embodiments include any of the methods described herein, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, neuroblastoma, pancreatic cancer, and colorectal cancer. Some embodiments are any of the methods described herein, wherein the cancer is non-small cell lung cancer. Some embodiments include any of the methods described herein, wherein the cancer is papillary thyroid carcinoma. Some embodiments include any of the methods described herein, wherein the cancer is neuroblastoma. Some embodiments include any of the methods described herein, wherein the cancer is pancreatic cancer. Some embodiments include any of the methods described herein, wherein the cancer is colorectal cancer.

[0379] Some embodiments relate to the use of any pharmaceutical compositions provided herein as medicines. Some embodiments relate to the use of any pharmaceutical compositions provided herein for the manufacture of medicines for treating abnormal cell growth.

[0380] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a fasting subject when administered at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject after administration of the pharmaceutical composition to the subject is [not specified]. max Between about 2 hours and about 5 hours, or between about 2.5 hours and about 4.7 hours, or between about 2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0381] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is [not specified]. max Between about 2 hours and about 5 hours, or between about 2.5 hours and about 4.7 hours, or between about 2.4 hours and about 4.7 hours, or between about 2.6 hours and about 4.8 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0382] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a fed state when administered at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is [not specified]. maxBetween about 4 hours and about 8 hours, or between about 4.6 hours and about 5.4 hours, or between about 4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0383] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is [not specified]. max Between about 4 hours and about 8 hours, or between about 4.6 hours and about 5.4 hours, or between about 4.5 hours and about 7.2 hours, or between about 4.2 hours and about 6.7 hours. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0384] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a fasting subject when administered at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C10 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject after administration of the pharmaceutical composition to the subject is [not specified in the original text]. max The concentration is between about 1200 nM and about 3500 nM, or between about 1500 nM and about 2800 nM, or between about 1490 nM and about 3030 nM, or between about 1670 nM and about 2930 nM. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0385] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C60 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is [not specified]. maxThe concentration is between about 1200 nM and about 3500 nM, or between about 1500 nM and about 2800 nM, or between about 1490 nM and about 3030 nM, or between about 1670 nM and about 2930 nM. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0386] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a fed state when administered at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C10 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject after administration of the pharmaceutical composition to the subject is [not specified in the original text]. max The concentration is between about 1500 nM and about 3500 nM, or between about 1810 nM and about 3070 nM, or between about 2210 nM and about 2990 nM, or between about 1990 nM and about 2810 nM. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0387] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject when administered to the subject at a total dose of about 600 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, wherein the C60 of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is [not specified]. max The concentration is between about 1500 nM and about 3500 nM, or between about 1810 nM and about 3070 nM, or between about 2210 nM and about 2990 nM, or between about 1990 nM and about 2810 nM. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidifier is fumaric acid. In some embodiments, at least one acidifier is tartaric acid. In some embodiments, the at least one acidifier is maleic acid. In some embodiments, the at least one acidifier is citric acid. In some embodiments, the at least one acidifier is betaine hydrochloride.

[0388] In some embodiments, a pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent is provided, wherein when in about 600 When the total dose of N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide is administered to a subject in a fasting state, the pharmaceutical composition provides pharmacokinetic profiles in the subject, wherein the AUC (0 to 120) of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the subject's plasma after administration of the pharmaceutical composition is between about 30,000 nM×hr and about 85,000 nM×hr, or between about 34,100 nM×hr and about 71,700 nM×hr, or between about 32,500 nM×hr and about 79,700 nM×hr. The values ​​are between nM×hr, or between about 37,100 nM×hr and about 77,300 nM×hr. In some embodiments, at least one acidifier is an organic acidifier. In some embodiments, at least one acidifier is selected from tartaric acid, maleic acid, fumaric acid, citric acid, and betaine hydrochloride. In some embodiments, at least one acidif...

Claims

1. A pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent.

2. The pharmaceutical composition according to claim 1, wherein it satisfies one or more of the following conditions: (1) The at least one acidifying agent is an organic acidifying agent; preferably selected from tartaric acid, maleic acid, fumaric acid, citric acid and betaine hydrochloride; (2) The molar ratio between the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifying agent is about 0.5 to about 2; (3) The pharmaceutical composition is in tablet or capsule form; (4) The pharmaceutical composition comprises about 25 mg to about 800 mg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; (5) After the pharmaceutical composition is stored in an open container at 40°C and 75% relative humidity for 3 months, less than about 2% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the pharmaceutical composition is degraded.

3. The pharmaceutical composition according to claim 2, wherein the at least one acidifying agent is tartaric acid; Alternatively, the at least one acidifying agent is fumaric acid; Alternatively, the fumaric acid may be in a micronized form; Alternatively, the at least one acidifying agent is maleic acid; Alternatively, the at least one acidifying agent is citric acid; Alternatively, the at least one acidifying agent is betaine hydrochloride.

4. The pharmaceutical composition according to claim 3, wherein the particle size of the fumaric acid is such that it passes through a 60-mesh sieve.

5. A pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one pharmaceutically acceptable excipient, wherein the pharmaceutical composition is in the form of a tablet or capsule, and wherein the tablet or capsule has a solubility profile wherein, when tested in a Type I USP basket method at 50 rpm in 500 mL sodium acetate buffer at pH 4.5 and about 37°C, at least about 30% of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide has been released from the tablet or capsule after about 60 minutes.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the pharmaceutical composition further comprises mannitol or isomalt; preferably, the pharmaceutical composition further comprises starch; more preferably, the weight ratio of mannitol or isomalt to starch in the pharmaceutical composition is about 1:1 to about 3:

1.

7. A pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and at least one acidifying agent, wherein the pharmaceutical composition provides a pharmacokinetic profile in a subject in a fasting state when administered to the subject, wherein the Tg of the N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide in the plasma of the subject is [not specified in the original text]. max Between approximately 2 and 6 hours.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition does not exhibit an eating effect when administered to a subject.

9. The pharmaceutical composition according to any one of claims 1 to 8, further comprising lactose, hydroxypropyl methylcellulose, crospovidone, microcrystalline cellulose, colloidal silica or magnesium stearate or any combination of two or more thereof; Preferably, the pharmaceutical composition comprises about 20% w / w to about 60% w / w N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, about 5% w / w to about 20% w / w tartaric acid, about 15% w / w to about 35% w / w lactose, about 1% w / w to about 10% w / w hydroxypropyl methylcellulose, about 1% w / w to about 5% w / w microcrystalline cellulose, about 1% w / w to about 10% w / w crospovidone, about 0.05% w / w to about 5% w / w colloidal silica, and about 0.1% w / w to about 5% w / w magnesium stearate; Alternatively, the pharmaceutical composition comprises about 40% w / w to about 50% w / w N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, about 10% w / w to about 15% w / w tartaric acid, about 25% w / w to about 30% w / w lactose, about 3% w / w to about 5% w / w hydroxypropyl methylcellulose, about 2% w / w to about 4% w / w microcrystalline cellulose, about 4% w / w to about 7% w / w crospovidone, about 0.1% w / w to about 1% w / w colloidal silica, and about 0.5% w / w to about 2% w / w magnesium stearate; More preferably, the lactose is anhydrous lactose.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein N-[5-(3,5-difluorobenzyl)-1H-indazole-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide and the at least one acidifier are present in the composition in the form of an admixture.

11. A pharmaceutical composition comprising N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide, tartaric acid, anhydrous lactose, hydroxypropyl methylcellulose, microcrystalline cellulose, crospovidone, colloidal silica, and magnesium stearate, wherein the composition is prepared in a method comprising: N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide; anhydrous lactose; hydroxypropyl methylcellulose; the first part of crospovidone; and tartaric acid are added together and blended to form a first blend; The first blend is sieved to form a sieved first blend; The sieved first blend is mixed to form a second blend; The second blend is sieved to form a sieved second blend; The sieved second blend is mixed to form a third blend; A first portion of magnesium stearate is added to the third blend and mixed to form a fourth blend; The fourth blend is compacted and ground to form the fifth blend; Microcrystalline cellulose, the second portion of cross-linked polyvinyl ketone, and colloidal silica are added to the fifth blend and mixed to form a sixth blend; The second portion of magnesium stearate is added to the sixth blend and mixed to form the pharmaceutical composition.

12. A method of treating a subject with cancer, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 11.

13. A method of treating a subject with ROS1, TrkA, TrkB or TrkC positive cancer or a combination thereof, the method comprising administering to the subject a pharmaceutical composition according to any one of claims 1 to 11.

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