Pharmaceutical formulations and dosing schedules for HIPPO-YAP pathway modulators

Abstract

A pharmaceutical formulation in solid dosage form of a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is provided herein. A method for treating cancer is also provided herein, comprising a pharmaceutical formulation in solid dosage form of a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Application No. 63 / 496,235, filed on April 14, 2023, which is incorporated herein by reference in its entirety. [Background technology]

[0002] YAP and TAZ are transcriptional co-activators of the Hippo pathway network, regulating cell proliferation, migration, and apoptosis. Suppression of the Hippo pathway promotes the translocation of YAP / TAZ to the nucleus, where YAP / TAZ interacts with transcriptional enhancer-associated domain (TEAD) transcription factors to co-activate the expression of target genes and promote cell proliferation. Overactivation of YAP and TAZ, and / or mutations, in one or more members of the Hippo pathway network is associated with many cancers. Inhibitors related to one or more members of the Hippo pathway network, such as YAP / TAZ inhibitors or inhibitors that modulate the interaction between YAP / TAZ and TEAD, are described herein. [Overview of the project]

[0003] In one embodiment, a pharmaceutical formulation is provided herein that contains a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide in a solid dosage form. In some embodiments, the pharmaceutical formulation is useful for the treatment of cancer.

[0004] In another embodiment, a method for treating cancer in a subject requiring treatment for cancer is provided herein by administering a pharmaceutical formulation described herein to the subject requiring treatment for cancer. In some embodiments, the method for treating cancer includes, for example, administering a pharmaceutical formulation in solid dosage form comprising a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide and an excipient, as disclosed herein. In some embodiments, the method for treating cancer includes, for example, administering a pharmaceutical formulation in solid dosage form comprising a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide and an excipient, as disclosed herein, wherein the pharmaceutical formulation is administered according to a dosing schedule described herein.

[0005] In one embodiment, a pharmaceutical formulation in solid dosage form is disclosed herein, comprising (a) about 20 w / w% to about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, (b) about 15 w / w% to about 40 w / w% of a first filler, (c) about 15 w / w% to about 40 w / w% of a second filler, (d) about 1 w / w% to about 10 w / w% of a first lubricant, (e) about 0.1 w / w% to about 1 w / w% of a second lubricant, (f) about 1 w / w% to about 5 w / w% of a disintegrant, and (g) about 0.1 w / w% to about 2 w / w% of a flow enhancer. In some embodiments, the pharmaceutical formulation contains about 25 w / w% to about 45 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 30 w / w% to about 40 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 37 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg. In some embodiments, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide is present in amounts of 25 mg, 50 mg, 100 mg, 125 mg, or 150 mg.In some embodiments, the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 50 mg. In some embodiments, the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 100 mg. In some embodiments, the pharmaceutical formulation contains about 20 w / w% to about 35 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 25 w / w% to about 30 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 27 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 20 w / w% to about 35 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 25 w / w% to about 30 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 27 w / w% of a second filler. In some embodiments, the first and second fillers are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the first filler is lactose. In some embodiments, lactose is lactose monohydrate. In some embodiments, the second filler is mannitol. In some embodiments, mannitol is mannitol 200SD. In some embodiments, the pharmaceutical formulation contains about 3 w / w% to about 7 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% to about 0.7 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% of a second lubricant. In some embodiments, about 0.3 w / w% of the second lubricant is intragranular, and about 0.2 w / w% of the second lubricant is extragranular.In some embodiments, the first and second lubricants are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the first lubricant is sodium lauryl sulfate. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the pharmaceutical formulation contains about 2 w / w% to about 4 w / w% of a disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 w / w% of a disintegrant. In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropylcellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% to about 1.5 w / w% of a flow enhancer. In some embodiments, the pharmaceutical formulation contains about 1 w / w% of a flow enhancer. In some embodiments, the flow enhancer is selected from silicates, silicon dioxide, and talc. In some embodiments, the flow enhancer is silicon dioxide. In some embodiments, the silicon dioxide is colloidal silicon dioxide.

[0006] In another embodiment, a pharmaceutical formulation in solid dosage form is disclosed herein, comprising (a) about 37 w / w% (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, (b) about 26.7 w / w% lactose monohydrate, (c) about 26.7 w / w% mannitol, (d) about 5 w / w% sodium lauryl sulfate, (e) about 0.5 w / w% magnesium stearate, (f) about 3 w / w% croscarmellose sodium, and (g) about 1 w / w% colloidal silicon dioxide.

[0007] In some embodiments, the pharmaceutical formulations disclosed herein have a half-life of at least 3 days. In some embodiments, the pharmaceutical formulations have a half-life of at least 7 days. In some embodiments, the pharmaceutical formulations have a half-life of 12 to 15 days. In some embodiments, the pharmaceutical formulations have a half-life of 12 days. In some embodiments, the solid dosage form is selected from powder, tablets, bite-disintegration tablets, chewable tablets, caplets, capsules, gel capsules, effervescent powders, rapidly disintegrating tablets, abuse-preventing tablets, controlled-release tablets, controlled-release caplets, controlled-release capsules, and aqueous suspensions produced from powder. In some embodiments, the solid dosage form is a capsule. In some embodiments, the capsule is a hard gelatin capsule. In some embodiments, the hard gelatin capsule contains gelatin and titanium dioxide. In some embodiments, the hard gelatin capsule further contains FD&C Red 40 and FD&C Blue 1. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a caplet. In some embodiments, the solid dosage form is a dry granulated blend.

[0008] In another embodiment, a method for treating cancer in a subject requiring treatment for cancer is disclosed herein, comprising administering a pharmaceutical formulation disclosed herein to the subject requiring treatment for cancer. In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

[0009] In another embodiment, a method for treating cancer in a subject requiring treatment for cancer is disclosed herein, comprising administering a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide to the subject requiring treatment for cancer, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least three days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered as an oral formulation. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in capsule form. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 25 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, or 100 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 50 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 100 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a three-week cycle, with a therapeutically effective amount administered daily for one week, followed by no administration for two weeks.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, the therapeutically effective amount is administered daily for one week, and then absent for two weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg doses. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for one week, followed by no administration for the next three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for one week, followed by no administration for the next three weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 150 mg doses. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next week.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next week, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg doses. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next 2 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 100 mg doses.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next 2 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg doses. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 15 days, followed by weekly administration for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg once daily for 15 days, followed by a dose of 50 mg once weekly for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg once daily for 15 days, followed by a dose of 100 mg once weekly for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg once daily for 15 days, followed by a dose of 100 mg once weekly for 3 weeks.

[0010] In another embodiment, a method for treating cancer in a subject requiring cancer treatment is disclosed herein, comprising administering 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily for two weeks, and then withholding (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide for the following two weeks. In some embodiments, subjects requiring cancer treatment are administered 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily for two weeks, and then (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is withheld for the following two weeks, and further, subjects requiring cancer treatment are administered a four-week course of saturation therapy. A method of treating cancer in subjects requiring cancer treatment involves administering 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily for two weeks, followed by a period of no administration for the next two weeks, wherein (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least two cycles.

[0011] In another embodiment, subjects requiring cancer treatment are administered 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily for two weeks, followed by a two-week period without administration of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, and then subjects requiring cancer treatment are administered a four-week cycle for two weeks. Disclosed herein is a method for treating cancer in a subject requiring cancer treatment, comprising administering 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily, followed by no administration for the next two weeks, wherein 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least eight cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least 12 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least 24 cycles.

[0012] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least two cycles. In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

[0013] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually incorporated by reference. [Brief explanation of the drawing]

[0014] Various aspects of this disclosure are specifically described in the attached claims. A better understanding of the features and merits of this disclosure can be obtained by referring to the following detailed description and attached drawings, which describe illustrative embodiments in which the principles of this disclosure are applied.

[0015] [Figure 1]A schematic diagram of the Hippo signaling network is shown. Hippo pathway components shaded in dark gray indicate components that inhibit YAP / TAZ activity. Hippo pathway components shaded in light gray indicate components that promote YAP / TAZ activity. Pointed and blunt arrows indicate activating and inhibitory interactions, respectively. Abbreviations: α-CAT (α-catenin), AJUB (Ajuba), AMOT (Angiomotin), β-TRCP (β-transducin repeat protein), CK1 (Casein kinase 1), CRB (Crumbs), E-CAD (E-cadherin), EX (extended), GPCR (G protein-coupled receptor), HIPK (Homeodomain interaction protein kinase), KIBRa (Kidney brain), LATS (Large tumor suppressor), LGL (Lethal giant larvae), MASK (Multiple ankyrin single KH), MER (Merlin), MOB (Mps one binder), MST (Mammalian sterile 20 (like), PALS (Lin-7 related protein), PATJ (Pals1-related tight junction protein), PP2A (protein dephosphorylation enzyme 2A), PTPN14 (tyrosine phosphatase protein nonreceptor type 14), RASSF (Ras-related factor), SAV (Salvador), SCRIB (Scribble), SIK (salt-inducible kinase), TAO (1001 amino acid protein), TAZ (transcription-coupled activator with PDZ-binding motif), TEAD (TEA domain protein), VGL4 (Vestigial-like 4), WBP2 (WW domain-binding protein 2), YAP (Yes-related protein), ZO (closed zone), ZYX (Zyxin). [Figure 2] A schematic diagram illustrating the Hippo signaling pathway regulated by Gα proteins is provided. [Figure 3] This document illustrates the design of a Phase 1 clinical trial, including key eligibility criteria, dose escalation, and dose expansion. [Figure 4A]The pharmacokinetics of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, in terms of mean plasma Cmax (ng / mL) versus dose (mg) (Figure 4A), are illustrated. [Figure 4B] The pharmacokinetics of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, as shown in mean plasma AUClast versus dose (mg) (Figure 4B), are illustrated. [Figure 4C] The pharmacokinetics of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, specifically the mean concentration (ng / mL) versus time (hours) on day 15 (Figure 4C), are illustrated. [Modes for carrying out the invention]

[0016] Hippo signaling network The Hippo signaling network (also known as the Salvador / Warts / Hippo (SWH) pathway) is a major regulator of cell proliferation, death, and differentiation. In some embodiments, the primary function of the Hippo signaling pathway is to negatively regulate the transcription-coupled activator Yes-related protein (YAP) and its paralog, the PDZ-binding motif-containing transcription-coupled activator (TAZ; also known as WWTR1) (Figure 1). The Hippo kinase cascade phosphorylates and represses YAP / TAZ by promoting their retention and degradation in the cytoplasm, thereby suppressing the growth-promoting functions regulated under YAP / TAZ. In its unphosphorylated / dephosphorylated state, YAP, also known as YAP1 or YAP65, is transported to the nucleus along with TAZ, where it interacts with the TEAD family of transcription factors to upregulate genes that promote proliferation and migration and suppress apoptosis. In some examples, the uncontrolled upregulation of these genes involved in proliferation, migration, and anti-apoptosis can lead to cancer development. In some cases, YAP / TAZ overexpression is associated with cancer.

[0017] Further core members of the Hippo signaling pathway include the serine / threonine kinases MST1 / 2 (homologs of Hippo / Hpo in Drosophila), Lats1 / 2 (homologs of Warts / Wts), and their adapter proteins Sav1 (homologs of Salvador / Sav) and Mob (MOBKL1A and MOBKL1B; homologs of Mats), respectively (Figure 1). Generally, MST1 / 2 kinases form a complex with the scaffolding protein Sav1, which phosphorylates and activates Lats1 / 2 kinase. Lats1 / 2 is also activated by the scaffolding protein Mob. Subsequently, activated Lats1 / 2 phosphorylates and inactivates YAP or its paralog, TAZ. Phosphorylation of YAP / TAZ leads to its nuclear export, retention in the cytoplasm, and degradation by the ubiquitin-proteasome system.

[0018] In some cases, Lats1 / 2 phosphorylates YAP in the [HXRXXS] consensus motif. YAP contains five [HXRXXS] consensus motifs, where X represents any amino acid residue. In some cases, Lats1 / 2 phosphorylates YAP in one or more of the consensus motifs. In some cases, Lats1 / 2 phosphorylates YAP in all five of the consensus motifs. In some cases, Lats1 / 2 phosphorylates at the S127 amino acid position. Phosphorylation of YAP at S127 promotes protein binding to 14-3-3 and causes cytoplasmic sequestration of YAP. Thus, mutations in YAP at the S127 position disrupt its interaction with 14-3-3 and subsequently promote nuclear translocation.

[0019] Further phosphorylation occurs at the S381 amino acid position in YAP. Phosphorylation of YAP at the S381 position and the corresponding site in TAZ stimulates both proteins to undergo further phosphorylation events by CK1δ / ε in the degradation motif, subsequently signaling interaction with β-TRCP E3 ubiquitin ligase, leading to polyubiquitination and degradation of YAP.

[0020] In some cases, Lats1 / 2 phosphorylates TAZ in the [HXRXXS] consensus motif. TAZ contains four [HXRXXS] consensus motifs, where X represents any amino acid residue. In some cases, Lats1 / 2 phosphorylates TAZ in one or more of the consensus motifs. In some cases, Lats1 / 2 phosphorylates TAZ in all four of the consensus motifs. In some cases, Lats1 / 2 phosphorylates at the S89 amino acid position. Phosphorylation of TAZ at S89 facilitates protein binding to 14-3-3 and causes cytoplasmic sequestration of TAZ. Thus, mutations in TAZ at the S89 position disrupt its interaction with 14-3-3 and subsequently promote nuclear translocation.

[0021] In some embodiments, phosphorylated YAP / TAZ accumulates in the cytoplasm and SCF β-TRCP This involves ubiquitination mediated by and subsequent proteasomal degradation. In some examples, the Skp, Cullin, F-box-containing complex (SCF complex) is a multi-protein E3 ubiquitin ligase complex that includes F-box family member proteins (e.g., Cdc4), Skp1, a crosslinking protein, and RBX1 containing a small RING finger domain that interacts with E2-ubiquitin-conjugating enzymes. In some cases, the F-box family includes more than 40 members, with exemplary members including F-box / WD repeat-containing protein 1A (FBXW1A, βTrCP1, Fbxw1, hsSlimb, plkappaBalpha-E3 receptor subunit) and S-phase kinase-related protein 2 (SKP2). In some embodiments, the SCF complex (e.g., SCF βTrCP1These enzymes interact with E1 ubiquitin activators and E2 ubiquitin conjugates to catalyze the transfer of ubiquitin to YAP / TAZ substrates. Exemplary E1 ubiquitin activators include those encoded by the genes UBA1, UBA2, UBA3, UBA5, UBA7, ATG7, NAE1, and SAE1. Exemplary E2 ubiquitin-conjugating enzymes include those encoded by the genes UBE2A, UBE2B, UBE2C, UBE2D1, UBE2D2, UBE2D3, UBE2E1, UBE2E2, UBE2E3, UBE2F, UBE2G1, UBE2G2, UBE2H, UBE2I, UBE2J1, UBE2J2, UBE2K, UBE2L3, UBE2L6, UBE2M, UBE2N, UBE2O, UBE2Q1, UBE2Q2, UBE2R1, UBE2R2, UBE2S, UBE2T, UBE2U, UBE2V1, UBE2V2, UBE2Z, ATG2, BIRC5, and UFC1. In some embodiments, ubiquitinated YAP / TAZ further undergoes a degradation process via the 26S proteasome.

[0022] In some embodiments, the Hippo pathway is regulated upstream by several different families of regulatory factors (Figure 1). In some examples, the Hippo pathway is regulated by G proteins and their coupled receptors, Crumbs complexes, upstream regulators of MST kinases, and adhesion junctions.

[0023] YAP / TAZ interaction with TEAD In some embodiments, unphosphorylated and / or dephosphorylated YAP / TAZ accumulate in the nucleus. Within the nucleus, YAP / TAZ interacts with the TEAD family of transcription factors (e.g., TEAD1, TEAD2, TEAD3, or TEAD4) to activate genes involved in anti-apoptosis and proliferation, such as CTFG, Cyr61, and FGF1.

[0024] In some embodiments, the compounds disclosed herein modulate the interaction between YAP / TAZ and TEAD. In some embodiments, the compounds disclosed herein bind to TEAD, YAP, or TAZ and prevent the interaction between YAP / TAZ and TEAD.

[0025] Regulation of YAP / TAZ Mediated by G Protein / GPCR In some embodiments, the Hippo pathway is regulated by the protein G protein-coupled receptor (GPCR) and G protein (also known as guanine nucleotide-binding protein) families (Figure 2). G proteins are molecular switches that transmit extracellular stimuli to cells via GPCRs. In some examples, there are two classes of G proteins, monomeric low molecular weight GTPases and heterotrimeric G protein complexes. In some examples, the latter class of complexes includes subunits of alpha (G α ), beta (G β ), and gamma (G γ ). In some cases, the G α subunit has several classes of G q / 11 α, G 12 / 13 α, G i / o α (G inhibitory, G others), and G s α (G stimulatory).

[0026] In some examples, G i α (G inhibitory), G o α (G others), G q / 11 α, and G 12 / 13 α-coupled GPCRs activate YAP / TAZ and promote nuclear translocation. In other examples, G s α (G stimulatory)-coupled GPCRs inhibit YAP / TAZ activity and cause YAP / TAZ degradation.

[0027] In some cases, G i α (G inhibitory), G o α (G others), G q / 11 α, and G 12 / 13α-coupled GPCRs activate YAP / TAZ by inhibiting Lats1 / 2 activity. In contrast, G s In some embodiments, α induces Lats1 / 2 activity, thereby promoting YAP / TAZ degradation.

[0028] G q family G q α(G q / 11 (also known as a protein) activates the inositol triphosphate (IP3) signaling pathway and phospholipase C (PLC) to release calcium (Ca) from intracellular storage. 2+ ) is involved in release. Activated PLC hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and IP3. In some cases, IP3 then diffuses through the cytoplasm to the ER, or to the sarcoplasmic reticulum (SR) in the case of muscle cells, and subsequently to Ca 2+ It binds to the inositol triphosphate receptor (InsP3R), which is a channel. In some cases, the above binding is Ca 2+ This causes the channel to open, thereby Ca 2+ Increases the release of into the cytoplasm.

[0029] In some embodiments, G q Examples of GPCRs that interact with α include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT2 and 5-HT3, α-1 adrenergic receptor, vasopressin type 1 receptor 1A and 1B, angiotensin II receptor type 1, calcitonin receptor, histamine H1 receptor, metabotropic glutamate receptor, group I, muscarinic receptors M1, M3, and M5, and trace amine-related receptor 1.

[0030] In some examples, several types of G q There is α, G q , G q / 11 , G q / 14 , and G q / 15 G is one example. qProteins are encoded by GNAQ. q / 11 This is coded by GNA11. q / 14 This is coded by GNA14. q / 15 This is coded by GNA15.

[0031] In some examples, G q Mutations or modifications of the alpha gene have been linked to cancer. Indeed, studies have shown that G q Mutations in α have been shown to promote uveal melanoma (UM) tumorigenesis. In some cases, approximately 80% of UM cases have been detected as containing mutations in GNAQ and / or GNA11.

[0032] In some examples, G q Mutations or modifications of the α gene have been associated with congenital disorders. In some cases, G q Alpha mutations have been observed in congenital disorders such as port-wine stains and / or Sturge-Weber syndrome. In some cases, approximately 92% of port-wine stain cases have a mutation in GNAQ. In some cases, approximately 88% of Sturge-Weber syndrome cases have a mutation in GNAQ.

[0033] G 12 / 13 family G 12 / 13 α regulates actin cytoskeleton remodeling in cells and controls cellular processes via guanine nucleotide exchange factors (GEFs). GEFs are involved in the activation of small GTPases, which act as molecular switches in various intracellular signaling pathways. Examples of small GTPases include the Ras-related GTPase superfamily (e.g., the Rho family, such as Cdc42) involved in cell differentiation, proliferation, cytoskeleton construction, vesicular transport, and nuclear transport.

[0034] In some embodiments, G 12 / 13GPCRs that interact with α include, but are not limited to, purine receptors (e.g., P2Y1, P2Y2, P2Y4, P2Y6), muscarinic acetylcholine receptors M1 and M3, thrombin receptors [protease-activated receptor (PAR)-1, PAR-2], thromboxane (TXA2), sphingosine 1-phosphate (e.g., S1P2, S1P3, S1P4, and S1P5), lysophosphatidic acid (e.g., LPA1, LPA2, LPA3), angiotensin II (AT1), and serotonin (5-HT1). 2c (and 5-HT4), somatostatin (sst5), endothelin (ET) A and ET B ), cholecystokinin (CCK1), V 1a Examples include vasopressin receptors, D5 dopamine receptors, fMLP formyl peptide receptors, GAL2 galanin receptors, EP3 prostanoid receptors, A1 adenosine receptors, α1 adrenergic receptors, BB2 bombesin receptors, B2 bradykinin receptors, calcium-sensing receptors, KSHV-ORF74 chemokine receptors, NK1 tachykinin receptors, and thyroid-stimulating hormone (TSH) receptors.

[0035] In some examples, G 12 / 13 α is G coded by GNA12 and GNA13 respectively. 12 Type and G 13 It is further subdivided into types.

[0036] G i / o family G i / o α (G inhibitory, G other) (G i / G0 or G i This protein inhibits the production of 3',5'-cyclic AMP (cAMP) from adenosine triphosphate (ATP) by suppressing adenylate cyclase activity, which converts ATP to cAMP.

[0037] In some embodiments, G iGPCRs that interact with α include, but are not limited to, 5-hydroxytryptamine receptors (5-HT receptors) type 5-HT1 and 5-HT5, muscarinic acetylcholine receptors such as M2 and M4, adenosine receptors such as A1 and A3, and α 2A , α 2B , and α 2C Adrenergic receptors, apelin receptors, calcium-sensing receptors, cannabinoid receptors CB1 and CB2, chemokine CXCR4 receptors, dopamine D2, D3, and D4, GABA B Receptors, glutamate receptors such as metabotropic glutamate receptor 2 (mGluR2), metabotropic glutamate receptor 3 (mGluR3), metabotropic glutamate receptor 4 (mGluR4), metabotropic glutamate receptor 6 (mGluR6), metabotropic glutamate receptor 7 (mGluR7), and metabotropic glutamate receptor 8 (mGluR8), histamine receptors such as H3 and H4 receptors, melatonin receptors such as melatonin receptor type 1 (MT1), melatonin receptor type 2 (MT2), and Examples include ratonin receptor type 3 (MT3), niacin receptors such as NIACR1 and NIACR2, opioid receptors such as δ, κ, and μ, and nociceptin receptors, prostaglandin receptors such as prostaglandin E receptor 1 (EP1), prostaglandin E receptor 3 (EP3), prostaglandin F receptor (FP), and thromboxane receptor (TP), somatostatin receptors sst1, sst2, sst3, sst4, and sst5, and trace amine-related receptors 8.

[0038] In some examples, several types of G i There is α, G i α1, G i α2, G i α3, G i α4, G o α, G t , G gust , and G z G is one example. i α1 is coded by GNAI1. G i α2 is coded by GNAI2. G iα3 is coded by GNAI3. G o α(a o The subunit is coded by GNAO1. t This is coded by GNAT1 and GNAT2. gust This is coded by GNAT3. G z It is coded by GNAZ.

[0039] G s family G s α(G stimulatory, G s Alpha subunit, or G s The protein (also known as G) activates the cAMP-dependent pathway through the activation of adenylate cyclase, which converts adenosine triphosphate (ATP) to 3',5'-cyclic AMP (cAMP) and pyrophosphate. In some embodiments, G s GPCRs that interact with α include, but are not limited to, 5-hydroxytryptamine receptor (5-HT receptor) types 5-HT4, 5-HT6, and 5-HT7, adrenocorticotropic hormone receptor (ACTH receptor) (also known as melanocortin receptor 2 or MC2R), and adenosine receptor A 2a Type and A 2b Examples include arginine vasopressin receptor 2 (AVPR2), β-adrenergic receptors β1, β2, and β3, calcitonin receptor, calcitonin gene-related peptide receptor, corticotropin-releasing hormone receptor, dopamine receptor D1-like family receptors such as D1 and D5, follicular-stimulating hormone receptor (FSH receptor), gastric suppressor polypeptide receptor, glucagon receptor, histamine H2 receptor, luteinizing hormone / choriogonadotropin receptor, melanocortin receptors such as MC1R, MC2R, MC3R, MC4R, and MC5R, parathyroid hormone receptor 1, prostaglandin receptors D2 and I2, secretin receptor, thyrotropin receptor, trace amine-related receptor 1, and boxfish opsins.

[0040] In some examples, there are two types of G sα, G s , and G olf There is. G s It is coded by GNAS. G olf This is coded by GNAL.

[0041] Further regulators of the Hippo signaling network In some embodiments, further regulators of the Hippo signaling pathway are the Crumbs (Crb) complex. The Crumbs complex is a key regulator of cell polarity and cell shape. In some examples, the Crumbs complex includes transmembrane CRB proteins that assemble a multiprotein complex that functions in cell polarity. In some examples, the CRB complex is complemented by members of the angiomotin (AMOT) family of adapter proteins that interact with components of the Hippo pathway. In some examples, studies have shown that AMOT directly binds to YAP, promotes YAP phosphorylation, and suppresses its nuclear localization.

[0042] In some cases, further regulators of the Hippo signaling pathway include regulators of the MST kinase family. MST kinases monitor the integrity of the actin cytoskeleton. In some cases, regulators include TAO kinases and cell polarity kinase PAR-1.

[0043] In some examples, further regulators of the Hippo signaling pathway include molecules of adherent junctions. In some examples, E-cadherin (E-cad) represses the nuclear localization and activity of YAP by regulating MST activity. In some embodiments, the E-cad-related protein α-catenin regulates YAP by sequestering the YAP / 14-3-3 complex in the cytoplasm. In other examples, members of the Ajuba protein family interact with Lats1 / 2 kinase activity, thereby preventing the inactivation of YAP / TAZ.

[0044] In some embodiments, additional proteins that interact directly or indirectly with YAP / TAZ include, but are not limited to, Merlin, protocadherin Fat1, MASK1 / 2, HIPK2, PTPN14, RASSF, PP2A, salt-inducible kinase (SIK), Scribble (SCRIB), Scribble-related protein Discs large (Dlg), KIBRA, PTPN14, NPHP3, LKB1, Ajuba, and ZO1 / 2.

[0045] In some embodiments, the compounds described herein are inhibitors of transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, the compounds described herein increase the phosphorylation of transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif, or decrease the dephosphorylation of transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, the compound increases the ubiquitination of transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif, or decreases the deubiquitination of transcriptional coactivator / Yes-associated protein transcriptional coactivator (TAZ / YAP) having a PDZ-binding motif.

[0046] In some embodiments, the compounds disclosed herein are inhibitors of one or more of the proteins encompassed by or related to the Hippo pathway. In some examples, the one or more proteins include the proteins shown in FIG. 1 or FIG. 2. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a G protein and / or its conjugated GPCR. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of a G protein. In some embodiments, the inhibitor of the Hippo pathway is a G q , G q / 11 , G q / 14 , and G q / 15 such as G qα-family protein, G 12 and G 13 such as the G of proteins 12 / 13 α-family, or G i α1, G i α2, G i α3, G i α4, G o α, G t , G gust , and G z such as the G of proteins i is an inhibitor of the α-family. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 11 . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 14 . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G q / 15 . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G 12 . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G 13 . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i α1. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i α2. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i α3. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G i α4. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G o α. In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G t . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G gust . In some embodiments, the inhibitor of the Hippo pathway is an inhibitor of G z .

[0047] In some embodiments, the Hippo pathway inhibitor is an inhibitor of the core protein of the Hippo pathway. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Sav1. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Mob. In some embodiments, the Hippo pathway inhibitor is an inhibitor of YAP. In some embodiments, the Hippo pathway inhibitor is an inhibitor of TAZ. In some embodiments, the Hippo pathway inhibitor is an inhibitor of TEAD.

[0048] In some embodiments, the Hippo pathway inhibitor is an inhibitor of proteins associated with ubiquitination and proteasome degradation pathways. In some embodiments, the Hippo pathway inhibitor is an inhibitor of proteasome degradation pathway proteins (e.g., 26S proteasome).

[0049] In some embodiments, the Hippo pathway inhibitor is an inhibitor of a protein in the Ra superfamily. In some embodiments, the Hippo pathway inhibitor is an inhibitor of a protein in the Rho family. In some embodiments, the Hippo pathway inhibitor is an inhibitor of Cdc42.

[0050] Cdc42 is a member of the Ras superfamily of low molecular weight GTPases. Specifically, Cdc42 belongs to the Rho family of GTPases, whose members are involved in diverse and important cellular processes such as gene transcription, cell-cell adhesion, and cell cycle progression. Cdc42 is involved in cell growth and polarity, and in some cases, Cdc42 is activated by guanine nucleotide exchange factors (GEFs). In some cases, inhibitors of Cdc42 are compounds disclosed herein.

[0051] In some embodiments, the Hippo pathway inhibitor is a deubiquitinating enzyme inhibitor. In some embodiments, the Hippo pathway inhibitor is a cysteine ​​protease or metalloprotease inhibitor. In some embodiments, the Hippo pathway inhibitor is a ubiquitin-specific protease inhibitor. USP47 is a member of the ubiquitin-specific protease (USP / UBP) superfamily of cysteine ​​proteases. In some embodiments, the compounds disclosed herein are inhibitors of USP47.

[0052] compound The compound disclosed herein, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, has the following structure:

[0053] [ka] This refers to compounds that possess [a certain characteristic].

[0054] Pharmaceutical preparations (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide and at least one pharmaceutically acceptable excipient in a solid dosage form.

[0055] In one aspect, this application is, (a) (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide in an amount of approximately 20 w / w% to approximately 50 w / w%, (b) A first filler in an amount of approximately 15 w / w% to approximately 40 w / w%, (c) A second filler in an amount of approximately 15 w / w% to approximately 40 w / w%, (d) A first lubricant in an amount of approximately 1 w / w% to approximately 10 w / w%, (e) A second lubricant in an amount of approximately 0.1 w / w% to approximately 1 w / w%, (f) Approximately 1 w / w% to approximately 5 w / w% disintegrant, and (g) Approximately 0.1 w / w% to 2 w / w% flow accelerator A pharmaceutical formulation in solid dosage form containing [the specified ingredient] is disclosed.

[0056] In some embodiments, the pharmaceutical formulation contains about 20 w / w% to about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 25 w / w% to about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 30 w / w% to about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 35 w / w% to about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 25 w / w% to about 45 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 30 w / w% to about 45 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 35 w / w% to about 45 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 30 w / w% to about 40 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 35 w / w% to about 40 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

[0057] In some embodiments, the pharmaceutical formulation contains about 20 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 25 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 30 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 35 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 37 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 40 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 45 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 50 w / w% of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

[0058] In some embodiments, the pharmaceutical formulation contains about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 300 mg, or about 400 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation contains about 25 mg, about 50 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 25 mg, about 50 mg, about 100 mg, about 150 mg, or about 200 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 25 mg, about 50 mg, or about 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

[0059] In some embodiments, the pharmaceutical formulation contains about 25 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 75 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 125 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 150 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 175 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 200 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the pharmaceutical formulation contains about 300 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide. In some embodiments, the pharmaceutical formulation contains about 400 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide.

[0060] In some embodiments, the fillers disclosed herein increase the bulk in a pharmaceutical formulation. In some embodiments, the pharmaceutical formulation further comprises about 15 w / w% to about 40 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% to about 35 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% to about 30 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% to about 35 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% to about 30 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 25 w / w% to about 30 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% of a first filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% of a first filler. In some embodiments, the pharmaceutical formulation contains about 25 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 26 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 27 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 28 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 29 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 30 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 35 w / w% of the first filler. In some embodiments, the pharmaceutical formulation contains about 40 w / w% of the first filler.

[0061] In some embodiments, the pharmaceutical formulation further comprises about 15 w / w% to about 40 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% to about 35 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% to about 30 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% to about 35 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% to about 30 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 25 w / w% to about 30 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 15 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 20 w / w% of a second filler. In some embodiments, the pharmaceutical formulation comprises about 25 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 26 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 27 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 28 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 29 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 30 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 35 w / w% of a second filler. In some embodiments, the pharmaceutical formulation contains about 40 w / w% of a second filler.

[0062] In some embodiments, the first and second fillers are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (starch 1500).

[0063] In some embodiments, the first filler is selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the first filler is lactose. In some embodiments, lactose is lactose monohydrate. In some embodiments, the first filler is lactose monohydrate. In some embodiments, the first filler is erythritol. In some embodiments, the first filler is sorbitol. In some embodiments, the first filler is mannitol. In some embodiments, mannitol is mannitol 200SD. In some embodiments, the first filler is mannitol 200SD. In some embodiments, the first filler is dicalcium phosphate. In some embodiments, the first filler is microcrystalline cellulose. In some embodiments, the first filler is silicified microcrystalline cellulose. In some embodiments, the first filler is starch. In some embodiments, the first filler is pregelatinized starch (starch 1500).

[0064] In some embodiments, the second filler is selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (starch 1500). In some embodiments, the second filler is lactose. In some embodiments, lactose is lactose monohydrate. In some embodiments, the second filler is lactose monohydrate. In some embodiments, the second filler is erythritol. In some embodiments, the second filler is sorbitol. In some embodiments, the second filler is mannitol. In some embodiments, mannitol is mannitol 200SD. In some embodiments, the second filler is mannitol 200SD. In some embodiments, the second filler is dicalcium phosphate. In some embodiments, the second filler is microcrystalline cellulose. In some embodiments, the second filler is silicified microcrystalline cellulose. In some embodiments, the second filler is starch. In some embodiments, the second filler is pregelatinized starch (starch 1500).

[0065] In some embodiments, the lubricants disclosed herein are compounds that prevent, reduce, or inhibit adhesion or friction between materials. In some embodiments, the pharmaceutical formulation further comprises about 1 w / w% to about 10 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 2 w / w% to about 10 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 3 w / w% to about 10 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 4 w / w% to about 10 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 5 w / w% to about 10 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1 w / w% to about 9 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation comprises about 1 w / w% to about 8 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% to about 7 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% to about 6 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% to about 5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 2 w / w% to about 8 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 3 w / w% to about 7 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 3 w / w% to about 6 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 4 w / w% to about 6 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 2 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 3 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 3.5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 4 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 4.5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 5.5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 6 w / w% of a first lubricant.In some embodiments, the pharmaceutical formulation contains about 6.5 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 7 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 8 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 9 w / w% of a first lubricant. In some embodiments, the pharmaceutical formulation contains about 10 w / w% of a first lubricant.

[0066] In some embodiments, the pharmaceutical formulation further comprises about 0.1 w / w% to about 1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.2 w / w% to about 1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.3 w / w% to about 1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.4 w / w% to about 1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.5 w / w% to about 1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1 w / w% to about 0.9 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1 w / w% to about 0.8 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation comprises about 0.1 w / w% to about 0.7 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 0.6 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 0.5 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% to about 0.7 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.4 w / w% to about 0.7 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% to about 0.7 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% to about 0.6 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.4 w / w% to about 0.6 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% to about 0.6 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.2 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.4 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.6 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.7 w / w% of a second lubricant.In some embodiments, the pharmaceutical formulation contains about 0.8 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 0.9 w / w% of a second lubricant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% of a second lubricant.

[0067] In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0 w / w% of the second lubricant is intragranular and about 0.5 w / w% is extragranular. In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0.1 w / w% of the second lubricant is intragranular and about 0.4 w / w% is extragranular. In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0.2 w / w% of the second lubricant is intragranular and about 0.3 w / w% is extragranular. In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0.3 w / w% of the second lubricant is intragranular and about 0.2 w / w% is extragranular. In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0.4 w / w% of the second lubricant is intragranular and about 0.1 w / w% is extragranular. In some embodiments, in a pharmaceutical formulation containing about 0.5 w / w% of a second lubricant, about 0.5 w / w% of the second lubricant is intragranular and about 0 w / w% is extragranular.

[0068] In some embodiments, the first lubricant and the second lubricant are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate.

[0069] In some embodiments, the first lubricant is selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the first lubricant is sodium laureth sulfate. In some embodiments, the first lubricant is sodium lauryl sulfate. In some embodiments, the first lubricant is magnesium stearate. In some embodiments, the first lubricant is stearic acid. In some embodiments, the first lubricant is sodium stearate. In some embodiments, the first lubricant is calcium stearate. In some embodiments, the first lubricant is ammonium lauryl sulfate. In some embodiments, the first lubricant is sodium stearyl fumarate.

[0070] In some embodiments, the second lubricant is selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate. In some embodiments, the second lubricant is sodium laureth sulfate. In some embodiments, the second lubricant is sodium lauryl sulfate. In some embodiments, the second lubricant is magnesium stearate. In some embodiments, the second lubricant is stearic acid. In some embodiments, the second lubricant is sodium stearate. In some embodiments, the second lubricant is calcium stearate. In some embodiments, the second lubricant is ammonium lauryl sulfate. In some embodiments, the second lubricant is sodium stearyl fumarate.

[0071] In some embodiments, the disintegrants disclosed herein promote the degradation or disintegration of the pharmaceutical formulation after administration. In some embodiments, the pharmaceutical formulation further comprises about 1 w / w% to about 5 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1 w / w% to about 4 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1 w / w% to about 3 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 1 w / w% to about 2 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 w / w% to about 5 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 w / w% to about 4 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2.5 w / w% to about 3.5 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation comprises about 2 w / w% to about 3 w / w% of the disintegrant. In some embodiments, the pharmaceutical formulation contains about 3 w / w% to about 4 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation contains about 1 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 2 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 2.5 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 3 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 3.5 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 4 w / w% of disintegrant. In some embodiments, the pharmaceutical formulation further contains about 5 w / w% of disintegrant.

[0072] In some embodiments, the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropylcellulose, and poly(vinyl alcohol). In some embodiments, the disintegrant is povidone. In some embodiments, the disintegrant is crospovidone. In some embodiments, the disintegrant is hypromellose. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is carboxymethylcellulose. In some embodiments, the disintegrant is hydroxypropylcellulose. In some embodiments, the disintegrant is poly(vinyl alcohol).

[0073] In some embodiments, the flow promoters disclosed herein improve the flow properties of powder mixtures. In some embodiments, the pharmaceutical formulation further comprises about 0.1 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.2 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.3 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.4 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.5 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.6 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.7 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation comprises about 0.8 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.9 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1 w / w% to about 2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.9 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.8 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.7 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.6 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.5 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.4 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.3 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.2 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% to about 1.1 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% to about 1.7 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% to about 1.5 w / w% of a flow promoter.In some embodiments, the pharmaceutical formulation contains about 0.7 w / w% to about 1.3 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.9 w / w% to about 1.1 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1 w / w% to about 1.5 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% to about 1 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.1 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.3 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.4 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.5 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.6 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.7 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.8 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 0.9 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.1 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.2 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.3 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.4 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.5 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.6 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.7 w / w% of the flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.8 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 1.9 w / w% of a flow promoter. In some embodiments, the pharmaceutical formulation contains about 2 w / w% of a flow promoter.

[0074] In some embodiments, the flow enhancer is selected from silicates, silicon dioxide, and talc. In some embodiments, the flow enhancer is a silicate. In some embodiments, the flow enhancer is silicon dioxide. In some embodiments, the silicon dioxide is colloidal silicon dioxide. In some embodiments, the flow enhancer is colloidal silicon dioxide. In some embodiments, the flow enhancer is talc.

[0075] In some embodiments, (a) Approximately 37 w / w% (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, (b) Lactose monohydrate at approximately 26.7 w / w%, (c) Approximately 26.7 w / w% mannitol, (d) Approximately 5 w / w% sodium lauryl sulfate, (e) Approximately 0.5 w / w% magnesium stearate, (f) Approximately 3 w / w% croscarmellose sodium, and (g) Approximately 1 w / w% colloidal silicon dioxide A pharmaceutical formulation in solid dosage form containing the above is disclosed herein.

[0076] In some embodiments, the pharmaceutical formulation has a half-life of at least 1 day. In some embodiments, the pharmaceutical formulation has a half-life of at least 2 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 3 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 4 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 5 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 6 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 7 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 8 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 9 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 10 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 11 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 12 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 13 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 14 days. In some embodiments, the pharmaceutical formulation has a half-life of at least 15 days.

[0077] In some embodiments, the pharmaceutical formulation has a half-life of 1 to 20 days. In some embodiments, the pharmaceutical formulation has a half-life of 2 to 19 days. In some embodiments, the pharmaceutical formulation has a half-life of 3 to 18 days. In some embodiments, the pharmaceutical formulation has a half-life of 4 to 17 days. In some embodiments, the pharmaceutical formulation has a half-life of 5 to 16 days. In some embodiments, the pharmaceutical formulation has a half-life of 6 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 7 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 8 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 9 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 10 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 11 to 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 to 15 days.

[0078] In some embodiments, the pharmaceutical formulation has a half-life of 1 day. In some embodiments, the pharmaceutical formulation has a half-life of 2 days. In some embodiments, the pharmaceutical formulation has a half-life of 3 days. In some embodiments, the pharmaceutical formulation has a half-life of 4 days. In some embodiments, the pharmaceutical formulation has a half-life of 5 days. In some embodiments, the pharmaceutical formulation has a half-life of 6 days. In some embodiments, the pharmaceutical formulation has a half-life of 7 days. In some embodiments, the pharmaceutical formulation has a half-life of 8 days. In some embodiments, the pharmaceutical formulation has a half-life of 9 days. In some embodiments, the pharmaceutical formulation has a half-life of 10 days. In some embodiments, the pharmaceutical formulation has a half-life of 11 days. In some embodiments, the pharmaceutical formulation has a half-life of 12 days. In some embodiments, the pharmaceutical formulation has a half-life of 13 days. In some embodiments, the pharmaceutical formulation has a half-life of 14 days. In some embodiments, the pharmaceutical formulation has a half-life of 15 days. In some embodiments, the pharmaceutical formulation has a half-life of 16 days. In some embodiments, the pharmaceutical formulation has a half-life of 17 days. In some embodiments, the pharmaceutical formulation has a half-life of 18 days. In some embodiments, the pharmaceutical formulation has a half-life of 19 days. In some embodiments, the pharmaceutical formulation has a half-life of 20 days.

[0079] Dosage form In some embodiments, pharmaceutical formulations comprising (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide as described herein are incorporated into solid unit dosage forms. The term “solid unit dosage form” means a dosage form intended to be swallowed as a single unit selected from the group consisting of powders, tablets, bite-disintegration tablets, chewable tablets, caplets, capsules, gel capsules, effervescent powders, rapidly disintegrating tablets, abuse-preventing tablets, controlled-release tablets, controlled-release caplets, controlled-release capsules, and aqueous suspensions produced from powders.

[0080] In some embodiments, the solid dosage form is a powder. In some embodiments, the solid dosage form is a tablet. In some embodiments, the solid dosage form is a chewable tablet. In some embodiments, the solid dosage form is a caplet. In some embodiments, the solid dosage form is a capsule. In some embodiments, the solid dosage form is a gel capsule. In some embodiments, the solid dosage form is an effervescent powder. In some embodiments, the solid dosage form is a rapidly disintegrating tablet. In some embodiments, the solid dosage form is an abuse prevention tablet. In some embodiments, the solid dosage form is a controlled-release tablet. In some embodiments, the solid dosage form is a controlled-release caplet. In some embodiments, the solid dosage form is a controlled-release capsule. In some embodiments, the solid dosage form is an aqueous suspension produced from the powder.

[0081] In some embodiments, the capsules disclosed herein are rigid gelatin capsules. In some embodiments, the rigid gelatin capsules comprise gelatin and titanium dioxide. In some embodiments, the rigid gelatin capsule is gelatin. In some embodiments, the rigid gelatin capsule is titanium dioxide. In some embodiments, the capsule is gelatin. In some embodiments, the capsule is titanium dioxide.

[0082] In some embodiments, the hard gelatin capsules disclosed herein further comprise FD&C Red 40 and FD&C Blue 1.

[0083] In some embodiments, the solid dosage form is a dry granulated blend.

[0084] method In some embodiments, the present disclosure provides a method for treating cancer in a subject requiring treatment for cancer, comprising administering a pharmaceutical formulation disclosed herein to the subject requiring treatment for cancer.

[0085] In some embodiments, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation disclosed herein, comprising (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide. In some embodiments, the Disclosure provides a method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a therapeutically effective amount of a pharmaceutical formulation disclosed herein, comprising (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide and at least one pharmaceutically acceptable excipient.

[0086] In some embodiments, the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid carcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer. In some embodiments, the cancer is mesothelioma. In some embodiments, the cancer is hepatocellular carcinoma. In some embodiments, the cancer is meningioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor. In some embodiments, the cancer is schwannoma. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is cutaneous neurofibroma. In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioblastoma. In some embodiments, the cancer is endometrial adenosquamous carcinoma. In some embodiments, the cancer is anaplastic thyroid carcinoma. In some embodiments, the cancer is gastric adenocarcinoma. In some embodiments, the cancer is esophageal adenocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian serous adenocarcinoma. In some embodiments, the cancer is melanoma. In some embodiments, the cancer is breast cancer.

[0087] In some embodiments, the present disclosure provides a method for treating cancer in a subject requiring treatment for cancer, comprising administering a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide to the subject requiring treatment for cancer, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 3 days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 4 days. In some embodiments, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 5 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 6 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 7 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 8 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 9 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 10 days.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 11 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 12 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 13 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 14 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 15 days. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 1 week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least 3 weeks.

[0088] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered as an oral formulation.

[0089] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in capsule form.

[0090] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 10 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 15 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 20 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 25 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 50 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 75 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 100 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 125 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 150 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 175 mg per day.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 200 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 225 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 250 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 275 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 300 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 325 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 350 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 375 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 400 mg per day.

[0091] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 100 mg, 150 mg, or 200 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, or 100 mg per day.

[0092] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 50 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 75 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 100 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 125 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 150 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 175 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 200 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 250 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 300 mg per day.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 350 mg per day. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 400 mg per day.

[0093] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for one week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for four weeks.

[0094] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered daily for one week, followed by no administration for the next two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 200 mg daily for one week, followed by no administration for the next two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 150 mg daily for one week, followed by no administration for the next two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 100 mg daily for one week, followed by no administration for the next two weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for one week, followed by no administration for the next two weeks.

[0095] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, and a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, and a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 200 mg daily for 2 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 150 mg daily for 2 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg daily for 2 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 3-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for 2 weeks, followed by no administration for the next week.

[0096] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 4-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered daily for one week, followed by no administration for the next three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a 4-week cycle, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 200 mg daily for one week, followed by no administration for the next three weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 150 mg daily for one week, followed by no administration for the next 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at a dose of 100 mg daily for one week, followed by no administration for the next 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for one week, followed by no administration for the next three weeks.

[0097] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, and a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, followed by no administration for the next 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, and a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 200 mg daily for 2 weeks, followed by no administration for the next 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 150 mg daily for 2 weeks, followed by no administration for the next 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg daily for 2 weeks, followed by no administration for the next 2 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for 2 weeks, followed by no administration for the next 2 weeks.

[0098] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide being administered daily for 3 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, with a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide being administered at a dose of 200 mg daily for 3 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 150 mg daily for 3 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg daily for 3 weeks, followed by no administration for the next week. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a 4-week cycle, or a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for 3 weeks, followed by no administration for the next week.

[0099] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 25 mg once daily for two weeks, followed by a dose of 100 mg once weekly. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg once daily for two weeks, followed by a dose of 100 mg once weekly. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 75 mg once daily for two weeks, followed by a dose of 100 mg once weekly. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg once daily for two weeks, followed by a dose of 100 mg once weekly.

[0100] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 15 days, followed by weekly administration for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg once daily for 15 days, followed by weekly administration of 50 mg for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg once daily for 15 days, followed by weekly administration of 100 mg for 3 weeks. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg once daily for 15 days, followed by a dose of 100 mg once weekly for 3 weeks.

[0101] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least one cycle. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least two cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least three cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least four cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 5 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 6 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 7 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 8 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least nine cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least ten cycles.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 11 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 12 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 18 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 24 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 36 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 48 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 60 cycles.

[0102] In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in one cycle. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in two cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in three cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in four cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 5 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 6 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 7 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 8 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in nine cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in ten cycles.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 11 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 12 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 18 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 24 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 30 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 36 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 48 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 60 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over 72 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over 84 cycles.In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over 96 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over 108 cycles. In some embodiments, a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over 120 cycles.

[0103] In some embodiments, 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for two weeks, and then not administered for the following two weeks. In some embodiments, 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for two weeks, followed by no administration for the next two weeks, and then 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for two weeks, followed by no administration for the next two weeks, and 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 8 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 12 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 24 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over at least 36 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least 48 cycles.In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least 60 cycles.

[0104] In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in one cycle. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in two cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in three cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in four cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 5 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 6 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 7 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 8 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 9 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 10 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 11 cycles.In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 12 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 18 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 24 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 30 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 36 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 48 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 60 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 72 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 84 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 96 cycles. In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 108 cycles.In some embodiments, 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 120 cycles.

[0105] Further embodiments provided herein include combinations of one or more of the specific embodiments described above.

[0106] disease cancer In some embodiments, the pharmaceutical formulations and methods disclosed herein are useful for the treatment of cancer. In some embodiments, pharmaceutical formulations and methods for treating cancer in subjects requiring treatment of cancer are provided herein, comprising administering to a subject requiring treatment of cancer a pharmaceutical formulation comprising a pharmaceutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide disclosed herein. In some embodiments, pharmaceutical formulations comprising a pharmaceutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide are provided herein for use in the treatment of cancer in subjects requiring treatment of cancer, comprising administering to a subject requiring treatment of cancer. In some embodiments, the use of a pharmaceutical formulation containing a pharmaceutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide disclosed herein in the manufacture of a drug for treating cancer is provided herein.

[0107] In some embodiments, cancer is mediated by the activation of a transcription-coupled activator / Yes-related protein transcription-coupled activator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, cancer is mediated by the modulation of the interaction of YAP / TAZ with TEAD. In some embodiments, cancer is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.

[0108] In some embodiments, cancer is a solid tumor. In some examples, cancer is a hematological malignancy. In some examples, the solid tumor is a sarcoma or carcinoma. In some examples, the solid tumor is a sarcoma. In some examples, the solid tumor is a carcinoma.

[0109] Examples of sarcomas include, but are not limited to, alveolar rhabdomyosarcoma, hydatidiform soft tissue sarcoma, ameloblastoma, angiosarcoma, chondrosarcoma, chordoma, clear cell sarcoma of soft tissue, dedifferentiated liposarcoma, desmoid, fibroplastic round cell tumor, embryonal rhabdomyosarcoma, epithelioid fibrosarcoma, epithelioid hemangioendothelioma, epithelioid sarcoma, nasal neuroblastoma, Ewing's sarcoma, extrarenal rhabdoid tumor, and extraskeletal myxoid chondrosarcoma. These include tumors, extraskeletal osteosarcoma, fibrosarcoma, giant cell tumor, hemangiopericytoma, infantile fibrosarcoma, inflammatory myofibroblastoma, Kaposi's sarcoma, leiomyosarcoma of bone, liposarcoma, liposarcoma of bone, malignant fibrous histiocytoma (MFH), malignant fibrous histiocytoma (MFH) of bone, malignant mesenchymal tumor, malignant peripheral nerve schwannoma, mesenchymal chondrosarcoma, myxofibrosarcoma, myxolytic liposarcoma, myxoinflammatory fibroblastic sarcoma, neoplasms with perivascular epithelioid cell differentiation, osteosarcoma, paraosteal osteosarcoma, neoplasms with perivascular epithelioid cell differentiation, periosteal osteosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, PNET / extraskeletal Ewing tumor, rhabdomyosarcoma, round cell liposarcoma, small cell osteosarcoma, solitary fibrous tumor, synovial sarcoma, and telangiectatic osteosarcoma.

[0110] Similar cancers include, but are not limited to, adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal carcinoma, appendiceal carcinoma, bile duct carcinoma (i.e., intrahepatic bile duct carcinoma), bladder carcinoma, brain tumor, breast carcinoma, cervical carcinoma, colon carcinoma, cancer of unknown primary origin (CUP), esophageal carcinoma, eye carcinoma, fallopian tube carcinoma, gastrointestinal carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, medulloblastoma, melanoma, oral carcinoma, ovarian carcinoma, pancreatic carcinoma, parathyroid disease, penile carcinoma, pituitary tumor, prostate carcinoma, rectal carcinoma, skin carcinoma, gastric carcinoma, ovarian carcinoma, laryngeal carcinoma, thyroid carcinoma, uterine carcinoma, vaginal carcinoma, and vulvar carcinoma. In some cases, liver carcinoma is primary liver carcinoma.

[0111] In some cases, cancer is selected from uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, stomach cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, cancer is uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, stomach cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, cancer is uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, cancer is uveal melanoma. In some cases, cancer is mesothelioma. In some cases, cancer is esophageal cancer. In some cases, cancer is liver cancer. In some cases, the cancer is primary liver cancer.

[0112] In some cases, cancer is a hematological malignancy. In some embodiments, hematological malignancies are leukemia, lymphoma, myeloma, non-Hodgkin lymphoma, Hodgkin lymphoma, T-cell malignancies, or B-cell malignancies. In some cases, hematological malignancies are T-cell malignancies. Exemplary T-cell malignancies include, but are not limited to, peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma, hematoblastic lymphoma, cutaneous T-cell lymphoma, adult T-cell leukemia / lymphoma (ATLL), blastic NK-cell lymphoma, enteropathy-type T-cell lymphoma, hematosplenic gamma-delta T-cell lymphoma, lymphoblastic lymphoma, nasal NK / T lymphoma, and treatment-associated T-cell lymphoma.

[0113] In some embodiments, hematological malignancies are B-cell malignancies. Exemplary B-cell malignancies include, but are not limited to, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, and non-CLL / SLL lymphoma. In some embodiments, cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, non-Burkitt lympho-high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large B-cell lymphoma, progenitor B-lymphoblastic lymphoma, B-cell pre-lymphoblastic leukemia, lymphoplasmacytic lymphoma, perisplenic zone lymphoma, plasmacytoma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0114] In some examples, cancer is recurrent or refractory cancer. In some embodiments, recurrent or refractory cancer is recurrent or refractory solid tumor. In some embodiments, recurrent or refractory solid tumor is recurrent or refractory sarcoma or recurrent or refractory cell tumor. In some embodiments, recurrent or refractory cell tumor includes adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal carcinoma, appendiceal carcinoma, bile duct carcinoma (i.e., intrahepatic bile duct carcinoma), bladder carcinoma, brain tumor, breast carcinoma, cervical carcinoma, colon carcinoma, cancer of unknown primary origin (CUP), esophageal carcinoma, eye carcinoma, fallopian tube carcinoma, gastrointestinal carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, medulloblastoma, melanoma, oral carcinoma, ovarian carcinoma, pancreatic carcinoma, parathyroid disease, penile carcinoma, pituitary tumor, prostate carcinoma, rectal carcinoma, skin carcinoma, gastric carcinoma, ovarian carcinoma, laryngeal carcinoma, thyroid carcinoma, uterine carcinoma, vaginal carcinoma, and vulvar carcinoma.

[0115] In some cases, recurrent or refractory cancer is selected from recurrent or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, recurrent or refractory cancer is recurrent or refractory uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, recurrent or refractory cancer is recurrent or refractory uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, recurrent or refractory cancer is recurrent or refractory uveal melanoma. In some cases, recurrent or refractory cancer is recurrent or refractory mesothelioma. In some cases, recurrent or refractory cancer is recurrent or refractory esophageal cancer. In some cases, recurrent or refractory cancer is recurrent or refractory liver cancer. In some cases, recurrent or refractory cancer is recurrent or refractory primary liver cancer.

[0116] In some cases, relapsed or refractory cancer is a relapsed or refractory hematological malignancy. In some embodiments, a relapsed or refractory hematological malignancy is a relapsed or refractory leukemia, a relapsed or refractory lymphoma, a relapsed or refractory myeloma, a relapsed or refractory non-Hodgkin lymphoma, a relapsed or refractory Hodgkin lymphoma, a relapsed or refractory T-cell malignancy, or a relapsed or refractory B-cell malignancy. In some cases, a relapsed or refractory hematological malignancy is a relapsed or refractory T-cell malignancy. In some cases, a relapsed or refractory hematological malignancy is a relapsed or refractory B-cell malignancy, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, non-Burkitt lympho-high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large B-cell lymphoma, progenitor B-lymphoblastic lymphoma, B-cell pre-lymphoblastic leukemia, lymphoplasmacytic lymphoma, perisplenic zone lymphoma, plasmacytoma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0117] In some cases, cancer is metastatic cancer. In some cases, metastatic cancer is metastatic solid tumor. In some cases, metastatic solid tumor is metastatic sarcoma or metastatic carcinoma. In some embodiments, metastatic cell tumors include adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, anaplastic carcinoma, large cell carcinoma, small cell carcinoma, anal carcinoma, appendiceal carcinoma, bile duct carcinoma (i.e., intrahepatic bile duct carcinoma), bladder carcinoma, brain tumor, breast carcinoma, cervical carcinoma, colon carcinoma, carcinoma of unknown primary origin (CUP), esophageal carcinoma, eye carcinoma, fallopian tube carcinoma, gastrointestinal carcinoma, kidney carcinoma, liver carcinoma, lung carcinoma, medulloblastoma, melanoma, oral carcinoma, ovarian carcinoma, pancreatic carcinoma, parathyroid disease, penile carcinoma, pituitary tumor, prostate carcinoma, rectal carcinoma, skin carcinoma, gastric carcinoma, ovarian carcinoma, laryngeal carcinoma, thyroid carcinoma, uterine carcinoma, vaginal carcinoma, and vulvar carcinoma.

[0118] In some cases, metastatic cancer is selected from metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, and meningioma. In some cases, metastatic cancer is metastatic uveal melanoma, mesothelioma, esophageal cancer, liver cancer, breast cancer, hepatocellular carcinoma, lung adenocarcinoma, glioma, colon cancer, colorectal cancer, gastric cancer, medulloblastoma, ovarian cancer, esophageal squamous cell carcinoma, sarcoma, Ewing's sarcoma, head and neck cancer, prostate cancer, or meningioma. In some cases, metastatic cancer is metastatic uveal melanoma, mesothelioma, esophageal cancer, or liver cancer. In some cases, metastatic cancer is metastatic uveal melanoma. In some cases, metastatic cancer is metastatic mesothelioma. In some cases, metastatic cancer is metastatic esophageal cancer. In some cases, metastatic cancer is metastatic liver cancer. In some cases, metastatic cancer is metastatic primary liver cancer.

[0119] In some cases, metastatic cancer is a metastatic hematological malignancy. In some embodiments, a metastatic hematological malignancy is metastatic leukemia, metastatic lymphoma, metastatic myeloma, metastatic non-Hodgkin lymphoma, metastatic Hodgkin lymphoma, metastatic T-cell malignancy, or metastatic B-cell malignancy. In some cases, a metastatic hematological malignancy is a metastatic T-cell malignancy. In some cases, a metastatic hematological malignancy is a metastatic B-cell malignancy, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), high-risk CLL, or non-CLL / SLL lymphoma. In some embodiments, cancer is follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, non-Burkitt lympho-high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large B-cell lymphoma, progenitor B-lymphoblastic lymphoma, B-cell pre-lymphoblastic leukemia, lymphoplasmacytic lymphoma, perisplenic zone lymphoma, plasmacytoma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary exudative lymphoma, or lymphomatoid granulomatosis.

[0120] In some cases, cancers include mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, anaplastic thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

[0121] Non-cancerous signs In some embodiments, the pharmaceutical formulations and methods disclosed herein are useful for the treatment of polycystic kidney disease. In some embodiments, the pharmaceutical formulations and methods disclosed herein are useful for the treatment of hepatic fibrosis. In some embodiments, a method for treating polycystic kidney disease in a subject requiring treatment of polycystic kidney disease is provided herein, comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of polycystic kidney disease. In some embodiments, a compound for use in the treatment of polycystic kidney disease in a subject requiring treatment of polycystic kidney disease is provided herein, comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of polycystic kidney disease. In some embodiments, the use of the compound disclosed herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating polycystic kidney disease is provided herein. In some embodiments, methods for treating hepatic fibrosis in subjects requiring treatment of hepatic fibrosis are provided herein, comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of hepatic fibrosis. In some embodiments, compounds for use in treating hepatic fibrosis in subjects requiring treatment of hepatic fibrosis are provided herein, comprising administering a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of hepatic fibrosis. In some embodiments, the use of a compound disclosed herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating hepatic fibrosis is provided herein.

[0122] congenital disease In some embodiments, the pharmaceutical formulations and methods disclosed herein are useful for the treatment of congenital disorders. In some embodiments, a method for treating a congenital disorder in a subject requiring treatment of the congenital disorder is provided herein, comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of the congenital disorder. In some embodiments, a compound for use in the treatment of a congenital disorder in a subject requiring treatment of the congenital disorder is provided herein, comprising administering a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof to a subject requiring treatment of the congenital disorder. In some embodiments, the use of the compound disclosed herein or a pharmaceutically acceptable salt thereof in the manufacture of a drug for treating a congenital disorder is provided herein. In some embodiments, the congenital disorder is mediated by the activation of a transcription-coupled activator / Yes-related protein transcription-coupled activator (TAZ / YAP) having a PDZ-binding motif. In some embodiments, the congenital disorder is characterized by a mutant Gα-protein. In some embodiments, the mutant Gα-protein is selected from G12, G13, Gq, G11, Gi, Go, and Gs. In some embodiments, the mutant Gα-protein is G12. In some embodiments, the mutant Gα-protein is G13. In some embodiments, the mutant Gα-protein is Gq. In some embodiments, the mutant Gα-protein is G11. In some embodiments, the mutant Gα-protein is Gi. In some embodiments, the mutant Gα-protein is Go. In some embodiments, the mutant Gα-protein is Gs.

[0123] In some embodiments, congenital disorders are the result of genetic abnormalities, intrauterine environment, morphogenesis-related errors, infection, epigenetic modifications in the parental germline, or chromosomal abnormalities. Examples of congenital disorders include, but are not limited to, Sturge-Weber syndrome, port-wine stain, Holt-Oram syndrome, abdominal wall defects, Becker muscular dystrophy (BMD), biotinidase deficiency, Charcot-Marie-Tooth disease (CMT), cleft lip, cleft palate, congenital adrenal hyperplasia, congenital heart defects, congenital hypothyroidism, congenital muscular dystrophy, cystic fibrosis, Down syndrome, Duchenne muscular dystrophy, fragile X syndrome, Friedreich's ataxia, galactosemia, abnormal hemoglobinosis, Krabbe disease, limb-girdle muscular dystrophy, medium-chain acyl-CoA dehydrogenase deficiency, myasthenia gravis, neural tube defects, phenylketonuria, Pompe disease, severe combined immunodeficiency (SCID), Stickler syndrome (or hereditary progressive arthropathy of the eye), spinal muscular atrophy, and trisomy 18. In some embodiments, the congenital disorder is Sturge-Weber syndrome or a port-wine stain. In some embodiments, the congenital disorder is Sturge-Weber syndrome. In some embodiments, the congenital disorder is a port-wine stain.

[0124] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field to which the claimed subject matter belongs. It will be understood that the general statements above and the detailed statements below are illustrative and descriptive, and not limited to any particular subject matter.

[0125] In this application, the use of the singular form includes the plural form unless otherwise specified. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include multiple references unless otherwise explicitly indicated. For example, the term "sample" includes multiple samples and mixtures thereof. In this application, the use of "or" means "and / or" unless otherwise specified. Furthermore, the use of the term "including" is not limited to other forms such as "include," "includes," and "included."

[0126] Where used herein, various embodiments may be presented in scope form. It should be understood that scope form is for convenience and brevity only and should not be construed as an irrevocable limitation to the scope of this disclosure. Therefore, scope descriptions should be considered to specifically disclose any possible sub-scopes and the individual numbers within those scopes. For example, a scope description such as 1–6 should be considered to specifically disclose sub-scopes such as 1–3, 1–4, 1–5, 2–4, 2–6, 3–6, and the individual numbers within those scopes, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the scope.

[0127] Where used herein, in some embodiments, ranges and quantities are expressed as specific values ​​or ranges preceded by “about.” “About” also includes the exact quantity. Thus, “about 5 μL” means “about 5 μL” and “5 μL.” Generally, the term “about” includes quantities expected to be within experimental error.

[0128] The chapter headings used herein are for structural purposes only and should not be construed as limiting the subjects described.

[0129] As used herein, the terms “individual,” “subject,” and “patient” mean any mammal. In some embodiments, the mammal is a human. In some embodiments, the mammal is a non-human. No term requires, or is not limited to, a situation characterized by supervision (e.g., continuous or intermittent) of a healthcare professional (e.g., physician, registered nurse, nurse practitioner, physician's assistant, ward staff, or hospice staff).

[0130] As used herein and in the appended claims, unless otherwise specified, the following terms have the meanings set forth below:

[0131] "Optional" or "at will" means that the event or situation described later may or may not occur, and that this description includes examples of both the event or situation occurring and the situation not occurring. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted, and that the description includes both substituted aryl radicals and aryl radicals that do not undergo substitution.

[0132] The terms “formulation” and “composition,” as used herein, are interchangeable and refer to a mixture of two or more compounds, elements, or molecules. In some embodiments, the terms “formulation” and “composition” may be used to refer to a mixture of one or more active agents with a carrier or other excipient.

[0133] Where used herein, “treatment,” “to treat,” “to alleviate,” or “to improve” are interchangeable herein. These terms refer to methods for obtaining beneficial or desirable outcomes, including, but not limited to, therapeutic and / or preventive benefits. “Therapeutic benefit” means the eradication or improvement of the underlying disease being treated. Similarly, therapeutic benefit is achieved in some embodiments by the eradication or improvement of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in the patient despite the patient having the underlying disease. With respect to preventive benefit, in some embodiments, the composition is administered to patients at risk of developing a particular disease, or patients reporting one or more physiological symptoms of the disease, even if the disease has not been diagnosed.

[0134] The terms “effective dose” or “therapeutically effective dose,” as used herein, refer to a sufficient amount of an administered drug or compound that reduces, to some extent, one or more of the symptoms of the disease or illness being treated. As a result, the signs, symptoms, or causes of the disease may be reduced and / or mitigated, or any other desired change may occur in the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing a compound as disclosed herein that is necessary to clinically significantly reduce the disease. The appropriate “effective” dose in any individual case may be determined using techniques such as dose escalation studies.

[0135] The terms “active agent,” “active drug,” “drug,” and “active ingredient,” and their variations, are used interchangeably to refer to drugs or substances that have a specific or selected physiological activity that can be measured when administered to a subject in a significant or effective amount.

[0136] While not intended to be constrained by any particular theory, certain solid forms are characterized by physical properties (e.g., stability, solubility, and dissolution rate) that are suitable for pharmaceutical and therapeutic dosage forms. Furthermore, while not intended to be constrained by any particular theory, certain solid forms are characterized by physical properties (e.g., density, compressibility, hardness, morphology, cleavage, tackiness, solubility, water absorption, electrical properties, thermal behavior, solid-state reactivity, physical stability, and chemical stability) that influence certain processes (e.g., yield, filtration, washing, drying, grinding, mixing, tableting, flowability, dissolution, formulation, and freeze-drying) that make a particular solid form suitable for the manufacture of a solid dosage form. Such properties can be determined using certain analytical chemistry techniques, including solid-state analysis techniques described herein and known in the art (e.g., X-ray diffraction, microscopy, spectroscopy, and thermal analysis). [Examples]

[0137] The following exemplary embodiments are representative of the stimulation, systems, and methods described herein and are not intended to limit them in any way.

[0138] This disclosure relates to (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide as described in U.S. Patent No. 11,420,935, which is incorporated herein by reference in whole.

[0139] Example 1. Preparation of a drug product Dosage form (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide was supplied as 25 mg and 100 mg capsules. These hard gelatin capsules were filled with a dry granule blend of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide and excipients, used for solid oral formulations. The 25 mg dose strength was provided in size 4 off-white capsules. The 100 mg dose strength was provided in size 0 Swedish orange capsules.

[0140] combination Table 1 shows the quantitative formulation and function of each component in the capsule.

[0141] [Table 1]

[0142] Table 2 shows the quantitative formulation of the capsule shell. All components within the capsule shell, in addition to the excipients for formulation, conform to the standards of the official compendium and are generally considered safe. The drug product shall not contain any novel excipients.

[0143] [Table 2]

[0144] Types of containers and seals for dosage forms (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide 25 mg capsules are packaged in 50 75 cc white round HDPE bottles with induction seals and child-resistant caps. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide 100 mg capsules are packaged in 25 75 cc white round HDPE bottles with induction seals and child-resistant caps.

[0145] Example 2 - Clinical Trial Figure 3 shows the experimental design, including the main eligibility criteria for the Phase 1 clinical trial, the Part 1 dose escalation, and the Part 2 dose expansion. Part 2 began with the first patient enrolled in the first expanded cohort, and consisted of a 4-week cycle of 100 mg / day for 2 weeks followed by a 2-week rest period.

[0146] Table 3 shows the baseline characteristics of cohorts 1-12 in Part 1 of the Phase 1 clinical trial.

[0147] [Table 3]

[0148] Table 4 details the dosage and dosing schedule of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered in Part 1 of the Phase 1 clinical trial.

[0149] [Table 4]

[0150] Generally, as shown in Figures 4A to 4C, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide resulted in dose-proportional exposure after oral administration. In Figure 4A, the higher the dose level of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, the greater the mean C between day 1 and day 15. max The difference in values ​​became larger. Average AUC was measured using various doses on day 1 and day 15. lastWhen measured, a similar pattern was found (Figure 4B). Furthermore, exposure on day 15 resulted in a very long half-life for (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, approximately seven times longer than on day 1 (Figure 4C). (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide resulted in sustained exposure even with an intermittent dosing schedule.

[0151] Example 3 - Non-clinical pharmacology Primary pharmacodynamics (tests supporting drug efficacy) (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide exhibits high-affinity direct interaction with TEAD proteins, promoting a significant shift in the melting points of purified recombinant TEAD1, TEAD2, TEAD3, and TEAD4 proteins in a thermal shift assay (TSA). (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide also exhibits an average IC50 of 4.9 nM in a reporter assay driven by a TEAD-responsive element. 50 It strongly inhibited YAP-TEAD transcriptional activity in a dose-dependent manner and did not affect the thymidine kinase (TK) promoter-driven reporter at micromolar concentrations.

[0152] In cell-based (transfected and overexpressed) TEAD palmitoylation assays, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide strongly inhibited palmitoylation of TEAD1 and TEAD3 proteins in these assays, but weakly inhibited palmitoylation of TEAD2 and did not inhibit palmitoylation of TEAD4. Similar TEAD selectivity of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide against endogenous TEAD proteins is demonstrated by the Acyl-PEGyl Exchange Gel-Shift (APEGS) assay in the human mesothelioma cell line NCI-H2373, which has a homologous deletion of the NF2 gene.

[0153] The TEAD protein is highly conserved between the human species and other mammalian species due to sequence homology. Using a cell-based endogenous TEAD palmitoylation assay, we empirically demonstrated that (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide inhibits TEAD palmitoylation in rat, rhesus monkey, cynomolgus monkey, and canine cells, as well as in human cells. These data support the selection of rats and cynomolgus monkeys to evaluate the toxicological safety of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

[0154] In some embodiments, frequent genetic alterations of components of the Hippo-YAP-TEAD pathway are observed in malignant mesothelioma, leading to constitutive YAP activation in over 70% of malignant mesotheliomas. Importantly, YAP, in cooperation with the TEAD transcription factor, has been shown to be functionally essential for cell proliferation and anchorage-independent growth in malignant mesothelioma. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide was found to potently suppress the proliferation of NF2-deficient (NCI-H226) and NF2-mutated (NCI-H2052, NCI-H2373) mesothelioma cell lines, but not the proliferation of NF2 wild-type mesothelioma cell lines (NCI-H28, NCI-H2452). Further testing of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide in a panel of 26 mesothelioma cell lines demonstrated potent efficacy in NF2-deficient or NF2-mutant / Merlin-negative mesothelioma cell lines, but showed 100-1000-fold lower activity in NF2 wild-type / Merlin-positive mesothelioma cells, demonstrating the compound's selectivity.

[0155] In some embodiments, CTGF and CYR61 are among the best-characterized target genes of YAP-TEAD. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide dose-dependently and significantly downregulated the expression of CTGF and CYR61, pathway target genes, in mouse NF2-deficient NCI-H226 tumors.

[0156] In establishing cell line-derived xenografts (CDXs) to evaluate the antitumor efficacy of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide in vivo, several NF2-deficient mesothelioma and NSCLC cell lines, including NCI-H2052, NCI-H2373, NCI-H226, ACC-MESO-1, and LOU-NH9, were tested. However, except for NCI-H226, the tumors in the mice did not grow very well. In mice with NCI-H226 tumors, the tumor size was approximately 107 mm. 3 Treatment was initiated when the condition was reached.

[0157] In several embodiments, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide significantly inhibited the growth of NCI-H226 tumors in mice in a dose-dependent manner. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide showed strong antitumor activity when administered orally once daily at 3 mg / kg and 10 mg / kg in a CDX model of NCI-H226 (tumor growth inhibition (TGI) = 80%, p = 0.00257, and 90%, p = 1.95e-05, respectively). When administered at a daily dose of 1 mg / kg, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide resulted in partial suppression of tumor growth (TGI = 32%). No adverse effects on body weight were observed during a 50-day long-term treatment period with daily administration of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

[0158] In some embodiments, NCI-H2373 is a human mesothelioma cell line with an isozygous deletion of the NF2 gene. This cell line does not promote tumor growth in mice. To obtain a second in vivo working model to evaluate the antitumor efficacy of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide during long-term treatment, NCI-H2373 tumors were sequentially passaged in mice to induce the NCI-H2373-Tu-P2 cell line, which was confirmed to be genetically related to NCI-H2373 by short tandem repeat (STR) profiling. Subsequently, efficacy tests of NCI-H2373 were performed by transplanting NCI-H2373-Tu-P2 tumor fragments into mice, with tumors growing to approximately 75-190 mm. 3 Treatment was initiated when the following was reached. (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide produced dose-dependent suppression of tumor growth without adverse effects on body weight.

[0159] In the PDX model of NF2-deficient NSCLC (LU-01-0407), the average tumor size was approximately 152 mm. 3 When the TGI reached a certain level, the in vivo efficacy of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide was also tested. Oral administration of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide at 30 mg / kg daily resulted in suppression of tumor growth (TGI = 71%, p = 0.015). No significant weight loss was observed during the 54-day study.

[0160] An in vivo efficacy study was conducted using the CDX model of NF2-deficient mesothelioma NCI-H226 to determine whether intermittent administration of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide was effective. Tumors were approximately 90-120 mm in size. 3When the TGI reached a certain level, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide was administered at different dose levels with different dosing schedules. Significant tumor growth inhibition and sustained tumor response were observed with (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at 30 mg / kg using a 7-day dosing / 14-day rest schedule, and with (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at 30 mg / kg using a 14-day dosing / 14-day rest schedule. Throughout the course of the 93-day study, these two intermittent dosing regimens of 30 mg / kg (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide prevented tumor growth (TGI = 92% and 95%, respectively). (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide administered at 10 mg / kg using a 7-day on / 7-day rest schedule and a 14-day on / 14-day rest schedule also showed significant inhibition of tumor growth and a sustained tumor response (TGI = 84% and 84%, respectively). In contrast, the benchmark group receiving a daily dose of 3 mg / kg began to show increased tumor growth after approximately 60 days (TGI eventually decreased to 72%). Furthermore, unlike tumor-bearing mice administered a daily dose of 3 mg / kg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, tumor-bearing mice administered at doses of 10 mg / kg or 30 mg / kg with intermittent rest periods continued to gain body weight, similar to tumor-bearing mice treated with the vehicle. Therefore, intermittent administration of higher doses of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is thought to maintain the efficacy of tumor growth inhibition while avoiding the potential adverse effects on weight gain during long-term treatment of tumor-bearing mice.

[0161] To identify further genes regulated by (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide, which may be used as PD biomarkers, formalin-fixed paraffin-embedded (FFPE) tumor samples collected 4 hours after the third daily dose were analyzed by NanoString's nCounter gene expression assay using a human metabolic pathway panel of 768 genes (Canopy Biosciences). IL6 was a significantly downregulated gene, with the largest multiplicative changes in (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide at 3 mg / kg and 10 mg / kg compared to the vehicle. Downregulation of IL6 expression was dose-dependent and correlated with the efficacy response in the same NCI-H226 CDX model. In some embodiments, the human IL-6 gene promoter region contains two putative TEAD binding sites, one of which is essential for YAP to promote IL-6 transcription. Therefore, by measuring transcription levels before and after treatment, IL-6 can be used as a PD biomarker, in addition to the well-characterized pathway target genes CTGF and CYR61. Furthermore, since IL-6 is a secreted cytokine, its expression level in circulation can be observed by ELISA analysis of plasma or serum samples.

[0162] overview (1) Indications and Use In one embodiment, (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is useful for the treatment of solid tumors with NF2 mutations or other mechanisms of YAP activation, including malignant pleural mesothelioma.

[0163] (2) Dosage and administration (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide can be provided as 25 mg or 100 mg capsules for oral administration for the treatment of solid tumors having NF2 mutations or other mechanisms of YAP activation, including malignant pleural mesothelioma.

[0164] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided only as examples. Those skilled in the art will be able to conceive of numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be used in carrying out the present invention. The following claims define the scope of the present invention and are intended to encompass the methods and structures and their equivalents within these claims.

Claims

1. A pharmaceutical preparation in solid dosage form, (a) (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide in an amount of approximately 20 w / w% to approximately 50 w / w%, (b) A first filler in an amount of approximately 15 w / w% to approximately 40 w / w%, (c) A second filler in an amount of approximately 15 w / w% to approximately 40 w / w%, (d) A first lubricant in an amount of approximately 1 w / w% to approximately 10 w / w%, (e) A second lubricant in an amount of approximately 0.1 w / w% to approximately 1 w / w%, (f) Approximately 1 w / w% to approximately 5 w / w% disintegrant, (g) Approximately 0.1 w / w% to approximately 2 w / w% flow accelerator Pharmaceutical preparations, including those mentioned above.

2. The pharmaceutical formulation according to claim 1, comprising approximately 25 w / w% to approximately 45 w / w% of the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

3. A pharmaceutical formulation according to claim 1 or 2, comprising approximately 30 w / w% to approximately 40 w / w% of the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

4. A pharmaceutical formulation according to any one of claims 1 to 3, comprising approximately 37 w / w% of the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide.

5. The pharmaceutical preparation according to any one of claims 1 to 4, wherein the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is present in an amount of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg.

6. The pharmaceutical preparation according to any one of claims 1 to 5, wherein the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is in an amount of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg.

7. The pharmaceutical preparation according to any one of claims 1 to 6, wherein the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is in an amount of 25 mg, 50 mg, 100 mg, 125 mg, or 150 mg.

8. The pharmaceutical preparation according to any one of claims 1 to 7, wherein the (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is present in an amount of 25 mg, 50 mg, or 100 mg.

9. The pharmaceutical preparation according to any one of claims 1 to 8, wherein the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg.

10. The pharmaceutical preparation according to any one of claims 1 to 9, wherein the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 50 mg.

11. The pharmaceutical preparation according to any one of claims 1 to 10, wherein the amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 100 mg.

12. A pharmaceutical preparation according to any one of claims 1 to 11, comprising approximately 20 w / w% to approximately 35 w / w% of the first filler.

13. A pharmaceutical preparation according to any one of claims 1 to 12, comprising approximately 25 w / w% to approximately 30 w / w% of the first filler.

14. A pharmaceutical preparation according to any one of claims 1 to 13, comprising approximately 27 w / w% of the first filler.

15. A pharmaceutical preparation according to any one of claims 1 to 14, comprising approximately 20 w / w% to approximately 35 w / w% of the second filler.

16. A pharmaceutical preparation according to any one of claims 1 to 15, comprising approximately 25 w / w% to approximately 30 w / w% of the second filler.

17. A pharmaceutical preparation according to any one of claims 1 to 16, comprising approximately 27 w / w% of the second filler.

18. The pharmaceutical formulation according to any one of claims 1 to 17, wherein the first filler and the second filler are independently selected from lactose, erythritol, sorbitol, mannitol, dicalcium phosphate, microcrystalline cellulose, silicified microcrystalline cellulose, starch, and pregelatinized starch (starch 1500).

19. The pharmaceutical preparation according to any one of claims 1 to 18, wherein the first filler is lactose.

20. The pharmaceutical preparation according to claim 19, wherein the lactose is lactose monohydrate.

21. The pharmaceutical preparation according to any one of claims 1 to 20, wherein the second filler is mannitol.

22. The pharmaceutical preparation according to claim 21, wherein the mannitol is mannitol 200SD.

23. A pharmaceutical formulation according to any one of claims 1 to 22, comprising approximately 3 w / w% to approximately 7 w / w% of the first lubricant.

24. A pharmaceutical formulation according to any one of claims 1 to 23, comprising approximately 5 w / w% of the first lubricant.

25. A pharmaceutical formulation according to any one of claims 1 to 24, comprising approximately 0.3 w / w% to approximately 0.7 w / w% of the second lubricant.

26. A pharmaceutical formulation according to any one of claims 1 to 25, comprising approximately 0.5 w / w% of the second lubricant.

27. The pharmaceutical formulation according to claim 26, wherein about 0.3 w / w% of the second lubricant is in the granules and about 0.2 w / w% of the second lubricant is outside the granules.

28. The pharmaceutical formulation according to any one of claims 1 to 27, wherein the first lubricant and the second lubricant are independently selected from sodium laureth sulfate, sodium lauryl sulfate, magnesium stearate, stearic acid, sodium stearate, calcium stearate, ammonium lauryl sulfate, and sodium stearyl fumarate.

29. The pharmaceutical formulation according to any one of claims 1 to 28, wherein the first lubricant is sodium lauryl sulfate.

30. The pharmaceutical formulation according to any one of claims 1 to 29, wherein the second lubricant is magnesium stearate.

31. A pharmaceutical preparation according to any one of claims 1 to 30, comprising approximately 2 w / w% to approximately 4 w / w% of the disintegrant.

32. A pharmaceutical preparation according to any one of claims 1 to 31, comprising approximately 3 w / w% of the disintegrant.

33. The pharmaceutical formulation according to any one of claims 1 to 32, wherein the disintegrant is selected from povidone, crospovidone, hypromellose, croscarmellose sodium, carboxymethylcellulose, hydroxypropylcellulose, and poly(vinyl alcohol).

34. The pharmaceutical preparation according to any one of claims 1 to 33, wherein the disintegrant is croscarmellose sodium.

35. A pharmaceutical preparation according to any one of claims 1 to 34, comprising approximately 0.5 w / w% to approximately 1.5 w / w% of the flow promoter.

36. A pharmaceutical preparation according to any one of claims 1 to 35, comprising approximately 1 w / w% of the flow promoter.

37. The pharmaceutical formulation according to any one of claims 1 to 36, wherein the flow promoter is selected from silicates, silicon dioxide, and talc.

38. The pharmaceutical preparation according to any one of claims 1 to 37, wherein the flow promoter is silicon dioxide.

39. The pharmaceutical preparation according to claim 38, wherein the silicon dioxide is colloidal silicon dioxide.

40. A pharmaceutical preparation in solid dosage form, (a) Approximately 37 w / w% (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthamide, (b) Approximately 26.7 w / w% lactose monohydrate, (c) Approximately 26.7 w / w% mannitol, (d) Approximately 5 w / w% sodium lauryl sulfate, (e) Approximately 0.5 w / w% magnesium stearate, (f) Approximately 3 w / w% croscarmellose sodium, and (g) Approximately 1 w / w% colloidal silicon dioxide Pharmaceutical preparations, including those mentioned above.

41. The pharmaceutical preparation is the pharmaceutical preparation according to any one of claims 1 to 40, wherein the pharmaceutical preparation has a half-life of at least 3 days.

42. The pharmaceutical preparation is the pharmaceutical preparation according to any one of claims 1 to 41, wherein the pharmaceutical preparation has a half-life of at least 7 days.

43. The pharmaceutical preparation is the pharmaceutical preparation according to any one of claims 1 to 42, having a half-life of 12 to 15 days.

44. The pharmaceutical preparation is the pharmaceutical preparation according to any one of claims 1 to 43, having a half-life of 12 days.

45. The pharmaceutical formulation according to any one of claims 1 to 44, wherein the solid dosage form is selected from powder, tablets, bite-disintegration tablets, chewable tablets, caplets, capsules, gel capsules, effervescent powders, rapidly disintegrating tablets, abuse-preventing tablets, release-controlled tablets, release-controlled caplets, release-controlled capsules, and aqueous suspensions produced from powder.

46. The pharmaceutical preparation according to any one of claims 1 to 45, wherein the solid dosage form is a capsule.

47. The pharmaceutical preparation according to any one of claims 46, wherein the capsule is a hard gelatin capsule.

48. The pharmaceutical formulation according to claim 47, wherein the hard gelatin capsule comprises gelatin and titanium dioxide.

49. The pharmaceutical preparation according to claim 47 or claim 48, wherein the hard gelatin capsule further comprises FD&C Red No. 40 and FD&C Blue No.

1.

50. The pharmaceutical preparation according to any one of claims 1 to 45, wherein the solid dosage form is a tablet.

51. The pharmaceutical preparation according to any one of claims 1 to 45, wherein the solid dosage form is a caplet.

52. The pharmaceutical preparation according to any one of claims 1 to 51, wherein the solid dosage form is a dried granulated blend.

53. A method for treating cancer in a subject requiring cancer treatment, comprising administering to the subject a pharmaceutical preparation described in any one of claims 1 to 52.

54. The method according to claim 53, wherein the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, undifferentiated thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

55. A method for treating cancer in a subject requiring cancer treatment, comprising administering a therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide to the subject requiring cancer treatment, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least three days.

56. The method according to claim 55, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered as an oral formulation.

57. The method according to claim 55 or claim 56, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in capsule form.

58. The method according to any one of claims 55 to 57, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is at least 25 mg per day.

59. The method according to any one of claims 55 to 58, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 300 mg, or 400 mg per day.

60. The method according to any one of claims 55 to 59, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, or 200 mg per day.

61. The method according to any one of claims 55 to 60, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, 100 mg, 125 mg, 150 mg, or 200 mg per day.

62. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg, 50 mg, or 100 mg per day.

63. The method according to any one of claims 55 to 62, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 25 mg per day.

64. The method according to any one of claims 55 to 62, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 50 mg per day.

65. The method according to any one of claims 55 to 62, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 100 mg per day.

66. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 150 mg per day.

67. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is 200 mg per day.

68. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least one week.

69. The method according to any one of claims 55 to 68, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least two weeks.

70. The method according to any one of claims 55 to 69, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for at least three weeks.

71. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a cycle length of three weeks, and the therapeutically effective amount is administered daily for one week, followed by no administration for two weeks.

72. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 3 weeks, the therapeutically effective amount is administered daily for 1 week and then not administered for 2 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg.

73. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a cycle length of 4 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for one week, and then not administered for the following three weeks.

74. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 1 week, and then not administered for the next 3 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 150 mg.

75. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a cycle length of 3 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, and then not administered for the following week.

76. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 3 weeks, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, and then not administered for the following week, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg.

77. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered over a cycle length of 4 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, and then not administered for the following 2 weeks.

78. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, and then not administered for the next 2 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 100 mg.

79. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in a cycle length of 4 weeks, the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 2 weeks, and then not administered for the following 2 weeks, and the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in 200 mg.

80. The method according to any one of claims 71 to 79, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least two cycles.

81. The method according to any one of claims 55 to 67, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered daily for 15 days, and then once weekly for 3 weeks.

82. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for 15 days, and then at a dose of 50 mg once weekly for 3 weeks.

83. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 50 mg daily for 15 days, and then at a dose of 100 mg once weekly for 3 weeks.

84. The method according to any one of claims 55 to 61, wherein the therapeutically effective amount of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered at a dose of 100 mg daily for 15 days, and then at a dose of 100 mg once weekly for 3 weeks.

85. A method for treating cancer in a subject requiring cancer treatment, comprising administering 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily to the subject requiring cancer treatment for two weeks, and then refraining from administering (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide for the following two weeks.

86. The method according to claim 85, further comprising administering to the subject requiring treatment for cancer 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily for two weeks in a cycle length of four weeks, and then not administering for the next two weeks, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least two cycles.

87. A method for treating cancer in a subject requiring cancer treatment, comprising administering 100 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily to the subject requiring cancer treatment for two weeks, and then withholding (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide for the next two weeks, and thereafter, the subject requiring cancer treatment A method comprising administering 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide daily to a subject subject for two weeks over a cycle length of four weeks, and then not administering it for the next two weeks, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered for at least two cycles.

88. The method according to claim 86 or 87, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least four cycles.

89. The method according to claim 86 or 87, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least eight cycles.

90. The method according to claim 86 or 87, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least 12 cycles.

91. The method according to claim 86 or 87, wherein the 50 mg of (R)-N-(1-hydroxypropan-2-yl)-5-(4-(trifluoromethyl)phenoxy)-2-naphthoamide is administered in at least 24 cycles.

92. The method according to any one of claims 55 to 91, wherein the cancer is mesothelioma, hepatocellular carcinoma, meningioma, malignant peripheral nerve sheath tumor, schwannoma, lung cancer, bladder cancer, cutaneous neurofibroma, prostate cancer, pancreatic cancer, glioblastoma, endometrial adenosquamous carcinoma, undifferentiated thyroid cancer, gastric adenocarcinoma, esophageal adenocarcinoma, ovarian cancer, ovarian serous adenocarcinoma, melanoma, or breast cancer.

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